Tag: clinical trial

Effects of recumbent isometric yoga on the daily functioning level of patients with myalgic encephalomyelitis/chronic fatigue syndrome: a randomized, controlled trial

Abstract:

Background: Although seated isometric yoga has been shown to reduce the fatigue and pain of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), some patients who are for the most part bedridden have difficulty practicing it. Many patients with this disease also suffer from fibromyalgia (FM). We developed a recumbent isometric yoga program for patients who were for the most part bedridden, including patients with comorbid FM. The aim of this study was to investigate the effect of this recumbent isometric yoga intervention with such patients.

Methods: This was a randomized, controlled trial of 48 adult patients (7 male, 41 female, age 20-70 years) with ME/CFS without satisfactory improvement after ≥ 3 months of conventional therapy. They were divided randomly into a yoga group (n = 24) and a control group (n = 24). The yoga group received conventional therapy with recumbent isometric yoga practice for ~ 12 weeks (25-min sessions with a yoga instructor at hospital visits and daily in-home sessions). The control group received conventional therapy alone. The effect of recumbent isometric yoga on the level of functioning was assessed by measuring Performance Status (PS). Fatigue was assessed with self-rated questionnaires, including the Chalder Fatigue Scale (FS) and Profile of Mood States (POMS). Adverse events and benefits were recorded for the yoga group.

Results: After the intervention period, the PS score of the yoga group was significantly lower than that of the control group (P < 0.001), suggesting an improvement in functioning level. The Chalder FS score decreased in both groups, but the decrease was greater in the yoga group than in the control group (P < 0.01). Subgroup analysis showed that the Chalder FS score was reduced significantly only in the yoga group in patients with severe disease (P < 0.001) and those with comorbid FM (P < 0.01), although the PS scores did not differ significantly. In the yoga group, a single practice session with a yoga instructor significantly reduced fatigue and increased vigor in patients with severe disease and patients with comorbid FM. Patients reported no serious adverse effects and many benefits of recumbent isometric yoga, including improvements in physical symptoms and brain fog, enhanced awareness of their limits to activities that cause post-exertional malaise, and promotion of behavioral changes to live better within their limits.

Conclusions: Recumbent isometric yoga is an effective adjunctive therapy for patients with ME/CFS, including those for the most part bedridden and those who have FM.

Trial registration: University Hospital Medical Information Network (UMIN CTR) UMIN000023472 (Registered Aug. 4, 2016) and UMIN000030051 (Registered Nov. 20, 2017).

Source: Oka T, Lkhagvasuren B, Yamada Y. Effects of recumbent isometric yoga on the daily functioning level of patients with myalgic encephalomyelitis/chronic fatigue syndrome: a randomized, controlled trial. Biopsychosoc Med. 2025 Oct 10;19(1):19. doi: 10.1186/s13030-025-00339-7. PMID: 41074089; PMCID: PMC12512564. https://pmc.ncbi.nlm.nih.gov/articles/PMC12512564/ (Full text)

Pacing with a heart rate monitor for people with myalgic encephalomyelitis/chronic fatigue syndrome and long COVID: a feasibility study

Abstract:

Background: People living with ME/CFS and LC frequently live with post-exertional malaise (PEM), which is associated with impairments in aerobic metabolism. They often use pacing with a heart rate monitor (HRM) to minimize time spent above the anaerobic threshold; however, there is limited research on the feasibility and efficacy.

Objective: To establish the acceptability, adherence, outcomes, and adverse events associated with pacing with an HRM for a future definitive study.

Methods: After informed consent and baseline measurements (including 10 min stand test, 5 questionnaires, accelerometry, heart rate variability, and lactate), participants were randomized into a control or intervention group using simple randomization and sealed envelopes. The intervention group used a heart rate monitor with weekly online HRM pacing advice (how to use the HRM, problem solving), and the control group received weekly online pacing advice (how to pace, problem solving). Follow-up measures were repeated, and semi-structured interviews were conducted at two and six months post-enrolment.

Results: 47 participants were recruited; however, recruiting people with LC was difficult due to wanting to use/already using HR monitoring. The interviews identified that the procedure was acceptable, and the majority of the participants completed the outcome measures. There were some changes from baseline to follow-up in all the outcome measures except the 10-minute stand test and accelerometry. There were no serious adverse events. Follow-up interviews identified 89% continued using HRM at 8 weeks and 66% after 6 months.

Conclusions: Studies of HRM are feasible and acceptable for ME/CFS and LC, although recruitment strategies should be reviewed for LC.

Clinical Trial registration number: ISRCTN10554129.

Source: Clague-Baker, N., Davenport, T. E., Wickens, B., Leeming, H., Dickinson, K., McBurney, E., … Hilliard, N. (2025). Pacing with a heart rate monitor for people with myalgic encephalomyelitis/chronic fatigue syndrome and long COVID: a feasibility study. Fatigue: Biomedicine, Health &amp; Behavior, 1–23. https://doi.org/10.1080/21641846.2025.2565103 https://www.tandfonline.com/doi/full/10.1080/21641846.2025.2565103#abstract (Full text)

Relationships between fatigue, cognitive function, and upright activity in a randomized trial of oxaloacetate for myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating condition characterized by fatigue, cognitive impairment, and reduced physical function. Oxaloacetate (OAA), a metabolic compound with potential mitochondrial and neuroprotective effects, has shown promise in reducing fatigue symptoms in ME/CFS. However, the interrelationships between fatigue, cognitive performance, and physical activity and their responsiveness to treatment remain poorly understood in ME/CFS.

Methods: This 90-day randomized, double-blind, controlled trial evaluated the effects of 2,000 mg/day OAA or a control of 2,000 mg rice flour in 82 adults with ME/CFS. Self-reported fatigue (Chalder Fatigue Questionnaire), cognitive function (DANA Brain Vital), and upright activity time (UP Time) were assessed at baseline and three follow-up visits. Linear mixed-effects models examined associations between fatigue severity and cognitive/physical function, with treatment group interactions. Responder status at the last visit (Visit 4) was classified based on ≥15% fatigue reduction and/or ≥10% cognitive improvement.

Results: The OAA group showed greater cognitive improvement over time, with a significant between-group difference at Visit 3, 60 days into the trial, (p = 0.034) and trends at other visits. Higher fatigue was significantly associated with reduced cognitive gains in the OAA group (β = −0.34, p < 0.0001), but not in controls. UP Time increased modestly in the OAA group, reaching significance at Visit 2, day 30 (p = 0.044), though fatigue was not a strong predictor of UP Time in either group. At Visit 4, day 90, Global and Fatigue Only Responders were more frequent in the OAA group, while Cognitive Only Responders were more frequent in controls, though group differences did not reach statistical significance (p = 0.10).

Conclusion: OAA supplementation was associated with improved cognitive performance and small improvement in UP Time in ME/CFS participants receiving OAA. Fatigue–cognition coupling was particularly strong in OAA-treated participants, suggesting a potentially targetable phenotype. These findings underscore the importance of multidimensional outcome measures in ME/CFS clinical trials and support the need for more research and trials of metabolic interventions in ME/CFS.

Source: Vernon Suzanne D. , Rond Candace , Sun Yifei , Roundy Shad , Bell Jennifer , Rond Bella , Kaufman David L. , Cash Alan B. , Yellman Brayden , Bateman Lucinda. Relationships between fatigue, cognitive function, and upright activity in a randomized trial of oxaloacetate for myalgic encephalomyelitis/chronic fatigue syndrome. Frontiers in Neurology, Volume 16 – 2025. DOI=10.3389/fneur.2025.1691147 ISSN=1664-2295 https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2025.1691147/full (Full text)

Solriamfetol improves daily fatigue symptoms in adults with myalgic encephalomyelitis/chronic fatigue syndrome after 8 weeks of treatment

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a long-term illness with no treatment options that address the disease directly. Solriamfetol is a selective dual norepinephrine-dopamine reuptake inhibitor that promotes wakefulness in obstructive sleep apnea and narcolepsy.

Aims: This study evaluated the efficacy and safety of solriamfetol for fatigue symptoms in adults with ME/CFS over 8 weeks of treatment.

Methods: This was a phase 4, double-blind, randomized, placebo-controlled trial of solriamfetol in adults with ME/CFS. Eligible participants (N = 38) were randomly assigned to receive 75 mg (titrated to 150 mg as needed) solriamfetol or placebo. Participants completed a battery of assessments at weekly visits. The primary outcome was Fatigue Symptom Inventory (FSI) scores, and the secondary outcome measure was Behavioral Rating Inventory of Executive Function for Adults (BRIEF-A), at Weeks 6 and 8. T-tests assessed the differences in mean change from baseline between solriamfetol and placebo. Adverse events were monitored throughout the study.

Results: At Week 8 (p = 0.039), but not Week 6 (p = 0.270), solriamfetol improved FSI severity compared to placebo. On the BRIEF-A global executive composite, solriamfetol improved more than placebo at Week 8 (p = 0.012), driven by improved metacognition index (p = 0.004), but not behavioral regulation index (p = 0.574). Solriamfetol was well tolerated, with most common AEs being sleep loss and headaches.

Conclusions: Solriamfetol demonstrated good safety and efficacy in improving fatigue and executive functioning in patients with ME/CFS. As a dual norepinephrine-dopamine reuptake inhibitor and wakefulness-promoting factors, solriamfetol has the potential to improve fatigue symptoms of ME/CFS.

Clinical trial number: NCT04622293.

Source: Young JL, Powell RN, Powell A, Welling LLM, Granata L, Saal J. Solriamfetol improves daily fatigue symptoms in adults with myalgic encephalomyelitis/chronic fatigue syndrome after 8 weeks of treatment. J Psychopharmacol. 2025 Sep 16:2698811251368371. doi: 10.1177/02698811251368371. Epub ahead of print. PMID: 40958377. https://journals.sagepub.com/doi/10.1177/02698811251368371

Pyridostigmine and low-dose naltrexone for ME/CFS: study protocol for the Life Improvement Trial (LIFT), a randomized, double-blind, placebo-controlled clinical trial

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, chronic disease with no FDA-approved treatments. This report describes a protocol for the Life Improvement Trial (LIFT), a randomized, double-blind, placebo-controlled clinical trial investigating the impact of low-dose naltrexone (LDN) and pyridostigmine (Mestinon) on physiological response, symptoms, and functionality of ME/CFS patients.

Methods: Participants (target n = 160) are recruited through clinics at Massachusetts General Hospital and Brigham and Women’s Hospital, and through Open Medicine Foundation’s StudyME registry. They are then randomized into one of four arms: LDN/pyridostigmine, LDN/placebo, placebo/pyridostigmine, placebo/placebo. Treatment is administered for 13 weeks after an initial screening period of up to 4 weeks. Primary outcomes are FUNCAP-55 score, peak oxygen utilization, heart rate recovery, and oxygen uptake efficiency slope. Secondary outcomes are scores from DSQ-PEM and PROMIS-29 surveys, DANA Brain Vital score, step count, heart rate, and heart rate variability.

Discussion: The results of this trial will provide novel insights into the efficacy of and predictors of response to LDN and pyridostigmine in ME/CFS. This may inform future treatment strategies for ME/CFS. The trial will also validate what primary and secondary outcomes to use in similar clinical trials.

Source: Danielle Meadows, Johanna Squires, Joshua Dibble et al. Pyridostigmine and low-dose naltrexone for ME/CFS: study protocol for the Life Improvement Trial (LIFT), a randomized, double-blind, placebo-controlled clinical trial, 04 March 2025, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-5626167/v1]

Beneficial effects of intermittent intravenous saline infusion in dysautonomic patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: a caseseries

Abstract:

Purpose. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating condition with no single, uniformly effective pharmacologic therapy. Dysautonomic features like orthostatic intolerance and postural tachycardia syndrome are common features in ME/CFS, severely affecting the patient´s quality-of-life. Intermittent saline infusion may reduce symptoms associated with dysautonomia, but this has not been tested scientifically in patients with ME/CFS.

In this case-series, 22 patients with ME/CFS and signs of dysautonomia and/or hypovolemia were treated every third week over 9 weeks with intravenous saline (9 mg/mL NaCl), using standard aseptic technique. Symptoms were monitored throughout the treatment regime, and a follow-up evaluation was conducted.

Results. At treatment start, patients were predominantly female (95%), at mean age 46 ± 10 years, and with a mean body hydration percentage of 48 ± 6. Self-reported health status revealed an overall symptom score of 47 ± 13 on a 0-96 scale, a median POTS score of 64 (IQR 16) on a 0-120 scale, and poor measures of quality-of-life (median 25 IQR 25, on a 0-100 scale) and abilityto-work (median 0, IQR 26, on a 0-100 scale). Following 9 weeks of intermittent saline infusion (mean volume 1600 ± 360 mL), self-reported composite symptom score, quality-of-life and POTS-related symptoms improved significantly (all p<0.001), as did ability-to-work (p<0.05).

Our data derived from a non-controlled case-series indicate health benefits from volume loading with intermittent infusion of saline among patients with ME/CFS, which may stimulate further studies on various forms of intravenous volume loading to patients with ME/CFS and dysautonomia.

Source: Per Sjogren, Helena Huhmar, Bo Christer Bertilson, Björn A Bragée, Olli Polo. Beneficial effects of intermittent intravenous saline infusion in dysautonomic patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: a caseseries. Front. Neurol., Sec. Autonomic Disorders, Volume 16 – 2025 | doi: 10.3389/fneur.2025.1601599 https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2025.1601599/abstract

Response to treatment in the Multiple Symptoms Study 3 trial

Letter:
Chistopher Burton and colleagues conducted an unblinded trial of a consultative intervention for 354 people with persistent physical symptoms but no identifiable “organic” cause. Patient Health Questionnaire-15 (PHQ-15) score, which is a brief, subjective, self-administered screen of severity of somatic complaints, was the primary outcome. This kind of trial design can be expected to produce modest positive outcomes, via expectation bias alone. No real-life, objective assessment of functioning was conducted.
The intervention involved up to four sessions with a general practitioner, offering patients “rational explanations” for their symptoms in the absence of known, falsifiable causes and helping patients to develop strategies for managing symptoms. Although the “rational explanations” are not described, they presumably did not include “organic” diseases or conditions.
Scores on the PHQ-15 range from 0 to 30. Recruited patients had scores from 10 to 20, indicating moderate severity. At the end of the study, the adjusted between-group difference of –1·82 did not reach the minimal clinically important difference of 2·3. The change is well within what would be expected from bias alone. The results therefore confirmed that the intervention was of limited, if any, practical benefit. However, the paper presents the findings as though they had shown the opposite.
Instead of the “rational explanations” promoted by the investigators, more straightforward and honest explanations—for example, we do not know what is causing symptoms—could easily have produced similar results. Patients desire resolution of symptoms and recovery of functions. The trial did not achieve this result. Post-intervention, participants continue to have an impaired quality of life and poor experiences of health care.
DT holds an academic position at the Center for Global Public Health at UC Berkeley, which is largely supported by crowdfunded donations directly to the university, many of them from patients with myalgic encephalomyelitis or chronic fatigue syndrome and related conditions that fall under the heading of persistent physical symptoms. JSC declares no competing interests.
Source: Joan S Crawford and David Tuller. Response to treatment in the Multiple Symptoms Study 3 trial.  The Lancet, Volume 405, Issue 10485, 1145 – 1146  https://link.springer.com/article/10.1007/s00421-025-05759-5 (Full text)

Assessing fatigue in myalgic encephalomyelitis/chronic fatigue syndrome patients before and after treatment with bright light therapy: A prospective randomized controlled crossover study

Abstract:

Objective: The aim of the current study was to test the effectiveness of treatment with bright light therapy (BLT) on fatigue and cognitive function in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A randomized-controlled cross-over study design was chosen in order to provide all patients access to BLT treatment and account for placebo effects.

Methods: In this study, a total of 36 outpatients with a diagnosis of ME/CFS according to the criteria of the Institute of Medicine (2015) were randomly assigned to a cross-over design starting out either with BLT or waitlist for the course of 2 weeks with a washout phase in between. Portable light boxes emitting full-spectrum visible light with a luminance intensity of 10,000 lux were used by the participants at home. Primary outcome of the study was fatigue as assessed by Chalder Fatigue Score (CFQ) and the secondary outcome variable was cognitive function assessed per standardized test battery (Test of Attentional Performance – TAP).

Results: The primary outcome variable fatigue was not significantly improved after treatment with BLT compared to wait list in the full crossover design, although fatigue scores improved immediately after two weeks of BLT. Additionally, patients showed decreased reaction time after treatment with BLT in a subtest of TAP compared to wait list. Over 45 % of patients were diagnosed with postural tachycardia syndrome.

Conclusion: BLT for two weeks is not effective for the treatment of fatigue in ME/CFS, but it might have beneficial effects on attention in patients with ME/CFS. The clinical trial is registered with www.

Clinicaltrials: gov (NCT06635928).

Source: Ludwig B, Hauer L, Böck M, Schillerwein-Kral C, Weyer L, Moser D, Zehetmayer S, Trimmel K, Seidel S. Assessing fatigue in myalgic encephalomyelitis/chronic fatigue syndrome patients before and after treatment with bright light therapy: A prospective randomized controlled crossover study. Sleep Med. 2025 Mar 14;129:369-374. doi: 10.1016/j.sleep.2025.03.003. Epub ahead of print. PMID: 40120538. https://www.sciencedirect.com/science/article/pii/S1389945725001200 (Full text)

Efficacy Of SARS–CoV-2 Specific Antiviral Therapy for Enteroviral Myalgic Encephalomyelitis/ChronicFatigue Syndrome

Abstract:

Background: Etiology remains elusive for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and no treatment exists. Antivirals had no efficacy in randomized clinical trials (RCT) for Epstein-Barr Virus and HHV-6. Enteroviruses (EV) have been implicated, but no antivirals are available. Many patients who received SARS–CoV-2-specific antiviral drugs for acute Covid-19 (COV19) infection experienced significant improvement of prior ME/CFS symptoms. This study summarizes their responses to antivirals for SARS-Cov-2.
Methods: Neutralizing Antibody (NA) for Coxsackievirus B (CVB)1-6 and Echovirus 6, 7, 9, 11, 30 were done by ARUP lab. Enterovirus Protein (EVP) of Peripheral Blood Leukocytes (PBL) was determined by Western Blot. ME/CFS patients fulfilled Canadian consensus criteria, and had either elevated NA for enteroviruses and/or positive EVP in PBL. ME/CFS patients hospitalized for acute COV19 infection and patients without COV19, were given 5-10 days of IV Remdesivir (Rem) +/- immune modulators. Controls: 20 ME/CFS patients seen concurrently without Remdesivir treatment. Other ME/CFS patients (non-COV19) were given Nirmaltrelvir/Ritonavir (PAX) daily for 10 days +/- one repeat. The energy index (EI) was monitored by the patients before, during and after treatment. Significant improvement was defined as > 30%.
Results: 15/20 (75%) ME/CFS patients – 10/12 hospitalized, 5/8 non-COV19 patients – responded to IV Rem 2-6 weeks after infusions; remission lasted 6-8 weeks to 6-9 months before relapse. Of Controls: 2/20 had mild improvement (< 0.001, X 2 ).

104/200 (52%) of PAX-treated ME/CFS patients improved, often within 2-3 days; all relapsed within days to weeks after treatment. 66%, 33% and 44% of CVB4+, CVB3+, non-CVB3,4+ patients responded to treatment, respectively. EVP decreased and increased with clinical response and relapse.

Conclusion: Rem and PAX demonstrated clinical efficacy in ME/CFS patients with chronic enterovirus infections. Placebo-controlled RCT will be needed to clarify the role of antivirals in ME/CFS.
Source: John K Chia, David Wang, P-2363. Efficacy Of SARS–CoV-2 Specific Antiviral Therapy for Enteroviral Myalgic Encephalomyelitis/ChronicFatigue Syndrome, Open Forum Infectious Diseases, Volume 12, Issue Supplement_1, February 2025, ofae631.2514, https://doi.org/10.1093/ofid/ofae631.2514 https://academic.oup.com/ofid/article/12/Supplement_1/ofae631.2514/7988721?login=false 

Qigong and Tai Chi for ME/CFS: A Systematic Review of Randomized Controlled Trials

Abstract:

Objective: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating illness with symptoms such as post-exertional malaise and cognitive dysfunction that can be challenging for patients to manage independently. Randomized controlled trials (RCTs) have examined mind-body and psychological approaches that teach patients coping skills for mitigating ME/CFS symptoms, including emerging literature on Qigong or Tai Chi instruction programs. This systematic review aims to summarize the characteristics of these trials and highlight potential areas for future optimization and refinement.

Methods: Ovid MEDLINE, Embase.com, Web of Science Core Collection, Cochrane CENTRAL, PsycINFO via Ovid, and ClinicalTrials.gov were searched in April 2023 using controlled vocabulary and keywords for the following eligibility criteria: Sample (ME/CFS), Design (RCT), Behavioral Intervention (mind-body or psychological interventions). Data extraction and reporting followed Cochrane and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Results: “Qigong” and “Tai Chi” yielded 142 and 80 abstracts, respectively. Of the 222 abstracts, full texts were available for 5 RCTs of Qigong (k = 5; N = 481). Notably, no trials of Tai Chi utilized a randomized control design. Among the 5 Qigong RCTs, the publication range was from 2012 to 2023. Details regarding intervention components and effects were summarized. Qigong intervention sessions (median = 12, mode = 10, 12) tended to last between 1-2 hours and occur across 5-12 weeks (median = 7, mode = 5). The Qigong interventions were all delivered in groups and incorporated at-home practice. Daily practice was a requirement (k = 4) or an advisement (k = 1). Patient-reported outcomes suggest an emerging evidence base for diffuse benefits on physical and emotional health outcomes.

Conclusions: Qigong interventions are promising, yet relatively understudied, in improving ME/CFS symptom severity and frequency. Future trials must implement standardized eligibility criteria for ME/CFS history, integrate Qigong or Tai Chi with other empirically supported mind-body and psychological practices, and assess long-term resiliency outcomes relevant to ME/CFS survivorship.

Source: Markwart M, Felsenstein D, Mehta DH, Sethi S, Tsuchiyose E, Lydson M, Yeh GY, Hall DL. Qigong and Tai Chi for ME/CFS: A Systematic Review of Randomized Controlled Trials. Glob Adv Integr Med Health. 2024 Nov 7;13:27536130241275607. doi: 10.1177/27536130241275607. PMID: 39524182; PMCID: PMC11544658. https://pmc.ncbi.nlm.nih.gov/articles/PMC11544658/ (Full text)