The researchers also found that treatment with the metabolic activators improved liver health and decreased the levels of inflammation, as shown by inflammatory markers.
Conducted by researchers at Science for Life Laboratory at KTH Royal Institute of Technology in Stockholm, in collaboration with the Sahlgrenska Academy in Gothenburg and King’s College, London, the human phase-three clinical study showed that patients with mild-to-moderate COVID-19 who were also receiving standard care experienced a 3.5 day reduction in recovery time when receiving the combination of metabolic activators:
- nicotinamide riboside (NR),
- N-acetyl-L-cysteine (NAC),
- L-carnitine tartrate.
All four activators are aimed at improving mitochondrial function. The results of the study build on findings from phase two clinical data.
Through a randomized, placebo-controlled, double-blind, phase three clinical trial, 309 outpatients at Umraniye Teaching and Research Hospital, University of Health Sciences, Istanbul, Turkey were randomly assigned on a 3:1 basis to receive the metabolic activators or placebo. Patients received the combined activators or placebo twice a day for 14 days and clinical status was evaluated through daily telephone check-ins.
“Our phase-three data shows that metabolic activators significantly improve the recovery, liver health, and markers of inflammation of patients with COVID-19,” says the study’s lead author, Adil Mardinoglu, professor at KTH and Kings College and research fellow at Science for Life Laboratory.
“Dysfunctional mitochondria have been implicated in worsened progression for COVID-19, and we are pleased to find that the combination of these metabolic activators helps to remedy the stress put on the body of an infected patient.”
The study was conducted in partnership with Stockholm-based ScandiBio Therapeutics AB and California-based ChromaDex (NASDAQ:CDXC), which provided one of the four ingredients (nicotinamide riboside) through the ChromaDex External Research Program (CERP).
Together with the strategic partner Viscoran (Turkey), a submission for drug approval has been submitted to the Ministry of Health in Turkey.
Since the beginning of the Coronavirus disease 2019 (COVID-19) pandemic, over 30 million confirmed cases and about 1 million COVID-19-related deaths have been reported globally (1). To immediately challenge COVID-19 burden, scientists worldwide are applying their expertise to the effort to a greater extent than any other time in history.
In this context, a large number of clinical data on COVID-19 have been published and numerous reports have demonstrated that people with metabolic abnormalities — hypertension, high blood sugar, obesity, high triglycerides and low HDL cholesterol — have greater risk of developing severe outcomes (2-6). Moreover, a large number of clinical trials have been performed for repositioning existing drugs for effective treatment of COVID-19 patients (7, 8).
Based on the outcome of these clinical studies remdesivir and favipiravir are approved by the United States FDA and Chinese FDA, respectively for the treatment of COVID-19 patients (9, 10).
Recently, we performed integrative analysis of multi-omics data on different metabolic conditions and found that combined metabolic cofactors supplementation (CMCS) consisting of L-serine, N-acetyl-L-cysteine (NAC), nicotinamide riboside (NR), and L-carnitine tartrate may be used for treatment of the patients with non-alcoholic fatty liver diseases (11, 12).
On the basis of this evidence, we conducted an animal toxicity study and a human calibration study with/without supplementation of combined metabolic cofactors, and demonstrated the safety of the CMCS (13). In that study, we also performed plasma metabolomics and proteomics profiling and revealed plasma level of metabolites associated with the antioxidant metabolism and proteins associated with the inflammation were significantly decreased with the CMCS.
To date, NAC, NR (categorized as a form of Vitamin B3, Niacin) and L-carnitine have also been used in human trials associated with viral diseases including COVID-19, and serine has been evaluated in immune system related disorders (Table S1).
Encouraged by the results of aforementioned studies, and the urgent nature of the pandemic, we performed a randomized, controlled, open label, placebo-controlled, phase 2 study to evaluate the efficacy, tolerability and safety of CMCS in ambulatory COVID-19 patients.
In this randomized, open-label, placebo-controlled, phase 2 trial involving ambulatory COVID-19 patients, we found that the combination of CMCS and hydroxychloroquine significantly reduced the average recovery time compared with hydroxychloroquine and placebo (6.6 days vs 9.3 days, respectively). Recovery was defined as the study patients self-reporting 0 symptoms. Moreover, there was a significant reduction in ALT, AST and LDH levels on day 14 compared to day 0. The adverse effects were uncommon, benign, and self-limiting.
The antiviral properties of repurposed drugs have gained considerable attention due to the lack of targeted treatments for emerging viruses. Numerous study results have been indicated the role of L-serine, NAC, NR, and L-carnitine tartrate in lung diseases and viral infectious diseases (14-23). These ingredients of CMCS have been known for pharmacological properties, side-effects, and dosing procedures, which takes advantage of the rapid development of clinical trials and COVID-19 treatment protocols.(14, 24)
While clinical signs of COVID-19 essentially manifest as respiratory tract infection, it has also been accompanied by systemic presentations. Among those, commonly reported gastrointestinal and hepatic manifestations include nausea/vomiting, diarrhea, and abnormal liver enzyme levels (e.g. elevations in ALT and AST) (25).
Furthermore, some studies have reported that liver deficiencies are correlated with worse outcomes including longer hospitalization, progression to severe COVID-19, intensive care unit admission, and mortality (26-29). A growing body of evidence shows the level of glutathione is not enough to maintain and regulate the thiol redox status of the liver in subjects with liver dysfunction due to the depletion of glycine (11).
Glycine can be synthesized via the interconversion of serine. It has been shown that the serine synthesis is downregulated in patients with non-alcoholic fatty liver disease and supplementation of serine enhanced homocysteine metabolism in mice and rats (30).
In a recent study, serine has also been shown to be an essential metabolite for modulation of adaptive immunity by supporting effector T cell responses (31). Depleted liver glutathione is also restored by the administration of N-acetylcysteine.
Similarly, L-carnitine and nicotinamide riboside both stimulate the transfer of fatty acids from cytosol to mitochondria have been identified as two additional cofactors that are depleted in liver diseases (32-35). Taken together, we envisage CMCS may improve clinical outcomes in COVID-19 by regulating energy metabolism and various metabolic pathways for carbohydrates, lipids, and amino acids.
Considerable numbers of COVID-19 patients are at risk of detrimental outcomes attributed to the systemic inflammatory responses described as the “cytokine storm”. This life-threatening condition is dependent on the downstream process leading to oxidative stress, dysregulation of iron homeostasis, hypercoagulability, and thrombocytopenia (36, 37).
In this context several studies have proposed that CMCS components may be effective to inhibit the production of proinflammatory molecules (e.g., IL6, CCL5, CXCL8, and CXCL10) and improve impaired mitochondrial functions by reducing enhanced oxidative damage, lipid peroxidation and disturbed glucose tolerance (38, 39).
Given the evidence of breaking the overactive immune response with CMCS components, early treatment with CMCS may be beneficial to reduce the progression risk that leads to severe respiratory distress, and lung damage.
Our trial has several limitations. First, to date, randomized clinical trials evaluating hydroxychloroquine have reported no evidence of clinical benefit for the treatment of COVID-19. However, in Turkey, the treatment of COVID-19 with short courses of hydroxychloroquine (5 days, if needed up to 10 days) has been recommended by the Ministry of Health for all patients that have positive PCR test results. T
herefore, in our study we cannot exclude the possible interaction of hydroxychloroquine treatment with CMCS. Second, the trial was not blinded and patients were within a single hospital setting. Third, we included patients up to 14 days after hospital administration, thus day 0 was the beginning of the symptoms for each patient between 24-48 hours.
In this trial we evaluated the efficacy and safety of CMCS when combined with the hydroxychloroquine therapy in patients with mild-to-moderate COVID-19, and found that combination therapy is safe and beneficial in patients with mild COVID-19 disease.
reference link: https://www.medrxiv.org/content/10.1101/2020.10.02.20202614v1.full
More information: Ozlem Altay et al, Combined Metabolic Activators Accelerates Recovery in Mild‐to‐Moderate COVID‐19, Advanced Science (2021). DOI: 10.1002/advs.202101222