Hydroxychloroquine, Oseltamivir and Azithromycin for the Treatment of COVID-19 Infection: An RCT

Study Overview
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Brief Summary
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To evaluate the effectiveness of Hydroxychloroquine Sulfate (200 mg orally 8hr thrice a day for 5 days) vs oseltamivir (75 mg orally twice a day for 5 days) vs Azithromycin (500 mg orally daily on day 1, followed by 250 mg orally twice a day on days 2-5) alone and in combination (in all seven groups), in clearing the coronavirus nucleic acid from throat and nasal swab and in bringing about clinical improvement on day 7 of follow-up (primary outcomes).

Detailed Description
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A scientific taskforce notified by the Ministry of Science and Technology of the Government of Pakistan will oversee a comprehensive cohort study. Within this cohort, a multicenter, adaptive, randomized controlled trial will evaluate, among eligible SARS-Cov-2 (COVID-19) infected patients receiving standard supportive care who consent to randomization following a new diagnosis in Pakistan, if Hydroxychloroquine Sulfate alone (control intervention) vs a series of alternatives (comparator interventions) including Oseltamivir and Azithromycin alone and in combination with Hydroxychloroquine Sulfate is effective in clearing the coronavirus and improving the clinical course of the disease. Those not consenting to randomization will be followed up for outcomes of SARS-Cov-2 infection with supportive care only. Findings of this study are expected to inform clinical care and public health protocols and policies for management of SARS-Cov-2.

Official Title
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Pakistan Randomized and Observational Trial to Evaluate Coronavirus Treatment

Conditions
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COVID 19

Intervention / Treatment
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* Drug: Hydroxychloroquine
* Drug: Oseltamivir
* Drug: Azithromycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed SARS-CoV-2 (COVID-19) infection by a positive test result Either gender Symptomatic for example fever, dry Cough, difficulty to breathe Exclusion Criteria: Confirmed absence of SARS-CoV-2 (COVID-19) infection by a negative test result Have chronic conditions such as heart disease, liver and kidney failure Pregnant or currently lactating Immunocompromise and/or systemic disease(s) On other antiviral drugs History of allergy to any of the drugs to be administered in this study

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: Adaptive design (sample size given below is indicative)
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control Intervention<br>Hydroxychloroquine | Drug: Hydroxychloroquine<br>* Hydroxychloroquine Sulfate (200 mg orally thrice a day for 5 days)<br>|
| Experimental: Comparator 1<br>Azithromycin | Drug: Azithromycin<br>* Azithromycin (500 mg orally once a day on day 1, followed by 250 mg orally daily on days 2-5)<br>|
| Experimental: Comparator 2<br>Oseltamivir | Drug: Oseltamivir<br>* Oseltamivir (75 mg orally twice a day for 5 days)<br>|
| Experimental: Comparator 3<br>Hydroxychloroquine + Azithromycin | Drug: Hydroxychloroquine<br>* Hydroxychloroquine Sulfate (200 mg orally thrice a day for 5 days)<br>Drug: Azithromycin<br>* Azithromycin (500 mg orally once a day on day 1, followed by 250 mg orally daily on days 2-5)<br>|
| Experimental: Comparator 4<br>Hydroxychloroquine + Oseltamivir | Drug: Hydroxychloroquine<br>* Hydroxychloroquine Sulfate (200 mg orally thrice a day for 5 days)<br>Drug: Oseltamivir<br>* Oseltamivir (75 mg orally twice a day for 5 days)<br>|
| Experimental: Comparator 5<br>Oseltamivir + Azithromycin | Drug: Oseltamivir<br>* Oseltamivir (75 mg orally twice a day for 5 days)<br>Drug: Azithromycin<br>* Azithromycin (500 mg orally once a day on day 1, followed by 250 mg orally daily on days 2-5)<br>|
| Experimental: Comparator 6<br>Hydroxyquinine + Oseltamivir + Azithromycin | Drug: Hydroxychloroquine<br>* Hydroxychloroquine Sulfate (200 mg orally thrice a day for 5 days)<br>Drug: Oseltamivir<br>* Oseltamivir (75 mg orally twice a day for 5 days)<br>Drug: Azithromycin<br>* Azithromycin (500 mg orally once a day on day 1, followed by 250 mg orally daily on days 2-5)<br>|
| No Intervention: Observational Cohort<br>Non-consenting to randomization | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Laboratory Result | The laboratory-based primary outcome will be turning test negative for COVID-19 on RT-qPCR calculated as viral load of < 150 i.u | Day 07 on follow-up | 
| Clinical Outcome | The clinical primary outcome will be improvement of two points on a seven-category ordinal scale shown below: Not hospitalized, able to resume normal activities Not hospitalized, but unable to resume normal activities Hospitalization, not requiring supplemental oxygen Hospitalization, requiring supplemental oxygen Hospitalization, requiring noninvasive mechanical ventilation Hospitalization, requiring invasive mechanical ventilation Death | Day 07 on follow-up |