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A Double-Blind, Placebo-Controlled, Randomized, Clinical Trial of the
TLR-3 Agonist Rintatolimod in Severe Cases of Chronic Fatigue Syndrome
David R. Strayer1*, William A. Carter1, Bruce C. Stouch2, Staci R.
Stevens3, Lucinda Bateman4, Paul J. Cimoch5, Charles W. Lapp6, Daniel
L. Peterson7, the Chronic Fatigue Syndrome AMP-516 Study Group**,
William M. Mitchell8*
1 Hemispherx Biopharma, Inc., Philadelphia, Pennsylvania, United
States of America, 2 BCS Consulting, Philadelphia, Pennsylvania,
United States of America, 3 University of the Pacific, Stockton,
California, United States of America, 4 Fatigue Consultation Clinic,
Salt Lake City, Utah, United States of America, 5 Center for Special
Immunology, Fountain Valley, California, United States of America, 6
Hunter-Hopkins Center, Charlotte, North Carolina, United States of
America, 7 Sierra Internal Medicine Associates, Incline Village,
Nevada, United States of America, 8 Vanderbilt University School of
Medicine, Nashville, Tennessee, United States of America
** For a list of the members of Chronic Fatigue Syndrome AMP-516
Clinical Study Group please see Table S2.
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a
severely debilitating disease of unknown pathogenesis consisting of a
variety of symptoms including severe fatigue. The objective of the
study was to examine the efficacy and safety of a TLR-3 agonist,
rintatolimod (Poly I: C12U), in patients with debilitating CFS/ME.
Methods and Findings
A Phase III prospective, double-blind, randomized, placebo-controlled
trial comparing twice weekly IV rintatolimod versus placebo was
conducted in 234 subjects with long-standing, debilitating CFS/ME at
12 sites. The primary endpoint was the intra-patient change from
baseline at Week 40 in exercise tolerance (ET). Secondary endpoints
included concomitant drug usage, the Karnofsky Performance Score
(KPS), Activities of Daily Living (ADL), and Vitality Score (SF 36).
Subjects receiving rintatolimod for 40 weeks improved intra-patient
placebo-adjusted ET 21.3% (p = 0.047) from baseline in an
intention-to-treat analysis. Correction for subjects with reduced
dosing compliance increased placebo-adjusted ET improvement to 28% (p
= 0.022). The improvement observed represents approximately twice the
minimum considered medically significant by regulatory agencies. The
rintatolimod cohort vs. placebo also reduced dependence on drugs
commonly used by patients in an attempt to alleviate the symptoms of
CFS/ME (p = 0.048). Placebo subjects crossed-over to receive
rintatolimod demonstrated an intra-patient improvement in ET
performance at 24 weeks of 39% (p = 0.04). Rintatolimod at 400 mg
twice weekly was generally well-tolerated.
Rintatolimod produced objective improvement in ET and a reduction in
CFS/ME related concomitant medication usage as well as other secondary outcomes.