ECTRIMS 2006 - New Advances in Clinical Trial Design [MedScape for Med Students}
Advances in clinical trial design and in the treatment of multiple sclerosis (MS) were presented during the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), September 27-30, 2006, in Madrid, Spain. The highlights of new findings are reviewed, and implications for clinical practice are discussed.

Clinical Trial Design

Is it ethical to continue to have placebo arms in MS treatment clinical trials? Because therapies exist for relapsing-remitting and secondary progressive MS, randomizing patients to placebo for 2 years has become more controversial. The placebo arm has been critical in measuring the placebo effect. Relapse rates of the placebo group can be reduced by 30% to 50% as patients transition from prestudy to the active placebo phase. Without information of patients on placebo, treatment effects would be overestimated.[1]

Options to avoid a placebo trial include designs that employ add-on therapy, an external placebo group, and an active comparator. The Safety and Efficacy of Natalizumab in Combination with Avonex (interferon beta-1a) (SENTINEL) trial is an example of add-on therapy because natalizumab was added to interferon beta-1a intramuscularly in half of the trial patients. With an external placebo group, such as the Sylvia Lawry data set, all patients can also be on active treatment in a clinical trial. However, historical control groups can have very different outcomes with the same inclusion criteria. For example, patients in different secondary progressive trials of interferon beta-1b had very different disease progression results, although patients were selected with the same inclusion criteria. Active comparator trials are another option in which one treatment is compared with an existing treatment.[2] For example, the Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) trial compares 2 doses of interferon beta-1b with glatiramer.

Criteria to ethically perform placebo trials in MS patients must start with informed consent, including the option of being randomized to not receive treatment. Patients should not have tolerated, failed, or refused current treatments. The trial design should be of short duration and have surrogate markers. Rules for patients to drop out of the trial for worsening disease should be clearly delineated. Equipoise is paramount in which the investigator is uncertain of the outcomes before placing patients on placebo.[1]

An important outcomes measure of the pivotal phase 3 MS trials has been confirmed progression of disability. Patients are considered to have confirmed progression with a documented Extended Disability Status Scale (EDSS) increase of greater than 1.0 point on 2 examinations 3-6 months apart. Butzkueven and colleagues[3] assessed whether the trial definition of "confirmed disability progression" equates with "long-term sustained" EDSS progression with the prospectively acquired global MSBase dataset. In their analysis of 4043 relapsing-remitting and secondary progressive patients from 33 contributing MS clinics, 981 had confirmed progression of disability on neurologic exams at least 3 months apart. After 2 years of confirmed disability progression in relapsing-remitting disease, 25% of patients' EDSS scores returned to baseline. After 5 years, 50% of relapsing-remitting patients with confirmed progression returned to baseline level of disability. Fifteen percent of patients with secondary progressive disease returned to baseline level of disability.

Early evaluation of new treatments frequently relies on MRI endpoints. Many trials, such as the 20-mg vs 40-mg glatiramer acetate phase 2 trial, have screened patients for enhancing lesions to assist in determining efficacy with fewer patients. Zhao and colleagues[4] examined the short-term changes in monthly gadolinium-enhancing lesion activity in patients with different initial activity levels. In the 65 placebo patients studied, 49% had no enhancing lesions at baseline. Of this group, 75% developed new lesions over 9 months. All patients with enhancing lesions at baseline had at least 2 more enhancing lesions over 9 months with monthly MRI scans.