Category: Clinical Trial

Response to Adamson et al. (2020): ‘Cognitive behavioural therapy for chronic fatigue and chronic fatigue syndrome: Outcomes from a specialist clinic in the UK’

Abstract:

In a paper published in the Journal of the Royal Society of Medicine, Adamson et al. (2020) interpret data as showing that cognitive behavioural therapy leads to improvement in patients with chronic fatigue syndrome and chronic fatigue. Their research is undermined by several methodological limitations, including: (a) sampling ambiguity; (b) weak measurement; (c) survivor bias; (d) missing data and (e) lack of a control group. Unacknowledged sample attrition renders statements in the published Abstract misleading with regard to points of fact. That the paper was approved by peer reviewers and editors illustrates how non-rigorous editorial processes contribute to systematic publication bias.

Source: Hughes BM, Tuller D. Response to Adamson et al. (2020): ‘Cognitive behavioural therapy for chronic fatigue and chronic fatigue syndrome: Outcomes from a specialist clinic in the UK’. J Health Psychol. 2021 Apr 10:13591053211008203. doi: 10.1177/13591053211008203. Epub ahead of print. PMID: 33840241. https://pubmed.ncbi.nlm.nih.gov/33840241/

Open-label study with the monoamine stabilizer (-)-OSU6162 in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Objectives: The purpose of the present study was to investigate the safety and tolerability of the monoaminergic stabilizer (-)-OSU6162 in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In addition, a potential therapeutic effect of (-)-OSU6162 in ME/CFS was evaluated by means of observer-rated scales and self-assessment rating scales.

Materials and methods: In the current study using an open-label single-arm design ME/CFS patient received treatment with (-)-OSU6162 during 12 weeks. The patients received the following doses of (-)-OSU6162: 15 mg b.i.d. during the first 4-week period, up to 30 mg b.i.d. during the second 4-week period and up to 45 mg b.i.d. during the third 4-week period, with follow-up visits after 16 and 20 weeks.

Results: Out of 33 included patients, 28 completed the 12 weeks treatment period. (-)-OSU6162 was well tolerated; only one patient discontinued due to an adverse event. Vital signs and physical examinations showed no abnormal changes. Blood analyses showed an increase in serum prolactin. Therapeutically, improvements were seen on the Clinical Global Impression of Change scale, the FibroFatigue scale, the Mental Fatigue Scale, the Fatigue Severity Scale, Beck Depression Inventory, and the Short Form 36 Health Survey Questionnaire.

Conclusions: (-)-OSU6162 is well tolerated in ME/CFS patients and shows promise as a novel treatment to mitigate fatigue and improve mood and health-related quality of life in ME/CFS. Obviously, the present results need to be confirmed in future placebo-controlled double-blind trials.

Source: Haghighi S, Forsmark S, Zachrisson O, Carlsson A, Nilsson MKL, Carlsson ML, Schuit RC, Gottfries CG. Open-label study with the monoamine stabilizer (-)-OSU6162 in myalgic encephalomyelitis/chronic fatigue syndrome. Brain Behav. 2021 Feb 2:e02040. doi: 10.1002/brb3.2040. Epub ahead of print. PMID: 33528911. https://onlinelibrary.wiley.com/doi/10.1002/brb3.2040 (Full text)

The draft updated NICE guidance for ME/CFS highlights the unreliability of subjective outcome measures in non-blinded trials

Abstract:

The National Institute for Health and Care Excellence (NICE) recently published its draft updated guideline on the diagnosis and management of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). NICE concluded that ME/CFS is a complex multisystem chronic medical condition for which graded exercise therapy should not be used and cognitive behavioural therapy is only a supportive therapy and not a treatment or cure. The draft guidance also highlighted the unreliability of subjective outcome measures in non-blinded trials. High quality randomised controlled ME/CFS trials are now needed to find pharmacological treatments that lead to substantial objective improvement and restore the ability to work.

Source: Vink M, Vink-Niese A. The draft updated NICE guidance for ME/CFS highlights the unreliability of subjective outcome measures in non-blinded trials. J Health Psychol. 2021 Jan 28:1359105321990810. doi: 10.1177/1359105321990810. Epub ahead of print. PMID: 33506707. https://pubmed.ncbi.nlm.nih.gov/33506707/

Effect of disease duration in a randomized Phase III trial of rintatolimod, an immune modulator for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Rintatolimod is a selective TLR3 agonist, which has demonstrated clinical activity for ME/CFS in Phase II and Phase III double-blind, placebo-controlled, randomized, multi-site clinical trials.

Methods and findings: A hypothesis-based post-hoc analysis of the Intent to Treat (ITT) population diagnosed with ME/CFS from 12 independent clinical sites of a Phase III trial was performed to evaluate the effect of rintatolimod therapy based on disease duration. The clinical activity of rintatolimod was evaluated by exercise treadmill tolerance (ETT) using a modified Bruce protocol. The ITT population (n = 208) was divided into two subsets of symptom duration. Patients with symptom duration of 2-8 years were identified as the Target Subset (n = 75); the remainder (<2 year plus >8 year) were identified as the Non-Target Subset (n = 133). Placebo-adjusted percentage improvements in exercise duration and the vertical rise for the Target Subset (n = 75) were more than twice that of the ITT population. The Non-Target Subset (n = 133) failed to show any clinically significant ETT response to rintatolimod when compared to placebo. Within the Target Subset, 51.2% of rintatolimod-treated patients improved their exercise duration by ≥25% (p = 0.003) despite reduced statistical power from division of the original ITT population into two subsets.

Conclusion/significance: Analysis of ETT from a Phase III trial has identified within the ITT population, a subset of ME/CFS patients with ≥2 fold increased exercise response to rintatolimod. Substantial improvement in physical performance was seen for the majority (51.2%) of these severely debilitated patients who improved exercise duration by ≥25%. This magnitude of exercise improvement was associated with clinically significant enhancements in quality of life. The data indicate that ME/CFS patients have a relatively short disease duration window (<8 years) to expect a significant response to rintatolimod under the dosing conditions utilized in this Phase III clinical trial. These results may have direct relevance to the cognitive impairment and fatigue being experienced by patients clinically recovered from COVID-19 and free of detectable SARS-CoV-2.

Source: Strayer DR, Young D, Mitchell WM. Effect of disease duration in a randomized Phase III trial of rintatolimod, an immune modulator for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. PLoS One. 2020 Oct 29;15(10):e0240403. doi: 10.1371/journal.pone.0240403. PMID: 33119613. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240403 (Full text)

Effectiveness a herbal medicine ( Sipjeondaebo-tang) on adults with chronic fatigue syndrome: A randomized, double-blind, placebo-controlled trial

Abstract:

Background: Sipjeondaebo-tang (SJDBT, Shi-quan-da-bu-tang in Chinese) is a widely prescribed herbal medicine in traditional Korean medicine. This study aimed to evaluate the effectiveness and safety of SJDBT for treating chronic fatigue syndrome (CFS).

Methods: Ninety-six eligible participants were randomly allocated to either the SJDBT or placebo groups in a 1:1 ratio. Nine grams of SJDBT or placebo granules were administered to the patients for 8 weeks. The primary outcome was the response rate, defined as the proportion of participants with a score of 76 or higher in the Checklist Individual Strength assessment. Other measurements for fatigue severity, quality of life, and qi/blood/yin/yang deficiency were included. Safety was assessed throughout the trial.

Results: At week 8, the response rate did not significantly differ between the groups (SJDBT: 35.4%; placebo: 54.2%; P = 0.101, effect size [95% confidence interval] = 0.021 [-0.177, 0.218]). However, the scores of the visual analogue scale (P = 0.001, -0.327 [-0.506, -0.128]), Fatigue Severity Scale (P = 0.020, 0.480 [0.066, 0.889]), and Chalder fatigue scale (P = 0.004, -0.292 [-0.479, -0.101]) for the SJDBT group showed significant improvements in fatigue severity at the endpoint. Quality of life was not significantly different. Furthermore, SJDBT significantly ameliorated the severity of qi deficiency compared to that in the placebo group. No serious adverse events were observed.

Conclusion: This trial failed to show a significant improvement in fatigue severity, as assessed by the CIS-deprived response rate. It merely showed that SJDBT could alleviate the severity of fatigue and qi deficiency in patients with CFS. However, the further study is needed to confirm the details.

Source: Shin S, Park SJ, Hwang M. Effectiveness a herbal medicine (Sipjeondaebo-tang) on adults with chronic fatigue syndrome: A randomized, double-blind, placebo-controlled trial. Integr Med Res. 2021 Jun;10(2):100664. doi: 10.1016/j.imr.2020.100664. Epub 2020 Sep 22. PMID: 33101925; PMCID: PMC7578262.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578262/ (Full study)

The effectiveness of cupping therapy on chronic fatigue syndrome: A single-blind randomized controlled trial

Abstract:

Background: and purpose: We investigated the effectiveness of cupping therapy with three different pressures in patients with chronic fatigue syndrome (CFS).

Materials and methods: The participants were randomly assigned to three groups, as follows: cupping pressure of -0.02 mpa (n = 38), -0.03 mpa (n = 38), or -0.05 mpa (n = 36). Each group received cupping treatment that consisted of 10 sessions over 5 weeks (2 sessions per week). The primary outcomes were Fatigue Scale (FS-14) score and Fatigue Assessment Instrument (FAI) score after 5 and 10 sessions. The secondary outcomes were the Self-Rating Anxiety Scale (SAS) score, the Self-Rating Depression Scale (SDS) score, and the Pittsburgh Sleep Quality Index (PSQI) score.

Results: There were 91 participants who completed the trial. After five sessions of treatment, the primary outcome of FS-14 score decreased by 3.20 (2.19, 4.21) in the -0.02 mpa group, by 2.39 (1.51, 3.27) in the -0.03 mpa group, and by 3.40 (2.28, 4.52) in the -0.05 mpa group (P = 0.667). After 10 sessions of treatment, the outcome of FS-14 score decreased by 5.00 (3.79, 6.21) in the -0.02 mpa group, by 4.06 (3.07, 5.05) in the -0.03 mpa group, and by 4.77 (3.52, 5.94) in the -0.05 mpa group (P = 0.929). And, the results were statistically different between 5 sessions and 10 sessions of treatment (P < 0.01). However, there were no statistical differences in FAI, SAS, SDS, and PSQI scores between the three groups after 5 sessions and 10 sessions of treatment.

Conclusions: In conclusion, cupping therapy has significantly relieved fatigue symptoms and improved emotion and sleep condition of CFS patients, and 10 sessions of treatment had superior results compared with 5 sessions in each group. Moreover, in 5 sessions of treatment, cupping with high pressure showed better improvement in fatigue syndromes and sleep condition according to effective rates.

Trial registration: Chinese clinical trial registry (ChiCTR1800017590); Ethical approval number: ChiECRCT-20180085.

Source: Meng XD, Guo HR, Zhang QY, et al. The effectiveness of cupping therapy on chronic fatigue syndrome: A single-blind randomized controlled trial. Complement Ther Clin Pract. 2020;40:101210. doi:10.1016/j.ctcp.2020.101210 https://pubmed.ncbi.nlm.nih.gov/32891286/

Effect of ginger-separated moxibustion on fatigue, sleep quality and depression in patients with chronic fatigue syndrome: a randomized controlled trial

Abstract:

Objective: To observe the effect of ginger-separated moxibustion on fatigue, sleep quality and depression in the patients with chronic fatigue syndrome.

Methods: A total of 62 patients with chronic fatigue syndrome were randomized into an observation group (31 cases, 3 cases dropped off) and a control group (31 cases, 2 cases dropped off). In the control group, the patients had normal diet and proper physical exercise. In the observation group, on the basis of the control group, the ginger-separated moxibustion was added at Zhongwan (CV 12), Shenque (CV 8) and Guanyuan (CV 4), 30 min each time, once every two days, 3 times weekly. Separately, before treatment and after 4 weeks of treatment, the MOS item short form health survey (SF-36), the Pittsburgh sleep quality index (PSQI) scale and the self-rating depression scale (SDS) were adopted to evaluate the degrees of fatigue, sleep quality and depression in the patients of the two groups.

Results: In the observation group, the score of each item of SF-36, the score of each item of PSQI and SDS score after treatment were all improved significantly as compared with those before treatment respectively (P<0.05, P<0.01). In the control group, the scores of overall health, vitality and mental health in SF-36 and the score of sleep time of PSQI after treatment were improved as compared with those before treatment respectively (P<0.05). After treatment, the score of each item of SF-36, the scores of sleep quality, sleep time, sleep efficiency and sleep disorders of PSQI, as well as SDS score in the observation group were all better than those in the control group respectively (P<0.01, P<0.05). The score of SF-36 was relevant to the scores of PSQI and SDS in the patients of chronic fatigue syndrome (r =0.331, P<0.05; r =-0.706, P<0.01). The improvement value of SF-36 score was closely related to the improvement value of SDS score in the observation group (r =-0.657, P<0.01).

Conclusion: The ginger-separated moxibustion effectively relieves fatigue and depression condition and improves sleep quality in the patients with chronic fatigue syndrome. The fatigue condition is relevant with sleep quality and depression condition to a certain extent in the patients.

Source: Lin YF, Zhu JF, Chen YD, et al. Zhongguo Zhen Jiu. 2020;40(8):816-820. doi:10.13703/j.0255-2930.20190722-k0001 https://pubmed.ncbi.nlm.nih.gov/32869588/

Effects of the prolong life with nine turn method (Yan Nian Jiu Zhuan) Qigong on patients with chronic fatigue syndrome: study protocol for a randomized controlled trial

Abstract:

Background: Chronic fatigue syndrome (CFS) is characterized by persistent fatigue, which often leads to physical and psychological damage. Cognitive behavioral therapy (CBT) is considered to be one of the most effective treatments. Prolong life with nine turn method (PLWNT) Qigong is a combination of complex two-way traffic path connecting the cognitive center and the enteric nerves. In this study protocol, we will explore the effectiveness of PLWNT for physical and mental fatigue, gastrointestinal function, depression, and sleep quality in patients with CFS using clinical effectiveness scales and functional magnetic imaging (fMRI).

Methods: A randomized controlled trial (RCT) consisting of 90 patients will be divided into a CBT and PLWNT group. Both of the groups will include a supervised intervention at the Shanghai University of Traditional Chinese Medicine once a week, and the remaining six days will be completed at home over 12 consecutive weeks. The primary outcome variable will be the Multidimensional Fatigue Inventory (MFI20). Secondary outcomes will evaluate the Short Form 36-item Health Survey (SF-36), the Pittsburgh Sleep Quality Index (PSQI), the Hospital Anxiety and Depression Scale (HADS), and brain activation will be explored using fMRI.

Results: This will be the first randomized controlled clinical trial to introduce the PLWNT method for the treatment of CFS. If these results demonstrate that CBT or PLWNT interventions are effective, they will provide a quality treatment plan for patients with chronic fatigue and optimize their guidance.

Trial registration: Clinical Trials Registry, NCT03496961, Registered on April 12, 2018.

Source: Xie F, Guan C, Cheng Z, Yao F, You Y. Effects of the prolong life with nine turn method (Yan Nian Jiu Zhuan) Qigong on patients with chronic fatigue syndrome: study protocol for a randomized controlled trial [published online ahead of print, 2020 Aug 4]. Ann Palliat Med. 2020;apm-19-461. doi:10.21037/apm-19-461 https://pubmed.ncbi.nlm.nih.gov/32787361/

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Efficacy of Repeat Immunoadsorption

Abstract:

(1) Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex neuroimmunological disease. There is evidence for an autoimmune mechanism for ME/CFS with an infection-triggered onset and dysfunction of ß2-adrenoreceptor antibodies (ß2AR-AB). In a first proof-of-concept study, we could show that IA was effective to reduce ß2AR-AB and led to improvement of various symptoms.

(2) Five of the ME/CFS patients who had clinical improvement following treatment with a five-day IA were retreated in the current study about two years later with a modified IA protocol. The severity of symptoms was assessed by disease specific scores during a follow-up period of 12 months. The antibodies were determined by ELISA.

(3) The modified IA treatment protocol resulted in a remarkable similar clinical response. The treatment was well tolerated and 80-90% decline of total IgG and ß2AR-AB was achieved. Four patients showed a rapid improvement in several clinical symptoms during IA therapy, lasting for six to 12 months. One patient had no improvement.

(4) We could provide further evidence that IA has clinical efficacy in patients with ME/CFS. Data from our pilot trial warrant further controlled studies in ME/CFS.

Source: Tölle M, Freitag H, Antelmann M, et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Efficacy of Repeat Immunoadsorption. J Clin Med. 2020;9(8):E2443. Published 2020 Jul 30. doi:10.3390/jcm9082443 https://pubmed.ncbi.nlm.nih.gov/32751659/

Intravenous Cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An Open-Label Phase II Study

Abstract:

Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease with high symptom burden, of unknown etiology, with no established treatment. We observed patients with long-standing ME/CFS who got cancer, and who reported improvement of ME/CFS symptoms after chemotherapy including cyclophosphamide, forming the basis for this prospective trial.

Materials and methods: This open-label phase II trial included 40 patients with ME/CFS diagnosed by Canadian criteria. Treatment consisted of six intravenous infusions of cyclophosphamide, 600-700 mg/m2, given at four-week intervals with follow-up for 18 months, extended to 4 years. Response was defined by self-reported improvements in symptoms by Fatigue score, supported by Short Form 36 (SF-36) scores, physical activity measures and other instruments. Repeated measures of outcome variables were assessed by General linear models. Responses were correlated with specific Human Leukocyte Antigen (HLA) alleles.

Results: The overall response rate by Fatigue score was 55.0% (22 of 40 patients). Fatigue score and other outcome variables showed significant improvements compared to baseline. The SF-36 Physical Function score increased from mean 33.0 at baseline to 51.5 at 18 months (all patients), and from mean 35.0 to 69.5 among responders. Mean steps per 24 h increased from mean 3,199 at baseline to 4,347 at 18 months (all patients), and from 3,622 to 5,589 among responders. At extended follow-up to 4 years 68% (15 of 22 responders) were still in remission. Patients positive for HLA-DQB1*03:03 and/or HLA-C*07:04 (n = 12) had significantly higher response rate compared to patients negative for these alleles (n = 28), 83 vs. 43%, respectively. Nausea and constipation were common grade 1-2 adverse events. There were one suspected unexpected serious adverse reaction (aggravated POTS) and 11 serious adverse events in eight patients.

Conclusion: Intravenous cyclophosphamide treatment was feasible for ME/CFS patients and associated with an acceptable toxicity profile. More than half of the patients responded and with prolonged follow-up, a considerable proportion of patients reported ongoing remission. Without a placebo group, clinical response data must be interpreted with caution. We nevertheless believe a future randomized trial is warranted. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02444091.

Copyright © 2020 Rekeland, Fosså, Lande, Ktoridou-Valen, Sørland, Holsen, Tronstad, Risa, Alme, Viken, Lie, Dahl, Mella and Fluge.

Source: Rekeland IG, Fosså A, Lande A, Ktoridou-Valen I, Sørland K, Holsen M, Tronstad KJ, Risa K, Alme K, Viken MK, Lie BA, Dahl O, Mella O, Fluge Ø. Intravenous Cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An Open-Label Phase II Study. Front Med (Lausanne). 2020 Apr 29;7:162. doi: 10.3389/fmed.2020.00162. eCollection 2020. https://www.frontiersin.org/articles/10.3389/fmed.2020.00162/full (Full text)