ME and CFS Abnormalities – Drug Trials

 

Following is a list of articles about drug trials in ME and CFS.

Links to the more than 1,000 peer-reviewed journal articles are listed on the ME and CFS Medical Abnormalities page of this website.

 

Brown AE, Dibnah B, Fisher E, Newton JL, Walker M. Pharmacological activation of AMPK and glucose uptake in cultured human skeletal muscle cells from patients with ME/CFS. Biosci Rep. 2018 May 8;38(3). PMID: 29654166

The aim of this study was to assess if AMP-activated protein kinase (AMPK) could be activated pharmacologically in ME/CFS. Primary skeletal muscle cell cultures from patients with ME/CFS and healthy controls were treated with either metformin or compound 991. Cellular ATP content was unaffected by treatment although ATP content was significantly decreased in ME/CFS compared with controls.

*

Eaton N, Cabanas H, Balinas C, Klein A, Staines D, Marshall-Gradisnik S. Rituximab impedes natural killer cell function in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients: A pilot in vitro investigation. BMC Pharmacol Toxicol. 2018 Mar 27;19(1):12. PMID: 29587879

This study reports significant decreases in NK cell lysis and a significant increase in NK cell degranulation following Rituximab incubation in vitro in CFS/ME patients, suggesting Rituximab may be toxic for NK cells.

*

Vorob’eva OV, Rusaya VV. Efficacy and safety of noophen in the treatment of chronic fatigue syndrome in patients with cerebrovascular insufficiency. Zh Nevrol Psikhiatr Im S S Korsakova. 2017;117(11):31-36. PMID: 29265084

This study assessed the efficacy and safety of noophen in the treatment of chronic fatigue syndrome in patients with cerebrovascular insufficiency. Treatment with noophen resulted in the marked decrease in the total intensity of fatigue measured with MFI-20.

*

Nilsson MKL, Zachrisson O, Gottfries CG, Matousek M, Peilot B, Forsmark S, Schuit RC, Carlsson ML, Kloberg A, Carlsson A. A randomised controlled trial of the monoaminergic stabiliser (-)-OSU6162 in treatment of myalgic encephalomyelitis/chronic fatigue syndrome. Acta Neuropsychiatr. 2018 Jun;30(3):148-157. PMID: 29212562

The monoaminergic stabiliser (-)-OSU6162 has in previous studies shown promising effects on mental fatigue after stroke and traumatic brain injury. This study investigated the safety and effectiveness of (-)-OSU6162 in patients with myalgic encephalomyelitis/chronic fatigue syndrome. When analysing the entire material (-)-OSU6162 was not found to differ significantly from placebo in alleviating fatigue in ME patients but was superior to placebo in counteracting fatigue in a subgroup of ME patients who received concomitant pharmacological treatment for depression.

*

Staud R, Kizer T, Robinson ME. Muscle injections with lidocaine improve resting fatigue and pain in patients with chronic fatigue syndrome. J Pain Res. 2017 Jun 26;10:1477-1486. PMID: 28721090

Previous research has implicated metaboreceptors of muscles to play an important role for chronic fatigue and pain. Therefore, the researchers hypothesized that blocking impulse input from deep tissues with intramuscular lidocaine injections would improve not only the pain but also fatigue of CFS patients. The results demonstrate that lidocaine injections reduce clinical fatigue of CFS patients significantly more than placebo, suggesting an important role of peripheral tissues for chronic fatigue.

*

Roerink ME, Bredie SJH, Heijnen M, Dinarello CA, Knoop H, Van der Meer JWM. Cytokine Inhibition in Patients With Chronic Fatigue Syndrome: A Randomized Trial. Ann Intern Med. 2017 Apr 18;166(8):557-564. PMID: 28265678

This project evaluated the effect of subcutaneous anakinra versus placebo on fatigue severity in female patients with CFS. Peripheral IL-1 inhibition using anakinra for 4 weeks does not result in a clinically significant reduction in fatigue severity in women with CFS and severe fatigue.

*

Lunde S, Kristoffersen EK, Sapkota D, Risa K, Dahl O, Bruland O, Mella O, Fluge Ø. Serum BAFF and APRIL Levels, T-Lymphocyte Subsets, and Immunoglobulins after B-Cell Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Myalgic Encephalopathy/Chronic Fatigue Syndrome. PLoS One. 2016 Aug 18;11(8):e0161226. PMID: 27536947

We have previously suggested clinical benefit from B-cell depletion using the monoclonal anti-CD20 antibody rituximab in a randomized and placebo-controlled study. Prolonged responses were then demonstrated in an open-label phase-II study with maintenance rituximab treatment. Using blood samples from patients in the previous two clinical trials, we investigated quantitative changes in T-lymphocyte subsets, in immunoglobulins, and in serum levels of two B-cell regulating cytokines during follow-up. Although no functional assays were performed, the lack of significant associations of T- and NK-cell subset numbers with B-cell depletion, as well as the lack of associations to clinical responses, suggest that B-cell regulatory effects on T-cell or NK-cell subsets are not the main mechanisms for the observed improvements in ME/CFS symptoms observed in the two previous trials. The modest increase in serum BAFF levels at baseline may indicate an activated B-lymphocyte system in a subgroup of ME/CFS patients.

*

Hall KT, Kossowsky J, Oberlander TF, Kaptchuk TJ, Saul JP, Wyller VB, Fagermoen E, Sulheim D, Gjerstad J, Winger A, Mukamal KJ. Genetic variation in catechol-O-methyltransferase modifies effects of clonidine treatment in chronic fatigue syndrome. Pharmacogenomics J. 2016 Oct;16(5):454-60. PMID: 27457818

Clonidine, an α2-adrenergic receptor agonist, decreases circulating norepinephrine and epinephrine, attenuating sympathetic activity. Although catechol-O-methyltransferase (COMT) metabolizes catecholamines, main effectors of sympathetic function, COMT genetic variation effects on clonidine treatment are unknown. Chronic fatigue syndrome(CFS) is hypothesized to result in part from dysregulated sympathetic function. A candidate gene analysis of COMT rs4680 effects on clinical outcomes in the Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL), a randomized double-blinded clonidine versus placebo trial, was conducted (N=104). Patients homozygous for rs4680 high-activity allele randomized to clonidine took 2500 fewer steps compared with placebo (Pinteraction=0.04). There were no differences between clonidine and placebo among patients with COMT low-activity alleles. Similar gene-drug interactions were observed for sleep (Pinteraction=0.003) and quality of life (Pinteraction=0.018). Detrimental effects of clonidine in the subset of CFS patients homozygous for COMT high-activity allele warrant investigation of potential clonidine-COMT interaction effects in other conditions.

*

Mitchell WM. Efficacy of rintatolimod in the treatment of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Expert Rev Clin Pharmacol. 2016 Jun;9(6):755-70. PMID: 27045557

Chronic fatigue syndrome/ Myalgic encephalomyelitis (CFS/ME) is a poorly understood seriously debilitating disorder in which disabling fatigue is an universal symptom in combination with a variety of variable symptoms. The only drug in advanced clinical development is rintatolimod, a mismatched double stranded polymer of RNA (dsRNA). Rintatolimod is a restricted Toll-Like Receptor 3 (TLR3) agonist lacking activation of other primary cellular inducers of innate immunity (e.g.- cytosolic helicases). Rintatolimod also activates interferon induced proteins that require dsRNA for activity (e.g.- 2′-5′ adenylate synthetase, protein kinase R).

*

Park SB, Kim KN, Sung E, Lee SY, Shin HC. Human Placental Extract as a Subcutaneous Injection Is Effective in Chronic Fatigue Syndrome: A Multi-Center, Double-Blind, Randomized, Placebo-Controlled Study. Biol Pharm Bull. 2016 May 1;39(5):674-9. PMID: 26911970

The aim of this study was to examine the effectiveness of subcutaneous injection of the human placental extract (HPE) on medically indescribable cases of chronic fatigue (CF) and safety in a randomized, double-blind, placebo-controlled clinical trial. The subcutaneous injection of HPE was effective in the improvement of chronic fatigue syndrome (CFS).

*

Fluge Ø, Risa K, Lunde S, Alme K, Rekeland IG, Sapkota D, Kristoffersen EK, Sørland K, Bruland O, Dahl O, Mella O. B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment. PLoS One. 2015 Jul 1;10(7):e0129898. PMID: 26132314

In a subgroup of ME/CFS patients, prolonged B-cell depletion with rituximab maintenance infusions was associated with sustained clinical responses. The observed patterns of delayed responses and relapse after B-cell depletion and regeneration, a three times higher disease prevalence in women than in men, and a previously demonstrated increase in B-cell lymphoma risk for elderly ME/CFS patients, suggest that ME/CFS may be a variant of an autoimmune disease.

*

Montoya JG, Kogelnik AM, Bhangoo M, Lunn MR, Flamand L, Merrihew LE, Watt T, Kubo JT, Paik J, Desai M. Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome. J Med Virol. 2013 Dec;85(12):2101-9. PMID: 23959519

Thirty CFS patients with elevated IgG antibody titers against HHV-6 and EBV were randomized 2:1 to receive valganciclovir (VGCV) or placebo for 6 months in a double-blind, placebo-controlled trial. VGCV patients experienced a greater improvement by MFI-20 at 9 months from baseline compared to placebo patients but this difference was not statistically significant. However, statistically significant differences in trajectories between groups were observed in MFI-20 mental fatigue subscore, FSS score, and cognitive function. Patients in the VGCV arm were 7.4 times more likely to be classified as responders. In the VGCV arm, monocyte counts decreased, neutrophil counts increased and cytokines were more likely to evolve towards a Th1-profile.

*

Strayer DR, Carter WA, Stouch BC, Stevens SR, Bateman L, Cimoch PJ, Lapp CW, Peterson DL; Chronic Fatigue Syndrome AMP-516 Study Group, Mitchell WM. A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome. PLoS One. 2012;7(3):e31334. PMID: 22431963

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

*

Watt T, Oberfoell S, Balise R, Lunn MR, Kar AK, Merrihew L, Bhangoo MS, Montoya JG. Response to valganciclovir in chronic fatigue syndrome patients with human herpesvirus 6 and Epstein-Barr virus IgG antibody titers. J Med Virol. 2012 Dec;84(12):1967-74. PMID: 23080504

This study investigated whether antibody titers against HHV-6 and EBV were associated with clinical response to valganciclovir in a subset of CFS patients. An uncontrolled, unblinded retrospective chart review was performed on 61 CFS patients treated with valganciclovir. Thirty-two patients (52%) were categorized as responders. Among these, 19 patients (59%) responded physically and 26 patients (81%) responded cognitively. After treatment, the average change in physical and cognitive functioning levels for all patients was +19% and +23%, respectively.

*

Lerner AM, Beqaj SH, Deeter RG, Fitzgerald JT. Valacyclovir treatment in Epstein-Barr virus subset chronic fatigue syndrome: thirty-six months follow-up. In Vivo. 2007 SepOct;21(5):707-13. PMID: 18019402

A group of CFS patients improved on the drug valacyclovir.

*

Kogelnik AM, Loomis K, Hoegh-Petersen M, Rosso F, Hischier C, Montoya JG. Use of valganciclovir in patients with elevated antibody titers against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) who were experiencing central nervous system dysfunction including long-standing fatigue. J Clin Virol. 2006 Dec;37 Suppl 1:S33-8. PMID: 17276366

CFS patients with high IgG antibody titers against HHV-6 and EBV who were suffering from central nervous system dysfunction and debilitating fatigue for more than one year (median 3 years, range 1-8 years) were treated with 6 months of valganciclovir in an open label study. Nine out of 12 (75%) patients experienced near resolution of their symptoms, allowing them all to return to the workforce or full time activities. In the nine patients with a symptomatic response to treatment, EBV VCA IgG titers dropped from 1:2560 to 1:640 and HHV-6 IgG titers dropped from a median value of 1:1280 to 1:320.

*

Vermeulen RC, Scholte HR. Azithromycin in chronic fatigue syndrome (CFS), an analysis of clinical data. J Transl Med. 2006 Aug 15;4:34. PMID: 16911783

The antibiotic azithromycin resulted in a decrease in symptoms in a subset of CFS patients, all of whom had lower levels of plasma acetylcarnitine. The authors speculate that the drug protected the patients from oxidative stress.

*

Lerner AM, Beqaj SH, Deeter RG, Dworkin HJ, Zervos M, Chang CH, Fitzgerald JT, Goldstein J, O’Neill W. A six-month trial of valacyclovir in the Epstein-Barr virus subset of chronic fatigue syndrome: improvement in left ventricular function. Drugs Today (Barc). 2002 Aug;38(8):549-61. PMID: 12582420

Valacyclovir may be effective when used to treat persistent Epstein-Barr virus (EBV) in CFS.

*

Drago F, Ranieri E, Pastorino A, Casazza S, Crovato F, Rebora A. Epstein-Barr virusrelated primary cutaneous amyloidosis. Successful treatment with acyclovir and interferon-alpha. Br J Dermatol. 1996 Jan;134(1):170-4. PMID: 8745909

The researchers present data that support an endogenous reactivation of EBV infection and suggest a causal relationship with primary amyloidosis.

*

See DM, Tilles JG. alpha-Interferon treatment of patients with chronic fatigue syndrome. Immunol Invest. 1996 Jan-Mar;25(1-2):153-64.PMID: 8675231

Therapy with alpha interferon had a significant effect on the quality of life in a subgroup of patients with CFS manifesting an isolated decrease in natural killer cell function.

*

Suhadolnik RJ, Reichenbach NL, Hitzges P, Adelson ME, Peterson DL, Cheney P, Salvato P, Thompson C, Loveless M, Müller WE, et al. Changes in the 2-5A 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. PMID: 7893988

In individuals that presented with elevated RNase L activity at baseline, therapy with poly(I)-poly(C12U) resulted in a significant decrease in both bioactive 2-5A and RNase L activity. Decrease in RNase L activity in individuals treated with poly(I)-poly(C12U) correlated with cognitive improvement.

*

Strayer DR, Carter WA, Brodsky I, Cheney P, Peterson D, Salvato P, Thompson C, Loveless M, Shapiro DE, Elsasser W, et al. A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome. Clin Infect Dis. 1994 Jan;18 Suppl 1:S88-95. PMID: 8148460

After 24 weeks, patients receiving poly(I).poly(C12U) had higher scores for both global performance and perceived cognition than did patients receiving placebo. In particular, patients given poly(I).poly(C12U) had increased Karnofsky performance scores, exhibited a greater ability to do work during exercise treadmill testing, displayed an enhanced capacity to perform the activities of daily living, had a reduced cognitive deficit, and required less use of other medications.

 

Links on this page are in orange (no underlining).