Introduction
Infection with SARS-CoV-2 leads to pronounced changes in the intestinal microbiome and also decay of tryptophan that are both related to disease severity. Supplementation of tryptophan metabolism using ileocolonic-release nicotinamide may stabilize the microbiome and alleviate COVID-19 symptoms.
Aims & Methods
This prospective, double-blind, randomized, placebo-controlled trial evaluated safety and efficacy of a 4-week intervention with a novel oral formulation of nicotinamide (1,000 mg/d) in symptomatic, unvaccinated, non-hospitalized outpatients with PCR-proven early COVID-19. The primary outcome was full recovery from reduced physical performance after 2 weeks in the prespecified symptomatic primary analysis population with at least one risk factor for severe COVID-19. Stools from a part of the patients (4 timepoints) were submitted to 16S rRNA (n=70) and shotgun metagenomics (n=18) sequencing.
Results
Screening of 7,013 patients resulted in randomization of 900 participants (nicotinamide or placebo (1:1), from which 867 received the investigational product and 500 qualified for the acute disease analysis population. 110 of 191 patients (57.6%) receiving nicotinamide and 80 of 188 patients receiving placebo (42.6%) recovered from their performance drop at week 2 (absolute difference, 15.0 percentage points; odds ratio, 1.33; 95% confidence interval, 1.03 to 1.70; P=0.004). Nicotinamide was also superior in the secondary endpoints ability to perform normal activities (P=0.009) and shortness of breath (P=0.012). Substantial effects on gut microbiome constitution were seen counteracting COVID-19 related changes. Reduction of tryptophan biosynthesis in the microbiome in placebo patients was restored and NAD salvage pathways were activated in nicotinamide-treated individuals. No relevant safety signals were observed.
Conclusion
Oral treatment with nicotinamide stabilized the gut microbiome against COVID-19 related changes and led to faster recovery of physical performance in symptomatic patients at risk for severe Covid-19. (Funded by the German Research Foundation [DFG], the State of Schleswig-Holstein and the UEG Research Prize; ClinicalTrials.gov number: NCT04751604)
Disclosure
SS reports indirect stock ownership in Gerion Biotech GmbH as well as consulting and personal fees from AbbVie, Allergosan, Amgen, Arena, BMS, Biogen, Celltrion, Celgene, Falk, Ferring, Fresenius, Galapagos/Gilead, HIKMA, I-Mab, Janssen, Lilly, Morphic, MSD, Mylan, Pfizer, Prometheus, Protagonist, Provention Bio, Sandoz/Hexal, Takeda, and Theravance.
GHW is employed part-time by CONARIS Research Institute AG (Kiel, Germany).
TB reports consulting fees, honoraria or other support from AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Merck, MSD, Novartis, Pfizer, and Roche.
KA reports consulting fees, honoraria or other support from AbbVie, Falk, Galapagos, Janssen, Pfizer, and Takeda.
ML reports a lecture honorarium and travel support by AstraZeneca.
PR reports stock ownership in Gerion Biotech GmbH and consulting fees from Takeda.