A multicenter, randomized, open-label, controlled trial to evaluate the efficacy and tolerability of hydroxychloroquine and a retrospective study in adult patients with mild to moderate coronavirus disease 2019 (COVID-19)

Cheng-Pin Chen; Yi-Chun Lin; Tsung-Chia Chen; Ting-Yu Tseng; Hon-Lai Wong; Cheng-Yu Kuo; Wu-Pu Lin; Sz-Rung Huang; Wei-Yao Wang; Jia-Hung Liao; Chung-Shin Liao; Yuan-Pin Hung; Tse-Hung Lin; Tz-Yan Chang; Chin-Fu Hsiao; Yi-Wen Huang; Wei-Sheng Chung; Chien-Yu Cheng; Shu-Hsing Cheng; on behalf of the Taiwan HCQ Study Group

doi:10.1371/journal.pone.0242763

Peer Review History

Original SubmissionJuly 1, 2020
8 Sep 2020 Decision Letter - Stephen L Atkin, Editor PONE-D-20-20024 A Multicenter, randomized, open-label, controlled trial to evaluate the efficacy and tolerability of hydroxychloroquine and a retrospective study in adult patients with mild to moderate Coronavirus disease 2019 (COVID-19) PLOS ONE Dear Dr. Cheng, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. The reviewers have issues regarding the statistical methods and study methodology that need to be addressed Please submit your revised manuscript by Oct 22 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. 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Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: No ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The authors present data from a Taiwan-based multi-center (11 publically funded hospitals) studies addressing the question of whether hydroxychloroquine has therapeutic efficacy for the treatment of COVID-19. Data is presented for an open label RCT (NCT04384380) and an observational retrospective study conducted for up to 14 days. There are limitations to the study that to a greater extent the authors have emphasized but a number of issues need to better emphasized and discussed. 1/ The authors have explained that recruitment was limited to few cases presenting in Taiwan. Only 33 were included for the RCT and 37 for the retrospective study. These numbers are very small. Furthermore, as can be seen from Table 1 there are very few who are classified as “moderate” – 2 for HCQ and 2 for SOC in the RCT and 5 and 3 respectively in the retrospective study. This needs to be better emphasized as the study data and conclusions really can only relate to mild cases AND comparatively also a young population ~30-35. Discussion could be added at lines 384/5 that due to few numbers the RCT data really only reflects that from young COVID-19 patients with mild symptoms. 2/ According to the study design lines 196-197 only those with moderate symptoms received antimicrobial treatment. Correct? If correct, emphasise that patients with mild symptoms only received HCQ or SOC. 2/ A clearer description of symptoms would be beneficial. For instance: i Cough? How was this defined? The majority of the patients are listed as presenting with cough. Is this persistent cough, or --? ii. Fever? How was this defined? Very few – one only had fever in the HCQ RCT. 3. PCR data for viral load was obtained every other day. Is it possible to compare the rates of decline of viral load for the RCT study HCQ vs SOC? 4. The authors have discussed their results in comparison with other published studies. I suggest adding comparison with the data from a large retrospective study from the Henry Ford Hospital in Detroit https://doi.org/10.1016/j.ijid.2020.06.099 published in the International J of Infectious Diseases (Dr Samia Arshad) et al that concludes that HCQ is effective and reduces mortality. However, note that the greater % of patients were also prescribed (cortico)steroids and median age was 64. Reviewer #2: I would very much hope that the authors would consider making their data available in a de-identified manner in a simple spreadsheet readable format like a comma separated variable file that could be readily ingested into a stats package. I have made comments in a track changed format in the attachment. The only additional query I would raise is that the authors need to acknowledge the small sample sizes of the two study cohorts they have reported on and to maybe also acknowledge that absence of evidence is not necessarily evidence of absence and that this is especially the case in small studies. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Chris R Triggle Reviewer #2: Yes:** Greg Fegan [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. Attachments Attachment Submitted filename: Pone_hcq_multicentered_rct_retrospective_covid19_GFmods.docx https://doi.org/10.1371/journal.pone.0242763.r001
Revision 1
15 Oct 2020 Author Response To the editors and reviewers, This rebuttal letter responds to each point raised by the academic editor and reviewers. The authors have prepared a marked-up copy that highlights the changes made to the original version, and also an unmarked version. The authors have deposited the protocols in protocols.io. DOI: dx.doi.org/10.17504/protocol.io.bmfak3ie The authors have ensured that the manuscript meets PLOS ONE's style requirements, including those for file naming. The item missed from the CONSORT flowchart was amended. The authors understand the importance of trial registration before recruiting the first participant in a study. The reasons for the delay in registering this study (after enrolment of participants started) were that the appendix of the protocol was in Mandarin and had to be translated to English to meet QC criteria; the registration of the clinical trial was accepted on May/12/2020, after the first enrollment on Apr/1/2020. However, the authors confirm that all ongoing and related trials for this drug/intervention are registered. This statement has been added under the subheading “Study design.” In the cover level, the corresponding author stated that she received research funding from the Hospital and Social Welfare Organizations Administration Commission, Ministry of Health and Welfare, Taiwan Biotech Co. Ltd. for their donation of investigational products. This funding source played no role in study design or conduction, data collection, analysis or interpretation, writing of the manuscript, or decision to submit it for publication. Furthermore, the commercial funding did not alter our adherence to PLOS ONE policies on the sharing of data and materials. As there are no legal or ethical concerns, the authors have shared the data publicly on figshare (DOI: https://doi.org/10.6084/m9.figshare.12631403.v1). Captions for Figure 3 and 4 have been added. Tables 3, 4, and 5 have also been added. Supporting information is provided at the end of the manuscript and the in-text citations have been updated accordingly. Reviewer #1: The authors present data from a Taiwan-based multi-center (11 publically funded hospitals) studies addressing the question of whether hydroxychloroquine has therapeutic efficacy for the treatment of COVID-19. Data is presented for an open label RCT (NCT04384380) and an observational retrospective study conducted for up to 14 days. There are limitations to the study that to a greater extent the authors have emphasized but a number of issues need to better emphasized and discussed. 1) The authors have explained that recruitment was limited to few cases presenting in Taiwan. Only 33 were included for the RCT and 37 for the retrospective study. These numbers are very small. Furthermore, as can be seen from Table 1 there are very few who are classified as “moderate” – 2 for HCQ and 2 for SOC in the RCT and 5 and 3 respectively in the retrospective study. This needs to be better emphasized as the study data and conclusions really can only relate to mild cases AND comparatively also a young population ~30-35. Discussion could be added at lines 384/5 that due to few numbers the RCT data really only reflects that from young COVID-19 patients with mild symptoms. Response: The authors have emphasized the limitations of the young population and mild illness in the “Results (line 255-259 of Page 13), “Discussion” (lines 412-418 of page 23), and “Conclusion” (line 438-439 of page 25). 2) According to the study design lines 196-197 only those with moderate symptoms received antimicrobial treatment. Correct? If correct, emphasise that patients with mild symptoms only received HCQ or SOC. Response: The subjects with mild symptoms did not receive antimicrobial treatment. The authors have clarified this in “Study design” (lines 196-198 of page 10). 3) A clearer description of symptoms would be beneficial. For instance: i Cough? How was this defined? The majority of the patients are listed as presenting with cough. Is this persistent cough, or --? ii. Fever? How was this defined? Very few – one only had fever in the HCQ RCT. Response: 1. The severity of cough was defined as mild (no symptomatic treatment), moderate (responsive to symptomatic treatment), and severe (symptomatic treatment given but without response). Most subjects had mild cough and the authors have added the data in “Results” (line 257 of page 13). 2. A central temperature of more than 38 °C is defined as fever (Table 1). 4) PCR data for viral load was obtained every other day. Is it possible to compare the rates of decline of viral load for the RCT study HCQ vs SOC? Response: The rates of decline are presented in Fig. 3 and the difference was not significant between the groups. 5) The authors have discussed their results in comparison with other published studies. I suggest adding comparison with the data from a large retrospective study from the Henry Ford Hospital in Detroit https://doi.org/10.1016/j.ijid.2020.06.099 published in the International J of Infectious Diseases (Dr Samia Arshad) et al that concludes that HCQ is effective and reduces mortality. However, note that the greater % of patients were also prescribed (cortico)steroids and median age was 64. Response: The retrospective study of Arshad et al. from Henry Ford Hospital was cited and discussed (lines 372-375 of page 20 and line 425-426 of page 22). Reviewer #2: I would very much hope that the authors would consider making their data available in a de-identified manner in a simple spreadsheet readable format like a comma separated variable file that could be readily ingested into a stats package. I have made comments in a track changed format in the attachment. The only additional query I would raise is that the authors need to acknowledge the small sample sizes of the two study cohorts they have reported on and to maybe also acknowledge that absence of evidence is not necessarily evidence of absence and that this is especially the case in small studies. Response: 1) In figshare (DOI: https://doi.org/10.6084/m9.figshare.12631403.v1), the authors have provided a simple spreadsheet readable format that can be readily ingested into a stats package. 2) The authors acknowledge that “Both the retrospective and randomized clinical studies performed here failed to demonstrate HCQ efficacy at shortening viral shedding in the majority of subjects presenting with mild COVID-19 symptoms. As the case number is small, absence of evidence is not necessarily evidence of absence…” and have added this statement in the “Conclusions” (lines 439-430 of pages 23 ). 3) The comments in the “track changed format” were replied as follows: i. What’s wrong with X-ray? Response: The authors would like to change them. ii. These adjacent statements seem contradictory. Response: The authors have clarified that cases of severe illness were not enrolled (lines 159-160 of page 8). iii. Is this simply related to study size given the allocation ratio? Response: The estimated sample size was 45 (Lane 194 of page 10). iv. Tense needs changing Response: Thank you. We have changed a number of phrases in the Methods from the future to the past and present tense, as appropriate. v. Suggest you rephrase to the trial was prospectively/retrospectively (delete accordingly) registered at (give URL) Response: The authors have stated that “this prospective randomized controlled clinical trial was registered at https://clinicaltrials.gov/ct2/show/NCT04384380?term=Hydroxychloroquine&cond=COVID-19&cntry=TW&draw=2&rank=1(NCT04384380). (lines 205-207 of page 10). vi. bit picky - but no hospitals are mentioned just geographic locales across Taiwan. Response: We have clarified that the study was conducted at the same 11 hospitals (line 148-151 of page 8). vii. Suggest you combine this into 3 columns eg mean and (sd) in one cell Response: Table 1 has been adjusted to use only three columns. viii. I take it that the 95% CI is (-37.1, 47.2) This needs clarifying. Would suggest you report all CIs as LB,UB not LB-UB) as you do in Table below Response: Your interpretation was correct. The data have been adjusted. Attachments Attachment Submitted filename: Pone_D_20_20024_Reply_reviewerscomments_nontrack.docx https://doi.org/10.1371/journal.pone.0242763.r002
10 Nov 2020 Decision Letter - Stephen L Atkin, Editor A multicenter, randomized, open-label, controlled trial to evaluate the efficacy and tolerability of hydroxychloroquine and a retrospective study in adult patients with mild to moderate Coronavirus disease 2019 (COVID-19) PONE-D-20-20024R1 Dear Dr. Cheng, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Stephen L Atkin, MD Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #2: (No Response) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: (No Response) ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #2: (No Response) ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #2: (No Response) ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #2: (No Response) ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #2: Yes:** Greg Fegan https://doi.org/10.1371/journal.pone.0242763.r003
Formally Accepted
18 Nov 2020 Acceptance Letter - Stephen L Atkin, Editor PONE-D-20-20024R1 A multicenter, randomized, open-label, controlled trial to evaluate the efficacy and tolerability of hydroxychloroquine and a retrospective study in adult patients with mild to moderate coronavirus disease 2019 (COVID-19) Dear Dr. Cheng: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Stephen L Atkin Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0242763.r004

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