Clinical Trial of Ivermectin Plus Doxycycline for the Treatment of Confirmed Covid-19 Infection

Study Overview
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Brief Summary
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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
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OBJECTIVES: General objectives: To observe the benefit (clinical and microbiological) of Ivermectin and Doxycycline in Confirmed Covid 19 cases. Specific objectives: To observe the clinical outcome in trial group and the placebo group. To observe the duration require controlling viral replication (negative RT-PCR) in the trial and placebo group. 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.

Official Title
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A Phase III Trial to Promote Recovery From Covid 19 With Combined Doxycycline and Ivermectin Along Standard Care

Conditions
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Covid19

Intervention / Treatment
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* Drug: Ivermectin and Doxycycline
* Drug: Standard of care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) more than 5 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patient will be randomized 1:1 to placaebo with standard care and combined doxycycline and ivermectin with standard care.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ivermectin and Doxycycline<br>Ivermactin 6 mg 2 tab stat, cap Doxycycline 100 mg 1 cap BD 5 days | Drug: Ivermectin and Doxycycline<br>* Ivermectin 6 mg, 2 tab stat and Doxycycline 100 mg twice daily for 5 days<br>* Other names: Imac and Doxibac;Drug: Standard of care<br>* Paracetamol, Vitamin D, Oxygen if indicated, Low molecular weight heparin, dexamethasone if indicated<br>|
| Placebo Comparator: Placebo<br>Standard treatment | Drug: Standard of care<br>* Paracetamol, Vitamin D, Oxygen if indicated, Low molecular weight heparin, dexamethasone if indicated<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Early Clinical Improvement | Number of patients have clinical improvement as described by WHO and Bangladesh local guideline with 7 days.. Body temperature remains normal for at least 3 days (ear temperature is lower than 37.5 °C). Respiratory symptoms are significantly improved. Lung imaging shows obvious improvement in lesions. There is no co-morbidities or complications which require hospitalization. SpO2, >93% without assisted oxygen inhalation. | 7 days | 
| Number of Participants With Late Clinical Recovery | Number of the patients required more than 12 days for clinical improvement as defined above. | 12 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Having Clinical Deterioration. | Number of patients deteriorating to next level of severity, like moderate, severe and death. That is from mild illness at presentation with subsequent follow up developed moderate, severe illness or death. Like wise from moderate illness at presentation developed severe illness or death. 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 Moderate illness: Respiratory symptoms such as cough and shortness of breath (or tachypnea in children) are present without signs of severe pneumonia. Severe illness:severe dyspnea, respiratory distress, tachypnea (> 30 breaths/min), and hypoxia (SpO2 < 90% on room air). | 1 month | 
| Number of Patients Remain Persistently Positive for RT-PCR of Covid-19 | Number of Patients remain positive for RT-PCR of Covid-19 at day 14 after the day of initial positivity. | 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Covid-19, Ivermectin