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CTRI Number  CTRI/2020/06/025849 [Registered on: 12/06/2020] Trial Registered Prospectively
Last Modified On: 21/09/2020
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group, Active Controlled Trial 
Public Title of Study   Study to Evaluate the Safety and Efficacy of a Combination of Nitazoxanide and Hydroxychloroquine Versus Hydroxychloroquine Alone in COVID-19 Patients 
Scientific Title of Study   A Randomized, Open Label, 2-Treatment Groups Clinical Trial Evaluating the Safety and Efficacy of a Combination of Nitazoxanide and Hydroxychloroquine Versus Hydroxychloroquine Alone in the Acute Treatment of Moderate COVID-19 Patients 
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
CVD-19-CD-001; Version 3.0; 21 May 2020  Protocol Number 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name   
Designation   
Affiliation   
Address 




 
Phone    
Fax    
Email    
 
Details of Contact Person
Scientific Query
 
Name  D Mallikarjuna Rao  
Designation  Senior Director 
Affiliation  Dr Reddys Laboratories Limited 
Address  Regulatory Affairs Proprietary Products Innovation Plaza, IPDO Survery No.54, Bachupally Village, Bachupally Mandal

Medchal
TELANGANA
500049
India 
Phone  914044346860  
Fax  914044346125  
Email  mallikarjunard@drreddys.com  
 
Details of Contact Person
Public Query
 
Name  D Mallikarjuna Rao  
Designation  Senior Director 
Affiliation  Dr Reddys Laboratories Limited 
Address  Regulatory Affairs Proprietary Products Innovation Plaza, IPDO Survery No.54, Bachupally Village, Bachupally Mandal


TELANGANA
500049
India 
Phone  914044346860  
Fax  914044346125  
Email  mallikarjunard@drreddys.com  
 
Source of Monetary or Material Support  
Dr. Reddy’s Laboratories Limited 8-2-337, Road No. 3 Banjara Hills, Hyderabad 500043  
 
Primary Sponsor  
Name  Dr Reddys Laboratories Limited 
Address  8-2-337, Road No.3, Banjara Hills, Hyderabad 500043  
Type of Sponsor  Pharmaceutical industry-Global 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study
Modification(s)  
No of Sites = 12  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Akshay Budhraja  Aakash Healthcare Super Speciality Hospital  Hospital plot road no. 201, Sector 3, Dwarka
New Delhi
DELHI 
9893322007

Dr.akshaybudhraja@gmail.com 
Dr Balachandra  BGS Global Institute of Medical Sciences  Professor and HOD, General Medicine 67, BGS Health and Education City, Uttarahalli Raod, Kengeri
Bangalore
KARNATAKA 
9845111559

drgbalachandra@gmail.com 
Dr Nischal Yalgi  Global Hospital and Research Institute  577/2, off Sinhgad raod, Near Dattawadi Police Chowky, Dattawadi
Pune
MAHARASHTRA 
8983377103

drnischalyalgi@gmail.com 
Dr Meenakshi Bhattacharya  Government Medical College  Department of Medicine Panchakki road
Aurangabad
MAHARASHTRA 
9922931527

mabhattacharya@gmail.com 
Dr Rajesh Gosavi   Government Medical College, Nagpur  Professor of Medicine, Hanuman Nagar, Ajni Rd, Medical Chowk, Ajni, Nagpur,
Nagpur
MAHARASHTRA 
9880225111

gosavirv@gmail.com 
Dr Badrinarayan  Hindu Mission Hospital  General Medicine, No. 103, GST road, West Tambaram
Chennai
TAMIL NADU 
8754595006

violinbadri@gmail.com 
Dr Ajay Jhaveri   Kasturba Hospital for Infectious diseases  Sane Guruji Marg, Chinchpokli,
Mumbai
MAHARASHTRA 
9867433330

drajayjhaveri@gmail.com 
Dr Chandan Chaudhary  Masina Hospital Trust  Sant Savta Marg, near Gloria church, Byculla (E)
Mumbai
MAHARASHTRA 
9822876893

Cchaudhri00@gmail.com 
Dr Sagar Sudhir Mandlik  Raddiant Plus Hospital  Consultant Chest Physician, Shreyas Plaza, Navshakti Chowk, Bhabhanagar
Nashik
MAHARASHTRA 
9225343885

sagarmandlik007@yahoo.com 
Dr Yogesh Sharma  Rajiv Gandhi Medical college and chatrapati Shivaji Maharaj Hospital  Professor and Head of Department, Department of Medicine, RGMC and CSMH, Belapur Road, Kalwa
Thane
MAHARASHTRA 
9820192129

dryogeshsharmamd@yahoo.com 
Dr Manoj Yadav  Rhythm Heart Institute  A Unit of Synergy Lifecare Pvt.Ltd., Near Siddharth bunglows, Sama-Savli road
Vadodara
GUJARAT 
9825060468

drmanojcr75@gmail.com 
Dr Manisha Mendiratta  Sarvodaya Hospital and Research Centre  Department of Respiratory Disease and Sleep Disorder YMCA Road, Sec- 8
Faridabad
HARYANA 
9953047124

manishagagan@gmail.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 12  
Name of Committee  Approval Status 
Aakash Healthcare Institutional Ethics Committee  Approved 
BGS Global Institute of Medical Sciences - IEC  Approved 
Ethics Committee Jaslok Hospital and Research  Approved 
IEC Sarvodaya Hospital and Research Centre  Approved 
Institutional Clinical Ethics Committee, RGMC and Chatrapati Shivaji Maharaj Hospital  Approved 
Institutional Ethics Committee (IEC-GMCA)  Approved 
Institutional Ethics Committee Hindu Mission Hospital  Approved 
Institutional Ethics Committee Masina Hospital  Approved 
Institutional Ethics Committee, Govt. Medical College, Nagpur  Approved 
Institutional Ethics Committee, Sai Sneh Hospital and Diagnostic Centre  Approved 
Navsanjeevani Hospital Ethics Committee  Approved 
Rhythm Heart Institute Ethics Committee  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  B972||Coronavirus as the cause of diseases classified elsewhere,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  Hydroxychloroquine  600 mg QD (on Days 1 and 2) followed by 200 mg BID (on Days 3 to 14) 
Intervention  Nitazoxanide and Hydroxychloroquine  Nitazoxanide: 1000 mg QD (on Days 1 and 2) followed by 500 mg BID (on Days 3 to 14) + Hydroxychloroquine: 600 mg QD (on Days 1 and 2) followed by 200 mg BID (on Days 3 to 14) 
Comparator Agent  Not Applicable  Not Applicable 
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  65.00 Year(s)
Gender  Both 
Details  Male, female and transgender patients aged ≥ 18 years and ≤ 65 years
2. Patients testing positive for SARS-CoV-2 by rRT-PCR on a nasopharyngeal or oropharyngeal swab
Note: A re-treated/ relapsed patient may be enrolled if he/she meets all of the following criteria:
a. Documented re-conversion on nasopharyngeal or oropharyngeal swab from negative to positive for SARS-CoV-2 OR nasopharyngeal or oropharyngeal swab continues to be positive for SARS-CoV-2 after previous treatment
AND
b. Clinical symptoms associated with COVID-19 (fever, cough, difficulty in breathing, fatigue, body ache, headache, diarrhea, nasal congestion) have either re-appeared after previous treatment OR continued to be present without improvement OR are aggravated
AND
c. Patient meet the below-mentioned criterion (# 3) for ‘moderate’ COVID-19 disease severity
3. Patients clinically assigned as ‘moderate’ (Pneumonia with no signs of severe disease, respiratory rate 15 to 30/minute, SpO2 90%-94%)
Note: The severity is as defined by the Guidance document on appropriate management of suspect/confirmed cases of COVID-19 published by the Ministry of Health & Family Welfare on 07 Apr 2020.
4. Females should have a negative serum pregnancy test at baseline; female patients of child bearing potential should either be abstinent or comply with one or more contraception methods (with low user dependency and failure rate of <1%) for the entire duration of the treatment period and until 90 days after receiving the last dose of study treatment
5. Able and willing to provide informed consent
6. Able to understand the trial requirements and comply with trial medications and assessments in the opinion of the Investigator
7. Agrees not to participate in other clinical studies within 30 days after the last administration of the study treatment 
 
ExclusionCriteria 
Details  1. Patients with hypersensitivity or a contra-indication to hydroxychloroquine or nitazoxanide
2. Patients with history of one or more known comorbidities at baseline:
a. Uncontrolled Hypertension (systolic blood pressure >180 mmHg diastolic blood pressure >100 mmHg), Ischemic Heart Disease, Cardiac Failure
b. Diabetes Mellitus
c. COPD, Asthma or Interstitial Lung Disease
d. Malignancy
e. Other severe underlying diseases (e.g., active bleeding, blood dyscrasias, severe malnutrition)
f. G6PD (Glucose-6-Phosphate Dehydrogenase) deficiency
g. Psoriasis or porphyria
h. Kidney Disease (Serum creatinine > 1.5 times upper limit)
i. Liver disease (e.g. Child Pugh score ≥ B or AST (Aspartate Transaminase) >3.5 times upper limit)
j. Cardiac conduction delay (QTc > 500 msec)
k. Retinopathy or macular degeneration
3. In case of patients with symptoms associated with COVID-19 at screening assessment (ie, one or more of fever, cough, sore throat, breathlessness, rapid respiratory rate, low oxygen saturation in blood, body ache, chills, chills with shaking, fatigue, headache, loss of smell, loss of taste, diarrhoea, nasal congestion or any other symptom considered by the Investigator to be reasonably associated with COVID-19), the first onset of symptoms was > 10 days before screening (not applicable for re-treated/relapsed patients).
4. Receiving or has received antiviral therapy (including oseltamivir, zanamivir, favipiravir, umifenovir, ribavirin, anti- retroviral therapy with lopinavir and ritonavir [LPR/r]), nitazoxanide or ivermectin within 28 days or chloroquine/hydroxychloroquine in the six months prior to baseline visit
5. Received biological therapy (especially, experimental ACE-2 decoy or decoy receptor/monoclonal antibody against interleukin-6, interferon alpha) in the 90 days prior to baseline visit.
6. Patients clinically assigned as having ‘severe’ COVID-19 disease [Severe Pneumonia (with respiratory rate ≥30/minute and/or SpO2 < 90% in room air) or Acute Respiratory Distress Syndrome or Septic shock], critically ill patients and those currently requiring or anticipated to imminently require one or more forms of extracorporeal life support (eg mechanical ventilation, extracorporeal membrane oxygenation) in the judgement of the Investigator (on basis of COVID-19 disease severity, rate of progression, co-morbidities or complications) at the time of Randomization
7. Any other therapy which may confound the interpretation of efficacy outcomes or increase safety risks to patients
8. Inability to take oral medication.
9. Patients with malabsorption or gastrointestinal abnormalities which may affect drug absorption
10. Current smoker or has quit smoking within last 3 months
11. Body Weight < 45 kg
12. Female patients who are pregnant or lactating
13. Patients who have received organ transplantation in the last 6 months or currently on immunosuppressive therapy (eg. Methotrexate, Cyclosporine, etc.)
14. Patients who are contemplating surgery/ female patients contemplating a pregnancy within 90 days after scheduled end of study treatment
15. Patients who are not suitable to participate in the study based on the Investigator’s judgement 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   Pharmacy-controlled Randomization 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
Change from baseline in mean viral load (determined by rRT-PCR on a nasopharyngeal/ oropharyngeal swab)  Day 14 or at discharge from hospital, whichever is earlier 
 
Secondary Outcome  
Outcome  TimePoints 
Change from baseline in mean viral load (determined by rRT-PCR on nasopharyngeal/ oropharyngeal swab)  Days 3, 7 and 10 
Percentage of patients showing negative conversion (of detectable SARS-CoV-2 viral RNA) on nasopharyngeal/oropharyngeal swab  Day 14 
Median time (no. of days) to negative conversion (of detectable SARS-CoV-2 viral RNA) on nasopharyngeal swab  From Day 1 of treatment to negative conversion 
Percentage of patients discharged from ‘isolation ward’ of COVID-management hospital facility  Day 1 to Day 14 
Mean/median time (no. of days) from start of treatment to discharge from hospital   Day 1 until discharge from hospital 
Mean change from baseline in patient’s clinical status on a 10-point ordinal scale (SOLIDARITY trial).  Days 3, 7, 10 and 14 
Mean change from baseline in National Early Warning Score 2 (NEWS-2) score  Days 3, 7, 10 and 14 
Percentage of patients requiring of treatment:
a. Management in intensive care unit (ICU)
b. Oxygen supplementation
c. Invasive mechanical ventilation 
Day 1 to Day 14 
Mean/median time (no. of days) to
a. Management in intensive care unit
b. Oxygen supplementation
c. Invasive mechanical ventilation 
Day 1 to Day 14 
Mean/ median time (no. of days) the patient is:
a. Managed in intensive care unit
b. On Oxygen supplementation
c. On Invasive mechanical ventilation 
Day 1 to Day 14 
Time to achieve symptom improvement of at least 30% in the COVID-19 symptoms sum score  Day 1 to Day 14 
Percentage of patients dying due to COVID-19 complication  Day 1 to Day 14 
Number (and percentage) of patients reporting treatment emergent adverse events (TEAEs)  Day 1 to Day 14 
Changes of parameters at each assessment during the study/follow-up period, compared to baseline for:
▪ Vital signs: body temperature, heart rate, respiratory rate, systolic/diastolic blood pressure and oxygen saturation.
▪ Clinical Laboratory assessments: hematology, serum chemistry, urinalysis.
▪ 12-lead ECG: Changes in heart rate, PR, QRS, QT and QTcB intervals 
Day 1 to Day 14 
 
Target Sample Size   Total Sample Size="158"
Sample Size from India="158" 
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" 
Phase of Trial   Phase 2 
Date of First Enrollment (India)   15/06/2020 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="0"
Months="6"
Days="0" 
Recruitment Status of Trial (Global)   Not Applicable 
Recruitment Status of Trial (India)  Not Yet Recruiting 
Publication Details   NIL 
Brief Summary  
COVID-19 is currently a major global public health crisis and in the absence of an effective vaccine and ‘herd’ immunity, there are no known interventions for effectively dealing with this pandemic (other than broad public-health measures like physical distancing and containment). At an individual COVID-19 patient level, there is a lack of proven specific treatment options that improve symptoms, influence disease severity progression and outcomes or aid the treating physician in better patient management. Different medicines and medicinal systems are being explored to find remedial measures for this new infection. Antiviral drugs, and other antimicrobial agents are being evaluated and being utilized off-label in treating patients, largely those with more severe COVID-19. However, no breakthrough has been achieved to date either in curtailing the pandemic or improving patient outcomes.
Hydroxychloroquine has had mixed outcomes in the treatment of COVID-19. Gautret et al, 202014 has shown the efficacy of Hydroxychloroquine when compared with the control group; other observational studies17, 18 have not shown convincing benefit to risk ratio however, these were non-randomized. It is already being used off-label for the treatment of COVID-19 in many countries, including India and the United States.
The other drugs namely, Nitazoxanide has been reported to have broad antiviral properties, in addition to antiparasitic properties for which it is approved. Nitazoxanide is currently approved in India (for Giardia lamblia and Crytosporidium parvum infections) and has been in use since many years with no major safety concerns.
In this study, we are also evaluating a combination regimen of Hydroxychloroquine and Nitazoxanide in comparison to a regimen of Hydroxychloroquine alone in treating patients assessed to have COVID-19 disease of moderate severity, to see if treatment of COVID-19 could be further optimized in terms of efficacy and safety.
 
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