Clinical Trial – Page 6 – American ME and CFS Society

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.

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)

Chronic fatigue syndrome treated by the traditional Chinese procedure abdominal tuina: a randomized controlled clinical trial

Abstract:

OBJECTIVE: To evaluate the effect of the traditional Chinese procedure abdominal Tuina (AT) on chronic fatigue syndrome (CFS).

METHODS: This randomized, single assessor-blinded clinical trial was carried out from May 2014 to April 2015. Eighty participants in the trial were divided randomly into two groups: experimental group and control. The experimental group (40 cases) was treated by AT and the control group (40 cases) by acupuncture. Each treatment was conducted once a day, 5 d for one course, at an interval of 2 d between each course. The whole treatment course lasted for 4 weeks. To ascertain the effect of AT and acupuncture, Fatigue Scale-14 (FS-14), Self-rating Anxiety Scale (SAS) and Hamilton Rating Scale for Depression (HAMD) scores were used before and after treatment. Patients were followed up for 3 months after treatment.

RESULTS: After treatment for 4 weeks, 77 patients (39 cases in the experimental group and 38 cases in the control group) completed the trial. The FS-14, SAS and HAMD scores decreased (P < 0.05) significantly compared with those before treatment in both groups. The FS-14 and HAMD (P < 0.05) scores in the experimental group were much lower than those in the control group. The difference in SAS scores between the two groups was not significant. In the final follow-up, CFS in two cases in the experimental group and three in the control group recurred, but the difference was not significant. The scores for the FS-14, SAS and HAMD in the experimental group were superior to those of the control group, and the difference was significant (P < 0.05). No serious adverse events and few adverse events were observed.

CONCLUSION: AT elicited a more efficacious effect than acupuncture alone on CFS.

Source: Li H, Wang J, Zhang W, Zhao N, Hai X, Sun Q, Sun S, Han Y, Zhang R, Ma F. Chronic fatigue syndrome treated by the traditional Chinese procedure abdominal tuina: a randomized controlled clinical trial. J Tradit Chin Med. 2017 Dec;37(6):819-826. https://www.ncbi.nlm.nih.gov/pubmed/32188192

Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and inducing disease tolerance

Abstract:

Myalgic encephalomyelitis, ME, previously also known as chronic fatigue syndrome (CFS) is a heterogeneous, debilitating syndrome of unknown etiology responsible for long-lasting disability in millions of patients worldwide. The most well-known symptom of ME is post-exertional malaise, but many patients also experience autonomic dysregulation, cranial nerve dysfunction and signs of immune system activation. Many patients also report a sudden onset of disease following an infection.

The brainstem is a suspected focal point in ME pathogenesis and patients with structural impairment to the brainstem often show ME-like symptoms. The brainstem is also where the vagus nerve originates, a critical neuro-immune interface and mediator of the inflammatory reflex which regulate systemic inflammation. Here we report the results of a randomized, placebo-controlled trial using intranasal mechanical stimulation (INMEST) targeting the vagus nuclei, and higher centers in the brain of ME-patients and induce a sustainable, ~30% reduction in overall symptom scores after eight weeks of treatment.

By performing longitudinal, systems-level monitoring of the blood immune system in these patients, we uncover chronic immune activation in ME, as well as immunological correlates of improvement that center around the IL-17 axis, gut-homing immune cells and reduced inflammation. The mechanisms of symptom relief remains to be determined, but transcriptional analyses suggest an upregulation of disease tolerance mechanisms. We wish for these results to bring some hope to patients suffering from ME and inspire researchers to help test our new hypothesis that ME is a condition caused by a failure of inducing disease tolerance upon infection and persistent immune activation.

Source: Lucie ST Rodriguez, Christian Pou, Lakshmikanth Tadepally, Jingdian Zhang, Constantin Habimana Mugabo, Jun Wang, Jaromir Mikes, Axel Olin, Yang Chen, Joanna Rorbach, Jan-Erik Juto, Tie-Qiang Li, Per Julin, Petter Brodin. Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and inducing disease tolerance. bioRxiv
doi: https://doi.org/10.1101/2020.02.20.958249 https://www.biorxiv.org/content/10.1101/2020.02.20.958249v1

Systematic review of randomized controlled trials for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)

Abstract:

BACKGROUND: Although medical requirements are urgent, no effective intervention has been proven for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). To facilitate the development of new therapeutics, we systematically reviewed the randomized controlled trials (RCTs) for CFS/ME to date.

METHODS: RCTs targeting CFS/ME were surveyed using two electronic databases, PubMed and the Cochrane library, through April 2019. We included only RCTs that targeted fatigue-related symptoms, and we analyzed the data in terms of the characteristics of the participants, case definitions, primary measurements, and interventions with overall outcomes.

RESULTS: Among 513 potentially relevant articles, 55 RCTs met our inclusion criteria; these included 25 RCTs of 22 different pharmacological interventions, 28 RCTs of 18 non-pharmacological interventions and 2 RCTs of combined interventions. These studies accounted for a total of 6316 participants (1568 males and 4748 females, 5859 adults and 457 adolescents). CDC 1994 (Fukuda) criteria were mostly used for case definitions (42 RCTs, 76.4%), and the primary measurement tools included the Checklist Individual Strength (CIS, 36.4%) and the 36-item Short Form health survey (SF-36, 30.9%). Eight interventions showed statistical significance: 3 pharmacological (Staphypan Berna, Poly(I):poly(C12U) and CoQ10 + NADH) and 5 non-pharmacological therapies (cognitive-behavior-therapy-related treatments, graded-exercise-related therapies, rehabilitation, acupuncture and abdominal tuina). However, there was no definitely effective intervention with coherence and reproducibility.

CONCLUSIONS: This systematic review integrates the comprehensive features of previous RCTs for CFS/ME and reflects on their limitations and perspectives in the process of developing new interventions.

Source: Kim DY, Lee JS, Park SY, Kim SJ, Son CG. Systematic review of randomized controlled trials for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). J Transl Med. 2020 Jan 6;18(1):7. doi: 10.1186/s12967-019-02196-9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943902/ (Full article)

Results of the feasibility phase of the managed activity graded exercise in teenagers and pre-adolescents (MAGENTA) randomised controlled trial of treatments for chronic fatigue syndrome/myalgic encephalomyelitis

Editor’s Comment: Graded exercise therapy (GET) has been widely discredited as a treatment for ME/CFS. It has caused permanent damage in some patients. Exercise of any type is not recommended for severely ill patients, as it can cause significant harm. No exercise program should be undertaken that employs a structured incremental increase in exercise for patients at any level of illness. ME/CFS is a highly variable disease that can fluctuate unpredictably between exacerbations and remissions, which prohibits a goal-oriented exercise regimen.

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) also known as myalgic encephalomyelitis (ME) is relatively common in young people and causes significant disability. Graded exercise therapy (GET) and activity management are recommended by the National Institute for Health and Care Excellence (NICE) despite a limited evidence-base for either treatment in paediatric CFS/ME. This paper reports on feasibility and acceptability measures from the feasibility phase of the ongoing MAGENTA randomised controlled trial (RCT) investigating GET versus activity management for young people with CFS/ME.

METHODS: Setting: Three specialist secondary care National Health Service (NHS) Paediatric CFS/ME services (Bath, Cambridge and Newcastle).Participants: Young people aged 8-17 years with a diagnosis of mild to moderate CFS/ME. Young people were excluded if they were severely affected, referred to cognitive behavioural therapy (CBT) at initial assessment or unable to attend clinical sessions.Interventions: GET and activity management delivered by physiotherapists, occupational therapists, nurses and psychologists. Families and clinicians decided the number (typically 8-12) and frequency of appointments (typically every 2-6 weeks).Outcome Measures: Recruitment and follow-up statistics. We used integrated qualitative methodology to explore the feasibility and acceptability of the trial processes and the interventions.

RESULTS: 80/161 (49.7%) of eligible young people were recruited at two sites between September 2015 and August 2016, indicating recruitment to the trial was feasible. Most recruitment (78/80; 97.5%) took place at one centre. Recruitment consultations, online consent and interventions were acceptable, with less than 10% in each arm discontinuing trial treatment. Response rate to the primary outcome (the SF36-PFS at 6 months) was 91.4%. Recruitment, treatment and data collection were not feasible at one centre. The site was withdrawn from the study.In response to data collected, we optimised trial processes including using Skype for recruitment discussions; adapting recruiter training to improve recruitment discussions; amending the accelerometer information leaflets; shortening the resource use questionnaires; and offering interventions via Skype. These amendments have been incorporated into the full trial protocol.

CONCLUSIONS: Conducting an RCT investigating GET versus activity management is feasible and acceptable for young people with CFS/ME.

TRIAL REGISTRATION: ISRCTN23962803 10.1186/ISRCTN23962803, date of registration: 03 September 2015.

Source: Brigden A, Beasant L, Gaunt D, Hollingworth W, Mills N, Solomon-Moore E, Jago R, Metcalfe C, Garfield K, Wray C, Trist A, Vilenchik V, Grayson C, Crawley E. Results of the feasibility phase of the managed activity graded exercise in teenagers and pre-adolescents (MAGENTA) randomised controlled trial of treatments for chronic fatigue syndrome/myalgic encephalomyelitis. Pilot Feasibility Stud. 2019 Dec 19;5:151. doi: 10.1186/s40814-019-0525-3. eCollection 2019. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924066/ (Full article)

Modification of Immunological Parameters, Oxidative Stress Markers, Mood Symptoms, and Well-Being Status in CFS Patients after Probiotic Intake: Observations from a Pilot Study

Abstract:

The present study discusses about the effects of a combination of probiotics able to stimulate the immune system of patients affected by Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). To this purpose, patients diagnosed according to Fukuda’s criteria and treated with probiotics were analyzed by means of clinical and laboratory evaluations, before and after probiotic administrations.

Probiotics were selected considering the possible pathogenic mechanisms of ME/CFS syndrome, which has been associated with an impaired immune response, dysregulation of Th1/Th2 ratio, and high oxidative stress with exhaustion of antioxidant reserve due to severe mitochondrial dysfunction. Immune and oxidative dysfunction could be related with the gastrointestinal (GI) chronic low-grade inflammation in the lamina propria and intestinal mucosal surface associated with dysbiosis, leaky gut, bacterial translocation, and immune and oxidative dysfunction.

Literature data demonstrate that bacterial species are able to modulate the functions of the immune and oxidative systems and that the administration of some probiotics can improve mucosal barrier function, modulating the release of proinflammatory cytokines, in CFS/ME patients. This study represents a preliminary investigation to verifying the safety and efficacy of a certain combination of probiotics in CFS/ME patients. The results suggest that probiotics can modify the well-being status as well as inflammatory and oxidative indexes in CFS/ME patients.

No adverse effects were observed except for one patient, which displayed a flare-up of symptoms, although all inflammatory parameters (i.e., cytokines, fecal calprotectin, ESR, and immunoglobulins) were reduced after probiotic intake. The reactivation of fatigue symptoms in this patient, whose clinical history reported the onset of CFS/ME following mononucleosis, could be related to an abnormal stimulation of the immune system as suggested by a recent study describing an exaggerated immune activation associated with chronic fatigue.

Source: Venturini L, Bacchi S, Capelli E, Lorusso L, Ricevuti G, Cusa C. Modification of Immunological Parameters, Oxidative Stress Markers, Mood Symptoms, and Well-Being Status in CFS Patients after Probiotic Intake: Observations from a Pilot Study. Oxid Med Cell Longev. 2019 Nov 23;2019:1684198. doi: 10.1155/2019/1684198. eCollection 2019. https://www.hindawi.com/journals/omcl/2019/1684198/ (Full study)

Efficacy and safety of Sijunzi Decoction for chronic fatigue syndrome with spleen deficiency pattern: study protocol for a randomized, double-blind, placebo-controlled trial

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS), which is characterized by severe and disabling fatigue, has become an extensively concerned medical disorder in clinical practice. Due to the unclear etiology, current treatments are symptomatic or need assistance from psychology and kinesiology. Under the immature conditions in China, many patients would seek help from traditional Chinese medicine (TCM), in which Chinese herbal medicine (CHM) is one of the main interventions. Sijunzi Decoction (SJZD) is a classical formula and has been utilized in improving fatigue symptoms for a long time. However, lack of rigorously-designed randomized controlled trial limits its application and generalization in CFS management. Hence, we design this clinical trial to assess the effectiveness and safety of SJZD for CFS.

METHODS: This is a single-center, randomized, double-blind, placebo-controlled trial. Two hundred and twelve patients with CFS will be recruited from public and equally allocated to SJZD group and placebo group. Based on the general education, these two groups will receive corresponding drugs twice a day for consecutive 2 months. The follow-up period will be 1 month. The primary outcome will be the change of Chalder fatigue scoring after treatment. Secondary outcomes include the short form-36 physical function subscale (SF36-PF), spleen deficiency rating scale, quality of life and self-rated clinical global impression (CGI) scales.

DISCUSSION: The four ingredients of SJZD are Renshen (Radix Ginseng), Baizhu (Rhizoma Atractylodis Macrocephalae), Fulin (Poria) and Zhigancao (Radix Glycyrrhizae Preparata), which show potential to alleviate CFS on the foundation of available studies. The results of this trial will provide high-quality clinical evidence for the application of SJZD, and hope to further support a new TCM choice in CFS treatment.

TRIAL REGISTRATION: ISRCTN23930966 (ISRCTN registry, registered on 28th May, 2019).

Source: Dai L, Zhou WJ, Wang M, Zhou SG, Ji G. Efficacy and safety of Sijunzi Decoction for chronic fatigue syndrome with spleen deficiency pattern: study protocol for a randomized, double-blind, placebo-controlled trial. Ann Transl Med. 2019 Oct;7(20):587. doi: 10.21037/atm.2019.09.136. https://www.ncbi.nlm.nih.gov/pubmed/31807568

Low-dose naltrexone in the treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract:

Background: Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a common medical condition that limits physical and cognitive functions, with no known effective medical treatment.

Methods: We report on the safety and effectiveness data accumulated in clinical practice when treating ME/CFS with low-dose naltrexone (LDN, 3.0 – 4.5 mg/day). The medical records from 218 patients who received ar diagnosis of ME/CFS and LDN treatment during 2010–2014 were retrospectively analyzed.

Results: Outcome data were available in 92.2% of patients with an average follow-up time of 1.7 years. A positive treatment response to LDN was reported by 73.9% of the patients. Most patients experienced improved vigilance/alertness and improved physical and cognitive performance. Some patients reported less pain and fever, while 18.3% of patients did not report any treatment response to LDN. Mild adverse effects (insomnia, nausea) were common at the beginning of the treatment. Neither severe adverse effects nor long-term adverse symptoms were reported.

Conclusions: The high frequency of treatment response and good safety profile observed in this retrospective open label study could prompt prospective controlled studies to confirm the feasibility of LDN in alleviating ME/CFS symptoms.

Source: Olli Polo, Pia Pesonen & Essi Tuominen (2019) Low-dose naltrexone in the treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2019.1692770 https://www.tandfonline.com/doi/full/10.1080/21641846.2019.1692770

Clinical efficacy of neurometabolic therapy of dissomical disorders in asthenic syndrome

Abstract:

AIM: To analyze the efficacy of cytoflavin in the complex treatment of sleep disorders in asthenic syndrome.

MATERIAL AND METHODS: One hundred patients with sleep disorders and asthenic syndrome of various etiology and severity were studied. The patients were divided into three groups depending on the type of therapy: the first group received intravenous infusions of cytoflavin for 10 days; the second group, in addition to cytoflavin, received per os melatonin (3 mg or 5 mg) at bedtime; the third group in addition to cytoflavin received per os zopiclone (7.5 mg) at bedtime.

RESULTS: On the 14th day of the study, a decrease in severity or complete relief of asthenia manifestations (according to the SHAS scale) and, accordingly, improvement or normalization of sleep in 97% of patients was found. At the same time, during polysomnographic study, the data obtained are characteristic for improving the quality of sleep phases mainly in the first and second groups of patients and, to a lesser extent, in the third group.

CONCLUSION: Cytoflavin effectively suppresses the main manifestations of asthenic syndrome, including sleep disorders.

Source: Esipov AV, Ivolgin AF, Khritinin DF, Katenko SV, Kazakov SP, Karakozov AG, Kalyagin IE, Levchenko OB, Molodova AI. Clinical efficacy of neurometabolic therapy of dissomical disorders in asthenic syndrome. Zh Nevrol Psikhiatr Im S S Korsakova. 2019;119(9):46-51. doi: 10.17116/jnevro201911909146. [Article in Russian; Abstract available in Russian from the publisher] https://www.ncbi.nlm.nih.gov/pubmed/31626218

Open Trial of Vitamin B12 Nasal Drops in Adults With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Comparison of Responders and Non-Responders

Abstract:

Introduction: A recent study reported a favorable effect of vitamin B12 injections/oral folic acid support in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients. Recently, vitamin B12 nasal drops were developed as an alternative to the vitamin B12 injections. As no data are available on efficacy of this formulation, we studied vitamin B12 serum levels, the physical activity scale of the RAND-36, the number of steps on an activity meter, and the fatigue and concentration scales of the CIS20r questionnaires, before and after 3 months of treatment in ME/CFS patients.

Methods and Results: Fifty-one patients completed all measurements. Forty-four were female. Mean age was 42 years, and mean disease duration was 16 years. Median vitamin B12 levels before treatment were 328 (244-429) pmol/l, and 973 (476-1,476) pmol/l after treatment.

Thirty-four patients reported a favorable response to treatment. In the non-responders, only a small but significant increase in vitamin B12 levels was observed. In contrast, in responders, the number of steps, the physical activity scale of the RAND-36, and the vitamin B12 serum levels increased significantly. The CIS20r fatigue scale decreased significantly, and the CIS20r concentration scale was unchanged.

Conclusions: Nasal drop vitamin B12 administration resulted in a significant increase in vitamin B12 serum levels and therefore may be effective. This pilot study suggest that the nasal drops may be used as an alternative to injections because two thirds of ME/CFS patients reported a positive effect, accompanied by an increased number of steps, improvement of the RAND-36 physical functioning scale and the CIS20r fatigue scale, and a significant increase in serum vitamin B12 levels.Copyright © 2019 van Campen, Riepma and Visser.

Source: van Campen CLM, Riepma K, Visser FC. Open Trial of Vitamin B12 Nasal Drops in Adults With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Comparison of Responders and Non-Responders. Front Pharmacol. 2019 Sep 20;10:1102. doi: 10.3389/fphar.2019.01102. eCollection 2019. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764214/ (Full article)