Category: Clinical Trial

Levocetirizine and montelukast in the COVID-19 treatment paradigm

Abstract:

Levocetirizine, a third-generation antihistamine, and montelukast, a leukotriene receptor antagonist, exhibit remarkable synergistic anti-inflammatory activity across a spectrum of signaling proteins, cell adhesion molecules, and leukocytes. By targeting cellular protein activity, they are uniquely positioned to treat the symptoms of COVID-19. Clinical data to date with an associated six-month follow-up, suggests the combination therapy may prevent the progression of the disease from mild to moderate to severe, as well as prevent/treat many of the aspects of ‘Long COVID,’ thereby cost effectively reducing both morbidity and mortality. To investigate patient outcomes, 53 consecutive COVID-19 test (+) cases (ages 3-90) from a well-established, single-center practice in Boston, Massachusetts, between March – November 2020, were treated with levocetirizine and montelukast in addition to then existing protocols [2]. The data set was retrospectively reviewed.

Thirty-four cases were considered mild (64%), 17 moderate (32%), and 2 (4%) severe. Several patients presented with significant comorbidities (obesity: n = 22, 41%; diabetes: n = 10, 19%; hypertension: n = 24, 45%). Among the cohort there were no exclusions, no intubations, and no deaths. The pilot study in Massachusetts encompassed the first COVID-19 wave which peaked on April 23, 2020 as well as the ascending portion of the second wave in the fall. During this period the average weekly COVID-19 case mortality rate (confirmed deaths/confirmed cases) varied considerably between 1 and 7.5% [37]. FDA has approved a multicenter, randomized, placebo-controlled, Phase 2 clinical trial design, replete with electronic diaries and laboratory metrics to explore scientific questions not addressed herein.

Source: May BC, Gallivan KH. Levocetirizine and montelukast in the COVID-19 treatment paradigm. Int Immunopharmacol. 2021 Dec 15;103:108412. doi: 10.1016/j.intimp.2021.108412. Epub ahead of print. PMID: 34942461; PMCID: PMC8673734. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8673734/ (Full text)

Intravenous immunoglobulin as an important adjunct in the prevention and therapy of coronavirus 2019 disease

Abstract:

The coronavirus disease-19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenged globally with its morbidity and mortality. A small percentage of affected patients (20%) progress into the second stage of the disease clinically presenting with severe or fatal involvement of lung, heart and vascular system, all contributing to multiple-organ failure. The so-called ‘cytokines storm’ is considered the pathogenic basis of severe disease and it is a target for treatment with corticosteroids, immunotherapies and intravenous immunoglobulin (IVIg).

We provide an overview of the role of IVIg in the therapy of adult patients with COVID-19 disease. After discussing the possible underlying mechanisms of IVIg immunomodulation in COVID-19 disease, we review the studies in which IVIg was employed. Considering the latest evidence that show a link between new coronavirus and autoimmunity, we also discuss the use of IVIg in COVID-19 and anti-SARS-CoV-2 vaccination related autoimmune diseases and the post-COVID-19 syndrome.

The benefit of high-dose IVIg is evident in almost all studies with a rapid response, a reduction in mortality and improved pulmonary function in critically ill COVID-19 patients. It seems that an early administration of IVIg is crucial for a successful outcome. Studies’ limitations are represented by the small number of patients, the lack of control groups in some and the heterogeneity of included patients. IVIg treatment can reduce the stay in ICU and the demand for mechanical ventilation, thus contributing to attenuate the burden of the disease.

Source: Danieli MG, Piga MA, Paladini A, Longhi E, Mezzanotte C, Moroncini G, Shoenfeld Y. Intravenous immunoglobulin as an important adjunct in the prevention and therapy of coronavirus 2019 disease. Scand J Immunol. 2021 Nov;94(5):e13101. doi: 10.1111/sji.13101. Epub 2021 Sep 16. PMID: 34940980; PMCID: PMC8646640. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8646640/ (Full text)

An Open-Label, Pilot Trial of HRG80™ Red Ginseng in Chronic Fatigue Syndrome, Fibromyalgia, and Post-Viral Fatigue

Abstract:

Chronic fatigue syndrome and fibromyalgia (CFS/FMS) affect 2.1% of the world’s population and ~10–25% of people who have had COVID-19. Previous clinical data suggested that a unique Panax ginseng (C.A. Meyer, family Araliaceae) root extract (HRG80™ Red Ginseng) often resulted in marked improvement. We aimed to study this hydroponic form of red ginseng root, containing high levels of rare ginsenosides, for improving energy, cognition, and stamina. This open-label prospective study included participants with severe CFS/FMS who took a daily supplement of HRG80 capsules (200–400 mg) or tablets (100–200 mg) for one month.
A total of 188 subject patients completed the one-month treatment trial. Of these, 60.1% rated themselves as improved, with 13.3% rating themselves as being much better. In this group, the mean composite score improved from 11.9 to 18.8 (p < 0.001), with a 67% average increase in energy, 44% average increase in overall well-being, 48% average improvement in mental clarity, 58% average composite improvement in the previous three measurements (primary outcome measure), 46% average improvement in sleep, 33% average decrease in pain, and 72% average increase in stamina. Our study showed that HRG80 red ginseng root powder resulted in a marked improvement in people with CFS and fibromyalgia. This included the subgroup with post-viral CFS/FMS.
Source: Teitelbaum J, Goudie S. An Open-Label, Pilot Trial of HRG80™ Red Ginseng in Chronic Fatigue Syndrome, Fibromyalgia, and Post-Viral Fatigue. Pharmaceuticals. 2022; 15(1):43. https://doi.org/10.3390/ph15010043 (Full text)

Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Greatly Improved Fatigue Symptoms When Treated with Oxygen-Ozone Autohemotherapy

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic syndrome characterized by fatigue as its major and most outstanding symptom. Previous evidence has supported the ability of ozone to relief ME/CFS related fatigue in affected patients.
Methods: A number of 200 ME/CFS previously diagnosed patients, (mean age 33 ± 13 SD years) were consecutively treated with oxygen-ozone autohemotherapy (O2-O3-AHT). Fatigue was evaluated via an FSS 7-scoring questionnaire before and following 30 days after treatment.
Results: Almost half (43.5%) of the treated patients evolved their FSS scale from the worst (7) to the best (1) score, assessing the highest improvement from being treated with O2-O3-AHT. Furthermore 77.5% of patients experienced significant ameliorations of fatigue, of 4–6 delta score. No patient showed side effects, yet experienced long lasting fatigue disappearance, by three months follow up.
Conclusions: Treatment with O2-O3-AHT greatly improves ME/CFS related fatigue, aside from sex and age distribution.
Source: Tirelli U, Franzini M, Valdenassi L, Pandolfi S, Berretta M, Ricevuti G, Chirumbolo S. Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Greatly Improved Fatigue Symptoms When Treated with Oxygen-Ozone Autohemotherapy. Journal of Clinical Medicine. 2022; 11(1):29. https://doi.org/10.3390/jcm11010029  https://www.mdpi.com/2077-0383/11/1/29/htm (Full text)

Compression Stockings Improve Cardiac Output and Cerebral Blood Flow during Tilt Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Patients: A Randomized Crossover Trial

Abstract:

Background and Objectives: Orthostatic intolerance (OI) is a clinical condition in which symptoms worsen upon assuming and maintaining upright posture and are ameliorated by recumbency. OI has a high prevalence in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Limited data are available to guide the treatment of OI in ME/CFS patients. We and others have previously described patient-reported subjective improvement in symptoms using compression stockings. We hypothesized that these subjective reports would be accompanied by objective hemodynamic improvements.
Materials and Methods: We performed a randomized crossover trial in 16 ME/CFS patients. Each underwent two 15-min head-up tilt table tests, one with and one without wearing knee-high compression stockings that provided 20–25 mm Hg compression. The order of the tests was randomized. We measured heart rate and blood pressure as well as cardiac output and cerebral blood flow (CBF) using extracranial Doppler of the internal carotid and vertebral arteries.
Results: There were no differences in supine measurements between the 2 baseline measurements. There were no differences in heart rate and blood pressure at either end-tilt testing period. Compared to the test with the stockings off, the mean percentage reduction in cardiac output during the test with compression stockings on was lower, 15 (4)% versus 27 (6)% (p < 0.0001), as was the mean percentage CBF reduction, 14 (4)% versus 25 (5)% (p < 0.0001).
Conclusion: In ME/CFS patients with orthostatic intolerance symptoms, cardiac output and CBF are significantly reduced during a tilt test. These abnormalities were present without demonstrable heart rate and blood pressure changes and were ameliorated by the use of compression stockings.
Source: van Campen CMC, Rowe PC, Visser FC. Compression Stockings Improve Cardiac Output and Cerebral Blood Flow during Tilt Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Patients: A Randomized Crossover Trial. Medicina. 2022; 58(1):51. https://doi.org/10.3390/medicina58010051 https://www.mdpi.com/1648-9144/58/1/51/htm  (Full text)

A Botanical Product Containing Cistanche and Ginkgo Extracts Potentially Improves Chronic Fatigue Syndrome Symptoms in Adults: A Randomized, Double-Blind, and Placebo-Controlled Study

Abstract:

Dietary therapy may be beneficial in alleviating symptoms of chronic fatigue syndrome (CFS), a disorder that is characterized by extreme fatigue and other symptoms, but the cause of which remains unclear. The aim of this study was to evaluate the protective effect of a botanical product containing cistanche (Cistanche tubulosa [Schenk] Wight) and ginkgo (Ginkgo biloba L.) extracts on adults with CFS in a randomized, double-blind, placebo-controlled clinical trial.

A total of 190 subjects (35-60 years old, non-obese) with CFS were randomized to receive one tablet of a low dose (120-mg ginkgo and 300-mg cistanche), a high dose (180-mg ginkgo and 450-mg cistanche) or a placebo once daily for 60 days. Blood samples and responses on the Chalder fatigue scale (CFQ 11), the World Health Organization’s quality of life questionnaire (WHOQOL), and the sexual life quality questionnaire (SLQQ) were collected at baseline and post-intervention.

CFS symptoms of impaired memory or concentration, physical fatigue, unrefreshing sleep, and post-exertional malaise were significantly improved (p < 0.001) in both of the treatment groups. The botanical intervention significantly decreased physical and mental fatigue scores of CFQ 11 and improved WHOQOL and SLQQ scores of the subjects (p < 0.01). Levels of blood ammonia and lactic acid in the treatment groups were significantly lower than those of the placebo group (low-dose: p < 0.05; high-dose: p < 0.01). In addition, the change in lactic acid concentration was negatively associated with the severity of CFS symptoms (p = 0.0108) and was correlated with the change in total physical fatigue score of the CFQ (p = 0.0302). Considering the trivial effect size, the results may lack clinical significance.

In conclusion, this botanical product showed promising effects in ameliorating the symptoms of CFS. Clinical trials with improved assessment tools, an expanded sample size, and an extended follow-up period are warranted to further validate the findings.

Clinical Trial Registration: https://clinicaltrials.gov/, identifier: NCT02807649.

Source: Kan J, Cheng J, Hu C, Chen L, Liu S, Venzon D, Murray M, Li S, Du J. A Botanical Product Containing Cistanche and Ginkgo Extracts Potentially Improves Chronic Fatigue Syndrome Symptoms in Adults: A Randomized, Double-Blind, and Placebo-Controlled Study. Front Nutr. 2021 Nov 26;8:658630. doi: 10.3389/fnut.2021.658630. PMID: 34901100; PMCID: PMC8662561.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8662561/ (Full study)

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.