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Biased assessment of blinding in a randomized placebo-controlled trial of oral methotrexate in chronic progressive multiple sclerosis.

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LETTERS
Recently, Dr Eugene Strandness, in an editorial published
Surgeql (1995;25:163-165), raised
in the Journal ofVu~-rxlar
several concerns about the Data Monitoring Committee
(DMC) of the North American Symptomatic Carotid Endarterectomy Trial (NASCET). Because of the importance of
the trial and the seriousness of the concerns, I asked a group
of four consultants (one from the National Heart, Lung, and
Blood Institute and three from outside of the National Institutes of Health) to meet and review the procedures used by
the National Institute of Neurological Disorders and Stroke
(NINDS), in organizing and guiding the Monitoring Committee for NASCET. T h e consultants looked specifically at
the question of whether the results of the trial were jeopardized in any way because of the issues raised by Dr Strandness
and found that they were not. They also found no evidence
for misconduct on behalf of N I N D S staff. The consultants
emphasized, however, that several aspects of the way in
which the DMC for NASCET has been operated could be
improved and suggested that N I N D S review the procedures
by which we organize and guide Data and Safety Monitoring
Committees. As a result of their suggestions the N I N D S is
now formulating a new set ofguidelines for these procedures.
These guidelines will be made available to the research community when they are completed. We are grateful to D r
Strandness for raising these issues and hope that we will be
able to serve the clinical research community even more effectively as a result of these changes.
sustained failure for 2 months or more on one of four functional tests (Expanded Disability Status Scale, Ambulation
Index, Box and Block, and 9-Hole Peg Test).
When such a sensitive measure of outcome is used, blinding becomes even more pertinent than it is already. In the
accompanying editorial, some concern was raised about “subtle unblinding effects” [2}. In this light, it might have been
preferable to also blind the study coordinator and unblind
only someone who is less involved with the actual trial 131.
The authors assessed the integrity of the blind by asking the
examining physician, study nurses, and patient individually
to choose between placebo, MTX, or ‘‘I don’t know,” for
each treatment allocation. The examining physician used the
third, obviously most acceptable, answer almost exclusively.
Indeed, this simple “I don’t know” would seem a more attractive and logical answer than a guess, when one is not supposed to have the slightest idea of the nature of the treatment
allocation. A better method would therefore have been to
let the assessors make a forced choice between MTX and
placebo, and, for example, compare the observed distribution
of guesses with the expected under a null hypothesis of 5 0 4
test.
correct answers, using a simple
Goodkin and co-workers El] have not fully convinced us
of the methodological rigor of their study and, apart from
that, did not provide convincing arguments that rhe difference in outcome between placebo and MTX that was observed in their study was clinically significant. On the other
hand, this type of study may well be useful as a sensitive
method for identifying promising treatments chat should be
evaluated in large-scale trials, designed to demonstrate larger
benefits of more convincing clinical significance.
Meanwhile, physicians who care for patients with chronic
progressive MS should ask them to participate in these new
clinical trials, instead of inducing unwarranted hope and
exposing them to treatments of unproven benefit.
Department of Health and Humun S e n k e s
National Institutu of Health
National lnstitirte of’ Neirrologicul Disorders und Stroke
Bethesda, AID 20891
Department of Neurology
Unizrrsity Hospital Dijkzigt
Dr Moleu‘aterplein40
3015 G D Rotterdam. The Netherlands
Guidelines for Data and
Safety Monitoring
Committees of NASCET
Zach W. Hall, PhD
R&erences
Biased Assessment of
Blinding in a Randomized
Placebo-controlled Trial
of Oral Methotrexate
in Chronic Progressive
Multiple Sclerosis
D. W. J. Dippel, MD, P. G. Oomes, MD,
and L. H. Visser. M D
In their interesting study, a randomized placebo-controlled
clinical trial of oral methotrexate (MTX) in patients with
chronic progressive multiple sclerosis (MS), Goodkin and
colleagues [I] used a very sensitive measure of outcome, ie,
1. Goodkin DE, Rudick RA, VanderBurg S, er al. Low dose (7.5
rng) oral methorrexate reduces the rate of progression in chronic
progressive multiple sclerosis. Ann Neurol 1995;37:30-40
2. Whitaker JN, Mitchell GW, Cutter GR. Clinical outcomes and
documentation of partial beneficial effects of immunotherapy for
multiple sclerosis. Ann Neurol 1995;37.5-6
3. Pocock CJ. Clinical trials. A practical approach. New York: Wiley, 198590-100
Reply
D. E. Goodkin
Drs Dippell, Oomes, and Visser express two important issues
regarding the methods of blinding study personnel and patients who were involved in our study of methotrexate in
chronic progressive multiple sclerosis (MS). The first issue is
the possibility that the results of our study were influenced
by the unblinded study coordinator. The second issue is the
832 Copyright 0 1995 by the American Neurological Association
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blinding, progressive, biased, tria, controller, randomized, methotrexate, oral, sclerosis, placebo, assessment, multiple, chronic
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