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

Strayer, David R.; Carter, William A.; Stouch, Bruce C.; Stevens, Staci R.; Bateman, Lucinda; Cimoch, Paul J.; Lapp, Charles W.; Peterson, Daniel L.; the Chronic Fatigue Syndrome AMP-516 Study Group; Mitchell, William M.

doi:10.1371/journal.pone.0031334

Cited by 84Fibromyalgia and Chronic Fatigue Syndrome ResearchLong-Term Effects of COVID-19Gastrointestinal motility and disorders

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

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Strayer, David R., Carter, William A., Stouch, Bruce C., Stevens, Staci R., Bateman, Lucinda, Cimoch, Paul J., Lapp, Charles W., Peterson, Daniel L. +2 more·2012·PLoS ONE

DOI 10.1371/journal.pone.0031334PMC PMC3303772

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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.

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Rintatolimod (ampligen), a specific activator of inflammatory mediator toll-like receptor 3, has been deployed in ME/CFS treatment for decades, with varying efficacy.
“Rintatolimod (ampligen), a specific activator of inflammatory mediator toll-like receptor 3 (TLR3) has been deployed in ME/CFS treatment for decades, with varying efficacy11,12.”
From Leveraging Prior Knowledge of Endocrine Immune Regulation in the Therapeutically-relevant Phenotyping of Women with Chronic Fatigue Syndrome (2019) · cites this paper as [11]
The Introduction (page unavailable) identifies rintatolimod as a selective TLR3 agonist and describes its use in CFS/ME trials and an authorized treatment protocol. The Results (page unavailable) show that patients’ exercise-tolerance responses varied. The paper does not establish that it had been deployed as a treatment for decades; it also states that no drug therapy was approved. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Rintatolimod is sometimes effective in ME/CFS, but a means of identifying good candidates for this treatment remains elusive.
“Likewise, rintatolimod (Ampligen) is sometimes effective11,12, but a means of identifying good candidates for this course of treatment remains similarly elusive.”
From Leveraging Prior Knowledge of Endocrine Immune Regulation in the Therapeutically-relevant Phenotyping of Women with Chronic Fatigue Syndrome (2019) · cites this paper as [11]

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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. PLoS One 2012
Strayer, D. R., Carter, W. A., Stouch, B. C., Stevens, S. R., Bateman, L., Paul, J., Peterson, D. L., & Mitchell, W. M. (2016)
Self-citation
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME): Characteristics of Responders to Rintatolimod
Strayer, D. R. (2015) · Journal of Drug Research and Development · doi:10.16966/2470-1009.103 · Cited by 4 · see citing works
Efficacy of rintatolimod in the treatment of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)
Mitchell, W. M. (2016) · Figshare · doi:10.6084/m9.figshare.3438866
Self-citation
Effect of disease duration in a randomized Phase III trial of rintatolimod, an immune modulator for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Strayer, D. R., Young, D. C., & Mitchell, W. M. (2020) · PLoS ONE · doi:10.1371/journal.pone.0240403 · Cited by 40 · see citing works
Self-citation
Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Chu, L., Bateman, L., Davenport, T. E., Stein, E., & Stevens, S. R. (2015) · Annals of Internal Medicine · doi:10.7326/l15-5174
Self-citation

Authors: Strayer, D. R., Carter, W. A., Stouch, B. C., Stevens, S. R., Bateman, L., Cimoch, P. J., Lapp, C. W., Peterson, D. L., the Chronic Fatigue Syndrome AMP-516 Study Group, & Mitchell, W. M.
Affiliations: University of the Pacific (US)
Vanderbilt University (US)
Corresponding author: Strayer, David R.
Mitchell, William M.
ORCID: Bateman, Lucinda
Lapp, Charles W.
Venue: PLoS ONE
Publisher: Public Library of Science (PLoS)
Published: 2012-03-14
Volume: 7
Issue: 3
Pages: e31334
ISSN: 1932-6203 (ISSN-L)
DOI: 10.1371/journal.pone.0031334
PMC: PMC3303772
OpenAlex: W2016920052
Cited by: 84
References: 45
Citations by year: 2026: 4 · 2025: 4 · 2024: 2 · 2023: 6 · 2022: 9 · 2021: 5 · 2020: 5 · 2019: 6 · 2018: 8 · 2017: 4 · 2016: 7 · 2015: 10 · 2014: 8 · 2013: 3 · 2012: 3
FWCI: 5.48
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: PLoS ONE (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Figshare (submittedVersion, cc-by)
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Fibromyalgia and Chronic Fatigue Syndrome Research
Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
Keywords: chronic fatigue syndrome, poly(I:C), exercise tolerance, medication use, Karnofsky performance status, activities of daily living, quality of life, tolerability, immunotherapy
MeSH terms: Adult, Demography, Double-Blind Method, Drug Therapy, Combination, Exercise Test, Female, Humans, Male, Placebos, Poly I-C, Poly U, Fatigue Syndrome, Chronic, Exercise Tolerance, Endpoint Determination, Toll-Like Receptor 3

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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

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