CONFIRM Trial Data Need Clarification in Oral MS Drug Story
The article, “With New Oral MS Drug, New Therapeutic Options” (May 2, http://bit.ly/11HcdZu) misinforms and misleads readers when it suggests that a statistically significant difference was found for reducing relapses between BG12 [dimethyl fumarate] and glatiramer acetate in the CONFIRM (COmparator and aN oral Fumarate In Relapsing remitting MS) trial.
To clarify, the CONFIRM trial was not designed as a direct comparison trial with a superiority design but was rather designed as a placebo-controlled trial for BG12 with glatiramer acetate as an active comparator.
In order to claim superiority of BG-12 over glatiramer acetate, a pre-specified analysis formulating a hypothesis with an assumed difference should have been made. Instead, the only direct comparisons between BG12 and glatiramer acetate were done post-hoc in a 2012 paper (Fox RJ, et al Placebo-Controlled Phase 3 Study of Oral BG-12 or Glatiramer in Multiple Sclerosis. N Engl J Med 2012;367:1087-97).
In this post-hoc analysis, there were no statistical differences between the FDA approved dose of BG12 (240 mg BID PO) and glatiramer acetate (20 mg QD SC) for annualized relapse rate, proportion of patients with a relapse, new T1 hypointense lesions, and time to disability progression. There was only a post-hoc statistical difference in new or enlarging hyperintense lesions on T2-weighted images.
As pointed out by the FDA reviewer, “although the sponsor argues that DMF [dimethyl fumarate] was superior to the active comparator, these data are essentially uninterpretable by design.”
We want to make sure readers know that the CONFIRM study was not designed to test the superiority or noninferiority of BG-12 versus glatiramer acetate (N Engl J Med 2013; 368:1652-1653).[The latter is manufactured by Teva Pharmaceuticals.]
Yiqun Hu, MD, PhD
Senior Medical Director
An Ethical Dilemma in Trial on Sleep Apnea and Alzheimer's Disease?
The article, “Obstructive Sleep Apnea Associated with Dementia Risk” (April 18, http://bit.ly/13vyuhX) sheds welcome light on sleep disorders, which are often omitted from differential diagnoses of various neurological symptoms including headache, neck pain, anxiety, depression, and fatigue, as well as cognitive decline. The study (and article) hopefully will prompt more attention by neurologists to this treatable condition.
Unfortunately, however, the two studies cited in the article raise a serious ethical question. [One report from this year's AAN annual meeting found that more than half of study participants who had obstructive sleep apnea (OSA) had developed dementia: http://bit.ly/117ex9T. The other referred to a 2011 study in the Journal of the American Medical Association (JAMA), which found that while the two conditions had been linked, it was unclear whether OSA began before the cognitive decline: http://1.usa.gov/13Gb0oo.] Both were observational studies in which patients with and without a sleep apnea diagnosis were identified and followed to determine the relative rates of development of dementia in the groups.
The AAN abstract involved mining data from another study; it was not clear whether the study was prospective. However, in the 2011 JAMA study, patients were diagnosed with sleep apnea and then followed without treatment. It is troubling that patients were allowed to go untreated for five years after the diagnosis of a serious but treatable disease which has well known medical consequences. Let's hope that in the future, sleep apnea is considered as seriously as other conditions in which placebo-controlled research is recognized to be unethical if effective treatment is available.
Elizabeth S. Rowe, PhD
Rowe Neurology Institute