A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome

David R Strayer, William A Carter, Bruce C Stouch, Staci R Stevens, Lucinda Bateman, Paul J Cimoch, Charles W Lapp, Daniel L Peterson, Chronic Fatigue Syndrome AMP-516 Study Group, William M Mitchell, Lucinda Bateman, Joseph R Bellesorte, Paul J Cimoch, Robert H Keller, Charles W Lapp, Alex J Mercandetti, Joseph John Jr, Morris Papernik, Daniel L Peterson, Richard N Podell, Bruce E Stein, Leslie vH Taylor, David R Strayer, William A Carter, Bruce C Stouch, Staci R Stevens, Lucinda Bateman, Paul J Cimoch, Charles W Lapp, Daniel L Peterson, Chronic Fatigue Syndrome AMP-516 Study Group, William M Mitchell, Lucinda Bateman, Joseph R Bellesorte, Paul J Cimoch, Robert H Keller, Charles W Lapp, Alex J Mercandetti, Joseph John Jr, Morris Papernik, Daniel L Peterson, Richard N Podell, Bruce E Stein, Leslie vH Taylor

Abstract

Background: 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: C(12)U), 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.

Conclusions/significance: Rintatolimod produced objective improvement in ET and a reduction in CFS/ME related concomitant medication usage as well as other secondary outcomes.

Trial registration: ClinicalTrials.gov NCT00215800.

Conflict of interest statement

Competing Interests: LB, BCS, RNP and CWL have consulted for, or received lecture fees from Hemispherx Biopharma. All clinical investigators received support budgets from Hemispherx Biopharma for the conduct of the clinical trial to support the New Drug Application (NDA) of Ampligen (rintatolimod) for the treatment of CFS. DRS, the Medical Director, and WAC, the CEO, of Hemispherx, both own stock and options in Hemispherx Biopharma. WAC and WMM are members of the Board of Directors for Hemispherx Biopharma and own stock and options. SRS has received non-rintatolimod related grant support from the CFIDS Association of America. A patent for the use of rintatolimod for CFS was granted to Hemispherx during the conduct of this study (patent number is 6,130,206 and the date is October 10, 2000). Hemispherx has several patents pending for CFS. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1. Flow Diagram of Study Patients.
Figure 1. Flow Diagram of Study Patients.

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