Abatacept (Orencia) Improved Arthritis in Kids, but Study Design Criticized

[Guest guest]

Abatacept (Orencia) Improved Arthritis in Kids, but Study Design Criticized

http://www.medpagetoday.com/Rheumatology/Arthritis/tb/10116

GENOA, Italy, July 14 -- Children with idiopathic arthritis unresponsive to

other drugs improved on abatacept (Orencia) compared with those given a

placebo, a randomized withdrawal trial found.

Action Points

Explain to patients who ask that children in this study who were treated

with abatacept (Orencia), a drug for adult rheumatoid arthritis, had fewer

arthritis flares than those given a placebo.

Explain that an editorial writer questioned the use in children of findings

from studies such as this one that are inadequately designed or powered to

provide convincing proof of efficacy and safety.

Arthritis flares occurred in only 20% of patients given abatacept versus in

53% of placebo patients, Nicolino Ruperto, M.D., of IRCCS Instituto G

Gaslini here, and colleagues reported in the July 15 issue of The Lancet.

Abatacept, a selective T-cell costimulation modulator, was approved by the

FDA in 2005 for adult rheumatoid arthritis.

In an accompanying comment, J. Lehman, M.D., of Cornell University in

New York, faulted the study's withdrawal design.

Because the children in the double-blind placebo group had originally been

given abatacept in the open-label phase of the study, the findings in the

randomized part of the study were compromised, he said.

To assess the safety and efficacy of abatacept, the researchers undertook a

double-blind, randomized controlled withdrawal trial from February 2004 to

June 2006. It included 190 patients, ages six to 17.

These children, the researchers wrote, had failed previous treatment with

disease-modifying anti-rheumatic drugs, including anti-tumor necrosis factor

(TNF) medications.

The patients, from 45 centers in Europe, Latin America, and the U.S., had a

history of active juvenile idiopathic arthritis involving at least five

joints and an inadequate response to, or intolerance to, at least one

disease-modifying anti-rheumatic drug.

Before entering the randomized phase of the study, all 190 patients were

given 10 mg/kg of abatacept intravenously in a four-month open-label period.

Of the 170 patients who completed this lead-in course, 47 did not respond to

the treatment according to predefined American College of Rheumatology

pediatric criteria and were excluded.

Of the patients who did respond, 60 were randomly assigned to receive 10

mg/kg of abatacept at 28-day intervals for six months, or until arthritis

flare, and 62 were randomized to placebo at the same dose and timing.

Flare, the primary endpoint, was defined as worsening of 30% or more in at

least three of six core variables, with at least 30% improvement in no more

than one variable.

Arthritis flares occurred in 33 of 62 placebo patients (53%) and 12 of 60

abatacept patients (20%) during the double-blind treatment (P=0.0003).

Median time to flare was six months for patients given placebo, but not

enough events occurred in the abatacept group to assess median time to flare

(P=0.0002), the researchers said.

The risk of flare in patients who continued abatacept was less than a third

of that for controls during the double-blind period (hazard ratio 0.31, 95%

CI 0.16 to 0.95).

During that period, the frequency of adverse events (headache, nausea,

cough, diarrhea, upper respiratory infections, fever) did not differ in the

study arms. Adverse events were recorded in 37 abatacept recipients (62%)

and 34 (55%) placebo recipients (P=0.47).

Only two patients -- controls -- had serious adverse events: hematoma in one

and varicella and encephalitis in another (P=0.50).

The trial also found that after six months of double-blind treatment, or at

the time to flare, 46 of 60 patients (77%) given abatacept had improved by

50% or more, compared with 32 (52%) of controls (P=0.0071).

The researchers also noted that clinical improvements during the open-label

treatment were maintained in many patients randomly assigned to placebo,

even though these patients had not received abatacept for as long as seven

months.

Study limitations included the fact that joint erosions were not discussed

(though these have never been included in a pediatric trial) and the

duration of the results was limited to one year. Long-term data for efficacy

and safety are still in progress.

Another limitation included the fact that few serious adverse events were

reported, although it was not possible to directly compare these results

with those reported for adult rheumatoid populations.

Abatacept will provide pediatric clinicians with another alternative for the

treatment of methotrexate-resistant patients, the researchers said.

" Further research will be needed to establish the proper role of abatacept

in comparison with other biological agents, and to address functional

outcomes, the prevention and healing of joint erosions, and other structural

damage in juvenile idiopathic arthritis, " the investigators concluded.

In the accompanying commentary, Dr. Lehman wrote that because only

responders to the drug were included in the randomization, the study

preselected responders to the placebo effect who might retain their response

throughout the study whether or not they were assigned to placebo in the

withdrawal phase.

Combined with carry-over effects, these factors could overestimate any

potential benefit and underestimate side-effects, obscuring the drug's true

risks and benefits, he said.

He pointed out that " because the study design preselects responders to

placebo, the possibility that an equal 30% of the active treatment group

responded to a placebo effect cannot be dismissed easily. ... Indeed,

despite statistical significance, the differences between those randomly

assigned to the continued active treatment or subsequent placebo were small,

if we assume an equal placebo response in both groups. "

In addition, Dr. Lehman noted that the placebo effect may have been enhanced

in children who may be eager to please their parents with news that the

treatment is working, and that proof of efficacy in adults is not

necessarily the same for children.

Pediatric rheumatologists have a responsibility to independently evaluate

the safety in children of drugs approved for adults, Dr. Lehman wrote. Many

clinicians argue that they also have a responsibility to separately evaluate

efficacy, which is true in an ideal world.

However, he said, " pediatric rheumatologists should consider the

countervailing responsibility not to unnecessarily enter children into

studies that subject them to placebo control with the possibility of flare

and worsening of their condition, when the studies are inadequately designed

or powered to provide convincing proof of efficacy and safety. "

Primary source: The Lancet

Source reference: Ruperto N, et al " Abatacept in children with juvenile

idiopathic arthritis: A randomized, double-blind, placebo-controlled

withdrawal trial " The Lancet 2008: DOI: 10.1016/S0140-6736(08)60998-8.

Additional source: The Lancet

Source reference: Lehman TJ " Are withdrawal trials in pediatric rheumatic

disease helpful? " The Lancet 2008: DOI: 10.1016/S0140-6736(08)60999-X.