Category: Clinical Trial

Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and optimizing 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 nerve endings in the nasal cavity, likely from the trigeminal nerve, possibly activating additional centers in the brainstem of ME-patients and correlating with a ∼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 signs of chronic immune activation in ME, as well as immunological correlates of improvement that center around 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 believe that these results are suggestive of ME as a condition explained by a maladaptive disease tolerance response following infection.

Source: Lucie Rodriguez, Christian Pou, Tadepally Lakshmikanth, 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 optimizing disease tolerance, Oxford Open Immunology, 2023;, iqad003, https://doi.org/10.1093/oxfimm/iqad003 (Full text available as PDF file)

Life changing response to successive surgical interventions on cranial venous outflow: A case report on chronic fatigue syndrome

Abstract:

Recognition of similarities between chronic fatigue syndrome and idiopathic intracranial hypertension (IIH) has raised suggestions that they might be connected, with chronic fatigue syndrome representing a mild version of IIH, sharing many of its symptoms, but without the signature features of elevated intracranial pressure that characterize the complete syndrome.

A further development of this idea factors in the effects of a cerebrospinal fluid leak, a known complication of IIH, to explain cases where symptoms seem out of proportion to the apparent physiological disturbance. Cranial venous outflow obstruction has been proposed as the pathological substrate.

We describe a patient with multiple symptoms, including headache and disabling fatigue, in which this model guided investigation and treatment. Specifically, CT and catheter venography identified focal narrowings of both jugular and the left brachiocephalic veins.

Treatment of brachiocephalic obstruction was not feasible. However, in separate surgical procedures, relief of jugular venous obstruction produced incremental and significant clinical improvements which have proven durable over the length of follow-up.

We suggest that investigating chronic fatigue syndrome under this model might not only bring benefit to individual patients but also will provide new insights into IIH and its relationship with spontaneous intracranial hypotension.

Source: Higgins JNP, Axon PR, Lever AML. Life changing response to successive surgical interventions on cranial venous outflow: A case report on chronic fatigue syndrome. Front Neurol. 2023 Mar 30;14:1127702. doi: 10.3389/fneur.2023.1127702. PMID: 37064208; PMCID: PMC10097901. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10097901/ (Full text)

Therapeutical interventions for myalgic encephalomyelitis/chronic fatigue syndrome; A review of phase IV Clinical trials

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling and complex illness with multifactorial etiology. Current clinical trials were examined to understand the characteristics of ME/CFS as well as possible therapeutical interventions.

Aim: To identify features of clinical trials related to ME/CFS registered at ClinicalTrials.gov, specifically, the therapeutical interventions used to manage the syndrome in phase IV.

Method: Analysis of all clinical trials registered at ClinicalTrials.gov for ME/CFS. Those clinical trials that employed a targeted therapy were included. The analysis identified a selection of clinical trials examining a targeted therapy for ME/CFS, providing a platform for further exploration of potential treatments.

Results: By November 19th, 2022, 151 clinical trials related to ME/CFS had been found. Interventional studies were the most prevalent type. However, the trials were restricted to specific continents and were not extensively conducted in pediatric patients. Micronutrients were the most commonly used intervention. Phase IV studies had fewer clinical trials with limited interventional measures. Only three out of nine studies completed pharmacological interventional studies, and of these, sodium oxybate was being used most frequently.

Conclusion: Among the clinical trials identified through this paper, there were few related to ME/CFS treatment. The interventions in the completed phase IV studies involved drugs that mainly interacted with the CNS, and more rarely that had an effect on blood vessels and blood perfusion. The limited number of phase IV clinical trials meant that the results were inconclusive.

Source: Alorfi, N. (2023). Therapeutical interventions for myalgic encephalomyelitis/chronic fatigue syndrome; A review of phase IV Clinical trials. Bulletin of Pharmaceutical Sciences. Assiut, (), -. doi: 10.21608/bfsa.2023.199974.1690 https://bpsa.journals.ekb.eg/article_294098.html

STIMULATE-ICP: A pragmatic, multi-centre, cluster randomised trial of an integrated care pathway with a nested, Phase III, open label, adaptive platform randomised drug trial in individuals with Long COVID: A structured protocol

Abstract:

Introduction: Long COVID (LC), the persistent symptoms ≥12 weeks following acute COVID-19, presents major threats to individual and public health across countries, affecting over 1.5 million people in the UK alone. Evidence-based interventions are urgently required and an integrated care pathway approach in pragmatic trials, which include investigations, treatments and rehabilitation for LC, could provide scalable and generalisable solutions at pace.

Methods and analysis: This is a pragmatic, multi-centre, cluster-randomised clinical trial of two components of an integrated care pathway (Coverscan™, a multi-organ MRI, and Living with COVID Recovery™, a digitally enabled rehabilitation platform) with a nested, Phase III, open label, platform randomised drug trial in individuals with LC. Cluster randomisation is at level of primary care networks so that integrated care pathway interventions are delivered as “standard of care” in that area. The drug trial randomisation is at individual level and initial arms are rivaroxaban, colchicine, famotidine/loratadine, compared with no drugs, with potential to add in further drug arms. The trial is being carried out in 6-10 LC clinics in the UK and is evaluating the effectiveness of a pathway of care for adults with LC in reducing fatigue and other physical, psychological and functional outcomes at 3 months. The trial also includes an economic evaluation which will be described separately.

Ethics and dissemination: The protocol was reviewed by South Central-Berkshire Research Ethics Committee (reference: 21/SC/0416). All participating sites obtained local approvals prior to recruitment. Coverscan™ has UK certification (UKCA 752965). All participants will provide written consent to take part in the trial. The first participant was recruited in July 2022 and interim/final results will be disseminated in 2023, in a plan co-developed with public and patient representatives. The results will be presented at national and international conferences, published in peer reviewed medical journals, and shared via media (mainstream and social) and patient support organisations.

Trial registration number: ISRCTN10665760.

Source: Forshaw D, Wall EC, Prescott G, Dehbi HM, Green A, Attree E, Hismeh L, Strain WD, Crooks MG, Watkins C, Robson C, Banerjee R, Lorgelly P, Heightman M, Banerjee A; STIMULATE-ICP trial team. STIMULATE-ICP: A pragmatic, multi-centre, cluster randomised trial of an integrated care pathway with a nested, Phase III, open label, adaptive platform randomised drug trial in individuals with Long COVID: A structured protocol. PLoS One. 2023 Feb 15;18(2):e0272472. doi: 10.1371/journal.pone.0272472. PMID: 36791116; PMCID: PMC9931100. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9931100/ (Full text)

Characteristics associated with physical functioning and fatigue in patients with chronic fatigue syndrome (CFS): secondary analyses of a randomized controlled trial

Abstract

Objective: This study aimed to explore associations at the group level between patient characteristics at baseline and the outcomes of physical functioning and fatigue in patients with chronic fatigue syndrome (CFS) participating in a randomized controlled trial on cognitive behavioural therapy (CBT).

Methods/design: Consecutively, 236 adult participants fulfilling the Centres for Disease Control and Prevention (CDC) 1994 criteria for CFS were randomly allocated to either 16 weeks of standard CBT, 8 weeks of Interpersonal CBT or a treatment as usual control group. In secondary analyses we investigated how gender, age, pain, anxiety, depression, memory and VO2max at baseline were associated with physical function and fatigue before and after treatment, controlling for the CBT-interventions and the baseline levels of the outcome measures.

For the two groups receiving CBT, a 1-year follow-up analysis was also done. Bivariate and multivariable linear regression was used to explore the targeted associations.

Results: At baseline, less pain (p < .001) and higher VO2max (p = 0.014) were associated with better physical function, while better memory (p = 0.001) and fewer depressive symptoms (p = 0.017) were associated with less fatigue. Better memory and physical function at baseline (p = 0.015 and p < .001, respectively) and male gender (p = 0.003) were associated with higher physical function post-intervention.

Male gender (p = 0.010) was associated with higher physical function at 1-year follow-up. Fatigue severity at baseline was the only variable associated with follow up scores for fatigue (p < .001).

Conclusion: Our findings show that fatigue and physical function were associated with different types of characteristics at baseline, indicating a heterogeneity among CFS patients.

Source: Merethe Eide Gotaas, Tormod Landmark, Anne S. Helvik & Egil A. Fors (2023) Characteristics associated with physical functioning and fatigue in patients with chronic fatigue syndrome (CFS): secondary analyses of a randomized controlled trial, Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2023.2175521 https://www.tandfonline.com/doi/full/10.1080/21641846.2023.2175521 (Full text)

Endothelial dysfunction in ME/CFS patients

Abstract:

Objective: A few earlier studies have found impaired endothelial function in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The present study investigated large-vessel and small-vessel endothelial function in patients with ME/CFS.

Study design: The study was a substudy of the RituxME trial, a national, multicenter, randomized, double-blind, placebo-controlled phase III study on the effect of rituximab vs. placebo in ME/CFS patients in Norway. Flow-mediated dilation (FMD) and post-occlusive reactive hyperemia (PORH) was measured at baseline and after 18 months of treatment in 39 patients and compared with healthy controls. Other outcome measures were symptom severity and various physical function measures.

Results: ME/CFS patients had markedly reduced FMD compared to healthy controls at baseline (5.1% vs. 8.2%, p< 0.0001, adjusted for arterial diameter and sex), and significantly lower microvascular regulation measured by PORH than healthy controls (1354 PU vs. 2208 PU, p = 0.002). There were no differences between the treatment and placebo groups in symptom changes or vascular measures. As a group, the ME/CSF patients experienced a slight, but significant improvement in clinical symptoms after 18 months. PORH, but not FMD, was similarly improved (1360 to 1834 PU, p = 0.028). There was no significant correlation between FMD and PORH. There were non-significant tendencies towards associations between symptom severity/physical function measures and lower FMD and PORH, and a significant correlation between PORH and steps per 24 hours at baseline.

Conclusions: ME/CFS patients had reduced macro- and microvascular endothelial function, indicating that vascular homeostasis may play a role in the clinical presentation of this disease.

Source: Sandvik MK, Sørland K, Leirgul E, Rekeland IG, Stavland CS, Mella O, Fluge Ø. Endothelial dysfunction in ME/CFS patients. PLoS One. 2023 Feb 2;18(2):e0280942. doi: 10.1371/journal.pone.0280942. PMID: 36730360; PMCID: PMC9894436. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894436/ (Full text)

A Systematic Review of Trials Currently Investigating Therapeutic Modalities for Post-Acute COVID-19 Syndrome and Registered on World Health Organization International Clinical Trials Platform

Abstract:

Background: Post-acute coronavirus 2019 (COVID-19) syndrome (PACS) is a well-recognized complex systemic disease that is associated with substantial morbidity. There is a paucity of established interventions to treat patients with this syndrome.

Objectives: To systematically review registered trials currently investigating therapeutic modalities for PACS.

Data sources: Search was conducted up to the 16th of September 2022 using the COVID-19 section of the World Health Organization (WHO) Internal Clinical Trials Registry Platform.

Study eligibility criteria, participants, and interventions: Interventional clinical trials of any sample size examining any therapeutic modality targeting persistent symptoms among individuals after diagnosis with COVID-19.

Methods: Data on trial characteristics and intervention characteristics were collected and summarized.

Results: After screening 17125 trials, 388 trials from 42 countries were eligible. 331 trials tested mono-therapeutic strategies, while 39 trials included a combination of interventions. Among the 824 primary outcomes identified, there were more than 300 different outcomes. Rehabilitation was the most employed class of intervention with 169 trials. We encountered 76 trials examining pharmacological agents of various classes with the most common agent being colchicine. Complementary and alternative medicine encompassed 64 trials exploring Traditional Chinese Medicine, Ayurveda, homeopathic medications, naturopathic medications, vitamins, dietary supplements, and botanicals. Psychotherapeutic and educational interventions were also employed with 12 and 4 trials, respectively. Other interventions including transcranial current direct stimulation, transcutaneous auricular vagus nerve stimulation, general electrical stimulation, cranial electrotherapy stimulation, various stem cell interventions, and oxygen therapy interventions were also employed.

Conclusion: We identified 388 registered trials with a high degree of heterogeneity exploring 144 unique interventions for PACS. Most target general alleviation of symptoms. There is a need for further high-quality and methodologically robust PACS treatment trials conducted with standardization of outcomes while following WHO’s recommendation for uniform evaluation and treatment.

Source: Fawzy NA, Shaar BA, Taha R, Arabi TZ, Sabbah BN, Alkodaymi MS, Omrani OA, Makhzoum T, Almahfoudh NE, Al-Hammad QA, Hejazi W, Obeidat Y, Osman N, Al-Kattan KM, Berbari EF, Tleyjeh IM. A Systematic Review of Trials Currently Investigating Therapeutic Modalities for Post-Acute COVID-19 Syndrome and Registered on World Health Organization International Clinical Trials Platform. Clin Microbiol Infect. 2023 Jan 12:S1198-743X(23)00009-5. doi: 10.1016/j.cmi.2023.01.007. Epub ahead of print. PMID: 36642173; PMCID: PMC9837206. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9837206/ (Full text)

Clinical effects of wasabi extract containing 6-MSITC on myalgic encephalomyelitis/chronic fatigue syndrome: an open-label trial

Abstract:

Background: Wasabi (Eutrema japonicum) is a common pungent spice used in Japan. 6-Methylsulfinylhexyl isothiocyanate (6-MSITC) found in the rhizome of wasabi has been shown to have anti-inflammatory and antioxidant effects, as well as improve neuroinflammation and memory. Therefore, we hypothesized that these effects would be beneficial for treating myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The present study was conducted to investigate the effectiveness of wasabi extract containing 6-MSITC on ME/CFS in an open-label trial.

Methods: Fifteen patients (3 males, 12 females, 20-58 years old) were orally administered wasabi extract (9.6 mg of 6-MSITC/day) for 12 weeks. The following parameters and test results were compared pre- and post-treatment: performance status (PS), self-rating questionnaires, pressure pain threshold (PPT) on the occiput, Trail Making test-A (TMT-A), and hemodynamic patterns determined by an active standing test.

Results: After treatment with 6-MSITC, PS improved significantly (p = 0.001). Although the scores on the 11-item Chalder Fatigue scale (CFS-11) and numerical rating scale (NRS) of fatigue did not show significant changes, subjective symptoms improved significantly, including headache frequency (4.1 to 3.0 times/week, p = 0.001) and myalgia (4.1 to 2.4 times/week, p = 0.019), NRS brain fog scores (5.7 to 4.5, p = 0.011), difficulty finding appropriate words (4.8 to 3.7, p = 0.015), photophobia (4.8 to 3.5, p = 0.008), and the Profile of Mood Status vigor score (46.9 to 50.0, p = 0.045). The PPT of the right occiput (17.3 to 21.3 kPa, p = 0.01) and TMT-A scores (53.0 to 38.1 s, p = 0.007) also changed, suggesting reduced pain sensitivity, and improved cognitive function, respectively. Orthostatic patterns determined by a standing test did not show remarkable changes. There were no serious adverse reactions.

Conclusion: This study suggests that 6-MSITC improves PS as well as subjective symptoms such as pain and cognitive dysfunction, and psychological vitality of patients with ME/CFS. It also improved cognitive performance and increased pain thresholds in these patients. 6-MSITC may be a promising therapeutic option especially for improving cognitive dysfunction associated with ME/CFS.

Source: Oka T, Yamada Y, Lkhagvasuren B, Nakao M, Nakajima R, Kanou M, Hiramatsu R, Nabeshima YI. Clinical effects of wasabi extract containing 6-MSITC on myalgic encephalomyelitis/chronic fatigue syndrome: an open-label trial. Biopsychosoc Med. 2022 Dec 12;16(1):26. doi: 10.1186/s13030-022-00255-0. PMID: 36510244. https://bpsmedicine.biomedcentral.com/articles/10.1186/s13030-022-00255-0 (Full text)

Coenzyme Q10 + alpha lipoic acid for chronic COVID syndrome

Abstract:

Chronic COVID syndrome is characterized by chronic fatigue, myalgia, depression and sleep disturbances, similar to chronic fatigue syndrome (CFS) and fibromyalgia syndrome. Implementations of mitochondrial nutrients (MNs) with diet are important for the clinical effects antioxidant. We examined if use of an association of coenzyme Q10 and alpha lipoic acid (Requpero®) could reduce chronic covid symptoms.

The Requpero study is a prospective observational study in which 174 patients, who had developed chronic-covid syndrome, were divided in two groups: The first one (116 patients) received coenzyme Q10 + alpha lipoic acid, and the second one (58 patients) did not receive any treatment. Primary outcome was reduction in Fatigue Severity Scale (FSS) in treatment group compared with control group. complete FSS response was reached most frequently in treatment group than in control group. A FSS complete response was reached in 62 (53.5%) patients in treatment group and in two (3.5%) patients in control group. A reduction in FSS core < 20% from baseline at T1 (non-response) was observed in 11 patients in the treatment group (9.5%) and in 15 patients in the control group (25.9%) (p < 0.0001).

To date, this is the first study that tests the efficacy of coenzyme Q10 and alpha lipoic acid in chronic Covid syndrome. Primary and secondary outcomes were met. These results have to be confirmed through a double blind placebo controlled trial of longer duration.

Source: Barletta MA, Marino G, Spagnolo B, Bianchi FP, Falappone PCF, Spagnolo L, Gatti P. Coenzyme Q10 + alpha lipoic acid for chronic COVID syndrome. Clin Exp Med. 2022 Aug 22. doi: 10.1007/s10238-022-00871-8. Epub ahead of print. PMID: 35994177.  https://link.springer.com/article/10.1007/s10238-022-00871-8 (Full text)

The Qigong of Prolong Life With Nine Turn Method Relieve Fatigue, Sleep, Anxiety and Depression in Patients With Chronic Fatigue Syndrome: A Randomized Controlled Clinical Study

Abstract

Background: Chronic fatigue syndrome (CFS) is a complex disease of unknown etiology and mechanism. The purpose of this study was to investigate the effect of Prolong Life with Nine Turn Method (PLWNT) Qigong exercise on CFS focusing on fatigue, sleep quality, depression, and anxiety.

Methods: A total of 90 participants diagnosed with CFS were randomly assigned into two parallel groups: PLWNT and cognitive behavioral therapy (CBT). The participants in the PLWNT or CBT group participated in qigong exercise or cognitive behavior education program, respectively, once a week in-person and were supervised online during the remaining 6 days at home, over 12 consecutive weeks. The primary outcome was fatigue (Multi-dimensional Fatigue Inventory 20 [MFI-20]), and secondary outcomes were sleep quality (Pittsburgh Sleep Quality Index [PSQI]), anxiety, depression (Hospital Anxiety and Depression Scale [HADS]), and changes in the Neuropeptide Y (NPY) of peripheral blood.

Results: The within-group comparisons of the PLWNT and CBT groups revealed significant improvement in both groups in MFI-20, PSQI, and HADS scores (P < 0.05). No significant difference were found between the PLWNT and CBT groups, even though the effective rate of the PLWNT group was 62.22%, which is slightly than 50.00% of the CBT group. The fatigue scores in the PLWNT group were positively correlated with sleep degree (r = 0.315) and anxiety degree (r = 0.333), only anxiety degree (r = 0.332) was found to be positively correlated with fatigue in the CBT group. The analysis of peripheral blood showed that NPY decreased after PLWNT intervention but increased significantly in the CBT.

Conclusion: The PLWNT qigong exercise has potential to be an effective rehabilitation method for CFS symptoms including fatigue, sleep disturbance, anxiety, and depression. Future studies should expand study sample size for in-depth investigation to determine the optimal frequency and intensity of PLWNT qigong intervention in CFS patients. The study was registered in the ClinicalTrials.gov database on April 12, 2018, with registration number NCT03496961.

Source: Xie F, You Y, Guan C, Xu J, Yao F. The Qigong of Prolong Life With Nine Turn Method Relieve Fatigue, Sleep, Anxiety and Depression in Patients With Chronic Fatigue Syndrome: A Randomized Controlled Clinical Study. Front Med (Lausanne). 2022 Jun 30;9:828414. doi: 10.3389/fmed.2022.828414. PMID: 35847786; PMCID: PMC9280429. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9280429/ (Full text)