Anti-COVID property of subcutaneous ivermectin in synergy with zinc among midlife moderately symptomatic patients: a structured summary of a study protocol for a randomised controlled trial
Authors: Ashraf Shoaib , Ashraf Sohaib , Farooq Iqra , Ashraf Sidra , Ashraf Moneeb , Imran Muhammad Ahmad , Kalsoom Larab , Akmal Rutaba , Ghufran Muhammad , Rafique Sundas , Akram Muhammad Kiwan , Habib Zaigham , Siddiqui Uzma Nasim , Ahmad Ammara , Arshad Shahroze , Virk Muhammad Abdul Rehman , Gul Mehak , Awais Abeer bin , Hassan Muhammad , Sherazi Syed Sami Hussain , Safdar Zartasha , Munir Isra , Khalid Hamna , Munir Khalid , Majeed Nighat , Alahmadi Yaser Masuod , Humayun Ayesha , Saboor Qazi Abdul , Ahmad Ali , Ashraf Muhammad , Izhar Mateen ,   DOCTORS LOUNGE Consortium, Hilal Abubakr , Muhammad Arz , Shaukat Zeeshan , Ahmad Sohail , Hayat Kanwal , Amjad Ghazala , Kousar Misbah , Hafsa Hadiqa Tul , Choudhary Zawar Ahmad , Hafeez Umair , Mughal Tayyab , Khalid Noman , Iqbal Qurat-ul-Ain , Umer Roa , Muzafar Tayyaba , Zulfiqar Sibgha , Alam Saadia Shahzad , Sarfraz Saulat , Anwar Muhammad Imran , Malik Amber , Mahmud Talha , Akmal Adeen , Nadeem Muhammad Faisal , Matti Nazish , Azam Muhammad , Majeed Nighat , Arshad Ali , Nawaz Khawar , Yousaf Muhammad Ismail Khalid , Baig Aadil Maqsood Atif Amin , Bilal Muhammad , Zahid Muhammad Nauman 
Published: September 2021

Abstract
Objectives
The study objective is to quantify the effectiveness of ivermectin (subcutaneous/oral IVM) in the presence or absence of zinc (Zn) for clinical and radiological improvement in coronavirus disease 2019 (COVID-19) patients with moderate severity.

Trial design
This quadruple-blinded, placebo-controlled randomized clinical trial will be a multiarmed multi-centered study with superiority framework.

Participants
Quinquagenarian and sexagenarian patients with moderate COVID-19 symptoms and positive severe respiratory syndrome coronavirus -2 (SARS-CoV-2) PCR will be included. Participants with co-morbidities and pregnant women will be excluded.
Patient recruitment will be done in Shaikh Zayed Medical Complex, Doctors Lounge and Ali Clinic in Lahore (Pakistan).

Intervention and comparator
The registered patients will be allocated in 6 groups (30 participants each). Patients will be taking subcutaneous IVM at 200 μg/kg/48 h (Arm A) or subcutaneous IVM at 200 μg/kg/48 h and oral Zn 20mg/8 h (Arm B) or oral IVM at 0.2 mg/kg/day (Arm C) or oral IVM at 0.2 mg/kg/day and oral Zn 20mg/8 h (Arm D) or alone oral Zn 20mg/8 h (Arm E) or placebo alone (Arm X). Patients in all arms will receive standard care and respective placebo (empty capsule 8 hourly and/or subcutaneous normal saline 2ml/48 h).

Main outcomes
Primary endpoints will be duration of symptomatic phase and SARS-CoV-2 clearance along with high resolution CT (HRCT) chest score and clinical grade scale (CGS) on day 6. 30-day mortality will be documented as a secondary endpoint. SARS-CoV-2 clearance will be calculated by second PCR on day 7. HRCT chest score will be measured by the percentage and lung lobes involvement on day 6 with a maximum score of 25. CGS will be recorded on a seven-point scale; grade 1 (not hospitalized, no evidence of infection and resumption of normal activities), grade 2 (not hospitalized, but unable to resume normal activities), grade 3 (hospitalized, not requiring supplemental oxygen), grade 4 (hospitalized, requiring supplemental oxygen), grade 5 (hospitalized, requiring nasal high-flow oxygen therapy and/or noninvasive mechanical ventilation), grade 6 (hospitalized, requiring ECMO and/or invasive mechanical ventilation) and grade 7 (death).

Randomisation
A simple lottery method will be used to randomly allocate scrutinized patients in 1:1:1:1:1:1 ratio in 6 groups.

Blinding (masking)
Patients, primary care physicians, outcome assessors and the data collection team will be blinded.

Numbers to be randomised (sample size)
180 participants will be randomized into six arms with five investigational and one placebo group.

Trial Status
Institutional Review Board Shaikh Zayed Post-Graduate Medical Complex, Lahore, Pakistan has approved the protocol (version 2.3) with ID SZMC/IRB/Internal0056/2020. The trial was approved on July 14, 2020, and enrolment started on July 30, 2020. The estimated completion date is October 30, 2021.

Trial registration
Clinical Trial has been retrospectively registered on www.clinicaltrials.gov with registration ID NCT04472585 dated July 16, 2020.

Full protocol
The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). With the intention of expediting dissemination of this trial, the conventional formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines.