Phase III: COVID-19

Medipol University, Bağcılar Research Hospital, İstanbul

·      Alanya Alaaddin Keykubat University, Faculty of Medicine, Department of Neurology, Antalya

·      Medipol University Bağcılar Research Hospital, İstanbul

·      Saglik Bilimleri University, Kanuni Sultan Süleyman Training and Research Hospital, Istanbul

·      Saglik Bilimleri University, Bakırköy Sadi Konuk Training and Research Hospital, Istanbul

·      Saglik Bilimleri University, Kartal Training and Research Hospital, Istanbul

·      Saglik Bilimleri University, Bağcılar Training and Research Hospital,Istanbul

·      Onsekiz Mart University, School of Medicine Hospital, Çanakkale

Treatment arm: Ambulatory-at home-treatment with hydroxychloroquine + dietary supplement consisting of serine, L-carnitine tartrate, N-acetylcysteine and nicotinamide riboside as compared to hydroxychloroquine + dietary supplement placebo

However, patients may be hospitalised during this initial examination period due to deterioration in their physical health or due to any medical condition which was not present at admission.

The primary objective is to assess the clinical efficacy of the combination of metabolic cofactors supplementation and hydroxychloroquine in COVID-19 patients.

For the primary purpose, the proportion of patients who were hospitalised during the course of disease until 14 days after the initial diagnosis of Covid-19 disease will be compared.

Patients who were hospitalised during the 14-day period, but at any time point after consenting will be evaluated as an end-point occurrence.

The following secondary safety objectives have been identified in this study:

• Number / characteristics of adverse event (AE), Serious Adverse Event (SAE) and treatment discontinuation due to study drug from the beginning of the study to the end of the follow-up period

• Number / features of all changes in haematology parameters evaluated as AE from the beginning of the treatment to the end of the follow-up period.

• Number / characteristics of all changes in selected biochemical parameters evaluated as AE from the beginning of the treatment to the end of the follow-up period.

• The changes in vital signs (systolic and diastolic blood pressures, pulse, respiratory rate, body temperature, pulse oximetry values), baseline values, and the status of treatment and follow-up visits

·      Comparison of plasma metabolomics and proteomics (including cytokines) as well as oral and gut microbiota analysis results obtained from two treatment arms

Phase III study will enrol 300 patients

A total of 300 COVID-19 disease patients will be randomized on a 3:1 basis to the combination metabolic cofactors supplementation and hydroxychloroquine or hydroxychloroquine+ placebo in eight clinical sites in Turkey.

·      Patients of both genders (females and males) over 18 years of age

·      Written informed consent obtained from the subjects prior to any procedures related to the study.

·      Understand all procedures to be applied within the scope of the study protocol

·      Ambulatory patients with symptoms diagnosed with COVID-19 with Chest tomography (CT) positivity in the last 72 hours

·      Patients with stable clinical course and who could be treated on an ambulatory basis

·      Patients who has partial oxygen saturation below 90% and require immediate hospitalisation after diagnosis

·      Patients, upon initial examination, decided to be hospitalised at the intensive care-unit

·      Inability or unwillingness to give written informed consent

·      At physician’s decision, the trial involvement will not be in patients’ best interest, or any condition that does not allow the protocol to be followed safely.

·      Patients considered as inappropriate for this study for any reason

·      Active participation in another clinical study

·      Uncontrolled Type 1 or type 2 diabetes

·      Severe liver disease (e.g. Child Pugh score ≥ C, AST>5 times upper limit)

·      Patients with known severe renal impairment (estimated glomerular filtration rate ≤30 mL/min/1.73 m2) or receiving continuous renal replacement therapy, hemodialysis, peritoneal dialysis

·      Significant cardiovascular co-morbidity (i.e. heart failure)

·      Patients with phenylketonuria (contraindicated for NAC)

·      Known allergy for substances used in the study

·      Pregnant or breastfeeding patients, or patients with positive pregnancy test in a pre-dose examination

·      Receipt of any experimental treatment for COVID-19 within the 30 days prior to the time of the screening evaluation.

The study subjects will be randomized on a 3:1 basis to the cofactor supplementation combination plus hydroxychloroquine treatment or hydroxychloroquine +placebo treatment.

During the Phase III part of the study, with a randomization rate of 3: 1, the group who received hydroxychloroquine+placebo treatment as a standard care group will include 75 volunteers; the hydroxychloroquine + cofactors supplementation group will consist of 225 volunteers.

The hydroxychloroquine + cofactors supplementation group will be applied the same dosage and duration of the hydroxychloroquine therapy. Additionally, cofactors supplementation mixture will be given for two weeks in doses indicated below (twice/day; one dose in the morning, one dose after dinner):

The total treatment period for the hydroxychloroquine will be 5 days and cofactors supplementation will be for 14 days. On the 14th day, patients will perform a last visit which will be their follow-up visit.

Visit 1 (Screening; Day 0):

The subjects will get the informed consent form and oral information on the study protocol.

After clinical and physical examination blood samples will be obtained for routine analysis outlined in the study protocol. Chest tomography (CT) will be performed. An ECG will also be performed.

Plasma samples will be taken for advanced metabolomics and proteomics (including cytokines) analysis in Sweden. Saliva and feces samples will be collected for metagenomic analysis and transferred to Sweden to assess changes in oral and gut microbiota during treatment. Whole genome sequencing will not be performed.

Eligible study subjects will be invited to the clinic for randomization to the active treatment and standard therapy groups. They will be asked to take the first dose and be observed for development of side effects. Patients who can tolerate the study agents will start to take co-factors supplementation (i.e., 2 dosage daily just after breakfast and dinner) for two weeks.

After initial dosing at the hospital patients will be instructed to stay at home during their treatment and will be asked to attend to the investigational site if symptoms are worsened during the 14-day period.

Visit 2 (Week 1; Day 7) – This visit will be performed if patient’s condition permits or patient has been hospitalised. If visit is performed, a clinical and physical examination, adverse events recording, metabolomics, proteomics and metagenomics analysis will be repeated as in Visit 1.

Visit 3 (Week 2, Day 14 (discharging from the hospital)): Clinical and physical examination, adverse events recording, hematologic and biochemical safety parameters, metabolomics, proteomics, and metagenomics analysis will be repeated as in Visit 1 and Visit 2.

After the visit 3, subjects will stop taking their supplements.

The primary objective is to assess the clinical efficacy of the combination of metabolic cofactors supplementation and hydroxychloroquine in COVID-19 patients based on the proportion of requirement of hospitalisation.

In both patient groups, plasma metabolomics and proteomics as well as oral and gut microbiota analysis will be included in the secondary efficacy evaluation.

Methodology