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CTRI Number  CTRI/2020/04/024904 [Registered on: 28/04/2020] Trial Registered Prospectively
Last Modified On: 28/04/2020
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group Trial 
Public Title of Study   Treatment of COVID19 : A randomised controlled trial 
Scientific Title of Study   Randomised Controlled Trial to compare efficacy of hydroxychloroquine alone and in combination with azithromycin in treatment of COVID-19  
Trial Acronym  HAZES  
Secondary IDs if Any  
Secondary ID  Identifier 
NIL  NIL 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  AirCmde V K Sashindran 
Designation  Principal Medical Officer 
Affiliation  Armed Forces Medical Services 
Address  Has Central Air Command Air Force Station Bamrauli Prayagraj

Allahabad
UTTAR PRADESH
211012
India 
Phone  919958826493  
Fax    
Email  vksashindran@gmail.com  
 
Details of Contact Person
Scientific Query
 
Name  AirCmde V K Sashindran 
Designation  Principal Medical Officer 
Affiliation  Armed Forces Medical Services 
Address  Has Central Air Command Air Force Station Bamrauli Prayagraj

Allahabad
UTTAR PRADESH
211012
India 
Phone  919958826493  
Fax    
Email  vksashindran@gmail.com  
 
Details of Contact Person
Public Query
 
Name  Col Anurag Khera 
Designation  Commanding Officer 
Affiliation  Armed Forces Medical Services 
Address  Field Hospital

Darrang
ASSAM
784521
India 
Phone  917507188003  
Fax    
Email  anuragkhera74@gmail.com  
 
Source of Monetary or Material Support  
Office of DGAFMS Ministry of Defence M Block New Delhi 110001 
 
Primary Sponsor  
Name  Director General Armed Forces Medical Services 
Address  Ministry of Defence Office of DGAFMS M Block New Delhi 110001  
Type of Sponsor  Other [Armed Forces Medical Services] 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study  
No of Sites = 6  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Snehangsh Dash  Air Force Hospital Gorakhpur  12 Air Force Hospital, Kunraghat Gorakhpur
Gorakhpur
UTTAR PRADESH 
919674905798

snehangsh@gmail.com 
Rajneesh Thakur  Air Force Hospital Kanpur  7 Air Force Hospital Nathu Singh Road Kanpur Cantt
Kanpur Nagar
UTTAR PRADESH 
918554828920

rajneesh2207@gmail.com 
Kuldeep Ashta  Base Hospital Delhi Cantt  Base Hospital Delhi Cantt New Delhi 110010
South West
DELHI 
919755136658

kuldeepashta@gmail.com 
Dheeraj Kumar  Base Hospital Luchnow  Base Hospital Lucknow Cantt
Lucknow
UTTAR PRADESH 
9829716515

dheerajkumar29@yahoo.com 
Col Sanjeevan Sharma  Command Hospital Lucknow  Command Hospital Central Command Lucknow Cantt
Lucknow
UTTAR PRADESH 
919310746620

sanjeevanzsharma@hotmail.com 
Ajay Kumar  Military Hospital Ahmedabad  MH Ahmedabad Ahmedabad
Ahmadabad
GUJARAT 
9630778573

ajay.billoo@gmail.com 
 
Details of Ethics Committee  
No of Ethics Committees= 7  
Name of Committee  Approval Status 
7 Air Force Hospital   Approved 
Base Hospital & Army College of medical Sciences Delhi  Approved 
Base Hospital Lucknow  Submittted/Under Review 
Command Hospital Lucknow  Submittted/Under Review 
HQ CAC Ethic Committee (Gorakhpur)  Approved 
HQ Central Air Command Ethics Committee  Approved 
MH Ahmedabad  Submittted/Under Review 
 
Regulatory Clearance Status from DCGI  
Status 
Not Applicable 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  B972||Coronavirus as the cause of diseases classified elsewhere, B338||Other specified viral diseases,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Comparator Agent  HCQ AZT  HCQ 400mg BD AZT 500mg OD D1 HCQ 400mg OD AZT 250 mg OD D2 - D5 
Intervention  HCQ high dose (HCQh)  HCQ 600mg BD D1 HCQ 300mg BD D2 - D5  
Intervention  Hydroxychloroquine sulfate (HCQs)  HCQ 400mg BD on D1 and 400 mg OD on D2 - 5  
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  85.00 Year(s)
Gender  Both 
Details  Age > 18 years
All sexes
Case definitions for inclusion in the study will include mild, moderately severe and severe cases as defined in the Guidance on appropriate treatment of suspect/confirmed case of COVI19 issued by Ministry of Health and Family Welfare, Govt of India on 07 Apr 2020.
Mild: Cases presenting with fever and/or upper respiratory tract illness (Influenza like Illness, ILI)
Moderate: Pneumonia with no signs of severe disease (Respiratory Rate 15 to 30/minute, SpO2 90%-94%).
Severe: Severe Pneumonia (with respiratory rate ≥30/minute and/or SpO2 < 90% in room air) or ARDS or septic shock

Laboratory confirmed SARS CoV-2 infection within last 10d or SARS CoV-2 test result pending with a high clinical suspicion as defined by:
Cough of <10d duration
Bilateral pulmonary infiltrates on chest X Ray / CT scan or new hypoxaemia defined as SpO2 <94% on room air
No alternative explanation for respiratory symptoms
Scheduled for admission or enrolled within 48h of hospital admission
 
 
ExclusionCriteria 
Details  Children < 18 years
Pregnant or lactating women
Symptoms of acute respiratory tract infection for > 10d before randomisation
More than 48h have elapsed between meeting inclusion criteria and randomisation
Seizure disorder
Known case of G6PD deficiency
Diagnosed long QT syndrome
QTc >500ms on ECG within 72h prior to enrolment
Chronic haemodialysis or GFR<20 ml/min
Psoriasis or porphyria cutanea tarda
Severe liver disease
Any subject who has received the following drugs in the 12h period before enrolment or who is likely to receive the following during the period of therapy with HCQ / HCQ + AZT / AZT: amiodarone, cimetidine, phenobarbitone, phenytoin, digoxin
Receipt of >1 dose of HCQ / AZT in 10 days prior to enrolment
Known allergic reactions to HCQ or azithromycin
Inability to take/receive enteral medication
Inability to be contacted on D14 for clinical outcome assessment (unless died in hospital) 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   An Open list of random numbers 
Blinding/Masking   Participant and Outcome Assessor Blinded 
Primary Outcome  
Outcome  TimePoints 
COVID Ordinal Outcomes Scale is defined as:
1. Death
2. Hospitalised on invasive mechanical ventilation or extracorporeal mechanical ventilation ( ECMO)
3. Hospitalised on non-invasive ventilation or high-flow nasal cannula oxygen therapy
4. Hospitalised on supplemental oxygen
5. Hospitalised not on supplemental oxygen
6. Not hospitalised with limitation of activity (due to continued symptoms)
7. Not hospitalised without limitation in activity (no symptoms) 
D14
 
 
Secondary Outcome  
Outcome  TimePoints 
All location, all-cause mortality assessed on D14 (Time frame- assessed on 14th day of starting treatment) Vital status of patient will be ascertained from medical record review, phone call to patient or proxy
 
D14 
All location, all-cause mortality on D28 (Time frame- assessed on 28th day of starting treatment) Vital status of patient will be ascertained from medical record. review, phone call to patient or proxy
 
D28 
COVID Ordinal Outcomes Scale on D2 (COOS will be determined for all patients on 2nd day of starting treatment).
 
D2 
COOS on D7 (COOS will be determined for all patients on 7th day of starting treatment)
 
D7 
COOS on D28 (COOS will be determined for all patients on 28th day day of starting treatment)
 
D28 
Oxygen-free days through D28 (28th day of starting treatment). Oxygen-free days is defined as 28 minus the duration of days through the 28 days when he received Oxygen therapy. Patients not surviving up to D28 will be passing a ventilator-free days value of zero.)
 
D28 
Ventilator-free days through D28 (28th day of starting treatment. Ventilator free days is defined as 28 minus the duration of ventilated days through the 28 days. Patients not surviving up to D28 will be assigned a ventilator-free days value of zero.)
 
D28 
Vasopressor-free days through D28 (28th day of starting treatment. Vasopressor free days is defined as 28 minus the duration of vasopressor support days through the 28 days. Patients not surviving up to D28 will be assigned a vasopressor-free days value of zero.)
 
D28 
ICU-free days through D28 (28th day of starting treatment. ICU free days is defined as 28 minus the duration of ICU days through the 28 days. Patients not surviving up to D28 will be assigned a ICU-free days value of zero.)
 
D28 
Hospital-free days through D28 (28th day of starting treatment. Hospital free days is defined as 28 minus the number of days from enrolment to discharge to home. If patient has not been discharged to home by D28 or dies during hospitalisation, he will be assigned a value of zero  D28 
Compare groups with regards to seizures to D28 (The number of patients who have seizures between starting treatment and 28th day will be determined)
 
D28 
Compare groups with regards to atrial or ventricular arrhythmia to D28 (The number of patients who have atrial or ventricular arrhythmias between starting treatment and 28th day will be determined)
 
D28 
Compare groups with regards to cardiac arrest to D28 (The number of patients who have cardiac arrests between starting treatment and 28th day will be determined)
 
D28 
Compare groups with regards to elevation of aspartate aminotransferase to D28 (The number of patients who have aspartate aminotransferase level more than two times upper limit of normal between starting treatment and 28th day will be determined)
 
D28 
Compare groups with regards to acute pancreatitis to D28 (The number of patients who have acute pancreatitis between starting treatment and 28th day will be determined)
 
D28 
Compare groups with regards to acute kidney injury to D28 (The number of patients who have acute kidney injury between starting treatment and 28th day will be determined)
 
D28 
Number of patients receiving renal replacement therapy to D28 (The number of patients who receive renal replacement therapy between starting treatment and 28th day will be determined)
 
D28 
Compare groups with regards to symptomatic hypoglycaemia to D28 (The number of patients who experience symptomatic hypoglycaemia between starting treatment and 28th day will be determined)
 
D28 
Compare groups with regards to neutropenia, lymphopaenia, anaemia or thrombocytopenia to D28 (The number of patients who have neutropenia, lymphopaenia, anaemia or thrombocytopenia between starting treatment and 28th day will be determined)
 
D28 
Compare groups with regards to severe dermatologic reaction to D28 (The number of patients who experience severe dermatologic reaction between starting treatment and 28th day will be determined)  D28 
 
Target Sample Size   Total Sample Size="300"
Sample Size from India="300" 
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 3 
Date of First Enrollment (India)   11/05/2020 
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="1"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)   Not Applicable 
Recruitment Status of Trial (India)  Not Yet Recruiting 
Publication Details   Will be published in indexed medical journal 
Brief Summary  

Study Rationale 



The study will follow all guidelines as mentioned in the Monitored Emergency Use of Unregistered and Investigational Interventions (MEURI) by the World Health Organisation.


No definite treatment is recommended for COVID19 caused by the novel SARS Cov-2. The current standard of care is only supportive. In vitro studies and  small clinical studies in China have demonstrated clinical efficacy of Chloroquine/hydroxychloroquine and combination therapy of hydroxychloroquine and azithromycin. Antiviral properties of Azithromycin have also been demonstrated. However, the exact dosage of the medication and duration of treatment are not well established. This study wants to  determine the efficacy of hydroxychloroquine in standard dose and high dose separately and standard dose in combination with azithromycin in treatment of COVID-19. If efficacy is proven, then early treatment will decrease infectivity of cases and also lead to quicker recovery which will decrease burden on healthcare facilities.


Background 


SARS CoV-2 is a novel corona virus that has led to a pandemic of respiratory illness with high mortality. It is predominantly spread by respiratory droplets and also by fomites [1]. Both asymptomatic and symptomatic patients can transmit the virus [2, 3, 4]. Average period of transmission is estimated to be 5 - 14 d but transmission upto 28 d is known. The disease was initially discovered when a series of unusual pneumonia cases were detected in Wuhan, China [5]. The commonest presentation is an influenza-like illness. Fever, dry cough and breathlessness are the commonest symptoms reported [6, 7]. Case Fatality Rate (CFR) at present is estimated to be between 0.25 - 3 [8] Elderly, those with heart disease, respiratory disease or diabetes and a combination of these are found to be at highest risk [9, 10]. No definite treatment is known and at present guidelines only recommend supportive care. A rapid cure can result in decreased period of infectivity and also decrease respiratory morbidity and mortality. Various trial drugs are being tested. Lopinavir-ritonavir combination has not been found to be effective in one study [11]. Hydroxychloroquine has been found to have both in vitro and in vivo antiviral properties. It also decreases progression to ARDS in patients with severe pneumonia by its immunomodulatory effects [12, 13, 14]. Various dosage regimes have been suggested based on modelling studies and small clinical observational studies. Yao and colleagues recommend a dose of hydroxychloroquine 400 mg BD on D1 and 400mg daily on D2 - 5 based on their modelling study [13]. Cumulative toxicity of chloroquine occurs beyond 5g and the drug has a large volume of distribution with an elimination half-life of 20 - 60d and with a tendency to accumulate in higher concentrations in metabolically active tissue than in the serum [15, 16].  

Azithromycin has also been shown to have antiviral activity especially against Ebola and Zika viruses. AZT induces antiviral responses in bronchial epithelial cells. AZT decreases viral replication of rhinovirus. Their combination is hypothesised to have synergistic effect but this has not been proven yet. The combination of HCQ +AZT has proven to be effective in Ebola. SARS Cov-2 clearance has been demonstrated in patients administered a combination of HCQ +AZT [17]. Other drugs like Remedesivir, favipravir and Chinese herbal medicines are all being studied in various trials [18, 19].

Both hydroxychloroquine and azithromycin are cheap, widely available and with a good safety profile. Hence, the imperative to prove their efficacy to treat COVID-19.


This study will compare three treatment regimens one with hydroxychloroquine (HCQ) in standard dose (HCQs) alone, hydroxychloroquine and azithromycin (AZT) and third with hydroxychloroquine in high dose (HCQh)  and determine which regime is the best to treat hospitalised patients with confirmed COVID-19 in armed forces hospitals.


Objectives:

1. To compare efficacy of HCQs  versus HCQ + AZT versus HCQh in treatment of COVID-19 among patients admitted to Indian Armed Forces Hospitals.


2. To compare safety of HCQ versus HCQ +AZT versus HCQh alone in treatment of COVID-19 among patients admitted to Indian Armed Forces Hospitals.



AI

References

  1. van Doremalen N, Morris D H, Holbrook M G, Gamble A et al. Aerosol and surface stability of SARS CoV-2 as compared with SARS CoV-1. New Engl J Med.2020 Mar17; DOI: 10.1056/NEJMc2004973
  2. Bai Y, Yao L, Wei T et al. Presumed asymptomatic carrier transmission of COVID-19. JAMA 2020 Feb21 (Epub, ahead of print)
  3. You L, Ryan F, Huang M et al. SARS CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med.doi:10.1056/NEJMc2001737
  4. Li R, Pei S,Chen B, Song Y, Zhang T, Yang W, Shaman J. Substantial, undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS CoV-2). Science. 2020 doi:10.1126/science.abb3221(2020)
  5. Zhu N, Zhang D, Wang W, Li X. A novel coronavirus from patients with pneumonia in China, 2019. New Eng J Med.2020, Jan 24;382:727-733
  6. Wu Z, McGoogan J Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China.JAMA. 2020Feb24; doi:10.1001/jama.2020.2648
  7. Boudama L, Lescure F-X, Lucet J-C, Yazdanpanah Y, Timsit J-F. Severe SARS-CoV-2 infections: practical considerations and management strategies for intensivists. Intensive Care medicine 2020; 46: 579-582
  8. Wilson N, Kvalsvig A, Barnard L T, Baker M G. Case-fatality risk estimation for COVID-19 calculated using a time lag for fatality. EID. 2020Jun; 26(6). DOI:10.3201/eid2606.200320.
  9. Zhou F, You T, u R, Fan G, Liu Y, Liu Z et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet.2020, Mar11; DOI: https:/doi.org/10.1016/S0140-6736(20)30566-3
  10. 10.Onder G, Rezza G, Brusaferro S. Case fatality rate and characteristics of patients dying in relation to OVID-19 in Italy. JAMA. 2020 Mar 23; doi: 10.1001/jama.2020.4683
  11. 11.CaoB,WangY,WenD,LiuW,WangJ,FanG,RuanL,SongB,CaiY,WeiM,LiX,XiaJ,ChenN,XiangJ,YuT,Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, Wang J, Liu X, Wang S, Wu X, Ge Q, He J, Zhan H, Qiu F, Guo L, Huang C, Jaki T, Hayden FG, Horby PW, Zhang D, Wang C. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020 Mar 18. doi: 10.1056/NEJMoa2001282. [Epub ahead of print]
  12. 12.Colson P, Rolain JM, Lagier JC, Brouqui P, Raoult D. Chloroquine and hydroxychloroquine as available weapons to !ght COVID-19. Int J Antimicrob Agents. 2020 Mar 4:105932. doi: 10.1016/j.ijantimicag.2020.105932. [Epub ahead of print] 
  13. 13.Yao X,Ye F, Zhang M, Cui C,Huang B, Niu P, Liu X, Zhao L, Dong E, Song C, Zhan S, Lu R, Li H,Tan W, Liu D.In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020 Mar 9. pii: ciaa237. doi: 10.1093/cid/ciaa237. [Epub ahead of print]
  14. 14.Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020 Mar 16;14(1):72-73].
  15. 15.Riou B, Barriot P, Rimailho A, Baud FJ. Treatment of severe chloroquine poisoning. N Engl J Med 1988; 318: 1–6. 
  16. 16.Ducharme J, Farinotti R. Clinical pharmacokinetics and metabolism of chloroquine. Clin Pharmacokinet 1996;31: 257–74] . 
  17. 17.Gautret P, Lagier J, Parola P, Hoang V, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents. In Press]
  18. 18.Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269- 271]
  19. 19. Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID19). Drug discoveries & Therapeutics. 2020; 14(1): 58-60
 
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