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.
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 . 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 . 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  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 . 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 . 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 . 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.
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.
- 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
- Bai Y, Yao L, Wei T et al. Presumed asymptomatic carrier transmission of COVID-19. JAMA 2020 Feb21 (Epub, ahead of print)
- 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
- 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)
- 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
- 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
- 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
- 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.
- 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.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.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.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.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.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.Riou B, Barriot P, Rimailho A, Baud FJ. Treatment of severe chloroquine poisoning. N Engl J Med 1988; 318: 1–6.
- 16.Ducharme J, Farinotti R. Clinical pharmacokinetics and metabolism of chloroquine. Clin Pharmacokinet 1996;31: 257–74] .
- 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.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. Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID19). Drug discoveries & Therapeutics. 2020; 14(1): 58-60