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All Studies   Meta Analysis    Recent:   

Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial

Self et al., JAMA, doi:10.1001/jama.2020.22240, ORCHID, NCT04332991
Nov 2020  
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Mortality -6% Improvement Relative Risk Mortality, day 14 -51% 7-point scale, day 28 -3% 7-point scale, day 14 2% 7-point scale, day 14 (b) 39% HCQ  ORCHID  LATE TREATMENT  DB RCT Is late treatment with HCQ beneficial for COVID-19? Double-blind RCT 477 patients in the USA (April - June 2020) No significant difference in outcomes seen c19hcq.org Self et al., JAMA, November 2020 FavorsHCQ Favorscontrol 0 0.5 1 1.5 2+
HCQ for COVID-19
1st treatment shown to reduce risk in March 2020
 
*, now with p < 0.00000000001 from 411 studies, recognized in 46 countries.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,300+ studies for 75 treatments. c19hcq.org
Early terminated very late stage (65% on supplemental oxygen) RCT with 242 HCQ and 237 control patients showing no significant difference in outcomes.
For the subgroup not on supplemental oxygen at baseline (relatively early treatment), the odds ratio for the 7 point outcome scale is: aOR 0.61 [0.34-1.08].
Dosage may be too low:
Dose in first 24 hours - 1g (compare to Boulware et al. 2g)
Dose in 5 days - 2.4g (compare to Boulware et al. 3.8g)
Dosage note: Boulware 2g within 24 hours includes the second day dose. Note two important differences with the RECOVERY/SOLIDARITY dosage which is believed to be dangerously high - in RECOVERY/SOLIDARITY the total dose is much higher, which is problematic because the half-life of HCQ is very long, and it is given to patients that are already in very serious condition.
Note the paper reports primary outcome values with OR>1 favoring HCQ, we have converted to OR<1 favoring HCQ. Subgroup analysis is in the supplemental appendix.
risk of death, 6.2% higher, RR 1.06, p = 0.85, treatment 25 of 241 (10.4%), control 25 of 236 (10.6%), NNT 455, adjusted per study, odds ratio converted to relative risk.
risk of death, 51.0% higher, RR 1.51, p = 0.28, treatment 18 of 241 (7.5%), control 14 of 236 (5.9%), adjusted per study, odds ratio converted to relative risk, day 14.
risk of 7-point scale, 3.1% higher, OR 1.03, p = 0.87, treatment 241, control 236, inverted to make OR<1 favor treatment, day 28, RR approximated with OR.
risk of 7-point scale, 2.0% lower, OR 0.98, p = 0.91, treatment 241, control 236, inverted to make OR<1 favor treatment, day 14, RR approximated with OR.
risk of 7-point scale, 39.0% lower, OR 0.61, p = 0.09, treatment 241, control 236, inverted to make OR<1 favor treatment, subgroup not on oxygen at baseline, day 14, RR approximated with OR.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Self et al., 9 Nov 2020, Double Blind Randomized Controlled Trial, USA, peer-reviewed, 33 authors, study period 2 April, 2020 - 19 June, 2020, average treatment delay 5.0 days, trial NCT04332991 (history) (ORCHID).
This PaperHCQAll
Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19
MD, MPH Wesley H Self, MD; Matthew W Semler, DO; Lindsay M Leither, MD, MSc Jonathan D Casey, MD, MPH Derek C Angus, MD Roy G Brower, MD, PhD Steven Y Chang, MD; Sean P Collins, MD John C Eppensteiner, MD Michael R Filbin, D Clark Files, MD Kevin W Gibbs, MD, MPH Adit A Ginde, MD Michelle N Gong, MS Frank E Harrell Jr, PhD Douglas L Hayden, MD, MSc Catherine L Hough, MD Nicholas J Johnson, MD Akram Khan, PhD Christopher J Lindsell, MD Michael A Matthay, MD Marc Moss, MD Pauline K Park, MD Todd W Rice, MD Bryce R H Robinson, MS David A Schoenfeld, PhD Nathan I Shapiro, MD, MPH Jay S Steingrub, MD Christine A Ulysse, MS Alexandra Weissman, MD, MPH Donald M Yealy, B Taylor Thompson, MD; Samuel M Brown
JAMA, doi:10.1001/jama.2020.22240
OBJECTIVE To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19. DESIGN, SETTING, AND PARTICIPANTS This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients. INTERVENTIONS Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237). MAIN OUTCOMES AND MEASURES The primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality. RESULTS Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, −0.2% [95% CI, −5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09]). CONCLUSIONS AND RELEVANCE Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults.
Author Contributions: Drs Schoenfeld and Hayden had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Schoenfeld and Self take responsibility for the trial overall. Conflict of Interest Disclosures: Dr Self reported receiving grants from the National Heart, Lung, and Blood Institute (NHLBI) during the conduct of the study and personal fees from Aerpio Pharmaceuticals outside the submitted work. Dr Semler reported receiving grants from the NHLBI during the conduct of the study. Dr Leither reported receiving grants from the NHLBI during the conduct of the study. Dr Casey reported receiving grants from the NHLBI during the conduct of the study. Dr Angus reported receiving grants from the NHLBI and National Center for Advancing Translational Sciences (NCATS) during the conduct of the study and personal fees from Ferring Pharmaceuticals, Bristol-Myers Squibb, and Bayer AG and stock from Alung Technologies. Dr Angus has patents pending through Ferring Pharmaceuticals and the University of Pittsburgh. Dr Chang reported receiving grants from the NHLBI during the conduct of the study and personal fees from PureTech Health and LaJolla Pharmaceuticals outside the submitted work. Dr Collins reported receiving grants from the NHLBI and personal fees from Vir Biotechnology outside the submitted U01HL123020). The REDCap data tools used for this study were supported by a grant from NCATS..
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placebo-controlled ' 'clinical trial of hydroxychloroquine for adults hospitalized with ' 'COVID-19.', 'volume': '17', 'author': 'Casey', 'year': '2020', 'journal-title': 'Ann Am Thorac Soc'}, { 'issue': '24', 'key': 'joi200119r17', 'doi-asserted-by': 'publisher', 'first-page': 'e906', 'DOI': '10.1161/CIRCULATIONAHA.120.047521', 'article-title': 'Considerations for drug interactions on QTc in exploratory COVID-19 ' 'treatment.', 'volume': '141', 'author': 'Roden', 'year': '2020', 'journal-title': 'Circulation'}, { 'issue': '9', 'key': 'joi200119r18', 'doi-asserted-by': 'publisher', 'first-page': '1036', 'DOI': '10.1001/jamacardio.2020.1834', 'article-title': 'Risk of QT interval prolongation associated with use of ' 'hydroxychloroquine with or without concomitant azithromycin among ' 'hospitalized patients testing positive for coronavirus disease 2019 ' '(COVID-19).', 'volume': '5', 'author': 'Mercuro', 'year': '2020', 'journal-title': 'JAMA Cardiol'}, { 'issue': '3', 'key': 'joi200119r20', 'doi-asserted-by': 'publisher', 'first-page': '199', 'DOI': '10.1016/0168-8510(90)90421-9', 'article-title': 'EuroQol: a new facility for the measurement of health-related quality ' 'of life.', 'volume': '16', 'author': 'EuroQol Group', 'year': '1990', 'journal-title': 'Health Policy'}, { 'issue': '10', 'key': 'joi200119r21', 'doi-asserted-by': 'publisher', 'first-page': '1727', 'DOI': '10.1007/s11136-011-9903-x', 'article-title': 'Development and preliminary testing of the new five-level version of ' 'EQ-5D (EQ-5D-5L).', 'volume': '20', 'author': 'Herdman', 'year': '2011', 'journal-title': 'Qual Life Res'}, { 'issue': '7', 'key': 'joi200119r22', 'doi-asserted-by': 'publisher', 'first-page': '828', 'DOI': '10.1164/rccm.201810-2050CP', 'article-title': 'Reappraisal of ventilator-free days in critical care research.', 'volume': '200', 'author': 'Yehya', 'year': '2019', 'journal-title': 'Am J Respir Crit Care Med'}, { 'issue': '8', 'key': 'joi200119r23', 'doi-asserted-by': 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'10.1038/s41586-020-2558-4', 'article-title': 'Hydroxychloroquine use against SARS-CoV-2 infection in non-human ' 'primates.', 'volume': '585', 'author': 'Maisonnasse', 'year': '2020', 'journal-title': 'Nature'}, { 'issue': '7826', 'key': 'joi200119r32', 'doi-asserted-by': 'publisher', 'first-page': '588', 'DOI': '10.1038/s41586-020-2575-3', 'article-title': 'Chloroquine does not inhibit infection of human lung cells with ' 'SARS-CoV-2.', 'volume': '585', 'author': 'Hoffmann', 'year': '2020', 'journal-title': 'Nature'}, { 'key': 'joi200119r33', 'article-title': 'Effect of hydroxychloroquine in hospitalized patients with COVID-19.', 'author': 'Horby', 'year': '2020', 'journal-title': 'N Engl J Med'}, { 'key': 'joi200119r34', 'doi-asserted-by': 'crossref', 'DOI': '10.1056/NEJMoa2019014', 'article-title': 'Hydroxychloroquine with or without azithromycin in mild-to-moderate ' 'COVID-19.', 'author': 'Cavalcanti', 'year': '2020', 'journal-title': 'N Engl J Med'}, { 'issue': '11', 'key': 'joi200119r35', 'doi-asserted-by': 'publisher', 'first-page': '1048', 'DOI': '10.1001/jama.2020.16349', 'article-title': 'Effect of remdesivir vs standard care on clinical status at 11 days in ' 'patients with moderate COVID-19: a randomized clinical trial.', 'volume': '324', 'author': 'Spinner', 'year': '2020', 'journal-title': 'JAMA'}, { 'issue': '10', 'key': 'joi200119r36', 'first-page': '994', 'article-title': 'Remdesivir for the treatment of COVID-19: preliminary report: reply.', 'volume': '383', 'author': 'Beigel', 'year': '2020', 'journal-title': 'N Engl J Med'}, { 'key': 'joi200119r37', 'doi-asserted-by': 'crossref', 'DOI': '10.1016/j.mehy.2020.109815', 'article-title': 'Does zinc supplementation enhance the clinical efficacy of ' 'chloroquine/hydroxychloroquine to win today’s battle against COVID-19?', 'volume': '142', 'author': 'Derwand', 'year': '2020', 'journal-title': 'Med Hypotheses'}, { 'key': 'joi200119r1', 'unstructured': 'Johns Hopkins University. Coronavirus resource center. Accessed July 28, ' '2020. https://coronavirus.jhu.edu/map.html'}, { 'key': 'joi200119r2', 'unstructured': 'World Health Organization. WHO coronavirus disease (COVID-19) dashboard. ' 'Accessed September 22, 2020. https://covid19.who.int/'}, { 'key': 'joi200119r11', 'unstructured': 'Massachusetts General Hospital. Massachusetts General Hospital COVID-19 ' 'treatment guidance. Accessed May 8, 2020. ' 'https://web.archive.org/web/20200410013441/https://www.massgeneral.org/assets/MGH/pdf/news/coronavirus/mass-general-COVID-19-treatment-guidance.pdf'}, { 'key': 'joi200119r12', 'unstructured': 'Vanderbilt University Medical Center. Clinical recommendations for ' 'treatment of COVID-19 adult patients. Accessed March 13, 2020. ' 'https://www.vumc.org/coronavirus/sites/default/files/COVID%20Documents/VUMC%20interim%20recommendations%20for%20clinical%20care%20of%20COVID%20patients%203.14.2020%20final.pdf'}, { 'key': 'joi200119r13', 'unstructured': 'National Institutes of Health (NIH). Coronavirus disease 2019 (COVID-19) ' 'treatment guidelines. Accessed June 30, 2020. ' 'https://www.covid19treatmentguidelines.nih.gov'}, { 'key': 'joi200119r19', 'unstructured': 'World Health Organization. WHO R&D blueprint: novel coronavirus: ' 'COVID-19 therapeutic trial synopsis. Accessed June 28, 2020. ' 'https://www.who.int/blueprint/priority-diseases/key-action/COVID-19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf'}, { 'key': 'joi200119r26', 'unstructured': 'RECOVERY Investigators. No clinical benefit from use of ' 'hydroxychloroquine in hospitalised patients with COVID-19: statement ' 'from the Chief Investigators of the Randomised Evaluation of COVid-19 ' 'thERapY (RECOVERY) Trial on hydroxychloroquine, 5 June 2020. Accessed ' 'June 28, 2020. ' 'https://www.recoverytrial.net/news/statement-from-the-chief-investigators-of-the-randomised-evaluation-of-covid-19-therapy-recovery-trial-on-hydroxychloroquine-5-june-2020-no-clinical-benefit-from-use-of-hydroxychloroquine-in-hospitalised-patients-with-covid-19'}, { 'key': 'joi200119r27', 'unstructured': 'Food and Drug Administration (FDA). Fact sheet for healthcare providers: ' 'emergency use authorization (EUA) of Veklury (remdesivir) for ' 'hospitalized pediatric patients weighing 3.5 kg to less than 40 kg or ' 'hospitalized pediatric patients less than 12 years of age weighing at ' 'least 3.5 kg. Accessed October 8, 2020. ' 'https://www.fda.gov/media/137566/download'}, { 'key': 'joi200119r28', 'unstructured': 'Medicines and Healthcare Products Regulatory Agency. MHRA suspends ' 'recruitment to COVID-19 hydroxychloroquine trials. Accessed October 10, ' '2020. ' 'https://www.gov.uk/government/news/mhra-suspends-recruitment-to-covid-19-hydroxychloroquine-trials'}, { 'key': 'joi200119r29', 'unstructured': 'Food and Drug Administration (FDA). Request for emergency use ' 'authorization for use of chloroquine phosphate or hydroxychloroquine ' 'sulfate supplied from the strategic national stockpile for treatment of ' '2019 coronavirus disease. Accessed July 2, 2020. ' 'https://www.fda.gov/media/136534/download'}, { 'key': 'joi200119r30', 'unstructured': 'Food and Drug Administration (FDA). Letter revoking EUA for chloroquine ' 'phosphate and hydroxychloroquine sulfate. Accessed July 2, 2020. ' 'https://www.fda.gov/media/138945/download'}], 'container-title': 'JAMA', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://jamanetwork.com/journals/jama/articlepdf/2772922/jama_self_2020_oi_200119_1606767652.12648.pdf', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2020, 12, 1]], 'date-time': '2020-12-01T12:52:29Z', 'timestamp': 1606827149000}, 'score': 1, 'resource': {'primary': {'URL': 'https://jamanetwork.com/journals/jama/fullarticle/2772922'}}, 'subtitle': ['A Randomized Clinical Trial'], 'short-title': [], 'issued': {'date-parts': [[2020, 12, 1]]}, 'references-count': 37, 'journal-issue': {'issue': '21', 'published-print': {'date-parts': [[2020, 12, 1]]}}, 'URL': 'http://dx.doi.org/10.1001/jama.2020.22240', 'relation': {}, 'ISSN': ['0098-7484'], 'subject': ['General Medicine'], 'container-title-short': 'JAMA', 'published': {'date-parts': [[2020, 12, 1]]}}
Late treatment
is less effective
Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
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