German Clinical Trials Register

Acronym/abbreviation of the study

COVit

URL of the study

No Entry

Brief summary in lay language

Based on the literature, it seems likely that a nutritional intervention with nicotinamide (a form of vitamin B3) can support the therapy of SARS-CoV-2 infection (COVID-19) by, e.g., improving the availability of tryptophan and its metabolism-supporting metabolites (e.g. NAD). A pilot phase of the COVit trial showed an effect of nicotinamide on the time to complete resolution of COVID-19 symptoms. In addition, diarrhoea is a common symptom of COVID-19. Therefore, in a second part of the study, 420 symptomatic patients each with confirmed SARS-CoV-2 infection are to take 1,000 mg nicotinamide (500 mg conventional nicotinamide and 500 mg nicotinamide released in a controlled manner in the intestine) or corresponding placebos per day in a blinded fashion for 4 weeks. The primary endpoint of the trial is the occurrence of individual COVID-19 symptoms at week 0, week 2 (primary analysis time point), week 4 and week 6 as well as after 6 months. Secondary endpoints are the severity of COVID-19 symptoms, the occurrence and severity of symptoms at the 6-month follow-up (post-COVID-19 syndrome, PCS), the levels of antibodies against the N protein and S protein of SARS-CoV-2 after at least 6 months, complete resolution of symptoms at 2, 4 and 6 weeks as well as the time from diagnosis to resolution of individual or all symptoms. Exploratory endpoints include the WHO clinical scale for COVID-19 and the development of severe COVID-19 (examination in an emergency department, hospitalization with a continuous oxygen requirement of at least 24 hours, intensive care requirement, ventilation requirement or death by COVID-19), changes in fatigue and quality of life, and various biomarkers. Patients will be approached and informed after positive testing and can give their informed consent for participation via a website. After randomised distribution of the trial supplements, patients will be interviewed by telephone about their disease course at baseline (week 0) and after 2, 4 and 6 weeks as well as after 6 months. Stool samples will be collected from up to 400 patients at week 0, week 2, week 4, week 6 and after 6 months. In addition to blood count and standard blood profile, various inflammatory markers and the metabolome, in particular tryptophan metabolism, will be examined in up to 20 selected patients. In these patients, the viral strain will also be determined by sequencing from nasopharyngeal swabs. In selected patients, the pharmacokinetics of nicotinamide, nicotinic acid and nicotinuric acid as well as of metabolites of nicotinamide and tryptophan will be investigated within the first 48 hours after a single dose of the trial supplementation. In the stool, changes in the microbiome (in 100–300 patients) as well as metagenome and metabolome (in a subgroup) will be analysed. The study is expected to produce rapid results on whether nicotinamide supplementation can alleviate the disease course of COVID-19. Moreover, a follow-up interview, a smell test, a cognitive test validated for phone surveys (T3MS) and a test for anti-SARS-CoV-2 antibodies after at least 6 months will be used to investigate whether the supplementation has any influence on PCS as well as the immune reaction and possibly vaccination against SARS-CoV-2.

Brief summary in scientific language

The availability of tryptophan and its metabolites, especially nicotinamide (a form of vitamin B3) as a building block of NAD and NADP, are important factors in the immune system. Dysregulation can lead to immune deficiency, but also to chronic inflammation (Nikolaus et al. 2017, Gastroenterology 153:1504; Agus et al. 2018, Cell Host Microbe 23:716; Sorgdrager et al. 2019, Front. Immunol. 10:2565; Taleb 2019, Front. Immunol. 10:2113; Pongratz et al. 2019, Clin. Exp. Rheumatol. 37:450). Particularly in the context of pneumonia, certain metabolites of tryptophan are important and can strengthen lung immune functions and counteract chronic changes caused by inflammatory reactions in the lungs (Heseler et al. 2008, FEMS Immunol. Med. Microbiol. 52:273; Suzuki et al. 2011, J. Infect. 63:215; Meier et al. 2017, Clin. Chem. Lab. Med. 55:1060; Tsay et al. 2019, J. Transl. Med. 17:304; Michaudel et al. 2020, Front. Immunol. 11:144; Takei et al. 2020, Arthritis Res. Ther. 22:20; Zhou et al. 2020, Sci. Rep. 10:4436). Supplementation with nicotinamide has a strong anti-inflammatory effect in both tryptophan-deficient and normally fed animals (Hashimoto et al. 2012, Nature 487:477; Waetzig & Seegert 2013, WO2013/186355; Bettenworth et al. 2014, Mol. Nutr. Food Res. 58:1474; Waetzig & Seegert 2015, WO2015/086838). Reduced levels of nicotinamide and thus NAD(P) also impede immune defence against coronaviruses (Heer et al. 2020, J. Biol. Chem. 295:17986) and cell metabolism, especially also of macrophages and epithelial cells. The latter in particular are subject to a critically high turnover rate in the gut and lungs. Another link to SARS-CoV-2 beyond inflammation and the immune system could also be the SARS-CoV-2 entry receptor ACE2, as the presence of ACE2 on the cell surface enables the uptake of tryptophan via the transporter B0AT1 (Hashimoto et al. 2012, Nature 487:477). In severe courses of influenza, as in chronic inflammation, increased tryptophan degradation and thus increased kynurenine levels are observed, and inhibition of tryptophan degradation has beneficial effects in animal models (Boergeling & Ludwig 2017, FEBS J. 284:218; Pizzini et al. 2019, Influenza Other Respir Viruses 13:603). In turn, there is evidence in a wide variety of virus types that nicotinamide can reduce viral replication and support the body's defence mechanisms, e.g. in vaccinia (Child et al. 1988, Virus Res. 9:119), HIV (Murray 2003, Clin. Infect. Dis. 36:453), enteroviruses (Moell et al. 2009, J. Med. Virol. 81:1082) or hepatitis B (Li et al. 2016, Arch. Virol. 161:621). Adequate supply of B vitamins and explicitly nicotinamide to strengthen the immune system is also recommended to combat SARS-CoV-2 infection (Zhang & Liu 2020, J. Med. Virol. 92:479; Gharote 2020, Ind. J. Med. Sci. 72:25; Shi et al. 2020, Cell Death Differ. 27:1451; Shakoor et al. 2021, Maturitas 144:108). Here, the improvement of the defence against secondary bacterial infections in disease models is particularly emphasised (Zhang & Liu 2020, J. Med. Virol. 92:479). In the COVit trial, 1,000 mg of nicotinamide are administered, which is far below potentially harmful doses of several grams per day and very close to the acceptable daily intake of 900 mg/day (OECD-SIDS 2002, SIDS Initial Assessment Report for SIAM 15, Boston, MA, 22-25 October 2002; EFSA 2014, EFSA J. 12:3759). Meanwhile, several publications suggest the use of nicotinamide in COVID-19, but there are no trial data in this regard (Heer et al. 2020, J. Biol. Chem. 295:17986; Gharote 2020, Ind. J. Med. Sci. 72:25; Shi et al. 2020, Cell Death Differ. 27:1451; Shakoor et al. 2021, Maturitas 144:108; Mehmel et al. 2020, Nutrients 12:1616). In the pilot phase of the COVit trial, patients received 1,000 mg of conventional nicotinamide or 245 mg of silica as a placebo-like dietary supplement. During a quality control of the data collection, it was surprisingly observed that considerably more patients in the nicotinamide arm were completely symptom-free already after two weeks of administration compared to the silica group. From the literature, depending on the patient population, very long convalescences can also be expected, e.g. 43 % symptom-free 14-21 days after positive SARS-CoV-2 test (Tenforde et al. 2020, MMWR Morb. Mortal. Wkly Rep. 69:993), <30 % without respiratory symptoms after one month (Marshall 2020, Nature 585:339), 32% symptom-free at 30 days and still only 34% at 60 days after SARS-CoV-2 diagnosis (Carvalho-Schneider et al. 2020, Clin. Microbiol. infect. 10.1016/j.cmi.2020.09.052), or only 12.6% symptom-free after a mean of 60 days (Carfi et al. 2020, JAMA 324:603). In addition, COVID-19 has been shown to be a systemic disease with an unexpectedly high gastrointestinal symptom frequency (Mitsuyama et al. 2020, J. Clin. Med. 9:3630). Recently, it has been published that the gut microbiome is also significantly and sometimes negatively affected by COVID-19 (Yeoh et al. 2021, Gut 70:698). The link between the gut microbiome and the metabolism of tryptophan and nicotinamide plays an important role in gut inflammation (Hashimoto et al. 2012, Nature 487:477; Waetzig & Seegert 2013, WO2013/186355; Bettenworth et al. 2014, Mol. Nutr. Food Res. 58:1474; Waetzig & Seegert 2015, WO2015/086838). Therefore, two different tablets, each containing 500 mg nicotinamide, will now be used as investigational preparations in the main phase of the COVit trial: the conventional immediate-release nicotinamide tablets from the pilot phase and the newly developed CICR-NAM (controlled-ileocolonic-release nicotinamide) tablets, which release the nicotinamide in a delayed and continuous fashion starting in the lower small intestine. This should increase the gastrointestinal beneficial effect of nicotinamide, specifically also on the microbiome and its interaction with the gut, as conventional nicotinamide is absorbed very quickly into the circulation (Fangmann et al. 2018, Diabetes Care 41:398). A trial with a CICR-NAM prototype have shown that systemic exposure resulting from this new dosage form will be lower than in the pilot phase of the study (Fangmann et al. 2018, Diabetes Care 41:398), in which exposure was already close to the acceptable daily intake anyway (see above). This will further reduce the already minimal risk of side effects.