Category: Clinical Trial

Why do some ME/CFS patients benefit from treatment with sodium dichloroacetate, but others do not?

Abstract:

Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is an enigmatic disease the pathogenesis of which remains elusive. Pragmatic proof-of-principle of the hypothetical mechanisms causing the clinical symptoms has been delivered, but it is hard to explain why some patients do respond favourably to treatment with sodium dichloroacetate (DCA), which enhances the activity of the mitochondrial enzyme pyruvate dehydrogenase, but other patients experience no benefit from this substance.

In a prospective trial including 35 ME/CFS patients, logistic regression analysis with stepwise elimination has identified 6 pre-treatment characteristics allowing for the differentiation between responders (n = 13) and non-reponders (n = 22) with high accuracy (P < 0.0001; area under the ROC-curve = 0.92). A formula was derived generating the probability of belonging to the group of responders. This finding may assist in selecting ME/CFS patients suitable for treatment with DCA, but requires further studies as to the predictive capacity of the derived formula.

Source: Comhaire F. Why do some ME/CFS patients benefit from treatment with sodium dichloroacetate, but others do not? Med Hypotheses. 2018 Nov;120:65-67. doi: 10.1016/j.mehy.2018.08.014. Epub 2018 Aug 25. https://www.ncbi.nlm.nih.gov/pubmed/30220343

Multidisciplinary rehabilitation treatment is not effective for myalgic encephalomyelitis/chronic fatigue syndrome: A review of the FatiGo trial

Abstract:

The FatiGo trial concluded that multidisciplinary rehabilitation treatment is more effective for chronic fatigue syndrome/myalgic encephalomyelitis in the long term than cognitive behaviour therapy and that multidisciplinary rehabilitation treatment is more cost-effective for fatigue and cognitive behaviour therapy for quality of life. However, FatiGo suffered from a number of serious methodological flaws. Moreover, it ignored the results of the activity metre, its only objective outcome. This jeopardizes the validity of FatiGo. Its analysis shows that there was no statistically significant difference between multidisciplinary rehabilitation treatment and cognitive behaviour therapy and neither are (cost-)effective. FatiGo’s claims of efficacy of multidisciplinary rehabilitation treatment and cognitive behaviour therapy for chronic fatigue syndrome/myalgic encephalomyelitis are misleading and not justified by their results.

Source: Mark Vink and Alexandra Vink-Niese. Multidisciplinary rehabilitation treatment is not effective for myalgic encephalomyelitis/chronic fatigue syndrome: A review of the FatiGo trial. Health Psychology Open. http://journals.sagepub.com/doi/10.1177/2055102918792648 (Full article)

Personalised relaxation practice to improve sleep and functioning in patients with chronic fatigue syndrome and depression: study protocol for a randomised controlled trial

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) and major depressive disorder (MDD) are both debilitating but heterogeneous conditions sharing core features of fatigue, unrefreshing sleep, and impaired functioning. The aetiology of these conditions is not fully understood, and ‘best-practice’ treatments are only moderately effective in relieving symptoms. Unrecognised individual differences in the response to such treatments are likely to underlie poor treatment outcomes.

METHODS/DESIGN: We are undertaking a two-group, parallel, randomised controlled trial (RCT) comparing the effects of a personalised relaxation intervention on sleep quality, daytime symptoms, and functioning in patients with CFS (n = 64) and MDD (n = 64). Following identification of the method that best enhances autonomic responding (such as heart rate variability), participants randomised to the active intervention will practise their recommended method nightly for 4 weeks. All participants will keep a sleep diary and monitor symptoms during the trial period, and they will complete two face-to-face assessments, one at baseline and one at 4 weeks, and a further online assessment to evaluate lasting effects of the intervention at 2 months. Assessments include self-report measures of sleep, wellbeing, and function and monitoring of autonomic responses at rest, in response to the relaxation method and during nocturnal sleep. Treatment outcomes will be analysed using linear mixed modelling.

DISCUSSION: This is the first RCT examining the effects of a personalised relaxation intervention, pre-tested to maximise the autonomic relaxation response, in patients with unrefreshing sleep and fatigue attributed to CFS or MDD. Detailed monitoring of sleep quality and symptoms will enable sensitive detection of improvements in the core symptoms of these debilitating conditions. In addition, repeated monitoring of autonomic functioning can elucidate mechanisms underlying potential benefits. The findings have translational potential, informing novel, personalised symptom management techniques for these conditions, with the potential for better clinical outcomes.

TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ANZCTR), ACTRN12616001671459 . Registered on 5 December 2016.

Source: Macnamara CL, Cvejic E, Parker GB, Lloyd AR, Lee G, Beilharz JE, Vollmer-Conna U. Personalised relaxation practice to improve sleep and functioning in patients with chronic fatigue syndrome and depression: study protocol for a randomised controlled trial. Trials. 2018 Jul 11;19(1):371. doi: 10.1186/s13063-018-2763-8.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042263/ (Full article)

KPAX002 as a treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a prospective, randomized trial

Abstract:

Mitochondrial dysfunction and a hypometabolic state are present in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). KPAX002 consists of low-dose methylphenidate hydrochloride to treat a hypometabolic state combined with key micronutrients intended to broadly support mitochondrial function.

The objective of this study was to evaluate KPAX002 as a treatment for fatigue and concentration disturbance symptoms in ME/CFS subjects. This phase 2 randomized, double-blinded, placebo-controlled trial was conducted at 4 sites in the United States. A total of 135 subjects with ME/CFS were randomly assigned to either KPAX002 (n=67) or placebo (n=68) for 12 weeks of treatment. The primary endpoint was change in the Checklist Individual Strength (CIS) total score from baseline to Week 12. Secondary measurements included visual analog scales for fatigue and concentration disturbance symptoms.

In the intent-to-treat population, the mean reduction in the CIS total score from baseline to week 12 for the KPAX002 and placebo groups was -16.9 (± 23.52) and -13.8 (± 22.15), respectively (95% confidence interval, -11.1, 4.0; P=0.359). On the visual analog scale for fatigue, the mean reduction from baseline to week 12 was -18.2 mm (± 25.05) and -11.1 mm (± 22.08) for the KPAX002 and placebo groups, respectively (95% confidence interval, -11.5, 2.3; P=0.189). The two groups demonstrating the most robust response to KPAX002 were subjects with more severe ME/CFS symptoms at baseline (P=0.086) and subjects suffering from both fatigue and pain (P=0.057). The incidence of adverse events was not statistically different between the two groups.

Treatment with KPAX002 resulted in a reduction in fatigue and concentration disturbance symptoms in multiple analyses. Two key subgroups of patients whose response approached statistical significance were identified.

Source: Jose G Montoya, Jill N Anderson, Danya L Adolphs, Lucinda Bateman, Nancy Klimas, Susan M Levine, Donn W Garvert, Jon D Kaiser. KPAX002 as a treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a prospective, randomized trial. Int J Clin Exp Med 2018;11(3):2890-2900 www.ijcem.com /ISSN:1940-5901/IJCEM0065685 (Full article)

Treating patients suffering from myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) with sodium dichloroacetate: An open-label, proof-of-principle pilot trial

Abstract:

Twenty-two consecutive patients suffering from refractory myalgic encephalitis/chronic fatigue syndrome (ME/CFS) were treated with an innovative nutriceutical containing sodium dichloroacetate in a proof-of-principle, pilot, open-label prospective cohort trial. Ten patients experienced significant improvement of their health condition with reduction to almost half of their score in the fatigue severity scale. In twelve patients treatment failed to exert any beneficial effect. In the latter patients several other diseases have commonly been revealed by extensive biological and imaging investigations. These preliminary findings sustain the hypothetical role of mitochondrial hypo-metabolism due to inhibition of the activity of the pyruvate dehydrogenase in the pathogenesis of primary ME/CFS, and suggest a possible benefit of nutriceutical treatment by sodium dichloroacetate.

Source: Comhaire F. Treating patients suffering from myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) with sodium dichloroacetate: An open-label, proof-of-principle pilot trial. Med Hypotheses. 2018 May;114:45-48. doi: 10.1016/j.mehy.2018.03.002. Epub 2018 Mar 5.   https://www.ncbi.nlm.nih.gov/pubmed/29602463

Rituximab impedes natural killer cell function in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients: A pilot in vitro investigation

Abstract:

BACKGROUND: A recent in vitro pilot investigation reported Rituximab significantly reduced natural killer (NK) cell cytotoxicity in healthy donors. Chronic fatigue syndrome/Myalgic encephalomyelitis (CFS/ME) is a debilitating disorder of unknown etiology. A consistent finding is a significant reduction in NK cell cytotoxicity. Rituximab has been reported having questionable potential therapeutic benefits for the treatment of CFS/ME, however, the potential effects of Rituximab on NK cell cytotoxicity in CFS/ME patients are yet to be determined.

METHODS: A total of eight CFS/ME patients (48.63 ± 15.69 years) and nine non-fatigued controls (NFC) (37.56 ± 11.06 years) were included using the Fukuda case definition. Apoptotic function, lytic proteins and degranulation markers were measured on isolated NK cells using flow cytometry following overnight incubation with Rituximab at 10 μg/ml and 100 μg/ml.

RESULTS: There was a significant reduction in NK cell lysis between CFS/ME patients and NFC following incubation with Rituximab at 100 μg/ml at 12.5:1 and 6.25:1 effecter-target (E:T) ratios (p < 0.05). However, there was no significant difference for NFC following incubation with Rituximab at 10 μg/ml and 100 μg/ml. There was no significant difference between CFS/ME patients and NFC for granzyme A and granzyme B prior to incubation with Rituximab and following overnight incubation with Rituximab at 10 μg/ml. There was a significant decrease in granzyme B in CFS/ME patients compared to NFC with 100 μg/ml of Rituximab prior to K562 cells stimulation (p < 0.05). There was a significant increase in CD107a (p < 0.05) and CD107b expression (p < 0.01) in NFC after stimulation with K562 cells prior to incubation with Rituximab. There was a significant increase in CD107b expression between CFS/ME patients and NFC prior to incubation with Rituximab and without stimulation of K562 cells (p < 0.01). Importantly, there was a significant increase in CD107b following overnight incubation with 100 μg/ml of Rituximab in NFC prior to K562 cells stimulation (p < 0.01).

CONCLUSION: 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. Caution should be observed in clinical trials until further investigations in a safe and controlled in vitro setting are completed.

Source: 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. doi: 10.1186/s40360-018-0203-8.   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870391/ (Full article)

Rethinking the treatment of chronic fatigue syndrome—a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT

Abstract:

Background: The PACE trial was a well-powered randomised trial designed to examine the efficacy of graded exercise therapy (GET) and cognitive behavioural therapy (CBT) for chronic fatigue syndrome. Reports concluded that both treatments were moderately effective, each leading to recovery in over a fifth of patients. However, the reported analyses did not consistently follow the procedures set out in the published protocol, and it is unclear whether the conclusions are fully justified by the evidence.

Methods: Here, we present results based on the original protocol-specified procedures. Data from a recent Freedom of Information request enabled us to closely approximate these procedures. We also evaluate the conclusions from the trial as a whole.

Results: On the original protocol-specified primary outcome measure – overall improvement rates – there was a significant effect of treatment group. However, the groups receiving CBT or GET did not significantly outperform the Control group after correcting for the number of comparisons specified in the trial protocol. Also, rates of recovery were consistently low and not significantly different across treatment groups. Finally, on secondary measures, significant effects were almost entirely confined to self-report measures. These effects did not endure beyond two years.

Conclusions: These findings raise serious concerns about the robustness of the claims made about the efficacy of CBT and GET. The modest treatment effects obtained on self-report measures in the PACE trial do not exceed what could be reasonably accounted for by participant reporting biases.

Source: Carolyn E. Wilshire, Tom Kindlon, Robert Courtney, Alem Matthees, David Tuller, Keith Geraghty and Bruce Levin. Rethinking the treatment of chronic fatigue syndrome—a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT. BMC PsychologyBMC series. Received: 29 May 2017; Accepted: 22 February 2018; Published: 22 March 2018.  https://doi.org/10.1186/s40359-018-0218-3 (Full article) © The Author(s) 2018.

Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME

Abstract:

Introduction: Infection-triggered disease onset, chronic immune activation and autonomic dysregulation in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) point to an autoimmune disease directed against neurotransmitter receptors. We had observed elevated autoantibodies against ß2 adrenergic receptors, and muscarinic 3 and 4 acetylcholine receptors in a subset of patients. Immunoadsorption (IA) was shown to be effective in removing autoantibodies and improve outcome in various autoimmune diseases.

Methods: 10 patients with post-infectious CFS/ME and elevated ß2 autoantibodies were treated with IA with an IgG-binding column for 5 days. We assessed severity of symptoms as outcome parameter by disease specific scores. Antibodies were determined by ELISA and B cell phenotype by flow cytometry.

Results: IgG levels dropped to median 0.73 g/l (normal 7–16 g/l) after the 4th cycle of IA, while IgA and IgM levels remained unchanged. Similarly, elevated ß2 IgG antibodies rapidly decreased during IA in 9 of 10 patients. Also 6 months later ß2 autoantibodies were significantly lower compared to pretreatment. Frequency of memory B cells significantly decreased and frequency of plasma cells increased after the 4th IA cycle. A rapid improvement of symptoms was reported by 7 patients during the IA. 3 of these patients had long lasting moderate to marked improvement for 6–12+ months, 2 patients had short improvement only and 2 patients improved for several months following initial worsening.

Conclusions: IA can remove autoantibodies against ß2 adrenergic receptor and lead to clinical improvement. B cell phenotyping provides evidence for an effect of IA on memory B cell development. Data from our pilot trial warrants further studies in CFS/ME.

Source: Carmen Scheibenbogen, Madlen Loebel, Helma Freitag, Anne Krueger, Sandra Bauer, Michaela Antelmann, Wolfram Doehner, Nadja Scherbakov, Harald Heidecke, Petra Reinke, Hans-Dieter Volk, Patricia Grabowski. Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME. PLOS ONE. Published: March 15, 2018 https://doi.org/10.1371/journal.pone.0193672 (Full article)

Investigating the effectiveness and cost-effectiveness of FITNET-NHS (Fatigue In Teenagers on the interNET in the NHS) compared to Activity Management to treat paediatric chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME): protocol for a randomised controlled trial

Abstract:

BACKGROUND: Paediatric chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is a relatively common and disabling condition. The National Institute for Health and Clinical Excellence (NICE) recommends Cognitive Behavioural Therapy (CBT) as a treatment option for paediatric CFS/ME because there is good evidence that it is effective. Despite this, most young people in the UK are unable to access local specialist CBT for CFS/ME. A randomised controlled trial (RCT) showed FITNET was effective in the Netherlands but we do not know if it is effective in the National Health Service (NHS) or if it is cost-effective. This trial will investigate whether FITNET-NHS is clinically effective and cost-effective in the NHS.

METHODS: Seven hundred and thirty-four paediatric patients (aged 11-17 years) with CFS/ ME will be randomised (1:1) to receive either FITNET-NHS (online CBT) or Activity Management (delivered via video call). The internal pilot study will use integrated qualitative methods to examine the feasibility of recruitment and the acceptability of treatment. The full trial will assess whether FITNET-NHS is clinically effective and cost-effective. The primary outcome is disability at 6 months, measured using the SF-36-PFS (Physical Function Scale) questionnaire. Cost-effectiveness is measured via cost-utility analysis from an NHS perspective. Secondary subgroup analysis will investigate the effectiveness of FITNET-NHS in those with co-morbid mood disorders.

DISCUSSION: If FITNET-NHS is found to be feasible and acceptable (internal pilot) and effective and cost-effective (full trial), its provision by the NHS has the potential to deliver substantial health gains for the large number of young people suffering from CFS/ME but unable to access treatment because there is no local specialist service. This trial will provide further evidence evaluating the delivery of online CBT to young people with chronic conditions.

TRIAL REGISTRATION: ISRCTN registry, registration number: ISRCTN18020851 . Registered on 4 August 2016.

Source: Baos S, Brigden A, Anderson E, Hollingworth W, Price S, Mills N, Beasant L, Gaunt D, Garfield K, Metcalfe C, Parslow R, Downing H, Kessler D, Macleod J, Stallard P, Knoop H, Van de Putte E, Nijhof  S, Bleijenberg G, Crawley E. Investigating the effectiveness and cost-effectiveness of FITNET-NHS (Fatigue In Teenagers on the interNET in the NHS) compared to Activity Management to treat paediatric chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME): protocol for a randomised controlled trial. Trials. 2018 Feb 22;19(1):136. doi: 10.1186/s13063-018-2500-3. https://www.ncbi.nlm.nih.gov/pubmed/29471861

Note: Update published December 19, 2019. https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-019-3895-1

Time to Reject the PACE Study

Abstract:

The PACE trial investigated the efficacy of graded exercise therapy and cognitive behavioral therapy for ME/CFS. The design and the implementation of the study were flawed, and the conclusions are contradicted by the data. It is time to reject the study.

https://www.researchgate.net/publication/320101462_Time_to_Reject_the_PACE_Study [Full article].

This is a translation of an article that was published in slightly shortened form in Läkartidningen, Stockholm, Sweden, on 28 September 2017. http://www.lakartidningen.se/

Link to the shortened article in Swedish: http://www.lakartidningen.se/Opinion/De-batt/2017/09/Dags-att-forkasta-PACE-studien/

Source: Helmfrid S, Edsberg J. Dags att förkasta PACE-studien. Lakartid-ningen. 2017;114:ETLE.