Uit een grootschalig fase III-onderzoek onder patiënten met ernstige ME/CVS (Karnofsky-score

40-60) blijkt dat Ampligen de inspannings(duur)vermogen in 40 weken sterk doet verbeteren.

Ook nam het medicijngebruik in de Ampligen-groep sterker af dan in de placebo-groep.

Dit is relevant omdat medicijnen in verband gebracht worden met een verlengd QT-interval.

Deze aanvullende fase III-studie was nodig in het kader van de "eeuwig durende" procedure om Ampligen (rintatolimod) op de markt te krijgen: klik hier, klik hier, klik hier, en klik hier.

De veronderstelde werking van Ampligen is deels gebaseerd op herstel van de RNase-L pathway door stimulatie van de TLR3-receptor en interferon-productie die daaruit voortvloeit.

Een klein overzicht van "oude" studies over RNase-L en (de werking van) Ampligen:

• RNA drug therapy acting via the 2-5A synthetase/RNase L pathway.

Ann N Y Acad Sci. 1993 Jun 23;685:756-7.

Suhadolnik RJ, Reichenbach NL, Hitzges PM, Ablashi DV, Strayer DR, Carter WA.

 

• A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome.

Clinical Infectious Diseases. 1994 Jan;18 Suppl 1:S88-95.

Strayer DR, Carter WA, Brodsky I, Cheney P, Peterson D, Salvato P, Thompson C, Loveless M, Shapiro DE, Elsasser W, et al.

 

• Upregulation of the 2-5A synthestase/RNase L antiviral pathway associated with chronic fatigue syndrome.

Clinical Infectious Diseases. 1994 Jan;18 Suppl 1:S96-104.

Suhadolnik RJ, Reichenbach NL, Hitzges P, Sobol RW, Peterson DL, Henry B, Ablashi DV, Müller WE, Schröder HC, Carter WA, et al.

 

• Changes in the 2-5S synthetase/RNase L antiviral pathway in a controlled clinical trial with poly(I)-poly(C12U) in chronic fatigue syndrome.

In Vivo. 1994 Jul-Aug;8(4):599-604.

Suhadolnik RJ, Reichenbach NL, Hitzges P, Adelson ME, Peterson DL, Cheney P, Salvato P, Thompson C, Loveless M, Müller WE, et al.

 

• Mismatched double-stranded RNA: polyI:polyC12U.

Drugs R D. 2004;5(5):297-304.

[No authors listed]

 

• Ampligen: a potential toll-like 3 receptor adjuvant for immunotherapy of cancer.

Vaccine. 2009 May 26;27(25-26):3401-4.

Jasani B, Navabi H, Adams M.

 

• Toll-like receptors as targets for immune disorders.

Trends Pharmacol Sci. 2011 Jul;32(7):435-42.

Keogh B, Parker AE.

RESEARCH ARTICLE

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

PLoS ONE 7(3): e31334. doi:10.1371/journal.pone.0031334.

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

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: 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.

Conclusions/Significance

Rintatolimod produced objective improvement in ET and

a reduction in CFS/ME related concomitant medication usage

as well as other secondary outcomes.

Funding

This study was funded, designed, and analyzed by Hemispherx Biopharma with oversight by the Food & Drug Administration (FDA) including statistical analysis. Following completion of FDA audits, the decision to publish was made.

Trial Registration

ClinicalTrials.gov NCT00215800

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0031334

Met dank aan Evelien en anderen.