Category: Clinical Trial

Clinical trial provides preliminary evidence of a cure for myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) and Long Covid

BURLINGAME, Calif., Sept. 2, 2021 /PRNewswire/ — Cortene Inc. announces publication of its InTiME clinical trial in which a short subcutaneous infusion of its experimental drug, CT38, achieved sustained symptom improvement in ME/CFS. The company intends to test CT38 in Long Covid, the post-acute stage of COVID-19 infection, which is considered by many to be the latest trigger for ME/CFS.

Cortene believes the CRFR2 pathway is upregulated and therefore overactive, leading to the wide variety of symptoms in ME/CFS. “The conventional approach would be to block the overactive pathway,” said Sanjay Chanda, PhD, Cortene’s Chief Development Officer. “Instead, our counterintuitive approach seeks to overstimulate CRFR2, causing it to downregulate, without the need for chronic treatment.”

CT38 was subcutaneously infused at one of four infusion rates for a maximum of 10.5 hours, in 14 ME/CFS patients. CT38 treatment was safe and generally well-tolerated. It was associated with significant reduction in mean 28-day, total daily symptom score (TDSS), which aggregated 13 patient-reported, daily symptom scores. At an infusion rate of 0.03 μg/kg/h, mean TDSS improved by 26% (p < 0.01, n = 7).

“Infusing CT38 is known to cause temporary cardiovascular changes and InTiME revealed that patients were significantly more sensitive to these changes than healthy subjects from a previous safety study,” said Hunter Gillies, MD, InTiME’s medical monitor. “These data support there being a pathological hypersensitivity in the CRFR2 pathway. Given that InTiME showed i) dose-dependent improvements in TDSS; and ii) additional infusions provide additional benefit, the next trial should test CT38 using longer or additional infusions. While infusion rates are somewhat limited by tolerability, it is total exposure at low rates that appears to drive symptom improvement.”

“The persistent improvement in symptoms over weeks using a limited exposure is encouraging. Many patients are still showing signs of improvement almost 2 years after treatment,” said Lucinda Bateman, MD, founder and Medical Director of the Bateman Horne Center, scientific advisor to Cortene, and the Principal Investigator of the InTiME study. “In fact, a few patients expressed a desire for ‘just a little bit more drug’.”

Full details of the trial have been peer reviewed and published in Frontiers in Systems Neuroscience, Acute corticotropin-releasing factor receptor type 2 agonism results in sustained symptom improvement in myalgic encephalomyelitis / chronic fatigue syndrome. The publication explains how the CRFR2 pathway controls homeostasis (maintaining biological system stability), how this pathway can become disrupted at the neuronal level leading to the individual symptoms of ME/CFS and how these same symptoms manifest in many other chronic diseases. Cortene plans to conduct additional trials in patients with ME/CFS and other diseases with similar symptoms using well-tolerated infusion rates and greater total exposure.

To view the full publication, please visit https://www.frontiersin.org/articles/10.3389/fnsys.2021.698240/full.

About ME/CFS
ME/CFS is an unexplained, life-long disease, usually triggered by infection, physical/mental trauma, or chemical exposure. Symptoms include diminished physical capacity, pain, sleep issues, cognitive impairment, orthostatic intolerance, among many others, which worsen with innocuous stimulation (referred to as post-exertional malaise) and are not improved by sleep. ME/CFS afflicts 3 million Americans. There are no approved therapeutics and quality of life is worse than in most chronic diseases.

About InTiME
InTiME was a proof-of-concept, single-site, open-label interventional trial, with patients blind as to dose, to investigate the safety and efficacy of CT38 in ME/CFS patients. Efficacy was assessed by a variety of endpoints, including patient-reported daily symptoms scores for each of 13 symptoms, general health (via SF-36), and continuous Fitbit™ monitoring. The primary endpoint was the change in the mean total daily symptom score over the 28-day periods immediately prior to the first treatment (pre-treatment) and immediately prior to exit from the trial (post-treatment).

About CT38
A proprietary peptide agonist, selective/specific for Corticotropin-Releasing Factor Receptor Type 2 (CRFR2).

About Cortene
Cortene Inc. (http://corteneinc.com, @CorteneInc) is a biopharmaceutical startup headquartered in Burlingame, CA, developing therapeutics for treating disorders related to disrupted homeostasis.

Contact: Michael Corbett, CBO, 408-373-7300, mcorbett@corteneinc.com, @CorteneInc on twitter.

Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multi-symptom disease with widespread evidence of disrupted systems. The authors hypothesize that it is caused by the upregulation of the corticotropin-releasing factor receptor type 2 (CRFR2) in the raphé nuclei and limbic system, which impairs the ability to maintain homeostasis. The authors propose utilizing agonist-mediated receptor endocytosis to downregulate CRFR2.

Materials and Methods: This open-label trial tested the safety, tolerability and efficacy of an acute dose of CT38s (a short-lived, CRFR2-selective agonist, with no known off-target activity) in 14 ME/CFS patients. CT38s was subcutaneously-infused at one of four dose-levels (i.e., infusion rates of 0.01, 0.03, 0.06, and 0.20 μg/kg/h), for a maximum of 10.5 h. Effect was measured as the pre-/post-treatment change in the mean 28-day total daily symptom score (TDSS), which aggregated 13 individual patient-reported symptoms.

Results: ME/CFS patients were significantly more sensitive to the transient hemodynamic effects of CRFR2 stimulation than healthy subjects in a prior trial, supporting the hypothesized CRFR2 upregulation. Adverse events were generally mild, resolved without intervention, and difficult to distinguish from ME/CFS symptoms, supporting a CRFR2 role in the disease. The acute dose of CT38s was associated with an improvement in mean TDSS that was sustained (over at least 28 days post-treatment) and correlated with both total exposure and pre-treatment symptom severity. At an infusion rate of 0.03 μg/kg/h, mean TDSS improved by −7.5 ± 1.9 (or −25.7%, p = 0.009), with all monitored symptoms improving.

Conclusion: The trial supports the hypothesis that CRFR2 is upregulated in ME/CFS, and that acute CRFR2 agonism may be a viable treatment approach warranting further study.

Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03613129.

Source: Gerard Pereira, Hunter Gillies, Sanjay Chanda, Michael Corbett, Suzanne D. Vernon, Tina Milani and Lucinda Bateman. Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front. Syst. Neurosci., 01 September 2021. https://doi.org/10.3389/fnsys.2021.69824 https://www.frontiersin.org/articles/10.3389/fnsys.2021.698240/full (Full text)

A randomized phase II remote study to assess Bacopa for Gulf War Illness associated cognitive dysfunction: Design and methods of a national study

Abstract:

Aims: Gulf War Illness (GWI) is a chronic, debilitating, multi-symptom condition affecting as many as one-third of the nearly 700,000 U.S. troops deployed to the Middle East during the 1990-1991 Gulf War (GW). The treatment of GWI relies on symptom management. A common challenge in studying the efficacy of interventions for symptom management is participant recruitment related to factors such as the burden of travelling to study sites and the widespread dispersion of Veterans with GWI. The goal of this study is to assess the efficacy of a novel low-risk therapeutic agent, Bacopa monnieri, for cognitive function in Veterans with GWI and to evaluate the utility of a remote patient-centric study design developed to promote recruitment and minimize participant burden.

Main methods: To promote effective participant recruitment, we developed a remote patient-centric study design. Participants will be recruited online through social media and through a web-based research volunteer list of GW Veterans. An online assessment platform will be used, and laboratory blood draws will be performed at clinical laboratory sites that are local to participants. Furthermore, the assigned intervention will be mailed to each participant.

Significance: These study design adaptations will open participation to Veterans nearly nationwide and reduce administrative costs while maintaining methodologic rigor and participant safety in a randomized, placebo-controlled phase II clinical trial.

Source: Cheema AK, Wiener LE, McNeil RB, Abreu MM, Craddock T, Fletcher MA, Helmer DA, Ashford JW, Sullivan K, Klimas NG. A randomized phase II remote study to assess Bacopa for Gulf War Illness associated cognitive dysfunction: Design and methods of a national study. Life Sci. 2021 Oct 1;282:119819. doi: 10.1016/j.lfs.2021.119819. Epub 2021 Jul 10. PMID: 34256038. https://pubmed.ncbi.nlm.nih.gov/34256038/

Kynurenine Clinical Trial for ME / CFS

Open Medicine Foundation is excited to announce its support of an initiation of a clinical trial to understand potential disturbances in the tryptophan metabolism and to test the benefits of treating people with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME / CFS) with Kynurenine. Kynurenine is naturally produced in the body, is a key metabolite in the tryptophan metabolism, and serves several roles in the immune system and inflammation. The Kynurenine clinical trial will be conducted at the ME / CFS Collaborative Research Center at Uppsala University under the supervision of Dr. Jonas Bergquist. OMF has provided support to initiate the study in a randomized, double-blind, placebo-controlled, crossover study. The purpose of the study is to evaluate whether kynurenine is directly connected to ME / CFS patient symptom severity.

Read more HERE.

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/