Clinical trial NCT04491994
Conditions: Covid19 Progression
Keywords: COVID-19 viral clearance , mild infection disease progression trial HCQ
Sponsor: UNICEF
Start date: 2020-04-10; Completion date: 2020-05-31
Enrollment: 540 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Brief Summary: Purpose of this study is to evaluate efficacy of hydroxychloroquine (HCQ) in reducing progression of Corona Virus Disease 2019 (COVID - 19) and achieving viral clearance.

Condition or disease :I COVID-19 ntervention/treatment :Drug: Hydroxychloroquine Sulfate Phase: Phase III

Detailed description:
This study explores efficacy of HCQ (400mg BD on D0 and 200mg BD D1-D5) in reducing progression of Mild Covid-19 patients and decreasing viral load.

Participants of study will be randomized 2:1 to receive either Active drug or standard of care (SOC) treatment respectively. We aim to demonstrate reduced COVID-19 progression and early viral clearance in individuals on HCQ therapy.

Arms: arm 1: Patients selected in supportive arm will be given daily standard doses of oral Vit C (2g), Vit D (alfacalcidiol 1µg), Zinc (50mg) and paracetamol (as required). arm 2: Patients selected in experimental arm will be given Tab HCQ (400mg BD on D0 followed by 200mg BD D1-D5) in addition to supportive treatment
Interventions: intervention 1: HCQ
Intervention descriptions: intervention 1: Tab HCQ 400mg 12 hourly day 0 followed by tab HCQ 200mg 12 hrly for next 5 days

Protocol documents:
Prot_SAP_000.pdf: 
Clearing the fog: Is Hydroxychloroquine effective in reducing Corona virus disease 2019 
progression: A randomized controlled trial 
Registration NO: ID: NCT04491994 
Date: 15 May 2020 
Study design, setting and participants: This single Centre, parallel open label randomized 
controlled trial was carried out during 10th April to 31st May 2020 at department of Pulmonology, 
Pakistan Emirates Military Hospital (PEMH) over 500 patients from both genders between 18-80 
years of age. The study design was approved by institutional ethical review committee. The study 
population was comprised of patients from both genders with Mild confirmed COVID-19 after 
their written consent. The study protocol and approval documents are available online at 
ClinicalTrials.gov with trial number of NCT04491994. 
Sample size calculation: Sample size was calculated using OPEN EPI with 5% level of 
Confidence and 80% power to detect a difference and enrolment ration 2:1 between intervention 
and control group, at a two-sided significance level of α=0.05, of 7 days in the median time to 
clinical improvement between the two groups, assuming that the median time in the SOC group 
was 14 days and assuming 55% efficacy of HCQ in preventing disease progression and achieving 
viral clearance at day 7. Calculated sample size was 467, however we used a sample size of 500. 
Enrolment procedure: During study period, 672 confirmed PCR positive cases were assessed for 
eligibility. 132 did not meet selection criteria and subsequently excluded. 540 patients were then 
enrolled and randomized. Further 20 patients were excluded from analysis as 15 withdrew consent 
and 5 became symptomatic before first dose of HCQ. During follow up 13 patients were found to 
be deviated from advised therapy and 7 were lost to follow up yielding a final study population of 


500. Figure 1 summarizes this process. Randomization rules were designed by Dr. Wasim 
Alamgir together with principal investigators and implemented by an independent statistician who 
was not involved in data analysis. Stratified random sampling was applied to stratify all eligible 
patients according to age, gender and comorbidities. Computerized random number generator was 
used and allocation was done in 2:1 sequence. Cards with each group assignment number randomly 
generated by computer were placed in sequentially numbered envelopes that were opened as the 
patients were enrolled 
Interventions: A total of 349 patients included in intervention group and 151 in control group.  In 
Hospital, HCQ was given to patients after written consent and after considering its 
contraindications. Three hundred and forty-nine (349) patients were included in intervention group 
and given HCQ in addition to standard of care treatment. After 12 hours of randomization HCQ 
was given. Standard dose of HCQ was 400 mg by mouth twice a day for day one followed by 200 
mg 12 hourly for next 5 days. The patients who did not give consent for treatment with HCQ or 
had a known allergy to HCQ or chloroquine or had another known contraindication to treatment 
with the study drug, including retinopathy, G6PD deficiency and QT prolongation served as 
controls. Controls were matched with participants on the basis of age, gender and co morbids and 
comprised of 151 patients. Standard of care (SOC) treatment comprised of daily oral Vit C (2gms), 
oral Zinc (50mg), oral Vit-D (alfacalcidol 1ug) and tablet Paracetamol (for body aches/fever), 
intravenous fluids, hemodynamic monitoring, and laboratory testing for SARS-CoV-2 and 
baseline blood parameters. Neither patients, nor investigators, nor statisticians were masked to 
treatment assignment. Lab staff who performed sampling for PCR, basic blood tests and other 
routine measurement were unaware of treatment information.  Data regarding age, co-morbidities, 
history of contact with a positive patient, days since contact, duration of symptoms, PCR status 


with date and base line labs/X-ray chest were recorded.  Any patient with day 0 CRP greater than 
6mg/dl, Absolute lymphocyte count (ALC) < 1000 or evidence of infiltrates on X-ray chest were 
excluded.  Daily temperature, respiratory rate (RR) and resting O2 saturation with pulse oximetry 
were monitored in all patients during their hospitalization. 
Operational definitions: A case was considered confirmed on the basis of positivity of RT-PCR 
of combined Oropharyngeal and Nasopharyngeal swabs. Severity of disease was defined as per 
criteria designed by WHO11. Mild disease meant Patients with uncomplicated upper respiratory tract 
viral infection having non-specific symptoms such as low-grade fever (fever < 100F for < 3 days), 
fatigue, body aches, cough (with or without sputum production), anorexia, muscle pain, sore throat, 
nasal congestion, anosmia, headache and rarely diarrhea, nausea, and vomiting.  PCR sampling 
was done on day 7 and 14 of admission. Any chronic health condition for which patients were on 
prior treatment was considered as co morbidity. After start of treatment, development of fever > 
101 F for > 72 hours, shortness of breath by minimal exertion (10-Step walk test), derangement of 
basic lab parameters (ALC < 1000 or raised CRP) or appearance of infiltrates on CXR during 
course of treatment was labeled as progression irrespective of PCR status. PCR status of patients 
was checked after 7 days and 14 days of initiation of treatment.  
Inclusion and exclusion criteria: Inclusion criteria included (1) Mild Corona virus disease 
(COVID-19) (2) PCR confirmed infection (3) Hospital admitted patients (4) 18-80 years age 
Exclusion criteria were (1) Moderate, severe and critical COVID-19 (2) day 0 CRP greater than 
6mg/dl, ALC < 1000 or evidence of infiltrates on X-ray chest (3) comorbidity with life expectancy 
less than 6 months (4) Contraindications to HCQ therapy. 
Outcomes: Primary outcome was disease progression within 5 days of start of treatment. This was 
defined by development of fever > 101 F for > 72 hours, shortness of breath by minimal exertion 


(10- Step walk test), derangement of basic lab parameters (ALC < 1000 or raised CRP) or 
appearance of infiltrates on CXR. Patients underwent 6 hourly axillary temperature check, daily 
10 feet walk test, daily Blood counts, CRP and X-Rays on day 0, 3 and 5.  
Secondary outcome was Viral clearance. PCR negativity on day 7 and 14 after admission was 
recorded.  
Statistical analysis: Statistical interpretation of data was performed using Statistical Package for 
Social Sciences (SPSS) version 23. Results were expressed as mean, standard deviation (±SD) 
for all continuous variables and frequency and percentage for categorical data. We used t-test 
and chi-square test as appropriate to the nature and distribution of the variables. A p-value < 0.05 
was considered statistically significant.