key: cord-0755954-c94ddrsd authors: SEV COVID trial group,; Panda, P. K. title: Safety and efficacy of antiviral therapy alone or in combination in COVID-19 - a randomized controlled trial (SEV COVID Trial) date: 2021-06-08 journal: nan DOI: 10.1101/2021.06.06.21258091 sha: a9d66fd489e07d24371ced3b83db713d4af9db6e doc_id: 755954 cord_uid: c94ddrsd Background Definitive antiviral treatment is not available for COVID-19 infection except remdesivir that even with many doubts. Various combination antivirals have been tried. Methods A single-center, open-label, parallel-arm, stratified randomized controlled trial evaluated the therapeutic potential of hydroxychloroquine and lopinavir-ritonavir in combination with ribavirin in COVID-19. Enrolled patients in severe category were randomized into three groups: A: standard treatment, B: hydroxychloroquine+ribavirin+standard treatment, or C: lopinavir+ritonavir+ribavirin+standard treatment; while non-severe category into two groups: A: standard treatment or B: hydroxychloroquine+ribavirin. Combination antivirals was given for 10 days and followed for 28 days. The primary endpoints were safety, symptomatic and laboratory recovery of organ dysfunctions, and time to SARS-CoV-2 RT-PCR negative report. Results Total 111 patients randomized: 24, 23, and 24 in severe category A, B, and C respectively, and 20 in each non-severe group. Two patients receiving ribavirin experienced drug induced liver injury and another developed QT prolongation after hydroxychloroquine. In the severe category, 47.6%, 55%, and 30.09% in A, B, and C groups respectively showed symptomatic recovery compared to 93.3% and 86.7% in A and B groups respectively in the non-severe category at 72hrs (P>0.05). Conclusions The results failed to show statistical superiority of the antiviral combination therapies to that of the standard therapy in both the severe and non-severe categories in symptomatic adult patients of COVID-19. However, results do indicate the benefit of non-standard interventional combination therapy in severe disease. Furthermore, the dose of ribavirin needs to be reconsidered in the Indian population. to that of the standard supportive therapy. 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 (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.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 June 8, 2021. ; https://doi.org/10.1101/2021.06.06.21258091 doi: medRxiv preprint 5 | P a g e received lopinavir + ritonavir + ribavirin + standard treatment; while "non-severe disease" category patients were randomized into two arms: non-severe A and B. Non-severe A received the standard treatment and non-severe B received HCQ + ribavirin + standard treatment. At the time of enrolment, demographic data were collected from the participants, including relevant data on their medical history, co-morbidities, as well as risk factors for severe COVID- 19 . Baseline investigations included a complete blood count, liver function tests, kidney function tests, glucose-6-phosphate dehydrogenase levels, and electrocardiography. Patients were followed up for 28 days from the day of enrolment. The randomization was done with a computer-based software "randomize R package" of version 1.4.2. Randomization was done in blocks of four and patients were stratified into non-severe and severe as per defined criteria of severity. In the severe category three parallel arms of interventions were compared while two in the non-severe category. The primary endpoints were safety, clinical recovery of symptoms and laboratory recovery of each organ involvement, and time to SARS-CoV-2 RT-PCR negative report of nasopharyngeal/throat swab specimen. Safety was determined by observing the frequency and severity of serious adverse events as per the division of acquired immune deficiency syndrome (DAIDS) (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Participants enrolled in severe strata were analyzed using One-way ANOVA followed by a post hoc test. An independent t-test was applied for the comparison of means between two arms in non-severe strata. We followed per-protocol analysis for the entire study. In the study, a total of 550 patients were screened and of which 111 patients were enrolled after randomization ( Fig. 1 ). 71 participants were enrolled in the severe category and of which 24, 23 and 24 participants were randomized in groups A, B, and C respectively. 40 participants were categorized into the non-severe category, 20 participants in each group A and B. Two participants: one from the severe B and one from non-severe B showed an adverse drug reaction in the form of elevated liver enzymes (after receiving 2.4gm ribavirin per oral stat followed by 1.2gm twice daily) which resolved after reduction of the doses to 1.2gm per oral stat followed by 0.6gm twice daily. One participant in the severe category B showed prolong QT prolongation on the 3rd day of administration of HCQ and hence the offending drug was discontinued and the trial discontinued for the same patient. Four participants from the non-severe A, three from the non-severe B, and two patients from the severe B had withdrawn from the trial. 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. Baseline characteristics: In the severe category, cough, shortness of breath, and fever were the primary reasons for participants to present in the health facility (Table 1) . Diabetes mellitus, COPD, hypertension, and asthma were the comorbidities with which the participants presented of which hypertension predominated. Similarly, in the non-severe category, participants presented with predominant complaints of fever, cough, and shortness of breath. Also, a trend of male predominance and older age groups were observed in all participants. Received allocated intervention Assessed for eligibility (n= 550 E n r o l m e n t 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. (Fig. 2) . However, the difference in clinical recovery status was not statistically significant among three groups in the severe category and two groups in the non-severe category. 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 June 8, 2021. (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 June 8, 2021. ; (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (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 June 8, 2021. ; The time to SARS-CoV-2 RT-PCR negative in nasopharyngeal swab specimen was also not significant among groups (Table 2 ). T T H E T I M E O F P R E S E N T A T I O N D U R A T I O N ( A T 7 (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Secondary outcome: Analysis of secondary outcomes using the concurrent randomization analysis revealed that all-cause mortality was lowest in category severe B followed by in category severe C and highest in category severe A without any intergroup statistical significance and no mortality was recorded in non-severe categories (Table 3) . Similarly, we found no significant increase in the frequency of respiratory progression in the non-severe category, however, in severe categories, the need for positive pressure (both non-invasive and invasive) ventilation at admission gradually declined during consecutive follow-ups in all three groups, least in severe group A, due to inadequate sample size it failed to reflect any statistically significant value. The average duration of hospital stays was two weeks for all severe groups. 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 June 8, 2021. ; This randomized controlled trial attempted to identify antiviral combination therapy for its potential benefits in the treatment of Covid-19 in both non-severe and severe manifestations of the same disease. Although with limited data, no statistically significant findings could be observed. However, with the available data in hand, certain observations are made that are consistent with the previously published studies involving the antivirals and the disease characteristics. The degree of shortness of breath and other organ dysfunctions were the primary factors that guided in categorizing the severity of COVID-19 infections and this system held as only one patient in the non-severe group progressed to severe symptoms during the trial period with the remaining participants in the category making an uneventful recovery. In the patient demographics, the predominance of the male sex group in all severities of the study groups is noteworthy. There are also additional findings of concomitant comorbid conditions of which hypertension appears to be the most common among others such as chronic cardiac diseases, COPD, and asthma. This may provide interest in future studies elaborating the intrinsic pathophysiology and disease outcomes concerning COVID-19 among the hypertensives (17) In the comparative study of the non-severe category between the participants receiving standard treatment and HCQ + ribavirin, nearly all patients showed recovery during the study period and a clear association between the treatment outcomes of the two intervention groups couldn't be made. Hence, from our study, it can be concluded that in future endeavors towards the management of COVID-19 patients, the decision to treat mild-moderate (non-severe) disease with any form of therapy regardless of their efficacy, it is noteworthy to mention that almost all recover without any difference in the duration of illness or mortality. This may rationalize the use of scarce health care resources during this pandemic (18) . On the other hand, in the severe category, our data also suggest that HCQ + ribavirin have prevented the progression to more severe respiratory disease, as shown by the lower proportion of patients progressing to the need of NIV and MV compared to the standard treatment group without any statistical significance. At the same time, no significant side effects are noted during the study period. Also, all-cause mortality is the lowest in the severe group B. Similar findings are also noted while comparing between the standard treatment group and lopinavir/ritonavir + 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. (19) . An amendment was also made in the trial to reduce the doses of ribavirin due to the development of deranged liver enzymes; when this change was implemented six patients had been enrolled in the trial, but only two had received ribavirin in two groups. However, this has given one good outcome that ribavirin shouldn't be used with 1800mg loading dose and 1200mg BD maintenance dose in the Indian population where it could lead to drug-induced liver injury. This trial establishes lesser ribavirin doses for Indians compared to the western population (20) . This trial did not complete full enrolment owing to the development of new studies suggesting remdesivir to have beneficial effects in O2 requiring patients and also more patients opting for newer agents during the trial period which becomes a major factor in premature discontinuation of the study for those participants (21). When we compare our study results with that of remdesivir, one conclusion that can be drawn is that these non-standard group of treatments can be used for clinical recovery of symptoms and laboratory abnormalities and need of oxygen/ventilator requirements without any mortality benefit similar to remidesivir study. Our study was also non-blinded and lacks heterogeneity of different populations being a singlecentered study. With emerging data suggesting COVID-19 to have a more protracted course, different outcomes may have been missed with the limited follow-up period. There are also emerging strains of new COVID-19 with variable degrees of disease manifestations in regards to severity and organ involvement. Hence, concern also arises about the efficacy of these drugs in those newer strains and hence needs further evaluation. The trial was also not devoid of challenges as it was conducted during a time of restricted travel and restricted entry of nonessential personnel. Monitoring visits often were performed remotely and strict implementation of isolation and other measures of infectious control was a major hindrance in drawing and processing samples in defined periods. There was also a shortage of trial-related supplies in between the study period such as reagents for the inflammatory markers. There was also the publication of results by the WHO from the Solidarity Trial in July 2020, which recommended discontinuation of HCQ and lopinavir/ritonavir arms and this harms enrolment of participants of our study (22). 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 June 8, 2021. ; Given the results of the findings of the study and availability of a variety of therapeutic approaches including novel antivirals, modifiers of the immune response, or other intrinsic pathways, antiviral combinations may have a role in improving clinical recovery in patients of COVID-19 with severe category whereas only standard therapy is required for non-severe category. Written informed consent was obtained from all participants. The authors declare that they have no competing interests. Funding: Non-funded. Authors' contributions: PKP conceived the trial. PKP, AB, BCS, GC, YAB designed the trial. BCS, BM, SS collected the data. All the authors are part of the trial management committee and were involved in the review, amendments, and approval of the final protocol. Evidence used to update the list of underlying medical conditions that increase a person's risk of severe illness from COVID-19 COVID-19 infection in kidney transplant recipients 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 Update: Characteristics of Symptomatic Women of Reproductive Age with Laboratory-Confirmed SARS-CoV-2 Infection by Pregnancy Status -United States Neurological Manifestations of COVID-19: A systematic review and current update Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis Gastrointestinal and Liver Manifestations of COVID-19 Cutaneous manifestations of COVID-19: Report of three cases and a review of literature The Science Underlying COVID-19: Implications for the Cardiovascular System COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro Advisory on the use of Hydroxychloroquin as prophylaxis for SARS-CoV-2 infection COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression 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. and Ritonavir in Patients Hospitalized With Coronavirus Disease Lopinavir/ritonavir combination therapy amongst symptomatic coronavirus disease 2019 patients in India: Protocol for restricted public health emergency use Novel coronavirus treatment with ribavirin: Groundwork for an evaluation concerning COVID-19 Hypertension in patients with coronavirus disease 2019 (COVID-19): A pooled analysis COVID-19) Treatment Guidelines. National Institutes of Health Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review Novel coronavirus treatment with ribavirin: Groundwork for an evaluation concerning COVID-19 Thanks to Prof Manoj Gupta, Prof UB Mishra of the institute for availing logistics required for the trial; to Dr. Arkapal Bandyopadhyay, Dr Ramanuj Samanta, Dr Rohit Walia, Dr Itish Patnaik, Dr Gaurav Chikara, Dr Ravi Gupta, and Dr Bharat Bhusan Bhardwaj, for helping protocol preparation and handling drug complications if any of the study participants; to Dr Deepjyoti Kalita and Dr Puneet Gupta for performing laboratory diagnosis of the study participants.