Treatment for COVID-19 in High-Risk Adult Outpatients

Study Overview
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Brief Summary
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This is a randomized trial for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in high-risk adults not requiring hospital admission.The overarching goal of this study is to assess the effectiveness of interventions on the incidence of lower respiratory tract infection (LRTI) progression among high-risk adult outpatients with SARS-CoV-2 infection to inform public health control strategies.

Detailed Description
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This is a randomized, multi-center, placebo-equivalent (ascorbic acid + folic acid)-controlled, blinded platform trial. Eligible participants will be enrolled and randomized to Hydrocychloroquine (HCQ) + placebo (folic acid), HCQ + azithromycin, lopinavir-ritonavir (LPV/r) or placebo (ascorbic acid + folic acid). Initially, this study will enroll up to 495 eligible adults ( with high risk for Lower respiratory tract infection (LRTI) progression at baseline who are PCR-confirmed SARS-CoV-2 infection (165 per arm). An additional cohort of 135 eligible adults without risk factors for LRTI progression at baseline who are PCR-confirmed SARS-CoV-2 infection will be enrolled for the co-primary virologic outcome. During the 28 study days, participants will take the medication, complete surveys, collect mid nasal swab for viral quantification, and assess symptoms for progression to LRTI. Additional arms will be added should new potential agents be discovered or combination treatments be proposed. In addition, arms may be dropped prior to completion if deemed futile or if there is a safety signal.

Official Title
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Efficacy of Novel Agents for Treatment of SARS-CoV-2 Infection Among High-Risk Outpatient Adults: An Adaptive Randomized Platform Trial

Conditions
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COVID-19, SARS-CoV-2

Intervention / Treatment
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* Drug: Ascorbic Acid
* Drug: Hydroxychloroquine Sulfate
* Drug: Azithromycin
* Drug: Folic Acid
* Drug: Lopinavir 200 MG / Ritonavir 50 MG [Kaletra]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women 18 to 80 years of age, inclusive, at the time of signing the informed consent Willing and able to provide informed consent Laboratory confirmed SARS-CoV-2 infection, with test results within past 72 hours COVID-19 symptoms, based on the following criteria: At least TWO of the following symptoms: Fever (≥ 38ºC), chills, rigors, myalgia, headache, sore throat, new olfactory and taste disorder(s), OR o At least ONE of the following symptoms: cough, shortness of breath or difficulty breathing (Lopinavir-Ritonavir Platform) Access to device and internet for Telehealth visits At increased risk of developing severe COVID-19 disease (at least one of the following) Age ≥60 years Presence of pulmonary disease, specifically moderate or severe persistent asthma, chronic obstructive pulmonary disease, pulmonary hypertension, emphysema Diabetes mellitus (type 1 or type 2), requiring oral medication or insulin for treatment Hypertension, requiring at least 1 oral medication for treatment Immunocompromised status due to disease (e.g., those living with human immunodeficiency virus with a CD4 T-cell count of <200/mm3) Immunocompromised status due to medication (e.g., persons taking 20 mg or more of prednisone equivalents a day, anti-inflammatory monoclonal antibody therapies, or cancer therapies) Body mass index ≥30 (self-reported) Exclusion Criteria: Known hypersensitivity to HCQ or other 4-aminoquinoline compounds Known hypersensitivity to azithromycin or other azalide or macrolide antibiotics Currently hospitalized Signs of respiratory distress prior to randomization, including respiratory rate >24 Current medications include HCQ Concomitant use of other anti-malarial treatment or chemoprophylaxis History of retinopathy of any etiology Psoriasis Porphyria Chronic kidney disease (Stage IV or receiving dialysis) Known bone marrow disorders with significant neutropenia (polymorphonuclear leukocytes <1500) or thrombocytopenia (<100 K) Concomitant use of digoxin, cyclosporin, cimetidine, amiodarone, or tamoxifen Known cirrhosis Known personal or family history of long QT syndrome History of coronary artery disease with a history of graft or stent History of heart failure, Class 2 or greater using the New York Heart Association functional class Taking medications associated with prolonged QT and known risk of torsades de points. These medications may include some antipsychotic and antidepressant medications. (Lopinavir-Ritonavir Platform) Taking medications associated with prolonged QT such as antipsychotic medications or antidepressants (e.g., citalopram, venlafaxine, and bupropion) and unable to stop during the trial Taking warfarin (Coumadin or Jantoven) Known history of glucose-6-phosphate-dehydrogenase deficiency History of myasthenia gravis

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Ascorbic acid and Folic acid<br>Ascorbic acid 500 mg orally twice on Day 1, followed by 250 mg orally twice daily for 9 days + folic acid 800 µg orally once on Day 1, followed by 400 µg orally once daily for an additional 4 days (Days 2 to 5) | Drug: Ascorbic Acid<br>* Eligible participants in a household randomized to this study arm will receive ascorbic acid only or ascorbic acid and additional drug therapy<br>* Other names: Placebo;Drug: Folic Acid<br>* Eligible participants in a household will receive folic acid and an additional intervention drug<br>* Other names: Placebo;|
| Experimental: Hydroxychloroquine and Folic Acid<br>HCQ 400 mg orally twice on Day 1, followed by 200 mg orally twice daily for an additional 9 days (Days 2 to 10) + placebo (folic acid 800 µg orally once on Day 1, followed by 400 µg orally once daily for an additional 4 days [Days 2 to 5]) | Drug: Hydroxychloroquine Sulfate<br>* Eligible participants in a household randomized to this study arm will receive hydrochloroquine and folic acid therapy<br>* Other names: Intervention A;Drug: Folic Acid<br>* Eligible participants in a household will receive folic acid and an additional intervention drug<br>* Other names: Placebo;|
| Experimental: Hydroxychloroquine and Azithromycin<br>HCQ 400 mg orally twice on Day 1, followed by 200 mg orally twice daily for an additional 9 days (Days 2 to 10) + azithromycin 500 mg orally once on Day 1, followed by 250 mg orally once daily for an additional 4 days (Days 2 to 5). | Drug: Hydroxychloroquine Sulfate<br>* Eligible participants in a household randomized to this study arm will receive hydrochloroquine and folic acid therapy<br>* Other names: Intervention A;Drug: Azithromycin<br>* Eligible participants in a household randomized to this study arm will receive hydrochloroquine and azithromycin therapy<br>* Other names: Intervention B;|
| Experimental: Lopinavir-ritonavir<br>LPV/r 800 mg-200 mg orally twice on Day 1, followed by 400 mg 100 mg orally twice daily for an additional 9 days (Days 2 to 10) | Drug: Lopinavir 200 MG / Ritonavir 50 MG [Kaletra]<br>* Eligible participants in a household randomized to this study arm will receive lopinavir-ritonavir therapy<br>* Other names: Intervention C;|
| Placebo Comparator: Ascorbic acid<br>Ascorbic acid 1 gm orally twice on Day 1, followed by 500 mg orally twice daily for 9 days | Drug: Ascorbic Acid<br>* Eligible participants in a household randomized to this study arm will receive ascorbic acid only or ascorbic acid and additional drug therapy<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Persons With Lower Respiratory Tract Infection (LRTI), Defined as Resting Blood Oxygen Saturation (SpO2<93%) Level Sustained for 2 Readings 2 Hours Apart and Presence of Subjective Dyspnea or Cough | Resting blood oxygen saturation (SpO2<93%) level sustained for 2 readings 2 hours apart and presence of subjective dyspnea or cough | 28 days from enrolment | 
| Number of Participants With Hospitalization or Mortality | Number of participants with hospitalization or mortality | Day 28 after enrolment | 
| Time to Clearance of Nasal SARS-CoV-2 | Time to clearance of nasal SARS-CoV-2, defined as 2 consecutive negative swabs | Day 1 through Day 14 after enrolment | 
| Time to Resolution of COVID-19 Symptom Resolution in Days | COVID-19 symptoms are based on the following criteria: At least TWO of the following symptoms: Fever (≥ 38ºC), chills, rigors, myalgia, headache, sore throat, new olfactory and taste disorder(s), OR At least ONE of the following symptoms: cough, shortness of breath or difficulty breathing, OR Severe respiratory illness with at least 1 of the following: Clinical or radiological evidence of pneumonia, OR Acute respiratory distress syndrome (ARDS), OR LRTI, defined by resting SpO2<93% sustained for 2 readings 2 hours apart AND presence of subjective dyspnea or cough Death or COVID-19-related hospitalizations will count as a failure to resolve symptoms. | Day 1 through Day 14 after enrolment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serious Adverse Events and Adverse Events Resulting in Treatment Discontinuation | Serious adverse events (including death and hospitalization) and adverse events resulting in treatment discontinuation | 28 days from enrolment | 
| COVID-19-related Hospitalization Days | Duration of hospitalization among persons who become hospitalized with COVID-19 disease | 28 days from enrolment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Outpatient, Treatment, COVID-19