A Study To Evaluate The Efficacy And Safety Of a Novel Niclosamide Suspension Formulation For COVID-19

A Phase III, Randomized, Placebo-controlled, Clinical Trial to Evaluate the Efficacy and Safety of Co-administered Niclosamide in Patients Treated With an Established Regimen for Novel Coronavirus Infectious Disease (COVID-19)

This study aims to investigate the potential antiviral efficacy and safety of a novel formulation of Niclosamide; a well-known antihelmintic agent, together with an established COVID-19 treatment regimen in patients.

The aim of this study is to evaluate the safety and efficacy profile of niclosamide from the test product (Niclosamide 200 mg/10 mL Suspension) in patients treated for the novel coronavirus infectious disease (COVID-19) in a placebo controlled phase III trial. Both treatment groups will receive an established treatment regimen against COVID-19 together with either niclosamide or placebo.

The efficacy and safety of the molecule is well-known and the properties of novel formulation is well-established. The promising in vitro results of niclosamide as an antiviral compound is well documented and make it an ideal candidate as a therapy against SARS-CoV 2 infection. A good safety profile is expected with solid antiviral activity.

The study will be performed in accordance with the relevant articles of the Declaration of Helsinki (1964) as revised in Tokyo (1975), Venice (1983), Hong Kong (1989), Somerset West, RSA (1996), Edinburgh (2000), Washington (2002), Tokyo (2004) and Seoul (2008) and Fortaleza (2013).

The medications for the established treatment regimen will be supplied by Ministry of Health to the study sites. The other study medications, Investigational product and placebo, together with relative documentation, will be supplied to clinical sites by the sponsor. Niclosamide 200 mg/10 mL Suspension and placebo will be supplied together with certificates of analysis by the company responsible for manufacturing of the test product(s).The packaging and labelling of niclosamide and placebo will be done according to the GMP and GCP requirements.

All subjects will receive either 200 mg/10 mL niclosamide suspension or 10 mL placebo three times a day for 5 days, together with an established COVID-19 treatment regimen according to the official guidance for COVID-19 Adult Treatment Algorithm of Republic of Turkey Ministry of Health. Dosings will be administered in accordance with the treatment randomization table throughout the treatment duration.

On each drug administration, the identity of the subject will be confirmed by checking the Identity Card. Administration of the study medication will be performed by the investigator(s) and nurse(s) and supervised by a second medical professional to ensure the correctness of drug administration. Also, a monitor may attend during this procedure. The administration of the study medication is to be followed by a mouth check, to be documented in the CRF and certified by the Investigator.

The statistical analysis will be done according to the provisions of ICH Topic E9, Statistical Principles for Clinical Trials (CPMP/ICH/363/96), September 1998.

Statistical analysis will be performed as a valid case analysis including all subjects in which no major protocol deviations occurred and all primary target variables are available for measurement.

If a subject is to be excluded from evaluation, this decision has to be justified in the Final Study Report.

Continuous variables will be expressed as means ± standard deviations (SD) for the normally distributed data or median with interquartile (IQR) for the skewed data. Correspondingly, two-sample independent t-test and Mann-Whitney U test will be used to detect the difference between groups. Categorical variables will be described as number (%) and compared by χ² test or Fisher's exact test as appropriate. Kaplan-Meier method will be used to estimate the cumulative probability of the endpoint. Cox proportional hazards regression model will be conducted to determine the potential risk factors associated with the endpoint. Statistical significance will be defined as p<α=0.0054 for interim analysis, p<α=0.0492 for final analysis using O'Brien-Fleming alpha adjustment. All analyses will be done with R project.

The expected percentage of treatment success is 75% in the experimental group and 50% in the control group. The sample size calculation yields that 170 subjects are needed (85 for each group) to achieve 90% power at α=0.05. Considering potential dropouts, the sample size is estimated as 200 subjects (100 subjects for each group). For interim analysis, 100 subjects (50 subjects for each group) will be evaluated.

Before being enrolled to the clinical study, the subject(s) must consent to participate in the study by signing the informed consent form in response to a complete written and verbal explanation of the nature, scope and possible consequences of the clinical study explained in an understandable way for him/her by the physician.

Each subject will give in writing her/his authorization that the study data may be given for review to the responsible Local and National Authorities.

The subject information and informed consent form will be provided in duplicate [one signed version (original 1) will be left at the investigator; the other signed version (original 2) will be forwarded to the subject].

Inclusion Criteria:

1. Being able to understand the study and to give a written informed consent

2. Adult hospitalized patients (aged ≥18) confirmed or suspected for COVID-19 according to the official General Information, Epidemiology and Diagnosis Guidance for COVID-19 (SARS-CoV-2 Infection) published by Republic of Turkey Ministry of Health showing at least one of the symptoms below:

   1. fever, cough, difficulty in breathing, sore throat, headache, muscle or body aches, new loss of taste or smell, diarreha without explanation of any cause than COVID-19 and history of herself/himself or her/his close contact presenting in the high-risk area of the disease within 14 days prior to the onset of symptoms or

   2. at least one of the symptoms of fever, cough, difficulty in breathing, sore throat, headache, muscle or body aches, new loss of taste or smell, diarrhea without explanation of any cause than COVID-19 and close contact with confirmed COVID-19 case within 14 days prior to symptoms or

   3. fever and at least one of the signs and symptoms of the severe acute respiratory infection (cough and difficulty in breathing) and need for hospitalization due to severe acute respiratory infection (SARI) explanation failure of the clinical features other than COVID-19 SARI: The need for hospitalization in a patient with acute respiratory infection due to fever, cough and dyspnea, tachypnea, hypoxemia, hypotension, wide radiological findings and consciousness developing in the last 14 days.

      or

   4. at least two of the signs and symptoms of fever, cough, difficulty in breathing, sore throat, headache, muscle or body aches, new loss of taste or smell, diarrhoea without explanation of any cause than COVID-19 or

3. Patients detected with SARS-COV-2 by molecular methods who meet the criteria for possible case of SARS-COV-2

Exclusion Criteria:

1. Who have allergy to niclosamide and/or any of the treatment agents and/or any of the excipients of the products,
2. Who is diagnosed as "severe or critical case" (e.g. pneumonia or severe pneumonia),
3. Whose National Early Warning Score 2 (NEWS2) score is indicated as "urgent" or "emergency",
4. Any history of bone marrow transplant, solid-organ transplant, immune compromising conditions, immunomodulatory therapy, haematologic malignancy,
5. Who have Multiple Sclerosis,
6. Who have electrolyte imbalance, chronic haemodialysis or glomerular filtration rate < 30 30 mL/min/1.73m2,
7. Who have history of serious cardiovascular diseases,
8. Who are diagnosed with another ongoing viral infection other than SARS CoV-2,
9. Who have macrophage activation syndrome,
10. Who have a need for coagulopathy treatment,
11. Who have severe liver disease,
12. Who is pregnant or nursing,
13. Who are not suitable to 1st articles of inclusion criteria,
14. Who is not eligible to swallow oral medications,
15. Who use vitamin C as supplementary medication during the study,
16. Who are included in another trial.