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

Pakistan Randomized and Observational Trial to Evaluate Coronavirus Treatment

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).

Study Overview

• Status: Completed
• Conditions: COVID 19
• Intervention / Treatment: Drug: Hydroxychloroquine; Drug: Azithromycin; Drug: Oseltamivir

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 550
• Phase: Phase 3

Contacts and Locations

Study Locations

• Pakistan
  • Faisalābad, Pakistan
    • Faislabad Medical University
  • Gujrānwāla, Pakistan
    • Gujranwala Medical College
  • Gujrāt, Pakistan
    • Nawaz Sharif Medical College
  • Islamabad, Pakistan
    • Szabmu-Pims
  • Lahore, Pakistan
    • Akram Medical Complex
  • Lahore, Pakistan
    • Fatima Jinnah Medical University
  • Lahore, Pakistan
    • King Edward Medical University-Mayo Hospital
  • Lahore, Pakistan
    • Lahore general hospital
  • Peshawar, Pakistan
    • Khyber Teaching Hospital
  • Rawalpindi, Pakistan
    • Rawalpindi Medical University
  • Sargodha, Pakistan
    • Sargodha Medical College

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Confirmed SARS-CoV-2 (COVID-19) infection by a positive test result
2. Either gender
3. Symptomatic for example fever, dry Cough, difficulty to breathe

Exclusion Criteria:

1. Confirmed absence of SARS-CoV-2 (COVID-19) infection by a negative test result
2. Have chronic conditions such as heart disease, liver and kidney failure
3. Pregnant or currently lactating
4. Immunocompromise and/or systemic disease(s)
5. On other antiviral drugs
6. History of allergy to any of the drugs to be administered in this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

8

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Shehnoor Azhar
• Investigators: Principal Investigator: Javed Akram, FRCP, University of Health Sciences Lahore

Publications and helpful links

General Publications

• Azhar S, Akram J, Shahzad M, Latif W, Khan KS. Protocol of Pakistan randomized and observational trial to evaluate coronavirus treatment among newly diagnosed patients with COVID-19: Azithromycin, Oseltamivir, and Hydroxychloquine. Pak J Med Sci. 2022 May-Jun;38(5):1401-1408. doi: 10.12669/pjms.38.5.5512.
• Akram J, Azhar S, Shahzad M, Latif W, Khan KS. Pakistan Randomized and Observational Trial to Evaluate Coronavirus Treatment (PROTECT) of Hydroxychloroquine, Oseltamivir and Azithromycin to treat newly diagnosed patients with COVID-19 infection who have no comorbidities like diabetes mellitus: A structured summary of a study protocol for a randomized controlled trial. Trials. 2020 Aug 8;21(1):702. doi: 10.1186/s13063-020-04616-4. Erratum In: Trials. 2020 Aug 22;21(1):733. Trials. 2022 Feb 15;23(1):150.

Study record dates

Study Major Dates

• Study Start (Actual): April 22, 2020
• Primary Completion (Actual): November 15, 2020
• Study Completion (Actual): November 22, 2020

Study Registration Dates

• First Submitted: April 4, 2020
• First Submitted That Met QC Criteria: April 4, 2020
• First Posted (Actual): April 8, 2020

Study Record Updates

• Last Update Posted (Actual): February 10, 2022
• Last Update Submitted That Met QC Criteria: January 27, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antirheumatic Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Azithromycin; Hydroxychloroquine; Oseltamivir
• Other Study ID Numbers: 12(06)/2016-Coord

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: On completion of study, investigators are open to participation in planned IPD projects with a prospective registration, subject to appropriate approvals

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No