Clinical trial NCT04523831
Conditions: Covid19
Keywords: Covid-19, Ivermectin
Sponsor: Dhaka Medical College
Start date: 2020-06-01; Completion date: 2020-09-10
Enrollment: 400 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
On 31 December 2019, the World Health Organization (WHO) was formally notified about a cluster of cases of pneumonia in Wuhan City, China. On 7 January the responsible virus was isolated and its genome sequence was shared on 12 January. It was named as COVID-19, a novel Coronavirus, SARS-CoV-2. It is a member of the Corona virus family which is RNA enveloped viruses.

Very rapidly the virus emerged as pandemic. Now it is dominating the lives of every people of this universe. Management of the COVID-19 relies on mainly supportive care and oxygen supplementation via non-invasive or mechanical ventilation in critical cases. Patients who are critically ill may also require vasopressor support and antibiotics for secondary bacterial infections.

There is no vaccine or highly effective antiviral drugs for COVID-19. Currently there is a tremendous effort around the world to develop effective preventive and therapeutic treatment for this disease.

World Health Organization has launched a non-blinded clinical trial (SOLIDARITY) to evaluate four candidate treatments (remdesivir, lopinavir/ritonavir, lopinavir/ritonavir/ interferon beta-1a, and chloroquine or hydroxychloroquine) versus standard of care in 18 countries worldwide. RECOVERY trial one of the largest trials to see the efficacy and safety of hydroxychloroquine revealed that they are no clear cut clinical benefit for COVID-19. Other drugs in the SOLIDARTY trial are quite expansive for resource limited countries like Bangladesh.

Study Published in the American Journal of Tropical Medicine advocates further research into Ivermectin for COVID-19 Treatment. The spotlight on Ivermectin was brought by Australian researchers from Monash University who demonstrated its efficacy against the SARS-CoV-2 coronavirus in vitro studies.

In different study Doxycycline also showed promising results in treatment of COVID 19 infection. It is highly lipophilic antibiotics that are known to chelate zinc component of matrix metalloprotienases (MMP). Corona viruses are known to rely heavily of MMPs for survival, cell infiltration and replication. It also has an anti-inflammatory effect which might be effective in combating cytokine storm of Covid-19 infection.

So it have been planned to conduct an experimental clinical trial using combination of ivermectin and doxycycline for treatment of COVID 19 along with the other standard care.

Detailed description:
OBJECTIVES:

General objectives:

To observe the benefit (clinical and microbiological) of Ivermectin and Doxycycline in Confirmed Covid 19 cases.

Specific objectives:

1. To observe the clinical outcome in trial group and the placebo group.
2. To observe the duration require controlling viral replication (negative RT-PCR) in the trial and placebo group.
3. To compare the outcome between the two groups.

RATIONALE:

Covid-19 is an emergent pandemic, threatens the life of millions of the people throughout the globe. There is increasing effort of the scientist to unveil a remedy of covid-19. Still it is unsuccessful. At present there is no other alternative other than experimenting the existent drug against the virus. There are several trials going throughout the globe. Among them Ivermectin showed good efficacy in vitro trial. Some clinical trial also proved it beneficial. The Doxycycline also has some anti viral role with its prominent anti-inflammatory role. Synergistic action of the two drugs might be proved some benefit in clinical trial. As both drugs are cheap and less toxic, if it does, it would be the blessing for the poor people of the globe.

METHODOLOGY:

Study type: Interventional Clinical trial Estimated enrollment: 200 participants per group

For superior trial, the formula is:

N=size per group; p=the response rate of standard treatment group; p0= the response rate of new drug treatment group; zx= the standard normal deviate for a one or two sided x; d= the real difference between two treatment effect; δ0= a clinically acceptable margin; S2= Polled standard deviation of both comparison groups.

All parameters were assumed as follows: p =0.40; p0=0.58; α=0.05;β=0.20; δ=0.18; δ0=0.10.

However, we are assuming that lost to follow up or refuse to include in trial will be 20%, that means 24. So at least 150 patients will be allocated randomly and power of this study will be 80%.

Allocation: Randomized Intervention model: Parallel assignment Intervention model description: Patient will be randomized 1:1 to placaebo with standard care and combined doxycycline and ivermectin with standard care.

Blinding: Double blind (The participant and the clinicians/data collectors will be unaware of the treatment the participant receives) Primary purpose: Treatment Official title: A phase III trial to promote recovery from covid 19 with combined Doxycycline and Ivermectin along standard care. Provider of placebo and active ingredients: Popular pharmaceutical limited Dosage of the drugs: Ivermactin 6 mg 2 tab stat, cap Doxycycline 100 mg 1 cap BD 5 days

Data collection technique:

Data will be collected by assigned. trained data collectors (Physician). Patient will be enrolled according to defined inclusion and exclusion criteria in the current research. Informed written consent will be obtained from the patient or their relatives. Each patient participating in the trial will be uniquely identified, and information such as his name, address is recorded in the trial 'subject number list'. Only the principle investigator will be aware about the allocation of the drugs. The patients and the data collectors will be unaware about the group allocation of the drugs. The Data will be reviewed by the co-investigators. It will be managed by principle and co-principle investigators in designated computer.

Clinical assessment (fever, cough, Anorexia, Temperature, pulse, blood pressure, respiratory rate, oxygen saturation) will be done every day. Routine investigation (CBC, ESR, CRP, Creatinine, RBS, SGPT, chest x-ray, D- Dimer) will be done at admission and at day 3, 5, 7, 10 and 14 day. In case of the clinical deterioration it would done according to necessity. RT-PCR will be done at day-0, Day 5, day 7 and day 14.

Standard care: both the experimental and placebo will receive the available standard of care, like-

* Paracetamol, Antihistamine, Cough suppressant, Vitamins
* Oxygen therapy according to indication and need
* Low molecular weight heparin according to indication
* Appropriate other broad spectrum antibiotics
* Other drugs for associated co- morbid condition

Management of the adverse events:

Drugs adverse effect will be monitored by a defined committee. The patient experiencing adverse effect of the drugs will be discontinued from the study. It will be managed with priority to the highest possible level by the hospital authority as well as the investigators.

If the patient progresses from mild to moderate or severe disease, the study will be continued and available management of the appropriate severity will be immediately started. The patient will be monitored closely.

Data analysis:

Data will be analyzed by computer with the help of SPSS (Statistical Package for Social Sciences) version 26. Unpaired t-test would be used for testing quantitative data and for testing qualitative data two sample z- test will be used. Comparing drug outcome in between two groups hazard ratio, Kaplan-Meire curve will be used.

Dropout management: Likelihood based methods such as mixed models will be used to estimate unbiased treatment effects, under assumptions regarding the missingness mechanisms.

Arms: arm 1: Ivermactin 6 mg 2 tab stat, cap Doxycycline 100 mg 1 cap BD 5 days arm 2: Standard treatment
Interventions: intervention 1: Ivermectin and Doxycycline intervention 2: Standard of care
Intervention descriptions: intervention 1: Ivermectin 6 mg, 2 tab stat and Doxycycline 100 mg twice daily for 5 days intervention 2: Paracetamol, Vitamin D, Oxygen if indicated, Low molecular weight heparin, dexamethasone if indicated

Protocol documents:
Prot_ICF_000.pdf: 
 
 
1
Research Protocol 
Version-2 
 
 
 
 
A Randomized, Double-Blind Placebo Controlled 
Clinical Trial of Ivermectin plus Doxycycline for the 
Treatment of Confirmed Covid -19 Infection 
 
 
Principal Investigator 
 
Dr. Reaz Mahmud 
FCPS (Medicine), MD (Neurology) 
Assistant Professor  
Department of Neurology 
Dhaka Medical College, Dhaka 
 
Trial Registration: ClinicalTrials.gov Identifier: NCT04523831. 
Document date: 26.08.20 
 
 


 
 
2
Amendment Approval 
 
 


 
 
3
 
Part A 
Project Title: A Randomized, Double-Blind Placebo Controlled Clinical Trial of Ivermectin 
plus Doxycycline for the Treatment of Confirmed Covid -19 Infection 
 
1. Principal Investigator: 
 
Name 
Designations & place of posting 
Dr. Reaz Mahmud 
Assistant 
Professor, 
Department 
of 
Neurology, Dhaka Medical College 
 
2. Co-Principal investigators: 
Name 
Designations & place of posting 
Professor Mujibur Rahman 
Professor and Head, Department of Medicine, 
Dhaka Medical College 
Dr. Iftikher Alam 
Assistant 
Professor, 
Department 
of 
Neurology, Dhaka Medical College 
Dr. Kazi Gias Uddin Ahmed 
Associate Professor and Head, Department of 
Neurology, Dhaka Medical College 
Dr. AKM. Humayon Kabir 
Associate 
Professor, 
Department 
of 
Medicine, Dhaka Medical College 
 
3. Co-investigators: 
Name 
Designations& place of posting 
Dr. S. K Jakaria Been Sayeed 
Indoor Medical Officer, Department of 
Medicine, Dhaka Medical College. 
Dr. Mahfuzul Haque 
Assistant Professor, Department of Medicine, 
Dhaka Medical College 
Dr.MD. Shahidul Islam 
Junior 
Consultant, 
Medecine, 
Sarkari 
Karmachari Hospital, Dhaka. 
DR. Mohammed Monirul Islam 
 
Assistant Surgeon, MoHFW 
 
 
Dr. Mohammad Aftab Russel 
Medical officer, OSD, MD Thesis part 
student, Department of Neurology, Dhaka 
Medical College 
Dr. Anindta Barshan 
Indoor Medical Officer, Department of 
Medicine, Dhaka Medical College 
Dr. Farhana Binte Monayem 
Medical 
Officer, 
Sarkari 
Karmachari 
Hospital,Dhaka. 
Dr. Mohammad Zaid Hossain 
Associate 
Professor, 
Department 
of 
Medicine, Dhaka Medical College 
Dr. Mohammad Abdullah Yusuf 
Assistant 
Professor, 
Department 
of 
Microbiology, 
National 
Institute 
of 
Neurosciences and Hospital. 


 
 
4
 
 
4. Place of the study/Institution(s): 
Covid-19 Dedicated Unit, Dhaka Medical College Hospital. 
5. Sponsoring/Collaborating Agencies: 
None 
6. Duration: 
03 months (June 2020 to August 2020). 
7. Date of Commencement: 
01, June 2020 
8. Date of Completion:  
25, August 2020 
9. Total Cost: Not estimated 
  
10. Other Support for Proposed Research: 
(1) Is this research project being   
 
 
 
 
No  
 
 
supported by any other source? 
(2) Has an application for funding of  
 
 
 
 
No  
 
 
this project been submitted to any  
 
 
other organization(s)? 
 
11.  
Date of Submission  : 16-06-2020 
 
 
 
 
 
 
 
 
 
 


 
 
5
 
: 
 
 
PART – B 
 
PRINCIPAL INVESTIGATOR(S) INFORMATION SHEET 
 
1.  
(i)  
Name :Dr. Reaz Mahmud 
 
(ii)  
Designation: Assistant Professor, Neurology 
 
(iii)  
Official Address with telephone: Dhaka Medical College Hospital, Dhaka. 
 
 
Phone: 01912270803 
(iv)     Present Residential Address with telephone: Road # 07, House # 13 
Abdullah bagh,  Uttar Badda, Badda Dhaka. 
4. Academic Background: 
 
Degree   
University                   
              Field                 
Year 
MBBS 
Dhaka University 
 
May,2003 
FCPS 
BCPS 
Medicine 
January,2013 
MD 
Dhaka University 
Neurology 
June,2015 
 
5. Field of Specialty: 
Medicine & Neurology 
 
 
 


 
 
6
 
6. (a)  Research Experience : 
1. Association between Hypertensive retinopathy and 
Lacunar stroke. 
Done for FCPS Dissertation 
2. Risk Factors and Morphological Differences of 
Ruptured Saccular Aneurysm in different sites of Anterior 
Circulation in Patients presenting with Subarachnoid 
Haemorrhage 
Done for MD thesis 
3. Recent sensitivity Pattern of Salmonella Typhi in a 
private hospital. 
Done for Research 
 
 
(b)  Other Experience: 
 
 
 
Teaching: 
 
 
 
1. Assistant Registrar cardiology NICVD, 03-08-09 to 21-06-10 
2. Assistant Registrar Medicine, Faridpur Medical college Hospital, Faridpur 23-06-10 to 
31-06-12 
 
Administration: 
 
Work as a Departmental Head, Critical Care Medicine, Sarkari Karmachari Hospital from 
01-11-2016 to 04-12-2019 
Others: 
 
 
 
 


 
 
7
5.  
Number of Scientific Publications:  
 
 
Sl No 
National/ 
International 
Original/ 
review 
Authorship 
Reference 
1 
National 
Original 
Co-author 
Ali M Y, Mahmud R. A case report on 
Lepra Reaction Type II.  Faridpur Medical 
college journal 2012;  2 : 93-97 
2 
National 
Original 
Author 
Mahmud R, Ali MY, Islam MS, Shanewaz 
S, Rabbani G, Manayem FB. Association 
Between Hypertensive Retinopathy and 
Lacunar Infarct- A Study in Faridpur  
Medical College Hospital. DCIMC J 2016; 
3(2):27-33 
 
3 
National 
Original 
Co-author 
Saha R, Mahmud R, Hossain MZ,Sarker 
PK. Families with Neurocutaneous 
Syndrome:Report of two cases.Dhaka Med 
Coll J 2013; 22(1): 102-107. 
 
4 
National 
Original 
Author 
Mahmud R, Habib M, Uddin S,Risk Factors 
and Morphological Differences of Ruptured 
Saccular Aneurysm in Different Sites of 
Anterior Circulation in Patients Presenting 
with Subarachnoid Haemorrhage. Journal of 
National 
Institute 
of 
Neurosciences 
Bangladesh. January 2017; 3(1):21-28. 
 
5 
National 
Original 
Author 
Islam K, Mahmud R. Recent sensitivity 
Pattern of Salmonell Typhi in a private 
hospital.J Medicine 2018; 19: 15-17 
6 
National 
Original 
Author 
Mahmud R, Habib M. Huntington's Disease 
with Retinitis Pigmentosa- a Case Report. 
Faridpur Med. Coll. J 2017;12(1):50-52. 
7 
National 
Original 
Co-Author 
Ghose, S., Ahmed, K. G., Chowdhury, A., 
Hasan, A., Saha, K., Mahmud, R., Joy, N., 
Biswas, R., Sarkar, M. S., Rahman, M. M., 
Sina, H., Arifuzzaman, M., Alam, I., 
Hossain, M. M., Karim, A., & Habib, M. 
(2018). 
Assessment 
of 
Initial 
Stroke 
Severity by National Institute Health Stroke 
Scale (NIHSS) Score at Admission. Journal 
of Dhaka Medical College, 26(2), 90-93. 
https://doi.org/10.3329/jdmc.v26i2.38765 
 


 
 
8
 
 
PART - C 
 
Project Title: A Randomized, Double-Blind Placebo Controlled Clinical Trial of 
Ivermectin plus Doxycycline for the Treatment of Confirmed Covid -19 Infection. 
1. Summary: 
On 31 December 2019, the World Health Organization (WHO) was formally notified about a 
cluster of cases of pneumonia in Wuhan City, China. On 7 January the responsible virus was 
isolated and its genome sequence was shared on 12 January.  It was named as COVID-19, a 
novel Coronavirus, SARS-CoV-2. It is a member of the Corona virus family which is RNA 
enveloped viruses. 
Very rapidly the virus emerged as pandemic. Now it is dominating the lives of every people 
of this universe. Till date 75,53,182 confirmed cases of COVID-19, including 
4,23,349 deaths, reported to WHO. In Bangladesh cases as well as the death tolls are also 
increasing exponentially (84,379 cases and 1,139 death). 
Management of the COVID-19 relies on mainly supportive care and oxygen supplementation 
via non-invasive or mechanical ventilation in critical cases. Patients who are critically ill may 
also require vasopressor support and antibiotics for secondary bacterial infections. 
There is no vaccine or highly effective antiviral drugs for COVID-19. Currently there is a 
tremendous effort around the world to develop effective preventive and therapeutic treatment 
for this disease.  
 World Health Organization has launched a non-blinded clinical trial (SOLIDARITY) to 
evaluate four candidate treatments (remdesivir, lopinavir/ritonavir, lopinavir/ritonavir/ 
interferon beta-1a, and chloroquine or hydroxychloroquine) versus standard of care in 18 
countries worldwide. RECOVERY trial one of the largest trials to see the efficacy and safety 
of hydroxychloroquine revealed that they are no clear cut clinical benefit for COVID-19. 
Other drugs in the SOLIDARTY trial are quite expansive for resource limited countries like 
Bangladesh. 
Study Published in the American Journal of Tropical Medicine advocates further research 
into Ivermectin for COVID-19 Treatment. The spotlight on Ivermectin was brought by 
Australian researchers from Monash University who demonstrated its efficacy against the 
SARS-CoV-2 coronavirus in vitro studies. 
In a recent international, multicenter, propensity-score matched case- controlled study using 
prospectively collected data on patients diagnosed with COVID 19 by Patel et al, observed 
substantial benefit using Ivermectin over standard care. 


 
 
9
In different study Doxycycline also showed promising results in treatment of COVID 19 
infection. It is highly lipophilic antibiotics that are known to chelate zinc component of 
matrix metalloprotienases (MMP). Corona viruses are known to rely heavily of MMPs for 
survival, cell infiltration and replication. It also has an anti-inflammatory effect which might 
be effective in combating cytokine storm of Covid-19 infection. 
So it have been planned to conduct an experimental clinical trial using combination of 
ivermectin and doxycycline for treatment of COVID 19 along with the other standard care. It 
would be a randomized double blind placebo controlled Trial. The study would be conducted 
on 200 confirmed cases of Covid- 19. Another 200 patients will receive placebo. 
The primary outcome would be the Days required for the Clinical improvement of the 
patients from the day of randomization. 
 Data will be analyzed using SPSS 20. Unpaired t-test would be used for testing quantitative 
data and for testing qualitative data two sample z- test would be used. For the comparison 
between two groups Hazard ratio, Kaplan-Meire curve, binary logistic regression would be 
used to see the outcome.  Result of the study and statistical analysis will be presented by 
tables, figures, graphs, diagrams, charts and photographs. All these will have own legends 
(i.e. title) and will be serially numbered. Discussion will be done on the basis of result 
obtained from the study and comparing with similar studies done at home and abroad. 
Summarization will be drawn after discussion. Conclusion will be drawn depending upon the 
results and discussion. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
10
 
PART - D 
INTRODUCTION 
On 31 December 2019, the World Health Organization (WHO) was formally notified 
about a cluster of cases of pneumonia in Wuhan City1. On 7 January the causative virus 
was isolated and its genome sequence was shared on 12 January. The cause of the severe 
acute respiratory syndrome that became known as COVID-19 was a novel corona virus, 
SARS-CoV-22. The virus Spread quickly through out the universe in quick succession. 
The World Health Organization (WHO) on March 11, 2020, has declared the novel 
Corona virus (COVID-19) outbreak a global pandemic3. 
 Phylogenetic analysis suggests that SARS-CoV-2 originated in animals, probably bats, 
and was transmitted to other animals before crossing into humans at the Huanan wet 
market in Wuhan City4-5.  It was the year 1918, when a new flu pandemic launched 
worldwide The  pandemic infected  3% to  5% percent  of  the  world's population  
including remote  Pacific  islands  and  the  Arctic. The Life expectancy dropped by about 
12 years6. The fatal casualties of the diseased had reached the number of the fifty million 
victims7.  
That dreadful experience might be compared with the recent ongoing pandemic. By 13 
june 2020, there have been 75,53,182 confirmed cases of COVID-19, including 
4,23,349 deaths, reported to WHO8. Most of the countries of the word are in strict 
lockdown state. Now it is dominating the lives of every people of this universe. The 
Economy of the world also constricted. In Bangladesh cases as well as the death tolls are 
also increasing exponentially. Our Economy is also shrinking day by day. 
While the clinical presentation of COVID-19 ranges from asymptomatic to fulminant and 
fatal, severe cases of infection can develop pneumonia, acute respiratory distress 
syndrome, sepsis and/or multiple organ failure which are not unique to coronavirus9. 
Death is due to pneumonia and possibly hyper-inflammation associated with cytokine 
storm syndrome10. 
Management of the COVID-19 relies on mainly supportive care. Approximately 14% of 
the Covid-19 patients develop severe disease that requires hospitalization and oxygen 
support, and 5% require admission to an intensive care unit11. 
There is no vaccine or specific antiviral drug for COVID-19 for which the people of the 
world are craving. 
Worldwide the scientific community has focused on developing and/or repurposing 
medicines that can target SARS-Cov 2 and help control the pandemic of COVID-19. 


 
 
11
Repurposing currently available medicines against COVID-19 has led to the development 
of hundreds of trials worldwide. Therapeutics under investigation includes various 
antiviral and immunomodulatory medicines12. 
Table: 1 All drugs used for COVID-19 in vitro lab and in vivo (clinical) human 
studies published from January 202013. 
 
 
 
 
 
 
 
 
 
Many studies carried out independently in small group of people but there is a risk that 
the trials will lack statistical strength.  
World Health Organization has launched a nonblinded clinical trial (SOLIDARITY) to 
evaluate four candidate treatments (remdesivir, lopinavir/ritonavir, lopinavir/ritonavir/ 
interferon beta-1a, and chloroquine or hydroxychloroquine) versus standard of care in 18 
countries worldwide14. 
Recently a publication in lancet journal claimed that they were unable to confirm a 
benefit of hydroxychloroquine or chloroquine, when used alone or with a macrolide, on 
in-hospital outcomes for COVID-19. Each of these drug regimens was associated with 
decreased in-hospital survival and an increased frequency of ventricular arrhythmias 
when used for treatment of COVID-19. The Findings were controversial. 
Other drugs in the SOLIDARTY trial are quite expansive as well as toxic for resource 
limited countries like ours. Study Published in the American Journal of Tropical 
Medicine advocates further research into Ivermectin for COVID-19 Treatment. It could 
emerge as a good drug candidate. It is cheap and less toxic. Dosing regimen is also 
simple. 
The spotlight on Ivermectin was brought by Australian researchers from Monash 
University who demonstrated its efficacy against the SARS-CoV-2 coronavirus in vitro 
studies16. 
Ivermectin has a broad spectrum antiviral activity. Recently it is found to be effective to 
Name of the Drug 
Name of the Drug 
Name of the drug 
Meplazumab(monoclona
l antibody) 
Darunavir(antiviral) 
Umifenovir/arbidol(
antiviral). 
Ivermectin  
Nelfinavir(antiviral) 
Lopinavir/ritonavir(
LPV/r)protease 
inhibitor  
Siltuximab(monoclonal 
antibody). 
Remdesivir(antiviral) 
 
Interferon-alphaα 
 
Danoprevir(antiviral) 
Corticosteroids . 
Interferon-beta β. 
Tocilizumab/IL-
6(monoclonal antibody). 
Chloroquine/hydroxychloroquine  Heparin  
Favipiravir(antiviral) 
Convalescent Plasma 
α-Lipoic acid  


 
 
12
combat infections of RNA viruses like human immunodeficiency virus (HIV)-1, 
influenza, west nile virus , Zika virus and dengue virus(DENV)17. 
Caly L etal demenostrate  ivermectin has antiviral action against the SARS-CoV-2 
clinical isolate in vitro, with a single dose able to control viral replication within 24–48 h 
in their system16. 
Importin (IMP) α/β1 30 is a heterodimer that binds to the SARS-CoV-2 cargo protein and 
moves it into the nucleus which reduces the host cell antiviral response. Ivermectin 
destabilizes the Impα/β1 heterodimer, prevents it from viral protein binding and thus 
from entering the nucleus.16, 17. 
Ivermectin has an established safety profile for human use although there is not enough 
evidence to make conclusions about the safety profile in pregnancy18. 
However, the in vivo antiviral potential of ivermectin has only been reported against the 
pseudorabies virus 19 and parvoviruses 20. 
Considering the promising result of the in vitro study, the clinical benefit of ivermectin 
therapy was evaluated in an observational registry-based study involving critically ill 
SARS-CoV-2-infected patients. Treatment with ivermectin at a dose of 150 μg/kg was 
found to be associated with a lower mortality rate and reduced healthcare resource use21 
The clinical efficacy and utility of ivermectin in SARS-CoV-2-infected patients are 
unpredictable at this stage, as we are dealing with a completely novel virus. 
The exact mechanism behind ivermectin is still under investigation but studies have 
found that a single treatment of ivermectin in a COVID-19 patient can cause the effect of 
a ~5000-fold reduction in viral RNA at 48 hours16.22. Due to an immensely significant 
decrease in viral load with just one dose, ivermectin holds a significant amount of 
promise and thus, warrants further investigation in humans. 
In a recent international, multicenter, propensity-score matched case- controlled study 
using prospectively collected data on patients diagnosed with COVID 19 by Patel et al, 
observed substantial benefit using Ivermectin over standard care16. They found that fewer 
patients died in the ivermectin group ( 7.3 versus 21.3 percent) and overall death rates 
were lower with ivermectin ( 1.4 versus 8.4 percent). 
Tetracyclines are antibiotics that are generally well-tolerated and widely available. They 
are generally used as broad spectrum antibiotics to treat different bacterial diseases as 
well as some atypical infection23. 
However, several authors have suggested they may be effective against different viruses 
as well. In a recent article, Mohit Sochi and Mahiyar Etminan , have suggested that they 
may be effective against COVID 1924. 
Tetracyclines are highly lipophilic antibiotics that are known to chelate zinc component 
of matrix metalloprotienases(MMP)25. Corona viruses are known to rely heavily of 


 
 
13
MMPs for survival,cell infiltration and replication, many of which have zinc as part of 
their MMP complex26. It may be possible that zinc chelating properties of tetracyclines 
may aid in inhibition of COVID 19 infection in humans. Some in vitro studies also 
suggested that tetracyclines may inhibit RNA replication on positive sense single 
stranded RNA viruses, like COVID 19. 
Second, teracyclines have well known anti-inflammatory effects. The anti-inflammatory 
mechanism of tetracyclines is complexe and not fully understood. However, it probably 
involves inactivation of MMPs, serine proteases and decrease production of 
inflammatory cytokines such as TNF-alpha, interleukin beta and IL-627. It has been 
suggested that cytokines play an important role in the pathogenesis of COVID 19 
including exacerbation of lung damage28,29. Several authors have suggested that 
tetracyclines may be used to treat inflammatory disorders including those caused by 
Corona viruses. 
Third, as they are highly lipophilic drugs, tetracycline has good tissue penetration in the 
lungs .This, along with their anti- inflammatory properties, might allow them to inhibit 
viral replication in the lung and reduce lung damage. The recommendation of using 
tetracyclines as treatment for Corona virus was previously suggested given that 
chemically modified tetracycline can prevent septic shock induced by ARDS30. 
 Based on the evidences, Mohit Sodhi et Al strongly urged international research groups 
to consider investigating the potential therapeutic efficacy of tetracycline in treating 
COVID 19. 
Compared with the original tetracycline, the synthetics, including minocycline and 
doxycycline, show a better pharmacokinetic profile than the first-generation tetracyclines 
when used orally, being rapidly and completely absorbed, even in elderly populations, 
with a longer half-life and excellent tissue penetration, with almost complete 
bioavailability31 
The rationale of using combination of ivermectin and doxycycline for treatment of 
COVID 19 is based on their antiviral and anti-inflammatory properties. Since the two 
drugs have different mode of action, their synergistic effect would be of value to contain 
the viral infection by targeting different sites of the pathogenesis of the disease. 
 
 
 
 
 


 
 
14
2.  
OBJECTIVES: 
 
General objectives:  
To observe the benefit (clinical and microbiological) of Ivermectin and Doxycycline in 
Confirmed Covid 19 cases. 
Specific objectives:  
1. To observe the clinical outcome in trial group and the placebo group. 
2. To observe the duration require for the recovery in the trial and placebo group 
3. To compare the outcome between the two groups. 
 
3.  
RATIONALE: 
Covid-19 is an emergent pandemic, threatens the life of millions of the people throughout 
the globe. There is increasing effort of the scientist to unveil a remedy of covid-19. Still it 
is unsuccessful. At present there is no other alternative other than experimenting the 
existent drug against the virus. There are several trials going throughout the globe. 
Among them Ivermectin showed good efficacy in vitro trial. Some clinical trial also 
proved it beneficial. The Doxycycline also has some anti-viral role with its prominent 
anti-inflammatory role. Synergistic action of the two drugs might be proved some benefit 
in clinical trial. As both drugs are cheap and less toxic, if it does, it would be the blessing 
for the poor people of the globe. 
 
4. METHODOLOGY: 
 
Study type: 
 
 
 Interventional Clinical trial 
Estimated enrollment:  
200 participants per group 
For superior trial, the formula is: 
 
N=size per group; p=the response rate of standard treatment group; p0= the response rate 
of new drug treatment group; zx= the standard normal deviate for a one or two sided x; d= 


 
 
15
the real difference between two treatment effect; δ0= a clinically acceptable margin; S2= 
Polled standard deviation of both comparison groups. 
 All parameters were assumed as follows: p =0.40; p0=0.58; α=0.05;β=0.20; δ=0.18; 
δ0=0.10. 
 
 
 
 
 However, we are assuming that lost to follow up or refuse to include in trial will be 20%, 
that means 24. So at least 150 patients will be allocated randomly and power of this study 
will be 80%. 
Allocation: 
  
Randomized:  Block randomization (Computer generated randomization code) 
Intervention model:  
Parallel assignment 
Intervention model description: Patient will be randomized 1:1 to placaebo with 
standard care and combined doxycycline and ivermectin with standard care. 
Blinding: Double blind (The participant and the clinicians/data collectors will be 
unaware of the treatment the participant receives)  
Primary purpose: Treatment 
Official title: A phase III trial to promote recovery from covid 19 with combined 
Doxycycline and Ivermectin along standard care. 
 
Provider of placebo and active ingredients: Popular pharmaceutical limited 
Dosage of the drugs: Ivermactin 6 mg 2 tab stat, cap Doxycycline 100 mg 1 cap BD 5 
days 
 
 


 
 
16
Content of the placebo:  
Placebo description of Ivermectin: Attached with Annexure 1 
 
 
 
 
 
 
 
 
 
 
 


 
 
17
Placebo Description of Doxycycline: Attached with Annexure II 
 
 
Estimated study date: 01 June, 2020 
Estimated primary completion date, 25 August 2020 
Estimated study completion date: September, 2020 
 
Inclusion Criteria: 
 
At least 18 years of age 
 
COVID-19 infection, confirmed by polymerase chain reaction (PCR) test within 3 days 
from enrollment 
 
Only mild and moderate COVID-19 infected cases 
 
Able to provide informed consent 
 
 
Exclusion Criteria: 
 
Unable to take oral medication 
 
Pregnant or breast feeding lady 
 
Patients with severe COVID symptoms or admission in ICU/HDU 


 
 
18
 
Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 X upper limit 
of normal (ULN) 
 
On non-invasive positive pressure ventilation or mechanical ventilation at time of study 
entry 
 
Known hypersensitivity to Doxycycline or ivermectin or its components. 
 
 
Research instruments:  
 
1. Informed consent form.  
2. Case record form 
 
 
 
 
 
Primary Outcome Measure:  
 
The number of days required for clinical improvement 
 
1. 
Early Clinical improvement of the patients  
How many days it requires to become the patient completely symptoms free 
[Time Frame: 7 days]  
2. 
Late clinical recovery  
How many days the symptoms persist  
[Time Frame: 12 days]  
Secondary Outcome Measure:  
1. Percentage of patients having clinical deterioration.  
Patients deteriorating to next level of severity, like moderate, severe and death 
[Time Frame: 1 month]  
2. Persistently positive for RT-PCR. 
Percentage of Covid-19 Patients repeatedly become positive for RT-PCR for 
Covid-19  
[Time Frame: 14 days] 
Data collection technique:  
Data will be collected by assigned. trained data collectors (Physician). 
Patient will be enrolled according to defined inclusion and exclusion criteria in the 
current research. Informed written consent will be obtained from the patient or their 
relatives. Each patient participating in the trial will be uniquely identified, and 
information such as his name, address is recorded in the trial 'subject number list'. Only 
the principle investigator will be aware about the allocation of the drugs.  The patients 


 
 
19
and the data collectors will be unaware about the group allocation of the drugs. The Data 
will be reviewed by the co-investigators. It will be managed by principle and co-principle 
investigators in designated computer.  
Clinical assessment (fever, cough, Anorexia, Temperature, pulse, blood pressure, 
respiratory rate, oxygen saturation) will be done every day. Routine investigation (CBC, 
ESR, CRP, Creatinine, RBS, SGPT, chest x-ray, D- Dimer) will be done at admission and 
at day 3, 5, 7, 10 and 14 day. In case of the clinical deterioration it would done according 
to necessity. RT-PCR will be done at day-0, Day 5, day 7 and day 14. 
 
Standard care: both the experimental and placebo will receive the available standard of 
care, like- 
 Paracetamol, Antihistamine, Cough suppressant, Vitamins 
 Oxygen therapy according to indication and need 
 Low molecular weight heparin according to indication 
 Appropriate other broad spectrum antibiotics 
 Other drugs for associated co- morbid condition 
 
 
Management of the adverse events: 
Drugs adverse effect will be monitored by a defined committee. The patient experiencing 
adverse effect of the drugs will be discontinued from the study. It will be managed with 
priority to the highest possible level by the hospital authority as well as the investigators.  
 
If the patient progresses from mild to moderate or severe disease, the study will be 
continued and available management of the appropriate severity will be immediately 
started. The patient will be monitored closely. 
 
Data analysis:  
Data will be analyzed by computer with the help of SPSS (Statistical Package for Social 
Sciences) version 20. To compare mean of the two group chi square will be used. Comparing 
drug outcome in between two group survival analysis by Kaplan-Meier curve will be done for the 
duration of recovery. Odds ratio will be formulated from linear logistic regression for early and 
late clinical recovery. Hazard ratio will be formulated from the cox regression analysis for 
severity conversion and persistence of the positivity. Crude odds ratio will be adjusted in cox 
proportional hazard ratio model.  Each Ivermectin-Doxycycline plus standard of care group will 
be compared with the placebo plus standard care group using the log-rank test, hazard ratio and 
95% CI.  Participants who were lost to follow up, died, discontinue drugs due to adverse effect 
will censored on the last study day. All P values will be two-sided and will be shown without 


 
 
20
adjustment for multiple testing. All analyses will be performed according to the intention to treat 
principle.  
Dropout management: Intention to treat measure will be taken 
Observation and Results: 
Result of the study and statistical analysis will be presented by tables, figures, graphs, 
diagrams, charts and photographs. All these would have own legends (i.e. title) and will 
be serially numbered. 
Discussion: 
Discussion will be done on the basis of result obtained from the study and comparing 
with similar studies done at home and abroad. 
 
Summary: 
Summarization will be drawn after discussion. 
Conclusion: 
Conclusion would be drawn depending upon the results and discussion 
Conflict of interest: 
Popular pharmaceutical will only provide drugs and the placebo. 
None of the investigators will receive remuneration from the pharmaceutical company.  
They will not get any access to data profile. 
 
Operational definition: 
(According to WHO guideline) 
Confirmed Covid-19:  
Cases with positive RT-PCR for Covid 19 irrespective of symptoms. 
Uncomplicated (mild) Illness 
These patients usually present with symptoms of an upper respiratory tract viral infection, 
including mild fever, cough (dry), sore throat, nasal congestion, malaise, headache, 
muscle pain, or malaise. Signs and symptoms of a more serious disease, such as dyspnea, 
are not present.   


 
 
21
Moderate Pneumonia 
Respiratory symptoms such as cough and shortness of breath (or tachypnea in children) 
are present without signs of severe pneumonia.  
Severe Pneumonia 
Fever is associated with severe dyspnea, respiratory distress, tachypnea (> 30 
breaths/min), and hypoxia (SpO2 < 90% on room air). However, the fever symptom must 
be interpreted carefully as even in severe forms of the disease, it can be moderate or even 
absent. Cyanosis can occur in children. In this definition, the diagnosis is clinical, and 
radiologic imaging is used for excluding complications. 
Acute Respiratory Distress Syndrome (ARDS) 
The diagnosis requires clinical and ventilatory criteria. This syndrome is suggestive of a 
serious new-onset respiratory failure or for worsening of an already identified respiratory 
picture. Different forms of ARDS are distinguished based on the degree of hypoxia. The 
reference parameter is the PaO2/FiO2: 
 
Mild ARDS: 200 mmHg < PaO2/FiO2 ≤ 300 mmHg. In not-ventilated patients or 
in those managed through non-invasive ventilation (NIV) by using positive end-
expiratorypressure (PEEP) or a continuous positive airway pressure (CPAP) ≥ 5 
cmH2O. 
 
Moderate ARDS: 100 mmHg < PaO2/FiO2 ≤ 200 mmHg. 
 
Severe ARDS: PaO2/FiO2 ≤ 100 mmHg.  
When PaO2 is not available, a ratio SpO2/FiO2 ≤ 315 is suggestive of ARDS. 
Chest imaging utilized includes chest radiograph, CT scan, or lung ultrasound 
demonstrating bilateral opacities (lung infiltrates > 50%), not fully explained by 
effusions, lobar, or lung collapse. 
Clinical improvement Criteria  
1. Body temperature remains normal for at least 3 days (ear temperature is lower than 
37.5 °C).  


 
 
22
2. Respiratory symptoms are significantly improved.  
3. Lung imaging shows obvious improvement in lesions.  
4. There is no co-morbidities or complications which require hospitalization.  
5. SpO2, >93% without assisted oxygen inhalation.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
23
 8.  
FLOW CHART of Study workup: 
Sl 
No 
Activities 
 
 
 
 
 
 
1st  
2nd 
3rd 
4th 
5th, 6 th, 7 th 
8th 
1 
Recruitment 
and  training 
of the field 
staff               
 
 
 
 
 
 
2 
Pretesting 
and 
finalization 
of the 
questionnaire 
 
 
 
 
 
 
3 
Consultative 
meeting 
 
 
 
 
 
 
4 
Data 
collection 
 
 
 
 
 
 
5 
Data entry 
and editing 
 
 
 
 
 
 
6 
Data analysis 
and draft 
report 
writing 
 
 
 
 
 
 
7 
Disseminatio
n of Results 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
24
9. ETHICAL IMPLICATIONS 
 
The following points will be considered during the study:  
1. Patients (subjects) and key relatives were clearly informed about the scope and 
limitation of the study.  
2. Written consent will be obtained from the patients (subjects) or from parents if patient 
(subject) is unable to give reliable information.  
3. Confidentiality of the patients (subjects) about personal information was strictly 
maintained.  
4. The study will not be causing any environmental hazard.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
25
10. REFERENCES:  
 
 
1. World Health Organization. GCM teleconference – Note for the Records. 10 January 
2020. Subject: Pneumonia in Wuhan, China. Available from: https: // www. who. int/ 
blueprint / 10-01-2020-nfr-gcm.pdf?ua=. 
2. World Health Organization. Novel coronavirus (2019-nCoV). Situation Report – 1. 21 
January 2020. Available from: https://www.who.int/docs/default-source /coronaviruse 
/situation-reports/20200121-sitrep-1-2019-ncov.pdf?sfvrsn=20a99c10_4. 
3. WHO Director-General's opening remarks at the media briefing on COVID-19 - 11 
March 
2020, 
available 
from:https://www.who.int/dg/speeches/detail/who-director-
general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020. 
4. Lu R, Zhao X,  Li J, Niu P,  Yang B, Wu H et al. Genomic characterisation and 
epidemiology of 2019 novel coronavirus: implications for virus origins and receptor 
binding. Lancet 2020; 395:565–74. 
5. Andersen KG,  Rambaut A, W. Ian Lipkin WI, Holmes EC, Garry RF. The proximal 
origin of SARS-CoV-2. Nature Med2020; 17 March. DOI: https://doi.org /10.1038/ 
s41591 -020-0820-9. 
6. Tsoucalas G, Kousoulis A, Sgantzos M. The 1918 Spanish Flu Pandemic, the Origins of 
the H1N1-virus Strain, a Glance in History. European Journal of Clinical and Biomedical 
Sciences. Vol. 2, No. 4, 2016, pp. 23-28. doi: 10.11648/j.ejcbs.20160204.11) 
7. Wilton P. Spanish flu outdid WWI in number of lives claimed. CMAJ. 1993; 148(11): 
2036-2037 
8. WHO Corona virus (Covid-19) Dashboard available fromhttps://extranet. who.int/ public 
emergency. 
9. Rodriguez-Morales AJ, Cardona-Ospina JA, Gutie´rrez-Ocampo E, Villamizar-Pen˜a R, 
Holguin-Rivera Y, Escalera-Antezana JP, et al. Clinical, laboratory and imaging features 
of COVID-19: a systematic review and meta-analysis. Travel Med Infect Dis. 2020; 
34:101623. 
10. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: 
consider cytokine storm syndromes and immunosuppression. Lancet 2020;395 
(10229):1033–4. 


 
 
26
11. Team NCPERE. Vital surveillances: the epidemiological characteristics of an outbreak of 
2019 novel coronavirus diseases (COVID-19) – China. China CDC Weekly. 
2020;2(8):113-22. 
12. World Health Organization.International Clinical Trial Registry Platform. COVID19 
trials. Available at:https://www.who.int/ictrp/en/ 
13. PAHO, Ongoing Living Update of Potential COVID-19 Therapeutics: summary of rapid 
systematic reviews. Availble at https://www.paho.org/en/documents/ongoing-living-
update-potential-covid-19-therapeutics-summary-rapid-systematic-reviews 
14. UN health chief announces global 'solidarity trial' to jumpstart search for COVID-19 
treatment". United Nations, World Health Organization. 18 March 2020. Retrieved 2 
April2020 
15. Mehra RM. Desai SS. Ruschitzka F. Patel AN.  Hydroxychloroquine or chloroquine with 
or without a macrolide for treatment of COVID-19: a multinational registry analysis. 
www.thelancet.com Published online May 22, 2020 https://doi.org/10.1016/S0140-
6736(20)31180-6. 
16. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM, The FDA approved Drug 
Ivermectin inhibits the replication of SARS-CoV-2 in vitro, Antiviral Research, https:// 
doi.org/10.1016/j.antiviral.2020.104787. 
17. Sundy N Y Y, Sarah C A, Chunxiao W, Alexander L, Marie A B, Natalie A B, David A 
J. The Broad Spectrum Antiviral Ivermectin Targets the Host Nuclear Transport Importin 
α/β1Heterodimer. j.antiviral May 2020;177:104760.doi: 10.1016 
18. Canga AG, Prieto AMS,  Liébana MJD, Martínez NF. The pharmacokinetics and 
interactions of ivermectin in humans--a mini-review. AAPS J 2008; 10 (1) : 42-46. 
19. Lv C, Liu W, Wang B, Dang R, Qiu L, Ren J, Yan C, Yang Z, Wang X. Ivermectin 
inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and 
proliferation of the virus in vitro and vivo. Antiviral Res. 2018;159:55–62. 
https://doi.org/10.1016/j.antiviral.2018.09.010. 
20. Nguyen KY, Sakuna K, Kinobe R, Owens L. Ivermectin blocks the nuclear location 
signal of parvoviruses in crayfish, Cherax quadricarinatus. Aquaculture. 2014;420–
421:288–94. https://doi.org/10.1016/j.aquaculture.2013.11.022. 


 
 
27
21. . Patel A, Desai S. Ivermectin in COVID-19 Related critical illness. SSRN. 2020. 
https://doi.org/10.2139/ssrn.3570270. 
22. Yavuz SS, Ünal S: Antiviral treatment of COVID-19. Turk J Med Sci. 2020, 50:611-619. 
10.3906/sag-2004-145 
23. Frieman, M., Yount, B., Heise, M., Kopecky-Bromberg, S.A., Palese, P., Baric, R.S., 
Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by 
sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi 
membrane, J Virol, 81 (18) (2007), pp. 9812-9824. 
24. M. O. Griffin, E. Fricovsky, G. Ceballos, and F. Villarreal, “Tetra-cyclines: a pleitropic 
family of compounds with promisingtherapeutic properties. Review of the literature,”The 
AmericanJournal of Physiology—Cell Physiology,vol.299,no.3,pp.C539–C548, 2010  
25. Sodhi M, Etminan M Theraputic potential for tetracycline in the treatment of Covid-19 
Pharmacotherapy 2020 May;40(5):487-488.doi: 10.1002/phar.2395. Epub 2020 May 4.  
26. Zakeri B, Wright GD. Chemical biology of tetracycline antibiotics. Biochem Cell 
Biol2008;86(2):124–36. 
27. Phillips JM, Gallagher T, Weiss SR. Neurovirulent murine coronavirus JHM.SD uses 
cellular zinc metalloproteases for virus entry and cell‐cell fusion. J Virol2017; 
91(8):e01564‐16. 
28. Henehan M, Montuno M, De Benedetto A. Doxycycline as an anti‐inflammatory agent: 
updates in dermatology. J Eur Acad Dermatol Venereol2017;31(11):1800–8. 
29. Kritas SK, Ronconi G, Caraffa A, Gallenga CE, Ross R, Conti P. Mast cells contribute to 
coronavirus‐induced inflammation: new anti‐inflammatory strategy [published online 
ahead of print, 2020 Feb 4]. J Biol Regul Homeost Agents2020;34(1). 
30. Griffin MO, Fricovsky E, Ceballos G, Villarreal F. Tetracyclines: a pleitropic family of 
compounds with promising therapeutic properties. Review of the literature. Am J Physiol 
Cell Physiol2010;299(3):C539–48. 
31. J. J. Leyden, K. Kaidbey, and E. H. Gans, “The antimicrobial effects in vivo of 
minocycline, doxycycline and tetracycline inhumans,”Journal of Dermatological 
Treatment, vol.7,no.4,pp.223–225, 1996. 
 


 
 
28
Patient Information Sheet 
(For the patients/respondents) 
  
 
(Please read the handout in front of patient/respondent and explain in local language and 
understandable way). 
The objective of this handout is to give you necessary information that will help you to take 
decision whether you will participate in this research work or not.  
 
1. About the study: 
To assess the differences in clinical and microbiologic outcome difference between the patients 
receiving ivermectin and doxycycline and the patient not having these. This research work will 
be conducted by the Department of Medicine, Dhaka Medical College, Dhaka. We want to 
include you as a study participant after receiving a written consent from you. I will explain you 
in a moment what are the components and your role in the study.   
2. Purpose of the study: 
 Find out the differences in clinical and microbiologic outcome difference between the patients 
receiving ivermectin and doxycycline and the patient not having these. 
 
3. Confidentiality: 
The information that we will collect from this research project will be kept confidential unless 
permitted by you. Information that will be collected from this study will only be used for 
research purpose. Your personal information will not be disclosed to anyone other than the 
investigators. 
 
4. Right to refuse or withdraw: 
You have all the right to refuse to participate in this study if you do not wish to do so. Refusing 
to participate will not affect your treatment in any way. You may stop participating in this study 
at any time you wish.  
 
 
 
5. Incentives: 


 
 
29
You will not be provided any incentives to take part in this research. You will be given honorium 
and conveyance expenditure if you are to come for this research work. 
 
6. Risks and discomforts: 
There is a slight risk that you may share some personal and confidential information by chance 
or that you may feel uncomfortable about some of the topics. However, we do not wish this to 
happen. You may refuse to give answer to any question or any portion of it if you need to do so. 
 
7. Benefits: 
You might not get direct benefit from this study. You will get appropriate treatment in this 
hospital after the diagnosis of your disease. Your participation is likely to help us to acquire 
more knowledge about this disease which may be of benefit to other patients of our country.  
 
8. Procedure of research: 
If you agree, we will enroll you as a study participant and will adopt the following procedures for 
your participation-  
 
  i. We will take signature/thumb impression in the attached consent form in  
      duplicate and a copy will be returned to you.  
  ii. We will ask you some questions to fill in a printed Case Record Form. 
  iii. You will be examined physically for the sake of this study. 
   
If you agree to participate in this study, please sign the attached consent form.  


 
 
30
INFORMED CONSENT FORM 
 
I, Mr/Mrs/Miss ……………………………………………., hereby giving informed consent 
willingly to participate in the study to be done by Dr. Reaz Mahmud. I agree to participate in the 
study voluntarily without any prejudice. I am fully convinced that during study I will not suffer 
from any serious physical or psychological problems. I am also informed that this study was 
carried out in the developed countries safely and my participation will bring fruitful result that 
will be beneficial for most patients in our country. I have right to withdraw myself from this 
study at any time. I shall not receive any financial benefit. I have understood that my personal 
information, medical records & laboratory tests will be kept strictly confidential & will be used 
for research purpose only.  
 
Signature/Thumb impression of participant/Guardian:…………………………. 
Date:  ……………………………… 
Name:  ………………………………………………… 
Address:  ……………………………………………… 
 …………………………………………………………. 
 …………………………………………………………. 
 
Signature of witness                                         Signature of Researcher 
Date:                                                                 Date:  
Name of witness:          


 
 
31
 
Project Title: A Randomized, Double-Blind Placebo Controlled Clinical Trial of 
Ivermectin plus doxycycline for the Treatment of Confirmed Covid -19 Infection 
Case Record Form  
 
 
 
 
      
 
 
 
 
 
 
 
 
Patient ID: …………… 
Demography 
 
1. Name:                                                                2.   Age:                          3. Sex:   M / F 
4.   Address:    
5. Epidemiological link: Y / N 
5.   Mobile No:  
6. Residency: Urban / Rural 
7.   Smoker:  Y / N         
8. Marital Status: Married / Single 
9. Education: Literate / Illiterate 
Date of starting symptoms 
Date of becoming Covid positive 
Hospital Admission Date 
Clinical Feature 
 
 
Trait 
 
Follow-up 
Yes-1, No-2 
 
On Enrollment 
D
2 
D3 
D4 
D-5 
D-6 
D-7 
D-8 
D-9 
D-
10 
D-
11 
D-
12 
D-
13 
D-
14 
Fever  
      Yes                 No 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cough 
      Yes                 No 
 
 
 
 
 
 
 
 
 
 
 
 
 
Running nose 
      Yes                 No 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sputum 
      Yes                 No 
 
 
 
 
 
 
 
 
 
 
 
 
 
Respiratory 
distress 
      Yes                 No 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sore throat 
      Yes                 No 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hoarseness of 
voice 
      Yes                 No 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest pain 
      Yes                 No 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diarrhoea 
      Yes                 No 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vomiting 
      Yes                 No 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anosmia 
      Yes                 No 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anorexia 
      Yes                 No 
 
 
 
 
 
 
 
 
 
 
 
 
 
Headache 
      Yes                 No 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confusion 
      Yes                 No 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
32
Obsrvation 
 
Investigations Profile 
 
Trait 
Value 
 
 
 
 
 
 
Admission 
D-3 
D-5 
D-7 
D-10 
D-14 
Hb 
 
 
 
 
 
 
WBC 
 
 
 
 
 
 
Neutrophil 
 
 
 
 
 
 
Lymphocyte 
 
 
 
 
 
 
Platelet 
 
 
 
 
 
 
ESR 
 
 
 
 
 
 
CRP 
 
 
 
 
 
 
RBS 
 
 
 
 
 
 
Creatinine 
 
 
 
 
 
 
SGPT 
 
 
 
 
 
 
D-Dimer 
 
 
 
 
 
 
Na 
 
 
 
 
 
 
K 
 
 
 
 
 
 
ECG 
 
 
 
 
 
 
Covid-19 
RT-PCR 
 
 
 
 
 
 
 
 
Radio-Imaging 
Trait 
Findings 
Chest X-Ray 
CT Chest 
 
Normal/ Consolidation ( unilateral or bilateral) / Patchy opacity 
Consolidation/ Ground Glass Opacity/nodule/ multifocal  
 
 
 
Principal Investigators: ………………..                                         Date: 
 
Trait 
 
Follow-up 
Yes-1, No-2 
 
On Enrollment 
D
2 
D3 
D4 
D-5 
D-6 
D-7 
D-8 
D-9 
D-
10 
D-
11 
D-
12 
D-
13 
D-
14 
Temperature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse rate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Respiratory Rate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oxygen 
saturation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Co- Morbidity 
DM/HTN/ IHD/ HF/ CKD/CLD/Asthma/COPD/Malignancy/ CTD 


 
 
33
 
Annexure-1 
 


 
 
34
Annexure II: 
 
 


 
 
35
DSM Board Minutes 
 
 
 
 


 
 
36
 
 
 
 
 
 
 
 

SAP_001.pdf: 
1 
 
A Randomized, Double-Blind Placebo Controlled Clinical Trial of 
Ivermectin plus Doxycycline for the Treatment of Confirmed Covid -19 
Infection 
 
STATISTICAL ANALYSIS PLAN 
 
Study Title: A Randomized, Double-Blind Placebo Controlled Clinical Trial of Ivermectin plus 
Doxycycline for the Treatment of Confirmed Covid -19 Infection 
Name of Test Drug: Ivermectin plus Doxycycline 
Study Number: ERC-DMC/ECC/2020/117 
Protocol Version (Date): Protocol version 2, Amendment 1.0 (25 August 2020)  
Analysis Type: Final Analysis  
Analysis Plan Version: Version 1.0 Analysis  
Plan Date: 26 August 2020  
Analysis Plan Author(s): Dr. Reaz Mehmud 
 
 
 
 
CONFIDENTIAL AND PROPRIETARY INFORMATION 
 
 
 
 
 
 
 
 
 


2 
 
 
TABLE OF CONTENTS  
STATISTICAL ANALYSIS PLAN........................................................................................................................1  
TABLE OF CONTENTS....................................................................................................................................2 
LIST OF IN-TEXT TABLES................................................................................................................................3  
LIST OF ABBREVIATIONS...............................................................................................................................5 
1. INTRODUCTION ........................................................................................................................................6  
1.1. Study Objectives.......................................................................................................................6  
1.2. Study Design......................................................................................................................6, 7, 8  
1.3. Sample Size and Power.............................................................................................................8 
2. TYPE OF PLANNED ANALYSIS ...................................................................................................................8  
 
2.1. Primary Analysis.......................................................................................................................8  
2.2. Final Analysis ...........................................................................................................................8 
 3. GENERAL CONSIDERATIONS FOR DATA ANALYSES.................................................................................9  
3.1. Analysis Sets.............................................................................................................................9  
3.1.1. All Randomized Analysis Set....................................................................................9  
3.1.2. Safety Analysis Set...................................................................................................9 
3.2. Subject Grouping ................................................................................................................9, 10  
3.2.1. Subject Subgroups for Efficacy Analyses.................................................................09  
3.2.2. Subject Subgroups for Safety Analyses ..................................................................10  
3.3. Missing Data and Outliers.......................................................................................................10  
3.3.1. Missing Data ...........................................................................................................10  
3.3.2. Outliers...................................................................................................................10  


3 
 
3.4. Data Handling Conventions and Transformations...............................................................................10  
3.5. Analysis Visit Windows........................................................................................................................10  
3.5.1. Definition of Study Day .......................................................................................................10  
3.5.2. Analysis Visit Windows........................................................................................................11  
3.5.3. Selection of Data in the Event of Multiple Records for an Analysis Visit Day......................11  
 
4. SUBJECT DISPOSITION ............................................................................................................................12  
4.1. Subject Enrollment and Disposition........................................................................................12  
4.2. Extent of Study Drug Exposure ..............................................................................................12 
4.2.1. Exposure to Study Drug ..........................................................................................12  
5. BASELINE CHARACTERISTICS.............................................................................................................12, 13 
 5.1. Demographics and Baseline Characteristics .........................................................................12  
5.2. Other Baseline Characteristics................................................................................................13 
  
5.3. Medical History.......................................................................................................................13  
6. EFFICACY ANALYSES .........................................................................................................................13, 14  
6.1. Primary Efficacy Endpoint.......................................................................................................13  
6.1.1. Definition of the Primary Efficacy Endpoint ...........................................................13  
6.1.2. Statistical Hypothesis for the Primary Efficacy Endpoint........................................13  
6.1.3 Primary analysis of primary end point………………………………………………………………….14 
6.1.4. Secondary Analysis of the Primary Efficacy Endpoint ............................................14 
7. SAFETY ANALYSES.............................................................................................................................14, 15  
7.1. Secondary Endpoint ...............................................................................................................14  
7.2. Adverse Events and Deaths....................................................................................................14 


4 
 
 7.2.1. Adverse Event Dictionary .....................................................................................14  
7.2.2. Adverse Event Severity..........................................................................................15  
7.2.3. Relationship of Adverse Events to Study Drug.......................................................15  
7.2.4. Serious Adverse Events..........................................................................................15  
7.2.5. Treatment-Emergent Adverse Events....................................................................15  
7.2.5.1. Definition of Treatment-Emergent Adverse Events ..............................15  
7.2.5.2. Incomplete Dates...................................................................................15  
7.2.6. Summaries of Adverse Events and Deaths...............................................15  
7.3. Laboratory Evaluations..........................................................................................................16  
7.3.1. Summaries of Numeric Laboratory Results ...........................................................16 
7.3.2. Graded Laboratory Values .....................................................................................17  
7.3.2.1. Treatment-Emergent Laboratory Abnormalities....................................17  
7.3.2.2. Summaries of Laboratory Abnormalities...............................................17  
7.5. Prior and Concomitant Medications.........................................................................30 
7.4. Subject Subgroup for Safety Endpoints .................................................................................17 
7.8. Changes from Protocol-Specified Safety Analyses..................................................................17 
8. SOFTWARE.................................................................................................................................17 
 
 
 
 
 
 
 


5 
 
LIST OF ABBREVIATIONS 
 
AE- adverse event  
 
ALT- alanine aminotransferase  
 
AST- aspartate aminotransferase 
 
CI- confidence interval  
 
CRF- case report form  
 
CSR- clinical study report  
 
DMC- data monitoring committee  
 
FAS- Full Analysis Set 
 
Hb- Hemoglobin 
 
HLT high-level term 
 
ICH International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)  
 
ITT- intent to treat  
 
LTT- lower-level term  
 
LOQ limit of quantitation 
 
MedDRA- Medical Dictionary for Regulatory Activities 
 
PCR-polymerase chain reaction  
 
PP - per protocol  
 
PT- preferred term  
 
SAP- statistical analysis plan  
 
SD- standard deviation  
 
SOC- standard of care  
 
TEAE- treatment-emergent adverse event  
 
WHO World Health Organization 
 
 
 
 
 
 
 
 
 
 
 
 


6 
 
 
1. INTRODUCTION  
This Phase 3 Randomized controlled trial was conducted in Dhaka Medical College Hospital, Dhaka, 
Bangladesh. Total 400 participant who met all eligibility criteria randomized to 1:1 into treatment 
group (Ivermectin plus Doxycycline plus standard care) and placebo plus standard care. 
This statistical analysis plan (SAP) describes the statistical analysis methods and data presentations 
for the final analysis.  
1.1 Study Objectives  
The purpose of this study is to provide Ivermectin and Doxycycline in Confirmed mild and moderate 
severity Covid 19 cases. 
The primary objective of this study is as follows:  
To observe the benefit (clinical and microbiological) of Ivermectin and Doxycycline in 
Confirmed mild to moderate Covid 19 cases. 
 
The secondary objective of this study is as follows:  
  
To evaluate the safety and tolerability of Ivermectin and Doxycycline to standard care.  
 
1.2 Study Design 
 
This is a randomized double blind placebo controlled trial in participants with mild to moderate 
covid-19 infection. 400 participants who meet all eligibility criteria randomized to 1:1 into one of 
the following treatment group 
Treatment group1: Ivermectin plus Doxycycline plus standard care 
Treatment group 2: Placebo plus standard care. 
 
 Key Eligibility Criteria 
Inclusion Criteria: 
 
At least 18 years of age 
 
COVID-19 infection, confirmed by polymerase chain reaction (PCR) test within 3 days from 
enrollment 
 
Only mild and moderate COVID-19 infected cases 
 
Able to provide informed consent 
 
Exclusion Criteria: 
 
Unable to take oral medication 
 
Pregnant or breast feeding lady 
 
Patients with severe COVID symptoms or admission in ICU/HDU 


7 
 
 
Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 X upper limit of 
normal (ULN) 
 
On non-invasive positive pressure ventilation or mechanical ventilation at time of study entry 
 
Known hypersensitivity to Doxycycline or Ivermectin or its components. 
 
Schedule of Assessments 
The date of randomization was considered Day 1 and all participants randomized to receive the 
drug received their initial dose on Day 1.  
On Days 1 through 14 or until discharge, or clinical improvement, whichever was later, clinical 
status, vital signs including respiratory status was measured and adverse events (AEs) was 
documented.  
Laboratory testing was advised at day 1, which included complete blood count, random blood 
glucose, creatinine, ALT, D- dimer, CRP, Ferritin and chest X-ray or CT chest which ever was 
feasible.  
If performed the patient who was treated as outpatient test results were documented in next visit 
or by online visit. 
In Hospitalized patient tests was advised at Days 1, 7 and according to treating physician’s need.  
RT-PCR for covid-19 was done 14 days after the initial positivity. 
Randomization  
Participants who meet eligibility criteria was randomized in a 1:1 ratio to one of the two 
treatment groups on Day one. A computer generated code number was used to level the drugs 
and the patient. The allocation was concealed by using sealed envelope. Randomization was not 
stratified.  
Site: 
Triage and inpatient of Covid dedicated unit of Dhaka Medical College Hospital 
 Duration of Treatment  
Participants received 12 mg of Ivermectin at day 1 and 100 mg Doxycycline twice daily for 5 days 
plus standard care as Active drug or placebo.  
Standard care: both the experimental and placebo will receive the available standard of care, like- 
 
Paracetamol, Antihistamine, Cough suppressant, Vitamins 
 
Oxygen therapy according to indication and need 
 
Low molecular weight heparin according to indication 
 
Appropriate other broad spectrum antibiotics 
 
Other drugs for associated co- morbid condition 
 


8 
 
 
 
Discontinuation Criteria  
The drugs were discontinued if patient developed any serious adverse effect. In this trial two 
patient developed erosive esophagitis and discontinued from the study. 
End of Study  
The end of the study was the last participant’s last observation (or visit). 
1.3 Sample Size and Power of the trial 
 
Total 400 patients were randomized in a 1:1 ratio to two treatment group. (200 participants per 
group).  
For superior trial, the formula is: 
 
N=1/2× [(Zα/2+Zβ)/ (arcsin√p-arcsin√P0] 2 
 
N=size per group; P=the response rate of standard treatment group; P0= the response rate 
of new drug treatment group; Zx= the standard normal deviate for a one or two sided x; d= 
the real difference between two treatment effect; δ0= a clinically acceptable margin; S2= 
Polled standard deviation of both comparison groups. 
All parameters were assumed as follows: P=0.40; P0=0.58; α=0.05; β=0.20 
Result for the superiority trial was 121. 
However, we are assuming that lost to follow up or refuse to include in trial will be 20%, that 
means 24. So at least 150 patients was required to be allocated randomly with the power of the 
study 80%. 
We had decided to enroll 200 patient for each arm. 
2. Type of Planned Analysis 
Primary Analysis: It was done when more than 2/3 patients were finished follow up. The DSM 
board reviewed the results on 25 August, 2020. 
Final Analysis: 
The final analysis for this study will be performed after all participants have completed the follow 
up, outstanding data queries have been resolved or adjudicated as unresolvable, and the data 
have been cleaned and finalized 


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3. General Consideration for Data analysis 
 
Analysis results will be presented using descriptive statistics.  
For categorical variables, the number and percentage of participants in each category will be 
presented; for continuous variables, the number of participants (n), mean, standard deviation 
(SD) will be presented.  
All statistical tests will be 2-sided and performed at the 5% significance level unless otherwise 
specified.  
By-subject listings will be presented for all participants in the All Randomized Analysis Set unless 
otherwise specified, and sorted by subject ID number, visit date, and time (if applicable).  
 
3.1. Analysis Sets  
 
Analysis sets define the participants to be included in an analysis. Analysis sets and their 
definitions are provided in this section. Participants included in each analysis set will be 
determined before database finalization. The analysis set will be included as a subtitle of each 
table, figure, and listing. A summary of the number and percentage of participants in each analysis 
set will be provided by treatment group, placebo group and in total. 
 
 3.1.1. All Randomized Analysis Set  
The All Randomized Analysis Set will include all participants who are randomized into the study. 
This is the final analysis set for by-subject listings.  
3.1.2 Full Analysis Set  
The analysis set for efficacy analysis is defined as the Full Analysis Set (FAS), which will include all 
participants who (1) are randomized into the study and (2) have received at least 1 dose of study 
treatment if randomized to treatment groups. Participants in the placebo arm who have had 
protocol Day 1 visit will be included in the FAS. Participants will be grouped according to the 
treatment to which they were randomized  
3.1.3. Safety Analysis Set  
The analysis set for safety analyses is defined as the Safety Analysis Set, which will include all 
participants who (1) are randomized into the study and (2) have received at least 1 dose of study 
treatment if randomized to the treatment groups. Participants in the placebo arm who have had 
protocol Day 1 visit will be included in the safety analysis set.  
 
3.2. Subject Grouping  
Participants will be grouped by randomized treatment (Active treatment and placebo) regardless of 
the actual number of days of treatment. 
  
3.2.1. Subject Subgroups for Efficacy Analyses  
The primary endpoint will be analyzed for the following participant subgroups:  
• Age (years): (a) < 40 and (b) 40-60 (c) >60 
• Sex at birth: (a) male and (b) female  
• Severity of illness (Mild and Moderate)  


10 
 
 
3.2.2. Subject Subgroups for Safety Analyses 
Incidence of all treatment-emergent AEs (TEAEs) will be summarized for the following 
participant subgroups:  
• Age (years): (a) < 40 and (b) 40-60 (c) >60 
• Sex at birth: (a) male and (b) female  
3.4. Missing Data and Outliers  
 
3.4.1. Missing Data 
Missing data can have an impact upon the interpretation of trial data. In general, values for 
missing data will not be imputed, unless methods for handling missing data are specified. In this 
study, a missing pre-treatment laboratory result would be treated as normal.  
 
3.4.2 Outliers  
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be done to evaluate the impact of outliers on efficacy or safety outcomes, 
unless specified otherwise. All data will be included in the analyses.  
 
3.5. Data Handling  
In general, age collected at Day 1 (in years) will be used for analyses and presented in listings.  
Laboratory data that are continuous in nature but are less than the lower limit of quantitation or 
above the upper limit of quantitation will be imputed as follows:  
• A value that is 1 unit less than the LOQ will be used to calculate descriptive statistics if the datum 
is reported in the form of “< x” (where x is considered the LOQ). For example, if the values are 
reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to calculate summary 
statistics. An exception to this rule is any value reported as < 1 or < 0.1, etc. For values reported 
as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to calculate summary statistics.  
• A value that is 1 unit above the LOQ will be used to calculate descriptive statistics if the datum 
is reported in the form of “> x” (where x is considered the LOQ). Values with decimal points will 
follow the same logic as above. • The LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “≤ x” or “≥ x” (where x is considered the LOQ). 
 
 3.6. Analysis Visit Windows  
 
3.6.1. Definition of Study Day 
 
Study Day 1/First Dose Date is defined as Participants randomized to any group as the day 
when the first dose of the drugs was taken as recorded on the Case record form. 
Recovery day is defined as the day from which patient’s symptoms improved for 3 successive 
day as defined by WHO improvement criteria. 
Total duration of illness was calculated from the onset of any symptoms related to COVID-
19 up to the day from which patient is improved clinically for 3 successive days. 


11 
 
Last Study Date is last days at which patient followed up for the last time  
Covid positive negative date: The date when sample was given. If it come positive it     
recorded as missing data. 
Baseline value is defined as the last value obtained on or prior to the first dose date (and 
time, if available) unless otherwise specified. 
 
3.6.2. Analysis Visit Windows  
 
Subject visits might not occur on protocol-specified days. As telephonic interview was taken for 
the outpatient participant patient might not available on a specific day. Therefore, for the 
purposes of analysis, observations will be assigned to analysis windows. The study day as 
defined in Section 3.6.2 will be used when data are summarized by visit.  
Vital signs were to be collected daily; therefore, windows are not assigned and results will be 
summarized for each Study Day.   
3.6.3. Selection of Data in the Event of Multiple Records for an Analysis Visit Day 
Depending on the statistical analysis method, single values may be required for each Study Day/ 
analysis window.  
If multiple valid, non-missing measurements exist for a Study Day/analysis window, records will 
be chosen based on the following rules if a single value is needed:  
 
• For baseline, the last non-missing value on or prior to the first dosing date of study drug will be 
selected, unless specified differently. If there are multiple records with the same time or no time 
recorded on the same day, the baseline value will be the average of the measurements for 
continuous data, or the measurement with the lowest severity for categorical data. 
 • For post baseline values:  
For windows spanning multiple days, the record(s) collected on the day closest to the nominal 
day will be selected. If there are 2 days equidistant from the nominal day, the later day will be 
selected.  
If there is more than 1 record on the selected day, values will be selected for analysis as follows:  
 
■ For PCR, if there is more than 1 record on the selected day, the latest value will be 
selected. If there are multiple records with the same time or no time recorded on the 
same day, the selected value will be the highest severity (ie, highest value or positive 
result). 
■ for laboratory values (other than PCR) and SpO2 and PaO2, if there is more than 1 
record on the selected day, the worst value will be selected.  
■ for other parameters, if there is more than 1 record on the selected day, the average 
will be taken for continuous data and the worst severity will be taken for categorical 
data, unless otherwise specified. 
 
 
 
 


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 4. SUBJECT DISPOSITION 
 
4.1. Subject Enrollment and Disposition  
The number and percentage of participants randomized at each investigator site will be 
summarized by treatment group (Active drug and placebo) and overall using the full Analysis Set. 
The denominator for this calculation will be the number of participants in the full Analysis Set.  
In addition, the number and percentage of the participants in the following categories will be 
summarized:  
• Completed study drug as recorded on the case record form  
• Prematurely discontinued study drug prior to completion of 5 days of dosing with 
summary of reasons for discontinuing study drug as recorded on the on the case record 
form . 
• Completed study  
• Prematurely discontinued from study prior to the data cut date (with summary of 
reasons for discontinuing study) as recorded on the on the case record form. 
4.2. Extent of Study Drug Exposure  
4.2.1. Exposure to Study Drug 
Number of doses received will be summarized by treatment group for participants 
randomized to both groups in the Safety Analysis Set.  
Time to premature discontinuation of study drug will be analyzed using the Kaplan-
Meier method by treatment group for participants randomized to both treatment 
groups. They will be censored at the last visit date. 
  
  
5. BASELINE CHARACTERISTICS  
5.1. Demographics and Baseline Characteristics  
Subject demographic data (e.g., sex, and age) will be summarized by treatment group and 
overall using descriptive statistics (n, mean, SD) for continuous data and by the number 
and percentage of participants for categorical data. The summaries of demographic data 
and baseline subject characteristics will be provided for the Safety Analysis Set.  
Age group (< 40, 40 to 60, > 60) will be summarized by treatment group and overall. For 
categorical data, the chi square test (i.e., general association statistic for nominal data 
and row mean scores for ordinal data [age group]) will be used to compare the 2 
treatment groups.  
For continuous data, the 2-sided independed t test will be used to compare the 2 
treatment groups.  
 
 
 


13 
 
5.2. Other Baseline Characteristics  
The following baseline disease characteristics will be summarized by treatment group 
and overall using descriptive statistics:  
 
Clinical features 
 
Duration of illness prior to prior to Study Day 1  
 
Initial severity of the patients 
For categorical data, the chi square will be used to compare the 2 treatment groups. For 
clinical status and continuous data, 2-sided independed t test will be used to compare 
the 2 treatment groups.  
5.3. Medical History  
Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is 
considered to be preexisting and should be documented as medical history. General 
medical history data will be collected at screening. The summary table will present the 
percentages of participants reporting each medical history.   
6. EFFICACY ANALYSES  
6.1. Primary Efficacy Endpoint  
The analysis of primary efficacy endpoint was Final Analysis. 
 6.1.1. Definition of the Primary Efficacy Endpoint  
Primary Outcome Measure:  
Primary Outcome was to see the number of days required for clinical improvement. 
1. 
Early Clinical improvement of the patients  
How many days it requires to become the patient completely symptoms free  
[Time Frame: 7 days]  
2. 
Late clinical recovery  
How many days the symptoms persist  
[Time Frame: 12 days] 
If a participant dies while hospitalized (as recorded on the Death CRF and Hospitalization CRF), 
the endpoint on the day of death  
If the participant is discharged alive and dies in home within 1 month the end point on the 
patient dies.  
6.1.2. Statistical Hypothesis for the Primary Efficacy Endpoint  
Null hypothesis: The odds of improvement for active drug group is the same as the odds of 
improvement for the placebo group with respect to clinical improvement a day 7 and day 12.  


14 
 
Alternative hypothesis: The odds of improvement for active drug group is different the odds of 
improvement for the placebo group with respect to clinical improvement a day 7 and day 12. 
6.1.3. Primary Analysis of the Primary Efficacy Endpoint  
Comparing drug outcome in between two group survival analysis by Kaplan-Meier curve will be 
done for the duration of recovery. Odds ratio will be formulated from linear logistic regression for 
early and late clinical recovery. Crude odds ratio will be adjusted in cox proportional hazard ratio 
model.  Each Ivermectin-Doxycycline plus standard of care group will compared with the placebo 
plus standard care group using the log-rank test, hazard ratio and 95% CI.  The FAS will be the 
primary analysis set for efficacy endpoint evaluation. The primary endpoint will be analyzed for 
each of the subgroups defined in Section 3.2.1 
6.1.4. Secondary Analysis of the Primary Efficacy Endpoint  
As supportive analyses of the primary endpoint, the following will be conducted for treatment 
group compared to the placebo arm:  
Secondary Outcome Measure:  
1. Percentage of patients having clinical deterioration.  
Patients deteriorating to next level of severity, like moderate, severe and death [Time 
Frame: 1 month]  
2. Persistently positive for RT-PCR. 
Percentage of Covid-19 Patients repeatedly become positive for RT-PCR for Covid-19  
[Time Frame: 14 days] 
Hazard ratio will formulated from the cox regression analysis for severity conversion and 
persistence of the positivity. The hazard ratio, 95% confidence interval, and p-value for comparing 
treatments will be provided. 
 
7. SAFETY ANALYSES 
Safety data will be summarized for the participants in the safety analysis set. 
7.1 Secondary Endpoint 
The secondary endpoint of the proportion of participants with any treatment emergent adverse 
events will be compared between two group using a Fisher’s Exact test. The point estimate of the 
treatment difference and the associated 95% confidence intervals will be provided 
7.2. Adverse Events and Deaths 
7.2.1Adverse Event Dictionary 
Clinical and laboratory adverse events (AEs) will be coded in SPSS using numeric value. 
7.2.2. Adverse Event Severity 
The severity of AEs will be graded using the Division of AIDS (DAIDS), Version 2.1 dated July 
2017. For each episode, the highest grade attained should be reported as defined in the grading 


15 
 
scale. The DAIDS scale is available at the following location: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
 Adverse events are graded by the investigator as Grade 1 (mild), Grade 2 (moderate), Grade 3 
(severe), Grade 4 (life threatening) or Grade 5 (fatal) according to toxicity criteria specified in the 
document above. The severity grade of events for which the investigator did not record severity 
will be left as “missing” for data listings. 
7.2.3. Relationship of Adverse Events to Study Drug 
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Related to Study Treatment.” Events for which the investigator did not record 
relationship to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing 
7.2.4. Serious Adverse Events 
Serious adverse events (SAEs) will be identified and captured as SAEs if AEs met the definitions 
of SAE specified in the study protocol.  
7.2.5. Treatment-Emergent Adverse Events 
Definition of Treatment-Emergent Adverse Events  
For participants randomized to either groups, treatment-emergent adverse events (TEAEs) are 
defined as 1 or both of the following:  
• Any AEs with an onset date on or after the study drug start date and no later than 30 
days after permanent discontinuation of study drug  
• Any AEs leading to premature discontinuation of study drug.  
For participants randomized to the placebo group, all AEs reported on or after protocol Day 1 
visit will be considered as treatment-emergent 
7.2.6. Summaries of Adverse Events and Deaths 
The number and percentage of participants who experienced at least 1 TEAE will be provided 
and summarized by system organ class, HLT, PT, and treatment group. Comparison will be done 
by Fisher-exact test. 
Data listings will be provided for the following:  
 
All AEs  
 
Study-Drug-Related AEs 
 
AEs with severity of Grade 3 or higher  
 
SAEs  
 
Study-Drug-Related SAEs (active treatment groups only)  
 
Deaths  
 
AEs leading to premature discontinuation of study drug (active treatment groups only) 


16 
 
 
7.3. Laboratory Evaluations 
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of study drug plus 30 days 
for the active groups if possible. For the placebo group all laboratory data will be included. The 
analysis will be based on values reported in conventional units. When values are below the LOQ, 
they will be listed as such, and the closest imputed value will be used for the purpose of calculating 
summary statistics as specified in Section 3.2.2. 
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, and PCR separately. Values falling outside 
of the reference range and/or having a severity grade of 1 or higher on the DAIDS Grading Scale 
will be flagged in the data listings, as appropriate. 
7.3.1. Summaries of Numeric Laboratory Results 
Descriptive statistics will be provided by treatment group for each laboratory test as follows: 
 • Baseline values  
• Values at each post baseline analysis window  
• Change from baseline at each post baseline analysis window  
• Percentage change from baseline to each post baseline analysis window (if specified 
A baseline laboratory value will be defined as the last non missing value obtained on or prior to 
the date (and time, if applicable) of first dose of active drug groups. For the placebo group a 
baseline laboratory value will be defined as the last non missing value obtained on or prior to the 
protocol Day 1 visit date. Change from baseline to a post baseline visit will be defined as the post 
baseline value minus the baseline value. The mean, median and SD will be displayed. Baseline and 
change from baseline will be compared between active group and the placebo group using the 2-
sided Wilcoxon Rank sum test. 
7.3.2. Graded Laboratory Values 
The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Event, Version 2.1 (July 
2017) will be used for assigning toxicity grades (0 to 4) to laboratory results for analysis. Grade 0 
includes all values that do not meet the criteria for an abnormality of at least Grade 1. For 
laboratory tests with criteria for both increased and decreased levels, analyses for each 
direction (ie, increased, decreased) will be presented separately. 
7.3.2.1. Treatment-Emergent Laboratory Abnormalities 
Treatment-emergent laboratory abnormalities are defined as values that increase at least 1 
toxicity grade from baseline at any post baseline time point, up to and including the date of last 
dose of study drug plus 30 days for either of the active drugs groups. For participants randomized 


17 
 
to the placebo group, all post baseline laboratory abnormalities in this study will be considered 
as treatment-emergent. 
 If the relevant baseline laboratory value is missing, any abnormality of at least Grade 1 observed 
within the time frame specified above will be considered treatment emergent. 
Laboratory data that are categorical will be summarized using the number and percentage of 
participants in the study with the given response at baseline and each scheduled post baseline 
visit. The following summaries (number and percentage of participants) for treatment-emergent 
laboratory abnormalities will be provided by laboratory test and treatment group; participants 
will be categorized according to the most severe post baseline abnormality grade for a given 
laboratory test: 
 
Treatment-emergent laboratory abnormalities  
 
Treatment-emergent Grade 3 and 4 laboratory abnormalities 
For all summaries of laboratory abnormalities, the denominator is the number of participants 
with non-missing post baseline values up to 30 days after last dosing date for the active drugs 
groups and the number of participants with non-missing post baseline values for the SOC 
group. A by-subject listing of laboratory abnormalities and Grade 3 or 4 laboratory 
abnormalities will be provided by subject ID number and visit in chronological order. 
7.4. Subject Subgroup for Safety Endpoints 
Incidence of all treatment-emergent AEs will be repeated within each subgroup defined in 
Section 3.2.2 using the safety analysis set 
7.5. Changes from Protocol-Specified Safety Analyses 
No change from the protocol-specified safety analysis is planned. 
 
8. SOFTWARE 
SPSS version 20.