Trial document




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  DRKS00021214

Trial Description

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Title

Improvement of the nutritional status regarding nicotinamide (vitamin B3) and the course of COVID-19 disease

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Trial Acronym

COVit

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URL of the Trial

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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 frequency of complete symptom resolution after 2 weeks of supplementation; secondary endpoints are the frequency of complete symptom resolution after 4 weeks of supplementation, the time from diagnosis to symptom resolution, the frequency of freedom from fatigue after 2 weeks of supplementation, and a development of severe COVID-19 (examination in an emergency department, hospitalisation with at least 24 hours of oxygen requirement, intensive care requirement, ventilator requirement or death). 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. Stool and urine samples will be collected from approximately 20 selected patients at week 0, week 1/2, 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 the blood. In these patients, the viral strain will also be determined by sequencing from nasopharyngeal swabs. In the stool, changes in the microbiome (in 100 patients) as well as metagenome and metabolome (in 20-30 patients) will be analysed. The study is expected to produce rapid results on whether nicotinamide supplementation can alleviate the disease course of COVID-19.

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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 10.1136/gutjnl-2020-323020). 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.

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Do you plan to share individual participant data with other researchers?

Yes

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Description IPD sharing plan:

The medical data including routine clinical findings are not pseudonymised. However, the patients and biospecimens of the trial are pseudonymised with a study patient ID as soon as the data are released for analysis. The assignment of the patient data to the study patient ID is kept within the recruitment centre. The recruitment centre is operated by the University Hospital Schleswig-Holstein (UKSH) and the Competence Network for Intestinal Diseases e.V. in Kiel. Outside the recruitment centre, only study patient IDs are handled. Since the project is under medical supervision, all staff members are subject to medical confidentiality. Disclosure of data to unauthorised third parties (especially employers or insurance companies) is excluded. Samples and information are passed on to scientific cooperation partners exclusively in pseudonymised form, i.e. without personal details. At the end of the research activities (after 15 years at the earliest), the samples and the associated data are destroyed.

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Organizational Data

  •   DRKS00021214
  •   2020/04/01
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  •   yes
  •   Approved
  •   A 107/20, Ethikkommission der Christian-Albrechts-Universität zu Kiel
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Secondary IDs

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Health Condition or Problem studied

  •   U07.1 -  Emergency use of U07.1
  •   ICD: U07.1: SARS-CoV-2
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Interventions/Observational Groups

  •   Nicotinamide, 1,000 mg/day p.o. (one each of 500-mg conventional and delayed-release nicotinamide tablets), for 4 weeks
  •   Placebo, p.o. (2 tablets), for 4 weeks
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Blinded
  •   patient/subject, investigator/therapist
  •   Placebo
  •   Treatment
  •   Parallel
  •   N/A
  •   N/A
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Primary Outcome

Frequency of complete symptom resolution after 2 weeks of dietary supplementation.

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Secondary Outcome

1. Frequency of complete symptom resolution after 4 weeks of dietary supplementation.
2. Time from diagnosis to complete symptom resolution.
3. Frequency of freedom from fatigue after 2 weeks of dietary supplementation.
4. Frequency of severe COVID-19, defined as achieving one of the following characteristics:
a. examination in an emergency department;
b. hospitalisation with continuous oxygen requirement of at least 24 hours;
c. intensive care requirement;
d. ventilation requirement;
e. death by COVID-19.

Exploratory endpoints include comparisons between findings from the pilot phase and the second part of the trial, changes in fatigue and quality of life and, in selected patients, changes in blood levels of tryptophan and its metabolites, changes in inflammatory markers, changes in blood cell counts and standard blood profiles, changes in the blood metabolome, the SARS-CoV-2 strain as well as changes in stool microbiome, metagenome and metabolome.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Actual
  •   2020/04/04
  •   840
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

SARS-CoV-2 infection confirmed by laboratory findings; the positive test must not date back more than 7 days.
Relevant infection symptoms, e.g. in the respiratory or gastrointestinal tract.
The patient has been able to give written consent via a website before any trial procedure is performed and can comply with the trial-dependent prerequisites and requirements.

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Exclusion Criteria

[---]*

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Addresses

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    • Klinik für Innere Medizin I (UKSH Campus Kiel)
    • Arnold-Heller-Str. 3
    • 24105  Kiel
    • Germany
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    • Klinik für Innere Medizin I, UKSH Campus Kiel
    • Mr.  Prof. Dr.  Stefan  Schreiber 
    • Arnold-Heller-Str 3
    • 24105  Kiel
    • Germany
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    • Klinik für Innere Medizin I, UKSH Campus Kiel
    • Mr.  Prof. Dr.  Stefan  Schreiber 
    • Arnold-Heller-Str 3
    • 24105  Kiel
    • Germany
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Sources of Monetary or Material Support

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    • Klinik für Innere Medizin I (UKSH, Campus Kiel)
    • Arnold-Heller-Str 3; Haus C, Haus K3
    • 24105  Kiel
    • Germany
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    • Dekanat der Medizinischen Fakultät Christian-Albrechts-Universität zu Kiel
    • Arnold-Heller-Str. 3 - Haus 807
    • 24105  Kiel
    • Germany
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    • Exzellenzcluster "Precision Medicine in Chronic Inflammation" (DFG EXC 2167)
    • Christian-Albrechts-Platz 4
    • 24118  Kiel
    • Germany
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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