Comparison of ABCR's

[Guest guest]

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.