Early Treatment of Vulnerable Individuals With Non-Severe SARS-CoV-2 Infection

Study Overview
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Brief Summary
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Coverage Africa is a nested study in the large Anticov platform trial that aims to generate data on new early treatment strategies for mild/moderate COVID-19 patients in resource-limited-settings to reduce the number progressing to severe forms requiring hospitalization, thereby relieving the burden on health care systems and contributing to flattening the curve in contexts where none pharmaceutical intervention such as quarantine are difficult to implement in large urban settings. Treating early when the virus is still present might also limit transmission. Coverage Africa will be conducted in Guinea and Burkina Faso. The main objective is to conduct an open-label, multicenter, randomized, adaptive platform trial to test the safety and efficacy of several marketed products, including antiviral therapies versus control in mild/moderate of coronavirus disease 2019 (Covid-19) in resource-limited-settings. The study aims to recruit 600 patients in both countries, one site in Guinea and two sites in Burkina Faso. The current assessed treatments are now the association of Fluoxétine/Budésonide compared with a control arm: paracetamol. The adaptive design trial will allow for the removal of drugs, or the addition of new study arms when new data becomes available. Data on the primary efficacy parameters and safety will be integrated with the primary endpoint based on an oxygen saturation percentage (SpO2) ≤ 93% or death within 14 days after randomization to treatment, including death for any reason. Study will run until August 2022. However, with the proposed adaptive design, the study could also be interrupted for success earlier than planned with the identification of a treatment that significantly reduces hospitalization rate as evidence by results from the primary endpoint.

Official Title
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Early Treatment of Vulnerable Individuals With Non-Severe SARS-CoV-2 Infection: A Multi-Arm Multi-Stage Randomized Trial (MAMS) to Evaluate the Effectiveness of Several Specific Treatments in Reducing the Risk of Clinical Worsening or Death in Sub-Saharan Africa (COVERAGE-Africa)

Conditions
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SARS-CoV2 Infection, Covid19, Covid19 Drug Treatment, Severe Acute Respiratory Syndrome Coronavirus 2

Intervention / Treatment
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* Drug: Nitazoxanide and Ciclésonide
* Drug: Telmisartan 20Mg Oral Tablet
* Drug: Paracetamol
* Drug: Fluoxétine and Budésonide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults 18 years of age at the time of screening or >= 40 years and presenting at least one comorbidity : high blood pressure; a known obesity and/ or a known and treated diabete. SARS-CoV-2 infection confirmed by molecular biology (RT-PCR on a nasopharyngeal or oropharyngeal swab) or by antigen test validated in the country according to national guidelines A viral syndrome with or without uncomplicated pneumonia, defined as blood oxygen saturation level (SpO2) >=94%. Mild Covid-19 symptoms with an onset < 7 days before inclusion. Signed written consent from the patient or his/her representative. No need an oxygen therapy according to international guidelines (WHO Progression Scale, grade 2 to 4) Accepting and having the ability to be reached by telephone throughout the study. Having designated a contact person who can be contacted in case of emergency. Accepted to be reached by phone along throughout the study Exclusion Criteria: Blood oxygen saturation level (SpO2) < 94%. Known hypersensitivity to investigational products Chronic treatment with inhaled corticosteroids (up to 30 days) Known history of renal or hepatic failure Abnormal physical examination findings: respiratory rate < 25 per minute; Clinical hypotension with associated signs justifying hospital care Feeling unwell for more than 7 days prior to screening. End-organ compromise requiring admission to a resuscitation or continuous care unit or short-term life-threatening comorbidity with life expectancy < 3 months. For any new antiviral included in the study, prior treatment with the antiviral, presence of contraindication to its use or intake of concomitant medication proscribed with its use. Patients with known suicidal thoughts, severe psychiatric disorders or major depression that is uncontrolled or controlled by one of the prohibited drugs Known history of long QT syndrome or severe ventricular cardiac arrhythmia (ventricular tachycardia, patients with recovered ventricular fibrillation) Unwilling or unable to comply with the requirements of the study protocol at any time during the study, e.g. no access to or not comfortable with use of a smartphone or with answering questions using a telephone, in the opinion of the Investigator or cannot use an inhalation chamber. Any other reason that makes it impossible to monitor the patient during the study. Enrolled in other clinical trials with unregistered drugs or with registered drugs that may interact with any of the study IPs or are contraindicated as concomitant therapy within the last 3 months prior to screening

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a multicentre, multiple country, randomised, open-label, adaptive, platform clinical study aiming to determine the efficacy and safety of various treatment regimens for prevention of the need for hospitalisation for specialised care due to severe progression of COVID-19. The study is designed with the ability to incorporate the adding or dropping of treatment arms and that will include similar inclusion and non-inclusion criteria, the same primary and secondary endpoints, common data entry procedures, a shared database and a single statistical methodology for analysis of the primary endpoint.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Paracetamol<br>Patients in this arm will receive paracetamol during 14 days | Drug: Paracetamol<br>* Tablets containing 500 mg of paracetamol. One to two tablets every 4-6 hours as required, to a maximum of 6 tablets (3 grams) daily in divided doses. Duration of treatment: up to 14 days<br>|
| Experimental: Nitazoxanide and Ciclésonide<br>Patients in this arm will receive the combination of ciclezonide (Alvesco® 160 µg ) / nitazoxanide (Netazox® 500 mg) during 14 days | Drug: Nitazoxanide and Ciclésonide<br>* Inhaled Ciclésonide: 320 mcg BID per day and Oral Nitazoxanide:2000 mg tablets daily (divided into two daily intakes of two tablets of nitazoxanide 500 mg) during 14 days.<br>|
| Experimental: Telmisartan<br>Patients in this arm will receive telmisartan (Micardis® 20 mg) during 10 days | Drug: Telmisartan 20Mg Oral Tablet<br>* 20 mg tablet daily<br>|
| Experimental: Fluoxétine and Budésonide<br>Patients in this arm will receive the combination of Fluoxétine (Fluoxétine Arrow® 40 mg ) / Budésonide (Budecort® 2*400 mcg) during 7 days | Drug: Fluoxétine and Budésonide<br>* Inhaled Budésonide: 400mcg BID per day and oral Fluoxétine : 80mg tablets daily (divided into two daily intakes of two tablets of Fluoxétine 40 mg) during 7 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SpO2 ≤ 93% within 14 days | Percentage of participant presenting an oxygen saturation percentage (SpO2) ≤ 93% or death within 14 days after randomization to treatment. | From inclusion (day 0) to day 14. | 
| Death within 14 days | Percentage of participant dead within 14 days after randomization to treatment, including death for any reason. | From inclusion (day 0) to day 14. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death within 28 days | Percentage of participant dead within 28 days after randomization to treatment, including death for any reason. | From inclusion (day 0) to day 28. | 
| Occurence of at least one grade 3 or 4 clinical or biological adverse event within 14 days | Occurence of at least one grade 3 or 4 clinical or biological adverse event within 14 days | From inclusion (day 0) to day 14. | 
| Number of hospitalizations due to severe progression | Hospitalisation due to aggravation of COVID-19, including hospitalisation's reason as described below Request of mechanical ventilation and/or Intensive Care Unit (ICU) Non-ICU hospitalisation, requiring supplemental oxygen Non-ICU hospitalisation, not requiring supplemental oxygen | From inclusion (day 0) to day 28. |