Re: Comparison of ABCR's

April 9, 2004

We have heard very little from anyone who has anything good to say about

Copaxone. It hadn't occurred to me that perhaps there are people who are

happy with it who are just quiet. I suppose it is natural to hear more from

those who have had unpleasant issues with it. Humankind is certainly

inclined to grumble about things we don't enjoy.

I'm sure my next visit to the neuro is going to involve another argument

about using or not using Copaxone. Anybody want to share their positive

experiences with this med? I've avoided it because I'm not interested in

injection site reactions or other side effects. Am I feeling too much

concern? Are there people here who feel it is helping? I hate taking any

kind of meds, and had chosen long ago to avoid the ABCs (there was no " R " at

the time I made my decision). Now that I'm seeing a neurologist a couple of

times a year again the subject comes up with each visit. If it really does

help without ugly side effects I should reconsider my position.

(MS)

----- Original Message -----

From: " yashagrawal " <yashagrawal@...>

Sent: Thursday, April 08, 2004 9:27 PM

Subject: [low dose naltrexone] Comparison of ABCR's

In view of the recent unjustified criticism of copaxone... atleast

this study claims that copa is better than the other conventional

drugs. LDN, may ofcourse be the best :-)

Yash

European Journal of Neurology

Volume 10 Issue 6 Page 671 - November 2003

doi:10.1046/j.1468-1331.2003.00669.x

A retrospective, observational study comparing the four available

immunomodulatory treatments for relapsing-remitting multiple

sclerosis

A. Carrá a , P. Onaha a , V. Sinay a,b , F. Alvarez b , G. Luetic

c , R. Bettinelli d , E. San Pedro d and L. Rodríguez e

We performed an observational, retrospective analysis of outcome in

a sequential cohort of patients with relapsing-remitting multiple

sclerosis (RRMS) in Argentina. Patients treated for 16 months with

interferon -1a (Avonex®; 30 g intramuscularly, once a week),

interferon -1a (Rebif®; 44 g subcutaneously, thrice weekly),

interferon -1b (Betaferon®; 250 g subcutaneously, every other

day) or glatiramer acetate (Copaxone®; 20 mg subcutaneously daily)

were compared with a non-treated group of patients. The different

treatment groups were similar in baseline demographic and clinical

variables. A significant fall in the annual relapse rate was

observed for all four treatments, with the largest effect observed

with glatiramer acetate (81% reduction in relapse rate, compared

with pre-treatment values). The proportion of patients remaining

relapse-free for the entire 16-month treatment period varied from

37% in untreated patients to 83% in the glatiramer acetate treated

group. No statistically significant changes in disability scores

were observed over the treatment period. This first such comparative

study in Latin America shows that treatment of multiple sclerosis

patients with immunomodulatory therapies in the context of current

standards of care in Argentina provides clinically important

benefit, and suggest that some of these therapies may be better than

others.

Introduction Go to: Choose Top of page Introduction << Methods

Results Discussion References

Over the last decade, several immunomodulatory therapies have been

introduced for the treatment of relapsing-remitting multiple

sclerosis (RRMS), providing for the first time a possibility to

modify the course of this progressively disabling autoimmune

neurological disease. These include three interferon preparations,

interferon -1a (Avonex®, Biogen, Cambridge, MA, USA; given

intramuscularly; IFN -1a i.m.), interferon -1a (Rebif®, Serono,

Geneva, Switzerland; given subcutaneously; IFN -1a s.c.),

interferon -1b (Betaferon®, Schering AG, Berlin, Germany; given

subcutaneously; IFN -1b s.c.), and an activator of anti-

inflammatory T cells, glatiramer acetate (Copaxone®, Teva

Pharmaceutical Industries, Kfar Sava, Israel; given subcutaneously;

GA s.c.). All these drugs have been demonstrated to decrease the

rate of relapse, slow the progression of disability, and to improve

markers of lesion load observed in magnetic resonance imaging

(Chofflon, 2000; Goodin et al., 2002; Khan et al., 2002; Simpson et

al., 2002).

Faced with the choice of these four agents, it is important for

clinicians to possess reliable comparative data on the efficacy and

safety of these treatments in order to make enlightened treatment

decisions (Khan et al., 2002). However, little such data is

available. Direct randomized controlled trials comparing these

agents pose important problems in terms of methodology, logistics

and cost, and no such trials have been performed. Kappos et al.

(1998) compared retrospectively the four pivotal studies, and

concluded that the effects of all agents on relapse were broadly

similar. Galetta et al. (2002) concluded that all four

immunomodulatory therapies had similar effects on several clinical

and biological outcome measures, although the immunogenicity of

interferons might be a discriminating tolerability issue. Moreover,

recent evidence-based treatment guidelines for multiple sclerosis by

the American Academy of Neurology also concluded that all four

immunomodulatory therapies were effective in reducing relapse rate

(Goodin et al., 2002). Khan et al. (2001) reported a first

prospective open-label comparative study between three of these

treatments (IFN -1a i.m., IFN -1b s.c. and GA). This study

reported that IFN -1b s.c. and GA may be somewhat more efficacious

than IFN -1a i.m. More recent studies have suggested that some

interferons may be more efficacious than others (Durelli et al.,

2002; Panitch et al., 2002), or that interferons slightly reduce the

number of patients who have exacerbation during first year of

treatment (Filippini et al., 2003) whilst and Witt (1998)

have shown that administration of IFN -1a i.m. and IFN -1b s.c.

induce different short-term biological responses.

Following the introduction of all four immunomodulatory therapies to

Argentina, we have decided to conduct an open-label comparative

study of these therapies under naturalistic treatment conditions.

The objective of the study was to evaluate the effects of these four

immunomodulatory therapies, compared with a non-treated group of

patients on annual relapse rate in RRMS. To our knowledge, this is

the first study to compare different immunomodulatory treatments for

multiple sclerosis.

Methods Go to: Choose Top of page Introduction Methods << Results

Discussion References

This study was an observational, retrospective analysis of a cohort

of patients with RRMS treated with immunomodulatory therapies in

five multiple sclerosis centres (private and public hospitals with

neurology departments) in Argentina. A no treatment control group

was included. The treatment period was from January 2001 to May 2002

(16 months).

This retrospective study included a sequential series of all

patients attending the five participating centres over the study

duration fulfilling retrospectively chosen inclusion criteria, which

were ascertained by reference to the patient notes. These criteria

selected patients between 16 and 61 years old fulfilling the Poser

criteria for definitive RRMS (Poser et al., 1983). Patients were

required to have scores on Expanded Disability Status Scale (EDSS)

(Kurtzke, 1983) in the range of 0-6.0, to have experienced at least

one relapse in the previous 2 years, and to have been clinically

stable for at least 30 days prior to inclusion. Exclusion criteria

were secondary progressive multiple sclerosis and the use of the

following prior treatments: chronic maintenance steroid therapy

(only acute treatment during previous relapses was acceptable),

immunomodulatory therapy and immunosuppressant therapy.

Before starting treatment, each patient underwent a baseline

neurological examination and an assessment of EDSS score. Patients

were treated with one of four immunomodulatory therapies:

interferon -1a (Avonex®; 30 g i.m. once a week), interferon -1a

(Rebif®; 44 g s.c. thrice weekly), interferon -1b (Betaferon®;

250 g s.c. every other day) and glatiramer acetate (Copaxone®; 20

mg s.c. daily). The choice of which treatment to use was at the

treating neurologist's discretion. Patients were provided with

information about treatments, and discussed the relative efficacy

and tolerability of the different possible treatments with

neurologist. Although use of immunomodulatory therapy is reimbursed

by the health service in Argentina, a number of patients were unable

to receive treatment because they had no social security coverage,

and these thus formed a no treatment control group. None of the

patients were switched to another treatment group during the course

of the study. The study duration was 16 months.

In the event of a relapse, this was confirmed by a neurological

examination performed by the treating neurologist, who initiated

appropriate treatment. The standard treatment was a 5-day course of

methylyprednisolone (Solumedrol®, Pfizer, Argentina; 1 g/day)

followed, if the neurologist considered this necessary by a

prednisolone (Deltisona®, Aventis Pharma, Argentina) taper for 30

days.

After treatment was initiated, each patient returned for scheduled

follow-up visits to the same neurologist every 3 months. Scores on

the EDSS rating scale were determined at each visit.

The principal outcome measure was incidence of relapse. This was

defined as new symptoms or worsening of previous symptoms lasting at

least 48 h, characterized by an increase of at least half a step on

the EDSS, an increase of at least two points on one of the seven

functional systems or an increase of at least one point on two or

more of the functional systems.

The incidence of disease progression was also recorded. This was

defined as an increase of at least one full step on the EDSS that

persisted for two consecutive visits and remained unchanged for at

least 12 weeks. Secondary outcome measures were the change in mean

EDSS score over the study period and the proportion of relapse-free

patients.

All the data were analysed at 16 months for all groups. The results

are shown as median values (25-75% quartile) for quantitative

variables, or as percentages for qualitative ones where appropriate.

Baseline demographic and clinical variables were compared between

the four treatment groups, as were pre- and post-treatment outcome

variables within each treatment group. Comparisons of categorical

variables were performed with the 2 test, whilst quantitative

variables were compared using analysis of variance (anova). Given

that inclusion into the different treatment arms was not randomized,

inter-group comparisons of treatment effects were not undertaken.

All tests were two-tailed and a probability level of < 0.05 was

taken to be significant. The data analysis was performed with Epi

6.04 software (Center for Disease Control, Atlanta, GA, USA).

The protocol was submitted to, and approved by, the Ethics Committee

of the Hospital Británico, Buenos Aires.

Results Go to: Choose Top of page Introduction Methods Results <<

Discussion References

The study included 134 patients who were distributed between

treatment groups as follows: IFN -1a i.m.: 26 patients; IFN -1b

s.c.: 20 patients; IFN -1a s.c.: 20 patients; GA: 30 patients; no

treatment: 38 patients. The baseline demographics and disease

variables for the five patient groups are presented in Table 1. The

average age of the patients was 40 years, and the average disease

duration 7.3 years. All patients had active disease, with most

having experienced at least two relapses over the previous 2 years.

The average EDSS score at inclusion was 2.05. All groups were

comparable at baseline for the following parameters: total number of

relapses in the previous 2 years and in the previous year, and EDSS

score at inclusion.

Over the 16-month study period, the number of relapses was

significantly lower compared with the pre-treatment period for all

the active treatments (P < 0.001; 2 test; Table 2). However, the

annual relapse rate in untreated patients increased from 0.54 to

0.71 (P < 0.001). The changes in annual relapse rate in the

different treatment groups before and after initiation of treatment

are presented in Fig. 1. These varied from a reduction of 49% in the

IFN -1a i.m. treatment group to one of 81% in the GA treatment

group.

The proportion of patients remaining relapse-free for the entire 16-

month treatment period varied from 60% in the IFN -1a s.c. and

IFN -1b s.c. groups to 83% in the GA group (Table 2). Only 37% of

untreated patients remained relapse-free. There was a slight fall in

the EDSS score over the 16-month study group in the IFN -1b s.c.

and GA treatment groups, and a slight rise in score in the untreated

patients (Fig. 2). However, none of these changes were statistically

significant.

Discussion Go to: Choose Top of page Introduction Methods Results

Discussion << References

This open-label, retrospective study compared the efficacy of

different immunomodulatory treatments for RRMS available in

Argentina. To our knowledge, this is the first such study reported

from South America. The retrospective nature of the study precluded

randomization, but allowed the impact of treatment to be assessed in

standard conditions of multiple sclerosis care in Argentina. Given

that all previously untreated patients consulting for multiple

sclerosis who fulfilled relatively broad inclusion criteria were

included, the sample evaluated can be considered representative of

the overall population of multiple sclerosis patients suitable for

immunomodulatory treatment in Argentina. However, considering the

average disease duration, it is important to highlight that most

patients have had a relatively low mean EDSS at baseline.

This is the first such observational study that has compared all

four immunomodulatory treatments currently available. Patients were

followed-up for 16 months following initiation of treatment. The

principal finding of the study was a significant reduction in the

annual relapse rate for all four drug therapies, compared with pre-

treatment relapse rates. No such reduction was observed in a

parallel group receiving no treatment. The proportion of relapse-

free patients was approximately twice as high in the groups

receiving immunomodulatory treatments compared with the no treatment

group. The proportion of relapse-free patients in the group

receiving no treatment (37%) may be due to either the short duration

of follow-up or due to their low EDSS score at baseline.

Concerning disability, we did not find a significant reduction in

EDSS score in any of the treatment groups, although there was a

trend towards improvement in the IFN -1b s.c. and GA groups. It is

possible that the 16-month treatment period was not sufficient to

demonstrate robust effects on this outcome measure.

Although the study has a number of limitations, notably the lack of

randomization between treatment groups, and the relatively small

numbers of patients included, naturalistic studies such as this have

certain intrinsic qualities. Immunomodulatory treatments for

multiple sclerosis have already demonstrated clear efficacy in a

series of double-blind, placebo-controlled, randomized clinical

trials including large numbers of patients (Galetta et al., 2002;

Goodin et al., 2002; Khan et al., 2002). The challenge for current

clinical research with these drugs is thus not so much to reiterate

these findings, but to demonstrate that the findings of the clinical

trial programme can be generalized to everyday standards of care.

Naturalistic studies such as the current one, can help address this

issue. The broad entry criteria ensure good representativity of the

study cohort, and the retrospective nature of the analysis allows

bias from doctor or patient expectations to be limited.

In addition, recent data across a variety of therapeutic areas

suggests that treatment effects seen in observational studies are

generally comparable with those found in randomized controlled

trials. For example, a recent meta-analysis of studies across 19

therapeutic areas showed that there were no significant differences

in size-effects between observational and randomized studies (Benson

and Hartz, 2000). Although this analysis did not extend to trials in

multiple sclerosis, there is no reason to think that the data from

observational studies such as the current one are intrinsically less

solid than data from randomized clinical trials.

The results can be compared with data previously obtained in

randomized clinical trials (Table 3). Although the patients included

in our study generally have less aggressive disease than those in

the clinical trials (at least in terms of relapse rates), and the

treatment duration differed between the studies, the impact of

treatment on annual relapse rates is quite comparable between the

two study paradigms. This similitude also extends to another open-

label comparative study of IFN -1a i.m., IFN -1b s.c., GA and no

treatment, performed in the United States (Khan et al., 2001; Table

3), and to an open-label prospective study of these four treatments

and intravenous immunoglobulin performed in Germany, as yet only

published in abstract form (Firzlaff et al., 2000).

Given the non-randomized nature of the study, no firm conclusions

can be drawn concerning the relative benefits of the different

immunomodulatory treatments. However, inspection of the data reveals

certain potential inter-group differences, with perhaps a somewhat

larger treatment responses for GA. Interestingly, the same order of

relative efficacy for the three therapies evaluated (IFN -1a i.m.,

IFN -1b s.c. and GA) in the prospective observational study by Khan

et al. (2001) was observed, although, again, patients were not

randomized. As GA has a different mechanism of action from the

interferons (Neuhaus et al., 2001), it is possible that the benefit

provided may not be identical. Potential treatment differences merit

scrutiny in a randomized prospective study.

In conclusion, this open-label, comparative observational study has

demonstrated that treatment of patients with RRMS with

immunomodulatory therapies in the context of current standards of

care for multiple sclerosis in Argentina provides clinically

important benefit. The study confirms the efficacy of all four

available immunomodulatory therapies in reducing relapse rates in

multiple sclerosis patients, and provides more tantalizing clues

that some of these therapies may be better than others.

April 9, 2004

I've never been to a Hardee's, don't like Burger King, Mcs, or 's, and am not really crazy about any kind of soda pop, maybe Mr Pibb every once in a while.

I do love pomegranates, but I'm not sure they're better than bananas or peaches. Just more complicated to eat.

Larry, you're confirming my earlier thoughts about the injectables, just when I was thinking I needed to take another look. I've been certain their effectiveness was limited at best, and really concerned about the side effects. Thanks for the nudge back to my original view. I'll give LDN a good long run before I reconsider even reconsidering the CRABs. I would still like to hear from users who have felt they derived benefit from them. A direct mail is fine; no need to clutter up everyone's mail with something that may be of no interest to all.

(MS)

----- Original Message -----

From: LarryGC

low dose naltrexone

Sent: Thursday, April 08, 2004 10:40 PM

Subject: Re: [low dose naltrexone] Comparison of ABCR's

Any reports on LDN are >about< LDN. Any reports on A, or B or C or R seem to be >FOR< "D" but also >AGAINST< X, Y & Z

Of course, whoever is paying for the report is going to make "D" look Better than X, Y & Z. That's why I decided back in 02 to not do any of them. If 3 agreed that ONE was the best, I may have considered it. But when I investigated A, I was told all that was wrong with B, C & R; when I checked out B, they ratted on A, R & C, etc, etc.

What's your preference? 's, Burger King, Mcs or Hardee's?

What's better, Coke or Pepsi?

----- Original Message -----

From: yashagrawal

low dose naltrexone

Sent: Friday, April 09, 2004 00:27

Subject: [low dose naltrexone] Comparison of ABCR's

In view of the recent unjustified criticism of copaxone... atleast this study claims that copa is better than the other conventional drugs. LDN, may ofcourse be the best :-)YashEuropean Journal of Neurology Volume 10 Issue 6 Page 671 - November 2003 doi:10.1046/j.1468-1331.2003.00669.x

April 9, 2004

Any reports on LDN are >about< LDN. Any reports on A, or B or C or R seem to be >FOR< "D" but also >AGAINST< X, Y & Z

Of course, whoever is paying for the report is going to make "D" look Better than X, Y & Z. That's why I decided back in 02 to not do any of them. If 3 agreed that ONE was the best, I may have considered it. But when I investigated A, I was told all that was wrong with B, C & R; when I checked out B, they ratted on A, R & C, etc, etc.

What's your preference? 's, Burger King, Mcs or Hardee's?

What's better, Coke or Pepsi?

----- Original Message -----

From: yashagrawal

low dose naltrexone

Sent: Friday, April 09, 2004 00:27

Subject: [low dose naltrexone] Comparison of ABCR's

In view of the recent unjustified criticism of copaxone... atleast this study claims that copa is better than the other conventional drugs. LDN, may ofcourse be the best :-)YashEuropean Journal of Neurology Volume 10 Issue 6 Page 671 - November 2003 doi:10.1046/j.1468-1331.2003.00669.x

April 9, 2004

http://brain.hastypastry.net/forums/showthread.php?t=7966

http://brain.hastypastry.net/forums/showthread.php?t=7910

There's 2 such discussions from C.

And you're right, most people are more apt to complain, than say good things. That's what I'm finding so amazing with LDN aren't keeping quiet about their successes and most of the complainers complaints are that they can't get it or their doc won't let them try it.

----- Original Message -----

From:

low dose naltrexone

Sent: Friday, April 09, 2004 01:24

Subject: Re: [low dose naltrexone] Comparison of ABCR's

We have heard very little from anyone who has anything good to say aboutCopaxone. It hadn't occurred to me that perhaps there are people who arehappy with it who are just quiet. I suppose it is natural to hear more fromthose who have had unpleasant issues with it. Humankind is certainlyinclined to grumble about things we don't enjoy.

April 9, 2004

- I started on Copaxone about 6 weeks ago. Before that I was on

Betaseron for 2 years; so I would have to say I love the Copaxone. Also I

was on the Avonex for a few months when I was initially diagnosed. The

interferons may help slow down disease progression but they certainly make

you feel crappy. I did'nt even realize how crappy-feeling the interferon

had made me until I switched to Copaxone because my mood is now 10x better.

The only side-effect I've had from copaxone is a stinging sensation that

lasts about 30 seconds and goes away. The injections are much easier with

Copaxone compared to Betaseron or Avonex because of the autoject device (its

a marvel of engineering because I can't even feel the needle going in). So

I would certainly recommend Copaxone, however I will be switching to

Antegren when it comes out. I think Antegren will be vastly more effective

and convenient (once monthly is 30x better than once daily!)

I have to wonder why your neuro is pushing you into it though; have you been

relapsing on the ldn or does he/she just not believe in it? If you've been

relapsing or getting worse then I would definitely advise using Copaxone.

If you haven't been getting worse then you might want to get an MRI to see

if you have any " fresh " lesions before you make a decision.

- Ben

>From: " " <jatrac1@...>

>Reply-low dose naltrexone

><low dose naltrexone >

>Subject: Re: [low dose naltrexone] Comparison of ABCR's

>Date: Thu, 8 Apr 2004 22:24:11 -0700

>

>We have heard very little from anyone who has anything good to say about

>Copaxone. It hadn't occurred to me that perhaps there are people who are

>happy with it who are just quiet. I suppose it is natural to hear more

>from

>those who have had unpleasant issues with it. Humankind is certainly

>inclined to grumble about things we don't enjoy.

>

>I'm sure my next visit to the neuro is going to involve another argument

>about using or not using Copaxone. Anybody want to share their positive

>experiences with this med? I've avoided it because I'm not interested in

>injection site reactions or other side effects. Am I feeling too much

>concern? Are there people here who feel it is helping? I hate taking any

>kind of meds, and had chosen long ago to avoid the ABCs (there was no " R "

>at

>the time I made my decision). Now that I'm seeing a neurologist a couple

>of

>times a year again the subject comes up with each visit. If it really does

>help without ugly side effects I should reconsider my position.

>

> (MS)

>

>----- Original Message -----

>From: " yashagrawal " <yashagrawal@...>

><low dose naltrexone >

>Sent: Thursday, April 08, 2004 9:27 PM

>Subject: [low dose naltrexone] Comparison of ABCR's

>

>In view of the recent unjustified criticism of copaxone... atleast

>this study claims that copa is better than the other conventional

>drugs. LDN, may ofcourse be the best :-)

>

>Yash

>

>European Journal of Neurology

>Volume 10 Issue 6 Page 671 - November 2003

>doi:10.1046/j.1468-1331.2003.00669.x

>

>A retrospective, observational study comparing the four available

>immunomodulatory treatments for relapsing-remitting multiple

>sclerosis

>A. Carrá a , P. Onaha a , V. Sinay a,b , F. Alvarez b , G. Luetic

>c , R. Bettinelli d , E. San Pedro d and L. Rodríguez e

>We performed an observational, retrospective analysis of outcome in

>a sequential cohort of patients with relapsing-remitting multiple

>sclerosis (RRMS) in Argentina. Patients treated for 16 months with

>interferon -1a (Avonex®; 30 g intramuscularly, once a week),

>interferon -1a (Rebif®; 44 g subcutaneously, thrice weekly),

>interferon -1b (Betaferon®; 250 g subcutaneously, every other

>day) or glatiramer acetate (Copaxone®; 20 mg subcutaneously daily)

>were compared with a non-treated group of patients. The different

>treatment groups were similar in baseline demographic and clinical

>variables. A significant fall in the annual relapse rate was

>observed for all four treatments, with the largest effect observed

>with glatiramer acetate (81% reduction in relapse rate, compared

>with pre-treatment values). The proportion of patients remaining

>relapse-free for the entire 16-month treatment period varied from

>37% in untreated patients to 83% in the glatiramer acetate treated

>group. No statistically significant changes in disability scores

>were observed over the treatment period. This first such comparative

>study in Latin America shows that treatment of multiple sclerosis

>patients with immunomodulatory therapies in the context of current

>standards of care in Argentina provides clinically important

>benefit, and suggest that some of these therapies may be better than

>others.

>

> Introduction Go to: Choose Top of page Introduction << Methods

>Results Discussion References

>

>Over the last decade, several immunomodulatory therapies have been

>introduced for the treatment of relapsing-remitting multiple

>sclerosis (RRMS), providing for the first time a possibility to

>modify the course of this progressively disabling autoimmune

>neurological disease. These include three interferon preparations,

>interferon -1a (Avonex®, Biogen, Cambridge, MA, USA; given

>intramuscularly; IFN -1a i.m.), interferon -1a (Rebif®, Serono,

>Geneva, Switzerland; given subcutaneously; IFN -1a s.c.),

>interferon -1b (Betaferon®, Schering AG, Berlin, Germany; given

>subcutaneously; IFN -1b s.c.), and an activator of anti-

>inflammatory T cells, glatiramer acetate (Copaxone®, Teva

>Pharmaceutical Industries, Kfar Sava, Israel; given subcutaneously;

>GA s.c.). All these drugs have been demonstrated to decrease the

>rate of relapse, slow the progression of disability, and to improve

>markers of lesion load observed in magnetic resonance imaging

>(Chofflon, 2000; Goodin et al., 2002; Khan et al., 2002; Simpson et

>al., 2002).

>

>Faced with the choice of these four agents, it is important for

>clinicians to possess reliable comparative data on the efficacy and

>safety of these treatments in order to make enlightened treatment

>decisions (Khan et al., 2002). However, little such data is

>available. Direct randomized controlled trials comparing these

>agents pose important problems in terms of methodology, logistics

>and cost, and no such trials have been performed. Kappos et al.

>(1998) compared retrospectively the four pivotal studies, and

>concluded that the effects of all agents on relapse were broadly

>similar. Galetta et al. (2002) concluded that all four

>immunomodulatory therapies had similar effects on several clinical

>and biological outcome measures, although the immunogenicity of

>interferons might be a discriminating tolerability issue. Moreover,

>recent evidence-based treatment guidelines for multiple sclerosis by

>the American Academy of Neurology also concluded that all four

>immunomodulatory therapies were effective in reducing relapse rate

>(Goodin et al., 2002). Khan et al. (2001) reported a first

>prospective open-label comparative study between three of these

>treatments (IFN -1a i.m., IFN -1b s.c. and GA). This study

>reported that IFN -1b s.c. and GA may be somewhat more efficacious

>than IFN -1a i.m. More recent studies have suggested that some

>interferons may be more efficacious than others (Durelli et al.,

>2002; Panitch et al., 2002), or that interferons slightly reduce the

>number of patients who have exacerbation during first year of

>treatment (Filippini et al., 2003) whilst and Witt (1998)

>have shown that administration of IFN -1a i.m. and IFN -1b s.c.

>induce different short-term biological responses.

>

>Following the introduction of all four immunomodulatory therapies to

>Argentina, we have decided to conduct an open-label comparative

>study of these therapies under naturalistic treatment conditions.

>The objective of the study was to evaluate the effects of these four

>immunomodulatory therapies, compared with a non-treated group of

>patients on annual relapse rate in RRMS. To our knowledge, this is

>the first study to compare different immunomodulatory treatments for

>multiple sclerosis.

>

> Methods Go to: Choose Top of page Introduction Methods << Results

>Discussion References

>

>This study was an observational, retrospective analysis of a cohort

>of patients with RRMS treated with immunomodulatory therapies in

>five multiple sclerosis centres (private and public hospitals with

>neurology departments) in Argentina. A no treatment control group

>was included. The treatment period was from January 2001 to May 2002

>(16 months).

>

>This retrospective study included a sequential series of all

>patients attending the five participating centres over the study

>duration fulfilling retrospectively chosen inclusion criteria, which

>were ascertained by reference to the patient notes. These criteria

>selected patients between 16 and 61 years old fulfilling the Poser

>criteria for definitive RRMS (Poser et al., 1983). Patients were

>required to have scores on Expanded Disability Status Scale (EDSS)

>(Kurtzke, 1983) in the range of 0-6.0, to have experienced at least

>one relapse in the previous 2 years, and to have been clinically

>stable for at least 30 days prior to inclusion. Exclusion criteria

>were secondary progressive multiple sclerosis and the use of the

>following prior treatments: chronic maintenance steroid therapy

>(only acute treatment during previous relapses was acceptable),

>immunomodulatory therapy and immunosuppressant therapy.

>

>Before starting treatment, each patient underwent a baseline

>neurological examination and an assessment of EDSS score. Patients

>were treated with one of four immunomodulatory therapies:

>interferon -1a (Avonex®; 30 g i.m. once a week), interferon -1a

>(Rebif®; 44 g s.c. thrice weekly), interferon -1b (Betaferon®;

>250 g s.c. every other day) and glatiramer acetate (Copaxone®; 20

>mg s.c. daily). The choice of which treatment to use was at the

>treating neurologist's discretion. Patients were provided with

>information about treatments, and discussed the relative efficacy

>and tolerability of the different possible treatments with

>neurologist. Although use of immunomodulatory therapy is reimbursed

>by the health service in Argentina, a number of patients were unable

>to receive treatment because they had no social security coverage,

>and these thus formed a no treatment control group. None of the

>patients were switched to another treatment group during the course

>of the study. The study duration was 16 months.

>

>In the event of a relapse, this was confirmed by a neurological

>examination performed by the treating neurologist, who initiated

>appropriate treatment. The standard treatment was a 5-day course of

>methylyprednisolone (Solumedrol®, Pfizer, Argentina; 1 g/day)

>followed, if the neurologist considered this necessary by a

>prednisolone (Deltisona®, Aventis Pharma, Argentina) taper for 30

>days.

>

>After treatment was initiated, each patient returned for scheduled

>follow-up visits to the same neurologist every 3 months. Scores on

>the EDSS rating scale were determined at each visit.

>

>The principal outcome measure was incidence of relapse. This was

>defined as new symptoms or worsening of previous symptoms lasting at

>least 48 h, characterized by an increase of at least half a step on

>the EDSS, an increase of at least two points on one of the seven

>functional systems or an increase of at least one point on two or

>more of the functional systems.

>

>The incidence of disease progression was also recorded. This was

>defined as an increase of at least one full step on the EDSS that

>persisted for two consecutive visits and remained unchanged for at

>least 12 weeks. Secondary outcome measures were the change in mean

>EDSS score over the study period and the proportion of relapse-free

>patients.

>

>All the data were analysed at 16 months for all groups. The results

>are shown as median values (25-75% quartile) for quantitative

>variables, or as percentages for qualitative ones where appropriate.

>Baseline demographic and clinical variables were compared between

>the four treatment groups, as were pre- and post-treatment outcome

>variables within each treatment group. Comparisons of categorical

>variables were performed with the 2 test, whilst quantitative

>variables were compared using analysis of variance (anova). Given

>that inclusion into the different treatment arms was not randomized,

>inter-group comparisons of treatment effects were not undertaken.

>All tests were two-tailed and a probability level of < 0.05 was

>taken to be significant. The data analysis was performed with Epi

>6.04 software (Center for Disease Control, Atlanta, GA, USA).

>

>The protocol was submitted to, and approved by, the Ethics Committee

>of the Hospital Británico, Buenos Aires.

>

> Results Go to: Choose Top of page Introduction Methods Results <<

>Discussion References

>

>The study included 134 patients who were distributed between

>treatment groups as follows: IFN -1a i.m.: 26 patients; IFN -1b

>s.c.: 20 patients; IFN -1a s.c.: 20 patients; GA: 30 patients; no

>treatment: 38 patients. The baseline demographics and disease

>variables for the five patient groups are presented in Table 1. The

>average age of the patients was 40 years, and the average disease

>duration 7.3 years. All patients had active disease, with most

>having experienced at least two relapses over the previous 2 years.

>The average EDSS score at inclusion was 2.05. All groups were

>comparable at baseline for the following parameters: total number of

>relapses in the previous 2 years and in the previous year, and EDSS

>score at inclusion.

>

>Over the 16-month study period, the number of relapses was

>significantly lower compared with the pre-treatment period for all

>the active treatments (P < 0.001; 2 test; Table 2). However, the

>annual relapse rate in untreated patients increased from 0.54 to

>0.71 (P < 0.001). The changes in annual relapse rate in the

>different treatment groups before and after initiation of treatment

>are presented in Fig. 1. These varied from a reduction of 49% in the

>IFN -1a i.m. treatment group to one of 81% in the GA treatment

>group.

>

>The proportion of patients remaining relapse-free for the entire 16-

>month treatment period varied from 60% in the IFN -1a s.c. and

>IFN -1b s.c. groups to 83% in the GA group (Table 2). Only 37% of

>untreated patients remained relapse-free. There was a slight fall in

>the EDSS score over the 16-month study group in the IFN -1b s.c.

>and GA treatment groups, and a slight rise in score in the untreated

>patients (Fig. 2). However, none of these changes were statistically

>significant.

>

> Discussion Go to: Choose Top of page Introduction Methods Results

>Discussion << References

>

>This open-label, retrospective study compared the efficacy of

>different immunomodulatory treatments for RRMS available in

>Argentina. To our knowledge, this is the first such study reported

>from South America. The retrospective nature of the study precluded

>randomization, but allowed the impact of treatment to be assessed in

>standard conditions of multiple sclerosis care in Argentina. Given

>that all previously untreated patients consulting for multiple

>sclerosis who fulfilled relatively broad inclusion criteria were

>included, the sample evaluated can be considered representative of

>the overall population of multiple sclerosis patients suitable for

>immunomodulatory treatment in Argentina. However, considering the

>average disease duration, it is important to highlight that most

>patients have had a relatively low mean EDSS at baseline.

>

>This is the first such observational study that has compared all

>four immunomodulatory treatments currently available. Patients were

>followed-up for 16 months following initiation of treatment. The

>principal finding of the study was a significant reduction in the

>annual relapse rate for all four drug therapies, compared with pre-

>treatment relapse rates. No such reduction was observed in a

>parallel group receiving no treatment. The proportion of relapse-

>free patients was approximately twice as high in the groups

>receiving immunomodulatory treatments compared with the no treatment

>group. The proportion of relapse-free patients in the group

>receiving no treatment (37%) may be due to either the short duration

>of follow-up or due to their low EDSS score at baseline.

>

>Concerning disability, we did not find a significant reduction in

>EDSS score in any of the treatment groups, although there was a

>trend towards improvement in the IFN -1b s.c. and GA groups. It is

>possible that the 16-month treatment period was not sufficient to

>demonstrate robust effects on this outcome measure.

>

>Although the study has a number of limitations, notably the lack of

>randomization between treatment groups, and the relatively small

>numbers of patients included, naturalistic studies such as this have

>certain intrinsic qualities. Immunomodulatory treatments for

>multiple sclerosis have already demonstrated clear efficacy in a

>series of double-blind, placebo-controlled, randomized clinical

>trials including large numbers of patients (Galetta et al., 2002;

>Goodin et al., 2002; Khan et al., 2002). The challenge for current

>clinical research with these drugs is thus not so much to reiterate

>these findings, but to demonstrate that the findings of the clinical

>trial programme can be generalized to everyday standards of care.

>Naturalistic studies such as the current one, can help address this

>issue. The broad entry criteria ensure good representativity of the

>study cohort, and the retrospective nature of the analysis allows

>bias from doctor or patient expectations to be limited.

>

>In addition, recent data across a variety of therapeutic areas

>suggests that treatment effects seen in observational studies are

>generally comparable with those found in randomized controlled

>trials. For example, a recent meta-analysis of studies across 19

>therapeutic areas showed that there were no significant differences

>in size-effects between observational and randomized studies (Benson

>and Hartz, 2000). Although this analysis did not extend to trials in

>multiple sclerosis, there is no reason to think that the data from

>observational studies such as the current one are intrinsically less

>solid than data from randomized clinical trials.

>

>The results can be compared with data previously obtained in

>randomized clinical trials (Table 3). Although the patients included

>in our study generally have less aggressive disease than those in

>the clinical trials (at least in terms of relapse rates), and the

>treatment duration differed between the studies, the impact of

>treatment on annual relapse rates is quite comparable between the

>two study paradigms. This similitude also extends to another open-

>label comparative study of IFN -1a i.m., IFN -1b s.c., GA and no

>treatment, performed in the United States (Khan et al., 2001; Table

>3), and to an open-label prospective study of these four treatments

>and intravenous immunoglobulin performed in Germany, as yet only

>published in abstract form (Firzlaff et al., 2000).

>

>Given the non-randomized nature of the study, no firm conclusions

>can be drawn concerning the relative benefits of the different

>immunomodulatory treatments. However, inspection of the data reveals

>certain potential inter-group differences, with perhaps a somewhat

>larger treatment responses for GA. Interestingly, the same order of

>relative efficacy for the three therapies evaluated (IFN -1a i.m.,

>IFN -1b s.c. and GA) in the prospective observational study by Khan

>et al. (2001) was observed, although, again, patients were not

>randomized. As GA has a different mechanism of action from the

>interferons (Neuhaus et al., 2001), it is possible that the benefit

>provided may not be identical. Potential treatment differences merit

>scrutiny in a randomized prospective study.

>

>In conclusion, this open-label, comparative observational study has

>demonstrated that treatment of patients with RRMS with

>immunomodulatory therapies in the context of current standards of

>care for multiple sclerosis in Argentina provides clinically

>important benefit. The study confirms the efficacy of all four

>available immunomodulatory therapies in reducing relapse rates in

>multiple sclerosis patients, and provides more tantalizing clues

>that some of these therapies may be better than others.

>

April 9, 2004

> Subject: Re: Comparison of ABCR's

I just have to mention that what's really comparing apples' and oranges

is

to compare the science proving ldn works with the science on the crabs.

LDN is so unproven that most docs don't even believe it COULD work.

While I think the evidence for the crabs is shaky, I must point out

that the evidence

for ldn isn't even shaky. It's non-existent... I've been doing my best

to collect some

evidence, but in truth, it wouldn't be hard to give a rat some ldn and

see what happens

with EAE or murine coronavirus...why hasn't it happened?

Perhaps the reason it hasn't happened is they don't want to dash

people's last hopes.

Of course now that ms may not be immunological, all the animal models

are in question,

but just because the mainstream answers are in question doesn't make

the alternatives

right...

I mean I'm really impressed with the learning and effort of the ldn

crew, but all I have to do

is sit and drink a beer with a knowledgeable researcher and I realize

that nobody here

knows anything solid at all...

April 9, 2004

HI JULIE-

I TAKE COPAXONE - AND HAVE HAD NO SIDE EFFECTS OR SITE

REACTIONS. REMEMBER, MS IS AN INSIDIOUS DISEASE - IT MAY BE

CHANGING WITHOUT ANY VISUAL SYMPTOMS. I'M COVERING ALL MY

BASES. I'VE TAKEN AVONEX TOO. ALSO BETASERON. BETASERON

MADE ME ILL. I DID HAVE SIDE EFFECTS WITH AVONEX BUT THEY

WENT AWAY OVER TIME. MY ADVICE - TRY THE INJECTIBLES UNTIL

YOU FIND ONE THAT GIVES FEWEST SIDE EFFECTS AND FITS YOUR

LIFESTYLE. WHEN I STARTED LDN, I STOPPED AVONEX BECAUSE OF

WHAT I READ ON THIS SITE - LDN IS COMPATIBLE ONLY WITH

COPAXONE. I'M GOING ON BLIND FAITH.

BESTAUNT

April 9, 2004

I believe Dr. Ian Zagon is doing research with mice. I believe he's the one on the patent with Dr. Bihari.

Do you want his email address? You can discuss the issue with him and report back to us.

----- Original Message -----

From: Bill Meikle

low dose naltrexone

Sent: Friday, April 09, 2004 10:21

Subject: [low dose naltrexone] Re: Comparison of ABCR's

> Subject: Re: Comparison of ABCR'sI just have to mention that what's really comparing apples' and oranges isto compare the science proving ldn works with the science on the crabs.LDN is so unproven that most docs don't even believe it COULD work.

April 9, 2004

thanks for sharing!!!

April 9, 2004

Despite the lack of science we have a significant number of people who think

they are seeing impressive benefits with LDN. I suppose we could be

deluding ourselves about some of the improvements we claim to have

experienced, but some of the changes are actually measurable and confirmed

by our doctors. For many of us the improvement in bladder issues alone

makes the drug worth the hassle of getting a prescription. While these are

not scientifically proven facts and the biological processes responsible for

the changes are not at all clear there is a growing amount of empirical

evidence that demonstrates LDN is doing something for many of us. Perhaps

eventually we will also have the science to back up our experience.

----- Original Message -----

From: " Bill Meikle " <bcmeikle@...>

Sent: Friday, April 09, 2004 7:21 AM

Subject: [low dose naltrexone] Re: Comparison of ABCR's

>

> > Subject: Re: Comparison of ABCR's

>

> I just have to mention that what's really comparing apples' and oranges

> is

> to compare the science proving ldn works with the science on the crabs.

>

> LDN is so unproven that most docs don't even believe it COULD work.

>

> While I think the evidence for the crabs is shaky, I must point out

> that the evidence

> for ldn isn't even shaky. It's non-existent... I've been doing my best

> to collect some

> evidence, but in truth, it wouldn't be hard to give a rat some ldn and

> see what happens

> with EAE or murine coronavirus...why hasn't it happened?

>

> Perhaps the reason it hasn't happened is they don't want to dash

> people's last hopes.

>

> Of course now that ms may not be immunological, all the animal models

> are in question,

> but just because the mainstream answers are in question doesn't make

> the alternatives

> right...

>

> I mean I'm really impressed with the learning and effort of the ldn

> crew, but all I have to do

> is sit and drink a beer with a knowledgeable researcher and I realize

> that nobody here

> knows anything solid at all...

>

April 9, 2004

Thanks Best.

----- Original Message -----

From: <BESTAUNT@...>

Sent: Friday, April 09, 2004 7:37 AM

Subject: Re: [low dose naltrexone] Comparison of ABCR's

> HI JULIE-

> I TAKE COPAXONE - AND HAVE HAD NO SIDE EFFECTS OR SITE

> REACTIONS. REMEMBER, MS IS AN INSIDIOUS DISEASE - IT MAY BE

> CHANGING WITHOUT ANY VISUAL SYMPTOMS. I'M COVERING ALL MY

> BASES. I'VE TAKEN AVONEX TOO. ALSO BETASERON. BETASERON

> MADE ME ILL. I DID HAVE SIDE EFFECTS WITH AVONEX BUT THEY

> WENT AWAY OVER TIME. MY ADVICE - TRY THE INJECTIBLES UNTIL

> YOU FIND ONE THAT GIVES FEWEST SIDE EFFECTS AND FITS YOUR

> LIFESTYLE. WHEN I STARTED LDN, I STOPPED AVONEX BECAUSE OF

> WHAT I READ ON THIS SITE - LDN IS COMPATIBLE ONLY WITH

> COPAXONE. I'M GOING ON BLIND FAITH.

> BESTAUNT

>

April 9, 2004

I have lots of 'hard evidence' about LDN. It is right here in my body. For

months I have lived a life I didn't think I could ever have again. " Hard

scientific evidence " is not the answer anyway, as each individual is

different, and a large percentage of the statistics contradict each other. I

know we have to use common sense and explore all evidence, but since when

has our own experience stopped being valued as being " real " evidence?

Lynda

> From: " Bill Meikle " <bcmeikle@...>

> <low dose naltrexone >

> Sent: Friday, April 09, 2004 7:21 AM

> Subject: [low dose naltrexone] Re: Comparison of ABCR's

>

> >

> > > Subject: Re: Comparison of ABCR's

> >

> > I just have to mention that what's really comparing apples' and oranges

> > is

> > to compare the science proving ldn works with the science on the crabs.

> >

> > LDN is so unproven that most docs don't even believe it COULD work.

> >

> > While I think the evidence for the crabs is shaky, I must point out

> > that the evidence

> > for ldn isn't even shaky. It's non-existent... I've been doing my best

> > to collect some

> > evidence, but in truth, it wouldn't be hard to give a rat some ldn and

> > see what happens

> > with EAE or murine coronavirus...why hasn't it happened?

> >

> > Perhaps the reason it hasn't happened is they don't want to dash

> > people's last hopes.

> >

> > Of course now that ms may not be immunological, all the animal models

> > are in question,

> > but just because the mainstream answers are in question doesn't make

> > the alternatives

> > right...

> >

> > I mean I'm really impressed with the learning and effort of the ldn

> > crew, but all I have to do

> > is sit and drink a beer with a knowledgeable researcher and I realize

> > that nobody here

> > knows anything solid at all...

> >

April 9, 2004

Jule,

Good for you that your taking the time to look into all of your options of the ABCR drugs. I've taken Copax for 3 years and both Avonex and Rebif, of all three I'm sure your aware that copax has the least side effects but you have to deal with a daily injection. While I was on C I did go into a remission . . .I was not convinced that the Copax made that happen, I was there prior to taking C. . . . anyway I hated the shot every morning so I went on Rebif. . . big mistake horrible side effects not only with R, but A as well! stayed off indictable for several years. Today I'm only taking LDN and doing well. If you don't mind the shot every day, it's into the fat just under the skin therefore it's taken fairly well with most people. You have to feel good about the management decision you make. I had to try them just to make sure I was making the right decision for me! Good Luck

p.s. Please also look into the right foods to eat and exercise program to follow, those are almost more important then the medication you choose!

From: [mailto:jatrac1@...] Sent: Friday, April 09, 2004 1:24 AMlow dose naltrexone Subject: Re: [low dose naltrexone] Comparison of ABCR's

We have heard very little from anyone who has anything good to say aboutCopaxone. It hadn't occurred to me that perhaps there are people who arehappy with it who are just quiet. I suppose it is natural to hear more fromthose who have had unpleasant issues with it. Humankind is certainlyinclined to grumble about things we don't enjoy.I'm sure my next visit to the neuro is going to involve another argumentabout using or not using Copaxone. Anybody want to share their positiveexperiences with this med? I've avoided it because I'm not interested ininjection site reactions or other side effects. Am I feeling too muchconcern? Are there people here who feel it is helping? I hate taking anykind of meds, and had chosen long ago to avoid the ABCs (there was no "R" atthe time I made my decision). Now that I'm seeing a neurologist a couple oftimes a year again the subject comes up with each visit. If it really doeshelp without ugly side effects I should reconsider my position. (MS)----- Original Message ----- From: "yashagrawal" <yashagrawal@...><low dose naltrexone >Sent: Thursday, April 08, 2004 9:27 PMSubject: [low dose naltrexone] Comparison of ABCR'sIn view of the recent unjustified criticism of copaxone... atleastthis study claims that copa is better than the other conventionaldrugs. LDN, may ofcourse be the best :-)YashEuropean Journal of NeurologyVolume 10 Issue 6 Page 671 - November 2003doi:10.1046/j.1468-1331.2003.00669.xA retrospective, observational study comparing the four availableimmunomodulatory treatments for relapsing-remitting multiplesclerosisA. Carrá a , P. Onaha a , V. Sinay a,b , F. Alvarez b , G. Lueticc , R. Bettinelli d , E. San Pedro d and L. Rodríguez eWe performed an observational, retrospective analysis of outcome ina sequential cohort of patients with relapsing-remitting multiplesclerosis (RRMS) in Argentina. Patients treated for 16 months withinterferon -1a (Avonex®; 30 g intramuscularly, once a week),interferon -1a (Rebif®; 44 g subcutaneously, thrice weekly),interferon -1b (Betaferon®; 250 g subcutaneously, every otherday) or glatiramer acetate (Copaxone®; 20 mg subcutaneously daily)were compared with a non-treated group of patients. The differenttreatment groups were similar in baseline demographic and clinicalvariables. A significant fall in the annual relapse rate wasobserved for all four treatments, with the largest effect observedwith glatiramer acetate (81% reduction in relapse rate, comparedwith pre-treatment values). The proportion of patients remainingrelapse-free for the entire 16-month treatment period varied from37% in untreated patients to 83% in the glatiramer acetate treatedgroup. No statistically significant changes in disability scoreswere observed over the treatment period. This first such comparativestudy in Latin America shows that treatment of multiple sclerosispatients with immunomodulatory therapies in the context of currentstandards of care in Argentina provides clinically importantbenefit, and suggest that some of these therapies may be better thanothers.Introduction Go to: Choose Top of page Introduction << MethodsResults Discussion ReferencesOver the last decade, several immunomodulatory therapies have beenintroduced for the treatment of relapsing-remitting multiplesclerosis (RRMS), providing for the first time a possibility tomodify the course of this progressively disabling autoimmuneneurological disease. These include three interferon preparations,interferon -1a (Avonex®, Biogen, Cambridge, MA, USA; givenintramuscularly; IFN -1a i.m.), interferon -1a (Rebif®, Serono,Geneva, Switzerland; given subcutaneously; IFN -1a s.c.),interferon -1b (Betaferon®, Schering AG, Berlin, Germany; givensubcutaneously; IFN -1b s.c.), and an activator of anti-inflammatory T cells, glatiramer acetate (Copaxone®, TevaPharmaceutical Industries, Kfar Sava, Israel; given subcutaneously;GA s.c.). All these drugs have been demonstrated to decrease therate of relapse, slow the progression of disability, and to improvemarkers of lesion load observed in magnetic resonance imaging(Chofflon, 2000; Goodin et al., 2002; Khan et al., 2002; Simpson etal., 2002).Faced with the choice of these four agents, it is important forclinicians to possess reliable comparative data on the efficacy andsafety of these treatments in order to make enlightened treatmentdecisions (Khan et al., 2002). However, little such data isavailable. Direct randomized controlled trials comparing theseagents pose important problems in terms of methodology, logisticsand cost, and no such trials have been performed. Kappos et al.(1998) compared retrospectively the four pivotal studies, andconcluded that the effects of all agents on relapse were broadlysimilar. Galetta et al. (2002) concluded that all fourimmunomodulatory therapies had similar effects on several clinicaland biological outcome measures, although the immunogenicity ofinterferons might be a discriminating tolerability issue. Moreover,recent evidence-based treatment guidelines for multiple sclerosis bythe American Academy of Neurology also concluded that all fourimmunomodulatory therapies were effective in reducing relapse rate(Goodin et al., 2002). Khan et al. (2001) reported a firstprospective open-label comparative study between three of thesetreatments (IFN -1a i.m., IFN -1b s.c. and GA). This studyreported that IFN -1b s.c. and GA may be somewhat more efficaciousthan IFN -1a i.m. More recent studies have suggested that someinterferons may be more efficacious than others (Durelli et al.,2002; Panitch et al., 2002), or that interferons slightly reduce thenumber of patients who have exacerbation during first year oftreatment (Filippini et al., 2003) whilst and Witt (1998)have shown that administration of IFN -1a i.m. and IFN -1b s.c.induce different short-term biological responses.Following the introduction of all four immunomodulatory therapies toArgentina, we have decided to conduct an open-label comparativestudy of these therapies under naturalistic treatment conditions.The objective of the study was to evaluate the effects of these fourimmunomodulatory therapies, compared with a non-treated group ofpatients on annual relapse rate in RRMS. To our knowledge, this isthe first study to compare different immunomodulatory treatments formultiple sclerosis.Methods Go to: Choose Top of page Introduction Methods << ResultsDiscussion ReferencesThis study was an observational, retrospective analysis of a cohortof patients with RRMS treated with immunomodulatory therapies infive multiple sclerosis centres (private and public hospitals withneurology departments) in Argentina. A no treatment control groupwas included. The treatment period was from January 2001 to May 2002(16 months).This retrospective study included a sequential series of allpatients attending the five participating centres over the studyduration fulfilling retrospectively chosen inclusion criteria, whichwere ascertained by reference to the patient notes. These criteriaselected patients between 16 and 61 years old fulfilling the Posercriteria for definitive RRMS (Poser et al., 1983). Patients wererequired to have scores on Expanded Disability Status Scale (EDSS)(Kurtzke, 1983) in the range of 0-6.0, to have experienced at leastone relapse in the previous 2 years, and to have been clinicallystable for at least 30 days prior to inclusion. Exclusion criteriawere secondary progressive multiple sclerosis and the use of thefollowing prior treatments: chronic maintenance steroid therapy(only acute treatment during previous relapses was acceptable),immunomodulatory therapy and immunosuppressant therapy.Before starting treatment, each patient underwent a baselineneurological examination and an assessment of EDSS score. Patientswere treated with one of four immunomodulatory therapies:interferon -1a (Avonex®; 30 g i.m. once a week), interferon -1a(Rebif®; 44 g s.c. thrice weekly), interferon -1b (Betaferon®;250 g s.c. every other day) and glatiramer acetate (Copaxone®; 20mg s.c. daily). The choice of which treatment to use was at thetreating neurologist's discretion. Patients were provided withinformation about treatments, and discussed the relative efficacyand tolerability of the different possible treatments withneurologist. Although use of immunomodulatory therapy is reimbursedby the health service in Argentina, a number of patients were unableto receive treatment because they had no social security coverage,and these thus formed a no treatment control group. None of thepatients were switched to another treatment group during the courseof the study. The study duration was 16 months.In the event of a relapse, this was confirmed by a neurologicalexamination performed by the treating neurologist, who initiatedappropriate treatment. The standard treatment was a 5-day course ofmethylyprednisolone (Solumedrol®, Pfizer, Argentina; 1 g/day)followed, if the neurologist considered this necessary by aprednisolone (Deltisona®, Aventis Pharma, Argentina) taper for 30days.After treatment was initiated, each patient returned for scheduledfollow-up visits to the same neurologist every 3 months. Scores onthe EDSS rating scale were determined at each visit.The principal outcome measure was incidence of relapse. This wasdefined as new symptoms or worsening of previous symptoms lasting atleast 48 h, characterized by an increase of at least half a step onthe EDSS, an increase of at least two points on one of the sevenfunctional systems or an increase of at least one point on two ormore of the functional systems.The incidence of disease progression was also recorded. This wasdefined as an increase of at least one full step on the EDSS thatpersisted for two consecutive visits and remained unchanged for atleast 12 weeks. Secondary outcome measures were the change in meanEDSS score over the study period and the proportion of relapse-freepatients.All the data were analysed at 16 months for all groups. The resultsare shown as median values (25-75% quartile) for quantitativevariables, or as percentages for qualitative ones where appropriate.Baseline demographic and clinical variables were compared betweenthe four treatment groups, as were pre- and post-treatment outcomevariables within each treatment group. Comparisons of categoricalvariables were performed with the 2 test, whilst quantitativevariables were compared using analysis of variance (anova). Giventhat inclusion into the different treatment arms was not randomized,inter-group comparisons of treatment effects were not undertaken.All tests were two-tailed and a probability level of < 0.05 wastaken to be significant. The data analysis was performed with Epi6.04 software (Center for Disease Control, Atlanta, GA, USA).The protocol was submitted to, and approved by, the Ethics Committeeof the Hospital Británico, Buenos Aires.Results Go to: Choose Top of page Introduction Methods Results <<Discussion ReferencesThe study included 134 patients who were distributed betweentreatment groups as follows: IFN -1a i.m.: 26 patients; IFN -1bs.c.: 20 patients; IFN -1a s.c.: 20 patients; GA: 30 patients; notreatment: 38 patients. The baseline demographics and diseasevariables for the five patient groups are presented in Table 1. Theaverage age of the patients was 40 years, and the average diseaseduration 7.3 years. All patients had active disease, with mosthaving experienced at least two relapses over the previous 2 years.The average EDSS score at inclusion was 2.05. All groups werecomparable at baseline for the following parameters: total number ofrelapses in the previous 2 years and in the previous year, and EDSSscore at inclusion.Over the 16-month study period, the number of relapses wassignificantly lower compared with the pre-treatment period for allthe active treatments (P < 0.001; 2 test; Table 2). However, theannual relapse rate in untreated patients increased from 0.54 to0.71 (P < 0.001). The changes in annual relapse rate in thedifferent treatment groups before and after initiation of treatmentare presented in Fig. 1. These varied from a reduction of 49% in theIFN -1a i.m. treatment group to one of 81% in the GA treatmentgroup.The proportion of patients remaining relapse-free for the entire 16-month treatment period varied from 60% in the IFN -1a s.c. andIFN -1b s.c. groups to 83% in the GA group (Table 2). Only 37% ofuntreated patients remained relapse-free. There was a slight fall inthe EDSS score over the 16-month study group in the IFN -1b s.c.and GA treatment groups, and a slight rise in score in the untreatedpatients (Fig. 2). However, none of these changes were statisticallysignificant.Discussion Go to: Choose Top of page Introduction Methods ResultsDiscussion << ReferencesThis open-label, retrospective study compared the efficacy ofdifferent immunomodulatory treatments for RRMS available inArgentina. To our knowledge, this is the first such study reportedfrom South America. The retrospective nature of the study precludedrandomization, but allowed the impact of treatment to be assessed instandard conditions of multiple sclerosis care in Argentina. Giventhat all previously untreated patients consulting for multiplesclerosis who fulfilled relatively broad inclusion criteria wereincluded, the sample evaluated can be considered representative ofthe overall population of multiple sclerosis patients suitable forimmunomodulatory treatment in Argentina. However, considering theaverage disease duration, it is important to highlight that mostpatients have had a relatively low mean EDSS at baseline.This is the first such observational study that has compared allfour immunomodulatory treatments currently available. Patients werefollowed-up for 16 months following initiation of treatment. Theprincipal finding of the study was a significant reduction in theannual relapse rate for all four drug therapies, compared with pre-treatment relapse rates. No such reduction was observed in aparallel group receiving no treatment. The proportion of relapse-free patients was approximately twice as high in the groupsreceiving immunomodulatory treatments compared with the no treatmentgroup. The proportion of relapse-free patients in the groupreceiving no treatment (37%) may be due to either the short durationof follow-up or due to their low EDSS score at baseline.Concerning disability, we did not find a significant reduction inEDSS score in any of the treatment groups, although there was atrend towards improvement in the IFN -1b s.c. and GA groups. It ispossible that the 16-month treatment period was not sufficient todemonstrate robust effects on this outcome measure.Although the study has a number of limitations, notably the lack ofrandomization between treatment groups, and the relatively smallnumbers of patients included, naturalistic studies such as this havecertain intrinsic qualities. Immunomodulatory treatments formultiple sclerosis have already demonstrated clear efficacy in aseries of double-blind, placebo-controlled, randomized clinicaltrials including large numbers of patients (Galetta et al., 2002;Goodin et al., 2002; Khan et al., 2002). The challenge for currentclinical research with these drugs is thus not so much to reiteratethese findings, but to demonstrate that the findings of the clinicaltrial programme can be generalized to everyday standards of care.Naturalistic studies such as the current one, can help address thisissue. The broad entry criteria ensure good representativity of thestudy cohort, and the retrospective nature of the analysis allowsbias from doctor or patient expectations to be limited.In addition, recent data across a variety of therapeutic areassuggests that treatment effects seen in observational studies aregenerally comparable with those found in randomized controlledtrials. For example, a recent meta-analysis of studies across 19therapeutic areas showed that there were no significant differencesin size-effects between observational and randomized studies (Bensonand Hartz, 2000). Although this analysis did not extend to trials inmultiple sclerosis, there is no reason to think that the data fromobservational studies such as the current one are intrinsically lesssolid than data from randomized clinical trials.The results can be compared with data previously obtained inrandomized clinical trials (Table 3). Although the patients includedin our study generally have less aggressive disease than those inthe clinical trials (at least in terms of relapse rates), and thetreatment duration differed between the studies, the impact oftreatment on annual relapse rates is quite comparable between thetwo study paradigms. This similitude also extends to another open-label comparative study of IFN -1a i.m., IFN -1b s.c., GA and notreatment, performed in the United States (Khan et al., 2001; Table3), and to an open-label prospective study of these four treatmentsand intravenous immunoglobulin performed in Germany, as yet onlypublished in abstract form (Firzlaff et al., 2000).Given the non-randomized nature of the study, no firm conclusionscan be drawn concerning the relative benefits of the differentimmunomodulatory treatments. However, inspection of the data revealscertain potential inter-group differences, with perhaps a somewhatlarger treatment responses for GA. Interestingly, the same order ofrelative efficacy for the three therapies evaluated (IFN -1a i.m.,IFN -1b s.c. and GA) in the prospective observational study by Khanet al. (2001) was observed, although, again, patients were notrandomized. As GA has a different mechanism of action from theinterferons (Neuhaus et al., 2001), it is possible that the benefitprovided may not be identical. Potential treatment differences meritscrutiny in a randomized prospective study.In conclusion, this open-label, comparative observational study hasdemonstrated that treatment of patients with RRMS withimmunomodulatory therapies in the context of current standards ofcare for multiple sclerosis in Argentina provides clinicallyimportant benefit. The study confirms the efficacy of all fouravailable immunomodulatory therapies in reducing relapse rates inmultiple sclerosis patients, and provides more tantalizing cluesthat some of these therapies may be better than others.

April 9, 2004

Thanks , I've always believed we can manage this condition better, for the most part, with diet and rational living. Unfortunately it is too easy to fudge here and there, and pretty soon you've abandoned the healthy diet.

I'm still opposed to the ABCRs because I have yet to hear anything that convinces me they are truly beneficial. And I've heard a lot of good reasons not to take them. For now I'll stick with LDN. I've been dealing with MS for many many years now without drugs, and done pretty well although the last year has been a bit tough. My son was in Kuwait and Iraq, and his post traumatic stress disorder has been pretty stressful for me too.

Since joining this message board I've heard from others who have used them and had my curiosity piqued, and with the pressure from my new neuro it seemed wise to ask how others have done on them.

Of course LDN IS a drug, but certainly one of the least harmful I've ever heard of. It's also the first I have ever taken for MS. I have occasionally used muscle relaxers but have not taken anything that acts on my immune system.

I just wish LDN didn't make my legs so stiff...

----- Original Message -----

From: Baden

low dose naltrexone

Sent: Friday, April 09, 2004 12:48 PM

Subject: RE: [low dose naltrexone] Comparison of ABCR's

Jule,

Good for you that your taking the time to look into all of your options of the ABCR drugs. I've taken Copax for 3 years and both Avonex and Rebif, of all three I'm sure your aware that copax has the least side effects but you have to deal with a daily injection. While I was on C I did go into a remission . . .I was not convinced that the Copax made that happen, I was there prior to taking C. . . . anyway I hated the shot every morning so I went on Rebif. . . big mistake horrible side effects not only with R, but A as well! stayed off indictable for several years. Today I'm only taking LDN and doing well. If you don't mind the shot every day, it's into the fat just under the skin therefore it's taken fairly well with most people. You have to feel good about the management decision you make. I had to try them just to make sure I was making the right decision for me! Good Luck

p.s. Please also look into the right foods to eat and exercise program to follow, those are almost more important then the medication you choose!

From: [mailto:jatrac1@...] Sent: Friday, April 09, 2004 1:24 AMlow dose naltrexone Subject: Re: [low dose naltrexone] Comparison of ABCR's

We have heard very little from anyone who has anything good to say aboutCopaxone. It hadn't occurred to me that perhaps there are people who arehappy with it who are just quiet. I suppose it is natural to hear more fromthose who have had unpleasant issues with it. Humankind is certainlyinclined to grumble about things we don't enjoy.I'm sure my next visit to the neuro is going to involve another argumentabout using or not using Copaxone. Anybody want to share their positiveexperiences with this med? I've avoided it because I'm not interested ininjection site reactions or other side effects. Am I feeling too muchconcern? Are there people here who feel it is helping? I hate taking anykind of meds, and had chosen long ago to avoid the ABCs (there was no "R" atthe time I made my decision). Now that I'm seeing a neurologist a couple oftimes a year again the subject comes up with each visit. If it really doeshelp without ugly side effects I should reconsider my position. (MS)----- Original Message ----- From: "yashagrawal" <yashagrawal@...><low dose naltrexone >Sent: Thursday, April 08, 2004 9:27 PMSubject: [low dose naltrexone] Comparison of ABCR'sIn view of the recent unjustified criticism of copaxone... atleastthis study claims that copa is better than the other conventionaldrugs. LDN, may ofcourse be the best :-)YashEuropean Journal of NeurologyVolume 10 Issue 6 Page 671 - November 2003doi:10.1046/j.1468-1331.2003.00669.xA retrospective, observational study comparing the four availableimmunomodulatory treatments for relapsing-remitting multiplesclerosisA. Carrá a , P. Onaha a , V. Sinay a,b , F. Alvarez b , G. Lueticc , R. Bettinelli d , E. San Pedro d and L. Rodríguez eWe performed an observational, retrospective analysis of outcome ina sequential cohort of patients with relapsing-remitting multiplesclerosis (RRMS) in Argentina. Patients treated for 16 months withinterferon -1a (Avonex®; 30 g intramuscularly, once a week),interferon -1a (Rebif®; 44 g subcutaneously, thrice weekly),interferon -1b (Betaferon®; 250 g subcutaneously, every otherday) or glatiramer acetate (Copaxone®; 20 mg subcutaneously daily)were compared with a non-treated group of patients. The differenttreatment groups were similar in baseline demographic and clinicalvariables. A significant fall in the annual relapse rate wasobserved for all four treatments, with the largest effect observedwith glatiramer acetate (81% reduction in relapse rate, comparedwith pre-treatment values). The proportion of patients remainingrelapse-free for the entire 16-month treatment period varied from37% in untreated patients to 83% in the glatiramer acetate treatedgroup. No statistically significant changes in disability scoreswere observed over the treatment period. This first such comparativestudy in Latin America shows that treatment of multiple sclerosispatients with immunomodulatory therapies in the context of currentstandards of care in Argentina provides clinically importantbenefit, and suggest that some of these therapies may be better thanothers.Introduction Go to: Choose Top of page Introduction << MethodsResults Discussion ReferencesOver the last decade, several immunomodulatory therapies have beenintroduced for the treatment of relapsing-remitting multiplesclerosis (RRMS), providing for the first time a possibility tomodify the course of this progressively disabling autoimmuneneurological disease. These include three interferon preparations,interferon -1a (Avonex®, Biogen, Cambridge, MA, USA; givenintramuscularly; IFN -1a i.m.), interferon -1a (Rebif®, Serono,Geneva, Switzerland; given subcutaneously; IFN -1a s.c.),interferon -1b (Betaferon®, Schering AG, Berlin, Germany; givensubcutaneously; IFN -1b s.c.), and an activator of anti-inflammatory T cells, glatiramer acetate (Copaxone®, TevaPharmaceutical Industries, Kfar Sava, Israel; given subcutaneously;GA s.c.). All these drugs have been demonstrated to decrease therate of relapse, slow the progression of disability, and to improvemarkers of lesion load observed in magnetic resonance imaging(Chofflon, 2000; Goodin et al., 2002; Khan et al., 2002; Simpson etal., 2002).Faced with the choice of these four agents, it is important forclinicians to possess reliable comparative data on the efficacy andsafety of these treatments in order to make enlightened treatmentdecisions (Khan et al., 2002). However, little such data isavailable. Direct randomized controlled trials comparing theseagents pose important problems in terms of methodology, logisticsand cost, and no such trials have been performed. Kappos et al.(1998) compared retrospectively the four pivotal studies, andconcluded that the effects of all agents on relapse were broadlysimilar. Galetta et al. (2002) concluded that all fourimmunomodulatory therapies had similar effects on several clinicaland biological outcome measures, although the immunogenicity ofinterferons might be a discriminating tolerability issue. Moreover,recent evidence-based treatment guidelines for multiple sclerosis bythe American Academy of Neurology also concluded that all fourimmunomodulatory therapies were effective in reducing relapse rate(Goodin et al., 2002). Khan et al. (2001) reported a firstprospective open-label comparative study between three of thesetreatments (IFN -1a i.m., IFN -1b s.c. and GA). This studyreported that IFN -1b s.c. and GA may be somewhat more efficaciousthan IFN -1a i.m. More recent studies have suggested that someinterferons may be more efficacious than others (Durelli et al.,2002; Panitch et al., 2002), or that interferons slightly reduce thenumber of patients who have exacerbation during first year oftreatment (Filippini et al., 2003) whilst and Witt (1998)have shown that administration of IFN -1a i.m. and IFN -1b s.c.induce different short-term biological responses.Following the introduction of all four immunomodulatory therapies toArgentina, we have decided to conduct an open-label comparativestudy of these therapies under naturalistic treatment conditions.The objective of the study was to evaluate the effects of these fourimmunomodulatory therapies, compared with a non-treated group ofpatients on annual relapse rate in RRMS. To our knowledge, this isthe first study to compare different immunomodulatory treatments formultiple sclerosis.Methods Go to: Choose Top of page Introduction Methods << ResultsDiscussion ReferencesThis study was an observational, retrospective analysis of a cohortof patients with RRMS treated with immunomodulatory therapies infive multiple sclerosis centres (private and public hospitals withneurology departments) in Argentina. A no treatment control groupwas included. The treatment period was from January 2001 to May 2002(16 months).This retrospective study included a sequential series of allpatients attending the five participating centres over the studyduration fulfilling retrospectively chosen inclusion criteria, whichwere ascertained by reference to the patient notes. These criteriaselected patients between 16 and 61 years old fulfilling the Posercriteria for definitive RRMS (Poser et al., 1983). Patients wererequired to have scores on Expanded Disability Status Scale (EDSS)(Kurtzke, 1983) in the range of 0-6.0, to have experienced at leastone relapse in the previous 2 years, and to have been clinicallystable for at least 30 days prior to inclusion. Exclusion criteriawere secondary progressive multiple sclerosis and the use of thefollowing prior treatments: chronic maintenance steroid therapy(only acute treatment during previous relapses was acceptable),immunomodulatory therapy and immunosuppressant therapy.Before starting treatment, each patient underwent a baselineneurological examination and an assessment of EDSS score. Patientswere treated with one of four immunomodulatory therapies:interferon -1a (Avonex®; 30 g i.m. once a week), interferon -1a(Rebif®; 44 g s.c. thrice weekly), interferon -1b (Betaferon®;250 g s.c. every other day) and glatiramer acetate (Copaxone®; 20mg s.c. daily). The choice of which treatment to use was at thetreating neurologist's discretion. Patients were provided withinformation about treatments, and discussed the relative efficacyand tolerability of the different possible treatments withneurologist. Although use of immunomodulatory therapy is reimbursedby the health service in Argentina, a number of patients were unableto receive treatment because they had no social security coverage,and these thus formed a no treatment control group. None of thepatients were switched to another treatment group during the courseof the study. The study duration was 16 months.In the event of a relapse, this was confirmed by a neurologicalexamination performed by the treating neurologist, who initiatedappropriate treatment. The standard treatment was a 5-day course ofmethylyprednisolone (Solumedrol®, Pfizer, Argentina; 1 g/day)followed, if the neurologist considered this necessary by aprednisolone (Deltisona®, Aventis Pharma, Argentina) taper for 30days.After treatment was initiated, each patient returned for scheduledfollow-up visits to the same neurologist every 3 months. Scores onthe EDSS rating scale were determined at each visit.The principal outcome measure was incidence of relapse. This wasdefined as new symptoms or worsening of previous symptoms lasting atleast 48 h, characterized by an increase of at least half a step onthe EDSS, an increase of at least two points on one of the sevenfunctional systems or an increase of at least one point on two ormore of the functional systems.The incidence of disease progression was also recorded. This wasdefined as an increase of at least one full step on the EDSS thatpersisted for two consecutive visits and remained unchanged for atleast 12 weeks. Secondary outcome measures were the change in meanEDSS score over the study period and the proportion of relapse-freepatients.All the data were analysed at 16 months for all groups. The resultsare shown as median values (25-75% quartile) for quantitativevariables, or as percentages for qualitative ones where appropriate.Baseline demographic and clinical variables were compared betweenthe four treatment groups, as were pre- and post-treatment outcomevariables within each treatment group. Comparisons of categoricalvariables were performed with the 2 test, whilst quantitativevariables were compared using analysis of variance (anova). Giventhat inclusion into the different treatment arms was not randomized,inter-group comparisons of treatment effects were not undertaken.All tests were two-tailed and a probability level of < 0.05 wastaken to be significant. The data analysis was performed with Epi6.04 software (Center for Disease Control, Atlanta, GA, USA).The protocol was submitted to, and approved by, the Ethics Committeeof the Hospital Británico, Buenos Aires.Results Go to: Choose Top of page Introduction Methods Results <<Discussion ReferencesThe study included 134 patients who were distributed betweentreatment groups as follows: IFN -1a i.m.: 26 patients; IFN -1bs.c.: 20 patients; IFN -1a s.c.: 20 patients; GA: 30 patients; notreatment: 38 patients. The baseline demographics and diseasevariables for the five patient groups are presented in Table 1. Theaverage age of the patients was 40 years, and the average diseaseduration 7.3 years. All patients had active disease, with mosthaving experienced at least two relapses over the previous 2 years.The average EDSS score at inclusion was 2.05. All groups werecomparable at baseline for the following parameters: total number ofrelapses in the previous 2 years and in the previous year, and EDSSscore at inclusion.Over the 16-month study period, the number of relapses wassignificantly lower compared with the pre-treatment period for allthe active treatments (P < 0.001; 2 test; Table 2). However, theannual relapse rate in untreated patients increased from 0.54 to0.71 (P < 0.001). The changes in annual relapse rate in thedifferent treatment groups before and after initiation of treatmentare presented in Fig. 1. These varied from a reduction of 49% in theIFN -1a i.m. treatment group to one of 81% in the GA treatmentgroup.The proportion of patients remaining relapse-free for the entire 16-month treatment period varied from 60% in the IFN -1a s.c. andIFN -1b s.c. groups to 83% in the GA group (Table 2). Only 37% ofuntreated patients remained relapse-free. There was a slight fall inthe EDSS score over the 16-month study group in the IFN -1b s.c.and GA treatment groups, and a slight rise in score in the untreatedpatients (Fig. 2). However, none of these changes were statisticallysignificant.Discussion Go to: Choose Top of page Introduction Methods ResultsDiscussion << ReferencesThis open-label, retrospective study compared the efficacy ofdifferent immunomodulatory treatments for RRMS available inArgentina. To our knowledge, this is the first such study reportedfrom South America. The retrospective nature of the study precludedrandomization, but allowed the impact of treatment to be assessed instandard conditions of multiple sclerosis care in Argentina. Giventhat all previously untreated patients consulting for multiplesclerosis who fulfilled relatively broad inclusion criteria wereincluded, the sample evaluated can be considered representative ofthe overall population of multiple sclerosis patients suitable forimmunomodulatory treatment in Argentina. However, considering theaverage disease duration, it is important to highlight that mostpatients have had a relatively low mean EDSS at baseline.This is the first such observational study that has compared allfour immunomodulatory treatments currently available. Patients werefollowed-up for 16 months following initiation of treatment. Theprincipal finding of the study was a significant reduction in theannual relapse rate for all four drug therapies, compared with pre-treatment relapse rates. No such reduction was observed in aparallel group receiving no treatment. The proportion of relapse-free patients was approximately twice as high in the groupsreceiving immunomodulatory treatments compared with the no treatmentgroup. The proportion of relapse-free patients in the groupreceiving no treatment (37%) may be due to either the short durationof follow-up or due to their low EDSS score at baseline.Concerning disability, we did not find a significant reduction inEDSS score in any of the treatment groups, although there was atrend towards improvement in the IFN -1b s.c. and GA groups. It ispossible that the 16-month treatment period was not sufficient todemonstrate robust effects on this outcome measure.Although the study has a number of limitations, notably the lack ofrandomization between treatment groups, and the relatively smallnumbers of patients included, naturalistic studies such as this havecertain intrinsic qualities. Immunomodulatory treatments formultiple sclerosis have already demonstrated clear efficacy in aseries of double-blind, placebo-controlled, randomized clinicaltrials including large numbers of patients (Galetta et al., 2002;Goodin et al., 2002; Khan et al., 2002). The challenge for currentclinical research with these drugs is thus not so much to reiteratethese findings, but to demonstrate that the findings of the clinicaltrial programme can be generalized to everyday standards of care.Naturalistic studies such as the current one, can help address thisissue. The broad entry criteria ensure good representativity of thestudy cohort, and the retrospective nature of the analysis allowsbias from doctor or patient expectations to be limited.In addition, recent data across a variety of therapeutic areassuggests that treatment effects seen in observational studies aregenerally comparable with those found in randomized controlledtrials. For example, a recent meta-analysis of studies across 19therapeutic areas showed that there were no significant differencesin size-effects between observational and randomized studies (Bensonand Hartz, 2000). Although this analysis did not extend to trials inmultiple sclerosis, there is no reason to think that the data fromobservational studies such as the current one are intrinsically lesssolid than data from randomized clinical trials.The results can be compared with data previously obtained inrandomized clinical trials (Table 3). Although the patients includedin our study generally have less aggressive disease than those inthe clinical trials (at least in terms of relapse rates), and thetreatment duration differed between the studies, the impact oftreatment on annual relapse rates is quite comparable between thetwo study paradigms. This similitude also extends to another open-label comparative study of IFN -1a i.m., IFN -1b s.c., GA and notreatment, performed in the United States (Khan et al., 2001; Table3), and to an open-label prospective study of these four treatmentsand intravenous immunoglobulin performed in Germany, as yet onlypublished in abstract form (Firzlaff et al., 2000).Given the non-randomized nature of the study, no firm conclusionscan be drawn concerning the relative benefits of the differentimmunomodulatory treatments. However, inspection of the data revealscertain potential inter-group differences, with perhaps a somewhatlarger treatment responses for GA. Interestingly, the same order ofrelative efficacy for the three therapies evaluated (IFN -1a i.m.,IFN -1b s.c. and GA) in the prospective observational study by Khanet al. (2001) was observed, although, again, patients were notrandomized. As GA has a different mechanism of action from theinterferons (Neuhaus et al., 2001), it is possible that the benefitprovided may not be identical. Potential treatment differences meritscrutiny in a randomized prospective study.In conclusion, this open-label, comparative observational study hasdemonstrated that treatment of patients with RRMS withimmunomodulatory therapies in the context of current standards ofcare for multiple sclerosis in Argentina provides clinicallyimportant benefit. The study confirms the efficacy of all fouravailable immunomodulatory therapies in reducing relapse rates inmultiple sclerosis patients, and provides more tantalizing cluesthat some of these therapies may be better than others.

April 10, 2004

Sounds like a great plan , have a great Easter.

From: [mailto:jatrac1@...] Sent: Friday, April 09, 2004 4:26 PMlow dose naltrexone Subject: Re: [low dose naltrexone] Comparison of ABCR's

Thanks , I've always believed we can manage this condition better, for the most part, with diet and rational living. Unfortunately it is too easy to fudge here and there, and pretty soon you've abandoned the healthy diet.

I'm still opposed to the ABCRs because I have yet to hear anything that convinces me they are truly beneficial. And I've heard a lot of good reasons not to take them. For now I'll stick with LDN. I've been dealing with MS for many many years now without drugs, and done pretty well although the last year has been a bit tough. My son was in Kuwait and Iraq, and his post traumatic stress disorder has been pretty stressful for me too.

Since joining this message board I've heard from others who have used them and had my curiosity piqued, and with the pressure from my new neuro it seemed wise to ask how others have done on them.

Of course LDN IS a drug, but certainly one of the least harmful I've ever heard of. It's also the first I have ever taken for MS. I have occasionally used muscle relaxers but have not taken anything that acts on my immune system.

I just wish LDN didn't make my legs so stiff...

----- Original Message -----

From: Baden

low dose naltrexone

Sent: Friday, April 09, 2004 12:48 PM

Subject: RE: [low dose naltrexone] Comparison of ABCR's

Jule,

Good for you that your taking the time to look into all of your options of the ABCR drugs. I've taken Copax for 3 years and both Avonex and Rebif, of all three I'm sure your aware that copax has the least side effects but you have to deal with a daily injection. While I was on C I did go into a remission . . .I was not convinced that the Copax made that happen, I was there prior to taking C. . . . anyway I hated the shot every morning so I went on Rebif. . . big mistake horrible side effects not only with R, but A as well! stayed off indictable for several years. Today I'm only taking LDN and doing well. If you don't mind the shot every day, it's into the fat just under the skin therefore it's taken fairly well with most people. You have to feel good about the management decision you make. I had to try them just to make sure I was making the right decision for me! Good Luck

p.s. Please also look into the right foods to eat and exercise program to follow, those are almost more important then the medication you choose!

From: [mailto:jatrac1@...] Sent: Friday, April 09, 2004 1:24 AMlow dose naltrexone Subject: Re: [low dose naltrexone] Comparison of ABCR's

We have heard very little from anyone who has anything good to say aboutCopaxone. It hadn't occurred to me that perhaps there are people who arehappy with it who are just quiet. I suppose it is natural to hear more fromthose who have had unpleasant issues with it. Humankind is certainlyinclined to grumble about things we don't enjoy.I'm sure my next visit to the neuro is going to involve another argumentabout using or not using Copaxone. Anybody want to share their positiveexperiences with this med? I've avoided it because I'm not interested ininjection site reactions or other side effects. Am I feeling too muchconcern? Are there people here who feel it is helping? I hate taking anykind of meds, and had chosen long ago to avoid the ABCs (there was no "R" atthe time I made my decision). Now that I'm seeing a neurologist a couple oftimes a year again the subject comes up with each visit. If it really doeshelp without ugly side effects I should reconsider my position. (MS)----- Original Message ----- From: "yashagrawal" <yashagrawal@...><low dose naltrexone >Sent: Thursday, April 08, 2004 9:27 PMSubject: [low dose naltrexone] Comparison of ABCR'sIn view of the recent unjustified criticism of copaxone... atleastthis study claims that copa is better than the other conventionaldrugs. LDN, may ofcourse be the best :-)YashEuropean Journal of NeurologyVolume 10 Issue 6 Page 671 - November 2003doi:10.1046/j.1468-1331.2003.00669.xA retrospective, observational study comparing the four availableimmunomodulatory treatments for relapsing-remitting multiplesclerosisA. Carrá a , P. Onaha a , V. Sinay a,b , F. Alvarez b , G. Lueticc , R. Bettinelli d , E. San Pedro d and L. Rodríguez eWe performed an observational, retrospective analysis of outcome ina sequential cohort of patients with relapsing-remitting multiplesclerosis (RRMS) in Argentina. Patients treated for 16 months withinterferon -1a (Avonex®; 30 g intramuscularly, once a week),interferon -1a (Rebif®; 44 g subcutaneously, thrice weekly),interferon -1b (Betaferon®; 250 g subcutaneously, every otherday) or glatiramer acetate (Copaxone®; 20 mg subcutaneously daily)were compared with a non-treated group of patients. The differenttreatment groups were similar in baseline demographic and clinicalvariables. A significant fall in the annual relapse rate wasobserved for all four treatments, with the largest effect observedwith glatiramer acetate (81% reduction in relapse rate, comparedwith pre-treatment values). The proportion of patients remainingrelapse-free for the entire 16-month treatment period varied from37% in untreated patients to 83% in the glatiramer acetate treatedgroup. No statistically significant changes in disability scoreswere observed over the treatment period. This first such comparativestudy in Latin America shows that treatment of multiple sclerosispatients with immunomodulatory therapies in the context of currentstandards of care in Argentina provides clinically importantbenefit, and suggest that some of these therapies may be better thanothers.Introduction Go to: Choose Top of page Introduction << MethodsResults Discussion ReferencesOver the last decade, several immunomodulatory therapies have beenintroduced for the treatment of relapsing-remitting multiplesclerosis (RRMS), providing for the first time a possibility tomodify the course of this progressively disabling autoimmuneneurological disease. These include three interferon preparations,interferon -1a (Avonex®, Biogen, Cambridge, MA, USA; givenintramuscularly; IFN -1a i.m.), interferon -1a (Rebif®, Serono,Geneva, Switzerland; given subcutaneously; IFN -1a s.c.),interferon -1b (Betaferon®, Schering AG, Berlin, Germany; givensubcutaneously; IFN -1b s.c.), and an activator of anti-inflammatory T cells, glatiramer acetate (Copaxone®, TevaPharmaceutical Industries, Kfar Sava, Israel; given subcutaneously;GA s.c.). All these drugs have been demonstrated to decrease therate of relapse, slow the progression of disability, and to improvemarkers of lesion load observed in magnetic resonance imaging(Chofflon, 2000; Goodin et al., 2002; Khan et al., 2002; Simpson etal., 2002).Faced with the choice of these four agents, it is important forclinicians to possess reliable comparative data on the efficacy andsafety of these treatments in order to make enlightened treatmentdecisions (Khan et al., 2002). However, little such data isavailable. Direct randomized controlled trials comparing theseagents pose important problems in terms of methodology, logisticsand cost, and no such trials have been performed. Kappos et al.(1998) compared retrospectively the four pivotal studies, andconcluded that the effects of all agents on relapse were broadlysimilar. Galetta et al. (2002) concluded that all fourimmunomodulatory therapies had similar effects on several clinicaland biological outcome measures, although the immunogenicity ofinterferons might be a discriminating tolerability issue. Moreover,recent evidence-based treatment guidelines for multiple sclerosis bythe American Academy of Neurology also concluded that all fourimmunomodulatory therapies were effective in reducing relapse rate(Goodin et al., 2002). Khan et al. (2001) reported a firstprospective open-label comparative study between three of thesetreatments (IFN -1a i.m., IFN -1b s.c. and GA). This studyreported that IFN -1b s.c. and GA may be somewhat more efficaciousthan IFN -1a i.m. More recent studies have suggested that someinterferons may be more efficacious than others (Durelli et al.,2002; Panitch et al., 2002), or that interferons slightly reduce thenumber of patients who have exacerbation during first year oftreatment (Filippini et al., 2003) whilst and Witt (1998)have shown that administration of IFN -1a i.m. and IFN -1b s.c.induce different short-term biological responses.Following the introduction of all four immunomodulatory therapies toArgentina, we have decided to conduct an open-label comparativestudy of these therapies under naturalistic treatment conditions.The objective of the study was to evaluate the effects of these fourimmunomodulatory therapies, compared with a non-treated group ofpatients on annual relapse rate in RRMS. To our knowledge, this isthe first study to compare different immunomodulatory treatments formultiple sclerosis.Methods Go to: Choose Top of page Introduction Methods << ResultsDiscussion ReferencesThis study was an observational, retrospective analysis of a cohortof patients with RRMS treated with immunomodulatory therapies infive multiple sclerosis centres (private and public hospitals withneurology departments) in Argentina. A no treatment control groupwas included. The treatment period was from January 2001 to May 2002(16 months).This retrospective study included a sequential series of allpatients attending the five participating centres over the studyduration fulfilling retrospectively chosen inclusion criteria, whichwere ascertained by reference to the patient notes. These criteriaselected patients between 16 and 61 years old fulfilling the Posercriteria for definitive RRMS (Poser et al., 1983). Patients wererequired to have scores on Expanded Disability Status Scale (EDSS)(Kurtzke, 1983) in the range of 0-6.0, to have experienced at leastone relapse in the previous 2 years, and to have been clinicallystable for at least 30 days prior to inclusion. Exclusion criteriawere secondary progressive multiple sclerosis and the use of thefollowing prior treatments: chronic maintenance steroid therapy(only acute treatment during previous relapses was acceptable),immunomodulatory therapy and immunosuppressant therapy.Before starting treatment, each patient underwent a baselineneurological examination and an assessment of EDSS score. Patientswere treated with one of four immunomodulatory therapies:interferon -1a (Avonex®; 30 g i.m. once a week), interferon -1a(Rebif®; 44 g s.c. thrice weekly), interferon -1b (Betaferon®;250 g s.c. every other day) and glatiramer acetate (Copaxone®; 20mg s.c. daily). The choice of which treatment to use was at thetreating neurologist's discretion. Patients were provided withinformation about treatments, and discussed the relative efficacyand tolerability of the different possible treatments withneurologist. Although use of immunomodulatory therapy is reimbursedby the health service in Argentina, a number of patients were unableto receive treatment because they had no social security coverage,and these thus formed a no treatment control group. None of thepatients were switched to another treatment group during the courseof the study. The study duration was 16 months.In the event of a relapse, this was confirmed by a neurologicalexamination performed by the treating neurologist, who initiatedappropriate treatment. The standard treatment was a 5-day course ofmethylyprednisolone (Solumedrol®, Pfizer, Argentina; 1 g/day)followed, if the neurologist considered this necessary by aprednisolone (Deltisona®, Aventis Pharma, Argentina) taper for 30days.After treatment was initiated, each patient returned for scheduledfollow-up visits to the same neurologist every 3 months. Scores onthe EDSS rating scale were determined at each visit.The principal outcome measure was incidence of relapse. This wasdefined as new symptoms or worsening of previous symptoms lasting atleast 48 h, characterized by an increase of at least half a step onthe EDSS, an increase of at least two points on one of the sevenfunctional systems or an increase of at least one point on two ormore of the functional systems.The incidence of disease progression was also recorded. This wasdefined as an increase of at least one full step on the EDSS thatpersisted for two consecutive visits and remained unchanged for atleast 12 weeks. Secondary outcome measures were the change in meanEDSS score over the study period and the proportion of relapse-freepatients.All the data were analysed at 16 months for all groups. The resultsare shown as median values (25-75% quartile) for quantitativevariables, or as percentages for qualitative ones where appropriate.Baseline demographic and clinical variables were compared betweenthe four treatment groups, as were pre- and post-treatment outcomevariables within each treatment group. Comparisons of categoricalvariables were performed with the 2 test, whilst quantitativevariables were compared using analysis of variance (anova). Giventhat inclusion into the different treatment arms was not randomized,inter-group comparisons of treatment effects were not undertaken.All tests were two-tailed and a probability level of < 0.05 wastaken to be significant. The data analysis was performed with Epi6.04 software (Center for Disease Control, Atlanta, GA, USA).The protocol was submitted to, and approved by, the Ethics Committeeof the Hospital Británico, Buenos Aires.Results Go to: Choose Top of page Introduction Methods Results <<Discussion ReferencesThe study included 134 patients who were distributed betweentreatment groups as follows: IFN -1a i.m.: 26 patients; IFN -1bs.c.: 20 patients; IFN -1a s.c.: 20 patients; GA: 30 patients; notreatment: 38 patients. The baseline demographics and diseasevariables for the five patient groups are presented in Table 1. Theaverage age of the patients was 40 years, and the average diseaseduration 7.3 years. All patients had active disease, with mosthaving experienced at least two relapses over the previous 2 years.The average EDSS score at inclusion was 2.05. All groups werecomparable at baseline for the following parameters: total number ofrelapses in the previous 2 years and in the previous year, and EDSSscore at inclusion.Over the 16-month study period, the number of relapses wassignificantly lower compared with the pre-treatment period for allthe active treatments (P < 0.001; 2 test; Table 2). However, theannual relapse rate in untreated patients increased from 0.54 to0.71 (P < 0.001). The changes in annual relapse rate in thedifferent treatment groups before and after initiation of treatmentare presented in Fig. 1. These varied from a reduction of 49% in theIFN -1a i.m. treatment group to one of 81% in the GA treatmentgroup.The proportion of patients remaining relapse-free for the entire 16-month treatment period varied from 60% in the IFN -1a s.c. andIFN -1b s.c. groups to 83% in the GA group (Table 2). Only 37% ofuntreated patients remained relapse-free. There was a slight fall inthe EDSS score over the 16-month study group in the IFN -1b s.c.and GA treatment groups, and a slight rise in score in the untreatedpatients (Fig. 2). However, none of these changes were statisticallysignificant.Discussion Go to: Choose Top of page Introduction Methods ResultsDiscussion << ReferencesThis open-label, retrospective study compared the efficacy ofdifferent immunomodulatory treatments for RRMS available inArgentina. To our knowledge, this is the first such study reportedfrom South America. The retrospective nature of the study precludedrandomization, but allowed the impact of treatment to be assessed instandard conditions of multiple sclerosis care in Argentina. Giventhat all previously untreated patients consulting for multiplesclerosis who fulfilled relatively broad inclusion criteria wereincluded, the sample evaluated can be considered representative ofthe overall population of multiple sclerosis patients suitable forimmunomodulatory treatment in Argentina. However, considering theaverage disease duration, it is important to highlight that mostpatients have had a relatively low mean EDSS at baseline.This is the first such observational study that has compared allfour immunomodulatory treatments currently available. Patients werefollowed-up for 16 months following initiation of treatment. Theprincipal finding of the study was a significant reduction in theannual relapse rate for all four drug therapies, compared with pre-treatment relapse rates. No such reduction was observed in aparallel group receiving no treatment. The proportion of relapse-free patients was approximately twice as high in the groupsreceiving immunomodulatory treatments compared with the no treatmentgroup. The proportion of relapse-free patients in the groupreceiving no treatment (37%) may be due to either the short durationof follow-up or due to their low EDSS score at baseline.Concerning disability, we did not find a significant reduction inEDSS score in any of the treatment groups, although there was atrend towards improvement in the IFN -1b s.c. and GA groups. It ispossible that the 16-month treatment period was not sufficient todemonstrate robust effects on this outcome measure.Although the study has a number of limitations, notably the lack ofrandomization between treatment groups, and the relatively smallnumbers of patients included, naturalistic studies such as this havecertain intrinsic qualities. Immunomodulatory treatments formultiple sclerosis have already demonstrated clear efficacy in aseries of double-blind, placebo-controlled, randomized clinicaltrials including large numbers of patients (Galetta et al., 2002;Goodin et al., 2002; Khan et al., 2002). The challenge for currentclinical research with these drugs is thus not so much to reiteratethese findings, but to demonstrate that the findings of the clinicaltrial programme can be generalized to everyday standards of care.Naturalistic studies such as the current one, can help address thisissue. The broad entry criteria ensure good representativity of thestudy cohort, and the retrospective nature of the analysis allowsbias from doctor or patient expectations to be limited.In addition, recent data across a variety of therapeutic areassuggests that treatment effects seen in observational studies aregenerally comparable with those found in randomized controlledtrials. For example, a recent meta-analysis of studies across 19therapeutic areas showed that there were no significant differencesin size-effects between observational and randomized studies (Bensonand Hartz, 2000). Although this analysis did not extend to trials inmultiple sclerosis, there is no reason to think that the data fromobservational studies such as the current one are intrinsically lesssolid than data from randomized clinical trials.The results can be compared with data previously obtained inrandomized clinical trials (Table 3). Although the patients includedin our study generally have less aggressive disease than those inthe clinical trials (at least in terms of relapse rates), and thetreatment duration differed between the studies, the impact oftreatment on annual relapse rates is quite comparable between thetwo study paradigms. This similitude also extends to another open-label comparative study of IFN -1a i.m., IFN -1b s.c., GA and notreatment, performed in the United States (Khan et al., 2001; Table3), and to an open-label prospective study of these four treatmentsand intravenous immunoglobulin performed in Germany, as yet onlypublished in abstract form (Firzlaff et al., 2000).Given the non-randomized nature of the study, no firm conclusionscan be drawn concerning the relative benefits of the differentimmunomodulatory treatments. However, inspection of the data revealscertain potential inter-group differences, with perhaps a somewhatlarger treatment responses for GA. Interestingly, the same order ofrelative efficacy for the three therapies evaluated (IFN -1a i.m.,IFN -1b s.c. and GA) in the prospective observational study by Khanet al. (2001) was observed, although, again, patients were notrandomized. As GA has a different mechanism of action from theinterferons (Neuhaus et al., 2001), it is possible that the benefitprovided may not be identical. Potential treatment differences meritscrutiny in a randomized prospective study.In conclusion, this open-label, comparative observational study hasdemonstrated that treatment of patients with RRMS withimmunomodulatory therapies in the context of current standards ofcare for multiple sclerosis in Argentina provides clinicallyimportant benefit. The study confirms the efficacy of all fouravailable immunomodulatory therapies in reducing relapse rates inmultiple sclerosis patients, and provides more tantalizing cluesthat some of these therapies may be better than others.

April 10, 2004

, I have never been on any of the CRABS but I WOULD LIKE TO SHARE MY

VISIT WITH ONE OF THE TOP NEUROS IN FLORIDA. THIS WILL FURTHER SUBSTANTIATE

IN OUR MINDS WHY DOCTORS ARE SO RELUCTANT TO ADVOCATE ANY TYPE OF

ALTERNATIVE TREATMENT. TWO DAYS AGO I GOT MY NEURO EXAM AND WE LOOKED AT MY

NEW MRI. STILL NO EVIDENCE OF ANY LESIONS AND HE TOLD ME I AM STRONG AS AN

OX. I HAVE BEEN ON LDN SINCE NOV. AND CALCIUM EAP INJECTIONS SINCE 1999. HE

TOLD ME CALCIUM EAP IS THE ONLY THING HE HAS EVER SEEN THAT CAN REVERSE CNS

DAMAGE. HE KNOWS IT WORKS AND CANNOT PRESCRIBE IT BECAUSE OF HIS REPUTATION

AS A NEURO. I SHOWED HIM THE LDN LITERATURE AND HE SUPPORTS ME IN MY

DECISION. THERE ARE TOO MAY ANECDOTAL SORIES ABOUT THESE TWO THERAPIES FOR

IT TO BE A HOAX. HOWEVER, I MUST ADD THAT THY ARE NOT MIRACLES BY

THEMSELVES. THIS MAY BE WHY SOME IMPROVE AND SOME MERELY STOP

PROGRESSION-DIET AND EXERCISE. IT CANNOT BE IGNORED BY SOMEONE WITHOUT MS SO

WHY DO SO MANY MSERS NEGLECT THIS PART OF THEIR WELLNESS. NOT BEING

JUDGEMENTAL, JUST WANT EVERYONE TO HAVE THE QUALITY OF LIFE THEY ARE

ENTITLED TO . HOPE AND FAITH, KATHY

----- Original Message -----

From: " " <jatrac1@...>

Sent: Friday, April 09, 2004 1:24 AM

Subject: Re: [low dose naltrexone] Comparison of ABCR's

> We have heard very little from anyone who has anything good to say about

> Copaxone. It hadn't occurred to me that perhaps there are people who are

> happy with it who are just quiet. I suppose it is natural to hear more

from

> those who have had unpleasant issues with it. Humankind is certainly

> inclined to grumble about things we don't enjoy.

>

> I'm sure my next visit to the neuro is going to involve another argument

> about using or not using Copaxone. Anybody want to share their positive

> experiences with this med? I've avoided it because I'm not interested in

> injection site reactions or other side effects. Am I feeling too much

> concern? Are there people here who feel it is helping? I hate taking any

> kind of meds, and had chosen long ago to avoid the ABCs (there was no " R "

at

> the time I made my decision). Now that I'm seeing a neurologist a couple

of

> times a year again the subject comes up with each visit. If it really

does

> help without ugly side effects I should reconsider my position.

>

> (MS)

>

> ----- Original Message -----

> From: " yashagrawal " <yashagrawal@...>

> <low dose naltrexone >

> Sent: Thursday, April 08, 2004 9:27 PM

> Subject: [low dose naltrexone] Comparison of ABCR's

>

> In view of the recent unjustified criticism of copaxone... atleast

> this study claims that copa is better than the other conventional

> drugs. LDN, may ofcourse be the best :-)

>

> Yash

>

> European Journal of Neurology

> Volume 10 Issue 6 Page 671 - November 2003

> doi:10.1046/j.1468-1331.2003.00669.x

>

> A retrospective, observational study comparing the four available

> immunomodulatory treatments for relapsing-remitting multiple

> sclerosis

> A. Carrá a , P. Onaha a , V. Sinay a,b , F. Alvarez b , G. Luetic

> c , R. Bettinelli d , E. San Pedro d and L. Rodríguez e

> We performed an observational, retrospective analysis of outcome in

> a sequential cohort of patients with relapsing-remitting multiple

> sclerosis (RRMS) in Argentina. Patients treated for 16 months with

> interferon -1a (Avonex®; 30 g intramuscularly, once a week),

> interferon -1a (Rebif®; 44 g subcutaneously, thrice weekly),

> interferon -1b (Betaferon®; 250 g subcutaneously, every other

> day) or glatiramer acetate (Copaxone®; 20 mg subcutaneously daily)

> were compared with a non-treated group of patients. The different

> treatment groups were similar in baseline demographic and clinical

> variables. A significant fall in the annual relapse rate was

> observed for all four treatments, with the largest effect observed

> with glatiramer acetate (81% reduction in relapse rate, compared

> with pre-treatment values). The proportion of patients remaining

> relapse-free for the entire 16-month treatment period varied from

> 37% in untreated patients to 83% in the glatiramer acetate treated

> group. No statistically significant changes in disability scores

> were observed over the treatment period. This first such comparative

> study in Latin America shows that treatment of multiple sclerosis

> patients with immunomodulatory therapies in the context of current

> standards of care in Argentina provides clinically important

> benefit, and suggest that some of these therapies may be better than

> others.

>

> Introduction Go to: Choose Top of page Introduction << Methods

> Results Discussion References

>

> Over the last decade, several immunomodulatory therapies have been

> introduced for the treatment of relapsing-remitting multiple

> sclerosis (RRMS), providing for the first time a possibility to

> modify the course of this progressively disabling autoimmune

> neurological disease. These include three interferon preparations,

> interferon -1a (Avonex®, Biogen, Cambridge, MA, USA; given

> intramuscularly; IFN -1a i.m.), interferon -1a (Rebif®, Serono,

> Geneva, Switzerland; given subcutaneously; IFN -1a s.c.),

> interferon -1b (Betaferon®, Schering AG, Berlin, Germany; given

> subcutaneously; IFN -1b s.c.), and an activator of anti-

> inflammatory T cells, glatiramer acetate (Copaxone®, Teva

> Pharmaceutical Industries, Kfar Sava, Israel; given subcutaneously;

> GA s.c.). All these drugs have been demonstrated to decrease the

> rate of relapse, slow the progression of disability, and to improve

> markers of lesion load observed in magnetic resonance imaging

> (Chofflon, 2000; Goodin et al., 2002; Khan et al., 2002; Simpson et

> al., 2002).

>

> Faced with the choice of these four agents, it is important for

> clinicians to possess reliable comparative data on the efficacy and

> safety of these treatments in order to make enlightened treatment

> decisions (Khan et al., 2002). However, little such data is

> available. Direct randomized controlled trials comparing these

> agents pose important problems in terms of methodology, logistics

> and cost, and no such trials have been performed. Kappos et al.

> (1998) compared retrospectively the four pivotal studies, and

> concluded that the effects of all agents on relapse were broadly

> similar. Galetta et al. (2002) concluded that all four

> immunomodulatory therapies had similar effects on several clinical

> and biological outcome measures, although the immunogenicity of

> interferons might be a discriminating tolerability issue. Moreover,

> recent evidence-based treatment guidelines for multiple sclerosis by

> the American Academy of Neurology also concluded that all four

> immunomodulatory therapies were effective in reducing relapse rate

> (Goodin et al., 2002). Khan et al. (2001) reported a first

> prospective open-label comparative study between three of these

> treatments (IFN -1a i.m., IFN -1b s.c. and GA). This study

> reported that IFN -1b s.c. and GA may be somewhat more efficacious

> than IFN -1a i.m. More recent studies have suggested that some

> interferons may be more efficacious than others (Durelli et al.,

> 2002; Panitch et al., 2002), or that interferons slightly reduce the

> number of patients who have exacerbation during first year of

> treatment (Filippini et al., 2003) whilst and Witt (1998)

> have shown that administration of IFN -1a i.m. and IFN -1b s.c.

> induce different short-term biological responses.

>

> Following the introduction of all four immunomodulatory therapies to

> Argentina, we have decided to conduct an open-label comparative

> study of these therapies under naturalistic treatment conditions.

> The objective of the study was to evaluate the effects of these four

> immunomodulatory therapies, compared with a non-treated group of

> patients on annual relapse rate in RRMS. To our knowledge, this is

> the first study to compare different immunomodulatory treatments for

> multiple sclerosis.

>

> Methods Go to: Choose Top of page Introduction Methods << Results

> Discussion References

>

> This study was an observational, retrospective analysis of a cohort

> of patients with RRMS treated with immunomodulatory therapies in

> five multiple sclerosis centres (private and public hospitals with

> neurology departments) in Argentina. A no treatment control group

> was included. The treatment period was from January 2001 to May 2002

> (16 months).

>

> This retrospective study included a sequential series of all

> patients attending the five participating centres over the study

> duration fulfilling retrospectively chosen inclusion criteria, which

> were ascertained by reference to the patient notes. These criteria

> selected patients between 16 and 61 years old fulfilling the Poser

> criteria for definitive RRMS (Poser et al., 1983). Patients were

> required to have scores on Expanded Disability Status Scale (EDSS)

> (Kurtzke, 1983) in the range of 0-6.0, to have experienced at least

> one relapse in the previous 2 years, and to have been clinically

> stable for at least 30 days prior to inclusion. Exclusion criteria

> were secondary progressive multiple sclerosis and the use of the

> following prior treatments: chronic maintenance steroid therapy

> (only acute treatment during previous relapses was acceptable),

> immunomodulatory therapy and immunosuppressant therapy.

>

> Before starting treatment, each patient underwent a baseline

> neurological examination and an assessment of EDSS score. Patients

> were treated with one of four immunomodulatory therapies:

> interferon -1a (Avonex®; 30 g i.m. once a week), interferon -1a

> (Rebif®; 44 g s.c. thrice weekly), interferon -1b (Betaferon®;

> 250 g s.c. every other day) and glatiramer acetate (Copaxone®; 20

> mg s.c. daily). The choice of which treatment to use was at the

> treating neurologist's discretion. Patients were provided with

> information about treatments, and discussed the relative efficacy

> and tolerability of the different possible treatments with

> neurologist. Although use of immunomodulatory therapy is reimbursed

> by the health service in Argentina, a number of patients were unable

> to receive treatment because they had no social security coverage,

> and these thus formed a no treatment control group. None of the

> patients were switched to another treatment group during the course

> of the study. The study duration was 16 months.

>

> In the event of a relapse, this was confirmed by a neurological

> examination performed by the treating neurologist, who initiated

> appropriate treatment. The standard treatment was a 5-day course of

> methylyprednisolone (Solumedrol®, Pfizer, Argentina; 1 g/day)

> followed, if the neurologist considered this necessary by a

> prednisolone (Deltisona®, Aventis Pharma, Argentina) taper for 30

> days.

>

> After treatment was initiated, each patient returned for scheduled

> follow-up visits to the same neurologist every 3 months. Scores on

> the EDSS rating scale were determined at each visit.

>

> The principal outcome measure was incidence of relapse. This was

> defined as new symptoms or worsening of previous symptoms lasting at

> least 48 h, characterized by an increase of at least half a step on

> the EDSS, an increase of at least two points on one of the seven

> functional systems or an increase of at least one point on two or

> more of the functional systems.

>

> The incidence of disease progression was also recorded. This was

> defined as an increase of at least one full step on the EDSS that

> persisted for two consecutive visits and remained unchanged for at

> least 12 weeks. Secondary outcome measures were the change in mean

> EDSS score over the study period and the proportion of relapse-free

> patients.

>

> All the data were analysed at 16 months for all groups. The results

> are shown as median values (25-75% quartile) for quantitative

> variables, or as percentages for qualitative ones where appropriate.

> Baseline demographic and clinical variables were compared between

> the four treatment groups, as were pre- and post-treatment outcome

> variables within each treatment group. Comparisons of categorical

> variables were performed with the 2 test, whilst quantitative

> variables were compared using analysis of variance (anova). Given

> that inclusion into the different treatment arms was not randomized,

> inter-group comparisons of treatment effects were not undertaken.

> All tests were two-tailed and a probability level of < 0.05 was

> taken to be significant. The data analysis was performed with Epi

> 6.04 software (Center for Disease Control, Atlanta, GA, USA).

>

> The protocol was submitted to, and approved by, the Ethics Committee

> of the Hospital Británico, Buenos Aires.

>

> Results Go to: Choose Top of page Introduction Methods Results <<

> Discussion References

>

> The study included 134 patients who were distributed between

> treatment groups as follows: IFN -1a i.m.: 26 patients; IFN -1b

> s.c.: 20 patients; IFN -1a s.c.: 20 patients; GA: 30 patients; no

> treatment: 38 patients. The baseline demographics and disease

> variables for the five patient groups are presented in Table 1. The

> average age of the patients was 40 years, and the average disease

> duration 7.3 years. All patients had active disease, with most

> having experienced at least two relapses over the previous 2 years.

> The average EDSS score at inclusion was 2.05. All groups were

> comparable at baseline for the following parameters: total number of

> relapses in the previous 2 years and in the previous year, and EDSS

> score at inclusion.

>

> Over the 16-month study period, the number of relapses was

> significantly lower compared with the pre-treatment period for all

> the active treatments (P < 0.001; 2 test; Table 2). However, the

> annual relapse rate in untreated patients increased from 0.54 to

> 0.71 (P < 0.001). The changes in annual relapse rate in the

> different treatment groups before and after initiation of treatment

> are presented in Fig. 1. These varied from a reduction of 49% in the

> IFN -1a i.m. treatment group to one of 81% in the GA treatment

> group.

>

> The proportion of patients remaining relapse-free for the entire 16-

> month treatment period varied from 60% in the IFN -1a s.c. and

> IFN -1b s.c. groups to 83% in the GA group (Table 2). Only 37% of

> untreated patients remained relapse-free. There was a slight fall in

> the EDSS score over the 16-month study group in the IFN -1b s.c.

> and GA treatment groups, and a slight rise in score in the untreated

> patients (Fig. 2). However, none of these changes were statistically

> significant.

>

> Discussion Go to: Choose Top of page Introduction Methods Results

> Discussion << References

>

> This open-label, retrospective study compared the efficacy of

> different immunomodulatory treatments for RRMS available in

> Argentina. To our knowledge, this is the first such study reported

> from South America. The retrospective nature of the study precluded

> randomization, but allowed the impact of treatment to be assessed in

> standard conditions of multiple sclerosis care in Argentina. Given

> that all previously untreated patients consulting for multiple

> sclerosis who fulfilled relatively broad inclusion criteria were

> included, the sample evaluated can be considered representative of

> the overall population of multiple sclerosis patients suitable for

> immunomodulatory treatment in Argentina. However, considering the

> average disease duration, it is important to highlight that most

> patients have had a relatively low mean EDSS at baseline.

>

> This is the first such observational study that has compared all

> four immunomodulatory treatments currently available. Patients were

> followed-up for 16 months following initiation of treatment. The

> principal finding of the study was a significant reduction in the

> annual relapse rate for all four drug therapies, compared with pre-

> treatment relapse rates. No such reduction was observed in a

> parallel group receiving no treatment. The proportion of relapse-

> free patients was approximately twice as high in the groups

> receiving immunomodulatory treatments compared with the no treatment

> group. The proportion of relapse-free patients in the group

> receiving no treatment (37%) may be due to either the short duration

> of follow-up or due to their low EDSS score at baseline.

>

> Concerning disability, we did not find a significant reduction in

> EDSS score in any of the treatment groups, although there was a

> trend towards improvement in the IFN -1b s.c. and GA groups. It is

> possible that the 16-month treatment period was not sufficient to

> demonstrate robust effects on this outcome measure.

>

> Although the study has a number of limitations, notably the lack of

> randomization between treatment groups, and the relatively small

> numbers of patients included, naturalistic studies such as this have

> certain intrinsic qualities. Immunomodulatory treatments for

> multiple sclerosis have already demonstrated clear efficacy in a

> series of double-blind, placebo-controlled, randomized clinical

> trials including large numbers of patients (Galetta et al., 2002;

> Goodin et al., 2002; Khan et al., 2002). The challenge for current

> clinical research with these drugs is thus not so much to reiterate

> these findings, but to demonstrate that the findings of the clinical

> trial programme can be generalized to everyday standards of care.

> Naturalistic studies such as the current one, can help address this

> issue. The broad entry criteria ensure good representativity of the

> study cohort, and the retrospective nature of the analysis allows

> bias from doctor or patient expectations to be limited.

>

> In addition, recent data across a variety of therapeutic areas

> suggests that treatment effects seen in observational studies are

> generally comparable with those found in randomized controlled

> trials. For example, a recent meta-analysis of studies across 19

> therapeutic areas showed that there were no significant differences

> in size-effects between observational and randomized studies (Benson

> and Hartz, 2000). Although this analysis did not extend to trials in

> multiple sclerosis, there is no reason to think that the data from

> observational studies such as the current one are intrinsically less

> solid than data from randomized clinical trials.

>

> The results can be compared with data previously obtained in

> randomized clinical trials (Table 3). Although the patients included

> in our study generally have less aggressive disease than those in

> the clinical trials (at least in terms of relapse rates), and the

> treatment duration differed between the studies, the impact of

> treatment on annual relapse rates is quite comparable between the

> two study paradigms. This similitude also extends to another open-

> label comparative study of IFN -1a i.m., IFN -1b s.c., GA and no

> treatment, performed in the United States (Khan et al., 2001; Table

> 3), and to an open-label prospective study of these four treatments

> and intravenous immunoglobulin performed in Germany, as yet only

> published in abstract form (Firzlaff et al., 2000).

>

> Given the non-randomized nature of the study, no firm conclusions

> can be drawn concerning the relative benefits of the different

> immunomodulatory treatments. However, inspection of the data reveals

> certain potential inter-group differences, with perhaps a somewhat

> larger treatment responses for GA. Interestingly, the same order of

> relative efficacy for the three therapies evaluated (IFN -1a i.m.,

> IFN -1b s.c. and GA) in the prospective observational study by Khan

> et al. (2001) was observed, although, again, patients were not

> randomized. As GA has a different mechanism of action from the

> interferons (Neuhaus et al., 2001), it is possible that the benefit

> provided may not be identical. Potential treatment differences merit

> scrutiny in a randomized prospective study.

>

> In conclusion, this open-label, comparative observational study has

> demonstrated that treatment of patients with RRMS with

> immunomodulatory therapies in the context of current standards of

> care for multiple sclerosis in Argentina provides clinically

> important benefit. The study confirms the efficacy of all four

> available immunomodulatory therapies in reducing relapse rates in

> multiple sclerosis patients, and provides more tantalizing clues

> that some of these therapies may be better than others.

>

April 10, 2004

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