Abatacept Improves Juvenile Idiopathic Arthritis in Randomised Withdrawal Trial, but Study Design Questioned

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Title: Abatacept Improves Juvenile Idiopathic Arthritis in Randomised Withdrawal Trial, but Study Design Questioned
URL: http://www.pslgroup.com/dg/225C3E.htm
Doctor's Guide
July 14, 2008

LONDON -- July 14, 2008 -- Abatacept is a rational alternative treatment for juvenile idiopathic arthritis (JIA) in children who do not respond to other treatments, according to the authors of a study published early online and in an upcoming edition of The Lancet.

However, an accompanying comment says the design of the study makes it difficult to determine the true effect of abatacept.

Nicolino Ruperto, MD, IRCCS Istituto G Gaslini Pediatria II, Largo Gaslini, Genova, Italy, and colleagues, aimed to assess abatacept in children with JIA who had failed previous treatments in a double-blind, randomised, multicentre, controlled, withdrawal trial.

The study enrolled 190 patients aged 6 to 17 years with a history of JIA who had at least 5 joints with active disease and inadequate response or intolerance to at least 1 disease-modifying antirheumatic drug.

In the open-label phase of the study, all 190 patients were given 10 mg/kg of abatacept intravenously for 4 months. Of the 170 patients who completed this lead-in course, 47 did not respond and were excluded.

Of the patients who did respond, 1 left the study, 60 were randomised to abatacept 10 mg/kg at 28-day intervals for 6 months -- or until a flare of arthritis -- and 62 received placebo. The primary endpoint was flare of arthritis.

The researchers found that flare occurred in 33 of 62 (53%) of the patients given placebo and 12 of 60 (20%) given abatacept. Median time to flare was 6 months in the placebo group, but not enough flare events occurred in the abatacept group to establish this figure.

The risk of flare in patients who continued abatacept was less than a third (31%) of that for placebo during the double-blind period. Rates of adverse events were similar but high in both groups -- 62% in the abatacept group and 55% in the placebo group.

The trial also showed that after 4 months of treatment in the lead-in course 95 patients (50%) reached a 50% level of response that increased to 77% (46/60) in the group of patients subsequently randomised to abatacept in the double-blind phase.

"Our data showed that abatacept had clinical benefits for patients, irrespective of juvenile idiopathic arthritis subtype ... The availability of abatacept will provide clinicians with another alternative for the treatment of methotrexate-resistant patients," the authors wrote.

In the accompanying comment, Thomas Lehman, MD, Division of Pediatric Rheumatology, Hospital for Special Surgery, New York, New York, says: "This design preselects responders to the placebo effect who might retain their response throughout the entire study period whether or not they are randomly assigned to placebo in the second phase."

"Combined with carryover effects, these factors can overestimate any potential benefit in clinical practice and underestimate side-effects, obscuring our knowledge of the drug's true risks and benefits."

He also discusses the possible "enhanced placebo effect" in children, who, for example, can be keen to please their parents with the news that a treatment is working, and that proof of efficacy in adults is not necessarily the same for children.

"Paediatric rheumatologists have a responsibility to independently evaluate the safety in children of drugs approved for use in adults with arthritis. Many clinicians argue that they also have a responsibility to separately evaluate efficacy, which is true in an ideal world," said Dr. Lehman.

"However, paediatric 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."

SOURCE: The Lancet

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