key: cord-0731800-c5fn8t7f authors: kamran, s. m.; Mirza, Z. e. H.; Naseem, A.; Saeed, F.; Azam, R.; Ullah, N.; Ahmad, W.; Saleem, S. title: Clearing the fog: Is HCQ effective in reducing COVID-19 progression: A randomized controlled trial date: 2020-08-04 journal: nan DOI: 10.1101/2020.07.30.20165365 sha: 2a524bc57aa0d8463d3ac70ce0373356884cdc3b doc_id: 731800 cord_uid: c5fn8t7f Objective: To analyze the efficacy of Hydroxychloroquine (HCQ) plus standard of care (SOC) compared with SOC alone in reducing disease progression in Mild COVID-19 Design: A single centre, open label randomized controlled trial Place and Duration: Pulmonology department, Pak emirates Military Hospital (PEMH) from 10 April 2020 to 31 May 2020. Methodology: Five hundred patients of both genders having age between 18-50 years who were PCR positive and had Mild COVID-19 were selected. Patients assigned to standard dose of HCQ (400mg 12 hourly day 1 then 200mg 12 hrly for next 4 days) plus SOC were 349 while 151 patients received SOC comprising of Vit C, Vit D, and Zinc only (control group). Primary outcome was progression of disease while secondary outcome was PCR negativity on day 7 and 14. The results were analyzed on SPSS version 23. P value <0.05 was considered significant. Results: Median age of intervention group (34 + 11.778 years) and control group (34 + 9.813 years). Disease progressed in 16 patients, 11 (3.15%) were in intervention group as compared to 5 (3.35%) in control group, (p value = 0.865). PCR negativity in intervention and control groups were (day 7, 182 (52.1%) vs. 54 (35.7%) (p value = 0.001), (day 14, 244 (69.9%) vs. 110 (72.8%) (p value = 0.508). Consecutive PCR negativity at day 7 and 14 was observed in 240 (68.8%) in intervention group compared to 108 (71.5%) in control group. (p value = 0.231). Conclusion: Addition of HCQ to standard of care treatment in Mild COVID-19 neither prevents disease progression nor is it significantly associated with successive PCR negativity on day 7 and 14. Beyond supportive care, there are currently no proven treatment options for coronavirus disease (COVID-19) 1 . As mortality in patients with critical category is quite substantial 2 , hence every effort has to be made to intervene early and aggressively in order to prevent progression of disease. Globally, approximately eight million confirmed cases of Covid-19 have been reported with an outcome based overall mortality of 5.51% 3 . In Pakistan, there is exponential rise in Covid-19 cases in last few months. Nevertheless, data from various international studies shows that 81% of patients have had mild to moderate disease, which includes non-pneumonia and pneumonia cases 4 . Management of mild disease is equally important as this is the main bulk involved in transmission of disease to others. It is well known fact that asymptomatic carriers and patients with mild disease are also the main sources of disease transmissibility 5 . Therefore, it is a matter of utmost importance to detect mild cases earlier and start some investigational treatment in carefully selected hospitalized patients. Different investigational treatment options have been tried in different severity categories of COVID-19. Out of many therapeutic off-label options, HCQ seems more suitable owing to its known safety profile, side effects, posology and drug interactions 6 . HCQ has been found to have good in vitro activity against SARS-CoV-2 7 and better safety profile than chloroquine 8 . A small study on 36 patients shows that hydroxychloroquine (HCQ) treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients 9 . Similarly, it has been hypothesized that HCQ might inhibit cytokine storm by reducing CD154 expression in T cells, thus reducing chances of disease progression 10 . Therapeutic role of HCQ can be determined by time required for virologic clearance as well as to see whether disease is getting worse or not on the basis of symptoms aggravation and monitoring laboratory markers of Cytokine release storm. In Pakistan, PEMH is All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 4, 2020. . https://doi.org/10.1101/2020.07.30.20165365 doi: medRxiv preprint the largest Covid-19 designated hospital in the country. This hospital has already treated more than 3000 Covid-19 patients so far including many asymptomatic and mild cases. On the basis of limited evidence available, HCQ was given after consent to Mild Covid-19 patients with an aim to achieve early viral clearance and prevent progression of disease. Later on, we analyzed the data to assess the response. This single Centre, parallel open label randomized controlled trial was carried out at department of Pulmonology, Pakistan Emirates Military Hospital (PEMH). The study design was approved by institutional ethical review committee. Five hundred admitted patients from both genders with Mild confirmed COVID-19 were included after their written consent. The study protocol and approval documents are available online. A case was considered confirmed on the basis of positivity of RT-PCR of combined Oropharyngeal and Nasopharyngeal swabs. Severity of disease was defined as per criteria designed by WHO 11 . Mild disease meant Patients with uncomplicated upper respiratory tract viral infection having non-specific symptoms such as lowgrade fever (fever < 100F for < 3 days), fatigue, body aches, cough (with or without sputum production), anorexia, muscle pain, sore throat, nasal congestion, anosmia, headache and rarely diarrhea, nausea, and vomiting. PCR sampling was done on day 7 and 14 of admission. Any chronic health condition for which patients were on prior treatment was considered as co morbidity. In Hospital, HCQ was given to patients after written consent and after considering its contraindications. Three hundred and forty-nine (349) patients were included in intervention group and given HCQ in addition to standard of care treatment. Standard dose of HCQ was 400 mg by mouth twice a day for day one followed by 200 mg 12 hourly for next 4 days. The patients who did not give consent for treatment with HCQ or had a known allergy to HCQ or chloroquine or had another known All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 4, 2020. . https://doi.org/10.1101/2020.07.30.20165365 doi: medRxiv preprint contraindication to treatment with the study drug, including retinopathy, G6PD deficiency and QT prolongation served as controls. Controls were matched with participants on the basis of age, gender and co morbids and comprised of 151 patients. Standard of care (SOC) treatment comprised of oral Vit C, oral Zinc, oral Vit-D and tablet Paracetamol (for body aches/fever), intravenous fluids, hemodynamic monitoring, and laboratory testing for SARS-CoV-2 and baseline blood parameters. Data regarding age, co-morbidities, history of contact with a positive patient, days since contact, duration of symptoms, PCR status with date and base line labs/X-ray chest were recorded. Any patient with day 0 CRP greater than 6mg/dl, Absolute lymphocyte count (ALC) < 1000 or evidence of infiltrates on X-ray chest were excluded. Daily temperature, respiratory rate (RR) and resting O2 saturation with pulse oximetry were monitored in all patients during their hospitalization. After start of treatment, development of fever > 101 F for > 72 hours, shortness of breath by minimal exertion (10- Step walk test), derangement of basic lab parameters (ALC < 1000 or raised CRP) or appearance of infiltrates on CXR during course of treatment was labeled as progression irrespective of PCR status. PCR status of patients was checked after 7 days and 14 days of initiation of treatment. Statistical interpretation of data was performed using Statistical Package for Social Sciences (SPSS) version 23. Results were expressed as mean, standard deviation (±SD) for all continuous variables and frequency and percentage for categorical data. We used t-test and chi-square test as appropriate to the nature and distribution of the variables. A p-value < 0.05 was considered statistically significant. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 4, 2020. . https://doi.org/10.1101/2020.07.30.20165365 doi: medRxiv preprint During the study, a total of 500 patients of Mild COVID-19 were included, with a mean age of 35.96 ± 11.2 years (intervention group: 34 + 11.778 vs. control group: 34 + 9.813), males 466 (93.2%) and females 34 (6.8%). Most patients were healthy young individuals with co-morbids only in 38 (7.6%). Diabetes Mellitus (DM) in 15 (3%) being the commonest disease. Positive contact history was found in 315 (63%) patients. Among constitutional symptoms, cough 163 (32.6%), low grade fever 133 (26.6%), body aches 96 (19.2%), anosmia 83(16.6%) and fatigue 56 (11.2%) were the most common. Less common symptoms were sore throat 33 (6.6%), diarrhea 21 (4.2%) and headache 21 (4.2%). Completely asymptomatic patients were 101 (20.2%). HCQ in addition to SOC treatment was given to intervention group comprising of 349 (69.8%) patients while 151 (30.2%) patients of control group received only SOC treatment. Among 16 patients who showed disease progression (Table-1 Overall, PCR negativity was observed in 236 (47.2%) patients on day 7 and in 354 (70.8%) patients on day 14. Effects of HCQ on PCR status of study population is given in Table 2 . Day wise PCR negativity in intervention and control groups respectively were as follows; (day 7: 182 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 4, 2020. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 4, 2020. . https://doi.org/10.1101/2020.07.30.20165365 doi: medRxiv preprint Chi-square test applied. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 4, 2020. Chi-square test applied. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 4, 2020. . https://doi.org/10.1101/2020.07.30.20165365 doi: medRxiv preprint 1 Although there was much hype about effectiveness of HCQ in treating COVID-19 but our study did not show any significant benefit of using HCQ. Firstly, HCQ did not prevent progression of disease in patients with or without co morbids although it was postulated to dampen cytokine release storm by Dan Zhou et al 10 . Secondly, as far as PCR negativity was concerned, its addition to supportive treatment showed significantly better early PCR negativity at day 7, but at day 14 there was not much difference in PCR negativity between the two studied groups. Nonetheless, it did not show any side effects in our study. We used the same doses of HCQ as used by Yao X et al 12 and no side effects were observed in their study also. Results of our study are also contrary to a highly publicized study done by Gao J et al 13 which showed early viral clearance and decreased rate of disease progression. Comparatively it was a study with smaller sample size (n=100) and they used Chloroquine instead of HCQ used in our study. As far as viral clearance at day 7 is concerned, our results are similar to that of non-randomized control trial from France by Gautret et al 9 . Their study showed significantly better viral clearance at day 6 of inclusion ((70% vs. 12.5%; P = 0.001) with use of 600mg/day of HCQ for 10 days. However, in addition to HCQ, they also used Azithromycin. Although highly rated initially, this study had only 20 participants in interventional arm out of which 6 removed from study due to intolerance to medication. In addition, it was a non-randomized trial containing major biases between studied groups, and patients were not followed till day 14 to see viral clearance again. In comparison, we followed patients at day 14 and found that a subset of day 7 PCR negatives turned positive again on day 14. This observation found in our study might be because of false negative PCR at day 7 owing to variable sensitivities of testing kits or a false positive PCR at day 14 due to presence of non-infective dead viral particles. When we compare results of our study All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 4, 2020. the study was done in mild cases and moderate/severe cases were not included so it cannot be determined whether HCQ is of any benefit in advanced COVID-19 or not. Thirdly, the patients were not followed up after discharge from the hospital hence, exact progression of disease could not be ascertained. Fourthly, we did not use quantitive RT-PCR to exactly determine the viral load which is a strong bias to affect viral clearance. Fifthly, PCR positivity at day 14 is of uncertain significance because it is now evident that after 10 th day onset of illness, presence of non-replicable viral nucleic acid material only, are being picked up by the PCR 18, 19 and such patients are regarded as non-infective. Finally, even with best sampling techniques, sensitivity of RT-PCR for SARS-CoV-2 ranges between 34-80% 20 so exact estimation of viral clearance will definitely remain under question. Despite the limitations, our study is first of its own kind in Pakistan which is reinforced by a larger sample size and relatively longer follow up time. Our study shows that addition of HCQ to supportive treatment in mild COVID-19 cases is not significantly associated with prevention of disease progression. Despite showing significantly early PCR negativity at day 7, day 14 PCR results are similar to that of non HCQ arm. The findings of our study correlate with the results of various clinical trials done internationally. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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