| CTRI Number |
CTRI/2020/06/025849 [Registered on: 12/06/2020] Trial Registered Prospectively |
| Last Modified On: |
14/06/2021 |
| 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
Modification(s)
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| Secondary ID |
Identifier |
| CVD-19-CD-001; Version 4.0; 14 July 2020 |
Protocol Number |
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Details of Principal Investigator or overall Trial Coordinator (multi-center study)
|
| Name |
|
| Designation |
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| Affiliation |
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| Address |
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| Phone |
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| Fax |
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| Email |
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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 |
|
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Source of Monetary or Material Support
|
| Dr. Reddy’s Laboratories Limited 8-2-337, Road No. 3 Banjara Hills, Hyderabad 500043 |
|
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Primary Sponsor
|
| Name |
Dr Reddys Laboratories Limited |
| Address |
8-2-337, Road No.3, Banjara Hills, Hyderabad 500043 |
| Type of Sponsor |
Pharmaceutical industry-Global |
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Details of Secondary Sponsor
|
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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 |
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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 |
|
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Regulatory Clearance Status from DCGI
|
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Health Condition / Problems Studied
|
| Health Type |
Condition |
| Patients |
(1) ICD-10 Condition: B972||Coronavirus as the cause of diseases classified elsewhere, |
|
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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
Modification(s)
|
| Age From |
18.00 Year(s) |
| Age To |
65.00 Year(s) |
| Gender |
Both |
| Details |
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, fatigue, shortness of breath, expectoration, myalgia, rhinorrhea, sore throat, diarrhea, anosmia, ageusia) 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 ≥24 breaths/minute, SpO2 <94% (90%-94%) on room air)
Note: The severity is as defined by the Clinical Management Protocol: COVID-19 published by the Ministry of Health & Family Welfare on 03 Jul 2020 (Appendix IV).
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 or 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. Uncontrolled Diabetes Mellitus
Note: Investigators may use clinical discretion to enrol well controlled diabetic patients who are either currently receiving or not currently receiving anti-diabetic medications.
c. COPD, Asthma or Interstitial Lung Disease
d. Malignancy
e. Other severe underlying diseases (e.g., active bleeding, blood dyscrasias, severe malnutrition)
f. G6PD 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, diarrhea, 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
Note: The severity is as defined by the Clinical Management Protocol: COVID-19 published by the Ministry of Health & Family Welfare on 03 Jul 2020 (Appendix IV).
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 |
|
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Method of Generating Random Sequence
|
Computer generated randomization |
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Method of Concealment
|
Pharmacy-controlled Randomization |
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Blinding/Masking
|
Open Label |
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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 |
|
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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 |
|
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Target Sample Size
|
Total Sample Size="158"
Sample Size from India="158"
Final Enrollment numbers achieved (Total)= "158"
Final Enrollment numbers achieved (India)="0" |
|
Phase of Trial
|
Phase 2 |
|
Date of First Enrollment (India)
|
15/06/2020 |
| Date of Study Completion (India) |
10/10/2020 |
| Date of First Enrollment (Global) |
Date Missing |
| Date of Study Completion (Global) |
Date Missing |
|
Estimated Duration of Trial
|
Years="0"
Months="6"
Days="0" |
Recruitment Status of Trial (Global)
Modification(s)
|
Not Applicable |
| Recruitment Status of Trial (India) |
Completed |
|
Publication Details
|
NIL |
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Individual Participant Data (IPD) Sharing Statement
|
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
|
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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. |