Hydroxychloroquine efficacy and safety in preventing SARS-CoV-2 infection and COVID-19 disease severity during pregnancy (COVID-Preg): a structured summary of a study protocol for a randomised placebo controlled trial

Raquel González; Laura García-Otero; Clara Pons-Duran; Elena Marbán-Castro; Anna Goncé; Elisa Llurba; Maria del Mar Gil; Miguel Ángel Rodríguez-Zambrano; Haily Chen; Máximo Ramírez; Azucena Bardají; Clara Menendez

Hydroxychloroquine efficacy and safety in preventing SARS-CoV-2 infection and COVID-19 disease severity during pregnancy (COVID-Preg): a structured summary of a study protocol for a randomised placebo controlled trial

González et al., Trials, doi:10.1186/s13063-020-04557-y, NCT04410562, Oct 2021

HCQ for COVID-19

1st treatment shown to reduce risk in March 2020, now with p < 0.00000000001 from 424 studies, used in 59 countries.

Lower risk for mortality, hospitalization, progression, recovery, cases, and viral clearance.

No treatment is 100% effective. Protocols combine treatments.

6,300+ studies for 210+ treatments. c19early.org

Meta Analysis

129 participant HCQ early treatment and prophylaxis RCT with results not reported over 4 years after completion.

37 HCQ RCTs have results missing long after expected1-37
The trials report a total of 20,747 patients, with 11 trials having actual enrollment of 3,487, and the remainder estimated.

Important missing comments or errors? Let us know.

1. Genton et al., #StayHome: Early Hydroxychloroquine to Reduce Secondary Hospitalisation and Household Transmission in COVID-19 (#StayHome), NCT04385264, clinicaltrials.gov/study/NCT04385264clinicaltrials.gov.

2. Hawari et al., The Potential Use of Nebulized Hydroxychloroquine for the Treatment of COVID-19, NCT05113810, clinicaltrials.gov/study/NCT05113810clinicaltrials.gov.

3. Ghanem-Zoubi et al., Hydroxychloroquine Post-Exposure Prophylaxis for Coronavirus Disease (COVID-19) Among Health-Care Workers, NCT04438837, clinicaltrials.gov/study/NCT04438837clinicaltrials.gov.

4. Gagneux-Brunon et al., Acceptability of a COVID-19 pre-exposure prophylaxis trial with hydroxychloroquine in French healthcare workers during the first wave of COVID-19 pandemic, Trials, doi:10.1186/s13063-021-05329-y.biomedcentral.com, doi.org.

5. Pineda et al., Prevention and Treatment With Hydroxychloroquine + Azithromycin of Acute Respiratory Syndrome Induced by COVID-19 (AMBUCOV), NCT04954040, clinicaltrials.gov/study/NCT04954040clinicaltrials.gov.

6. Aston et al., Hydroxychloroquine vs. Azithromycin for Outpatients in Utah With COVID-19 (HyAzOUT), NCT04334382, clinicaltrials.gov/study/NCT04334382clinicaltrials.gov.

7. Al Ansari et al., Post Exposure Prophylaxis in Healthcare Workers Exposed to COVID-19 Patients (HCQ-COVID19), NCT04437693, clinicaltrials.gov/study/NCT04437693clinicaltrials.gov.

8. Abayomi et al., A multi-centre, randomized, double-blind, placebo-controlled clinical trial of the efficacy and safety of chloroquine phosphate, hydroxychloroquine sulphate and lopinavir/ritonavir for the treatment of COVID-19 in Lagos State: study protocol for a randomized controlled trial, Trials, doi:10.1186/s13063-021-05675-x.biomedcentral.com, doi.org.

9. González et al., Hydroxychloroquine efficacy and safety in preventing SARS-CoV-2 infection and COVID-19 disease severity during pregnancy (COVID-Preg): a structured summary of a study protocol for a randomised placebo controlled trial, Trials, doi:10.1186/s13063-020-04557-y.biomedcentral.com, doi.org.

10. Nanni et al., PROTECT Trial: A cluster-randomized study with hydroxychloroquine versus observational support for prevention or early-phase treatment of Coronavirus disease (COVID-19): A structured summary of a study protocol for a randomized controlled trial, Trials, doi:10.1186/s13063-020-04527-4.biomedcentral.com, doi.org.

11. Granados-Montiel et al., New prophylaxis regimen for SARS-CoV-2 infection in health professionals with low doses of hydroxychloroquine and bromhexine: a randomised, double-blind placebo clinical trial (ELEVATE Trial), BMJ Open, doi:10.1136/bmjopen-2020-045190.bmj.com, doi.org.

12. Kara et al., Efficacy and Safety of Hydroxychloroquine and Favipiravir in the Treatment of Mild to Moderate COVID-19, NCT04411433, clinicaltrials.gov/study/NCT04411433clinicaltrials.gov.

13. Chauffe et al., Hydroxychloroquine as Prophylaxis for COVID-19 in Healthcare Workers (HCQPreP), NCT04363450, clinicaltrials.gov/study/NCT04363450clinicaltrials.gov.

14. Moraes et al., Comparative Study of Hydroxychloroquine and Ivermectin in COVID-19 Prophylaxis, NCT04384458, clinicaltrials.gov/study/NCT04384458clinicaltrials.gov.

15. Borrie et al., COVID-19 PEP- High-risk Individuals in Long-term and Specialized Care - Canada, NCT04397328, clinicaltrials.gov/study/NCT04397328clinicaltrials.gov.

16. James et al., PROLIFIC ChemoprophylaxisTrial (COVID-19), NCT04352933, clinicaltrials.gov/study/NCT04352933clinicaltrials.gov.

17. Morales-Asencio et al., Prevention of COVID19 Infection in Nursing Homes by Chemoprophylaxis With Hydroxychloroquine, NCT04400019, clinicaltrials.gov/study/NCT04400019clinicaltrials.gov.

18. Mordmüller et al., Hydroxychloroquine for COVID-19 (COV-HCQ), NCT04342221, clinicaltrials.gov/study/NCT04342221clinicaltrials.gov.

19. Gül et al., Clinical Trial For Early SARS-CoV-2 (COVID-19) Treatment, NCT04981379, clinicaltrials.gov/study/NCT04981379clinicaltrials.gov.

20. Abu-Helalah et al., Chemoprevention Clinical Trial of COVID-19: Hydroxychloroquine Post Exposure Prophylaxis (APCC-19), NCT04597775, clinicaltrials.gov/study/NCT04597775clinicaltrials.gov.

21. Okasha et al., Hydroxychloroquine and Nitazoxanide Combination Therapy for COVID-19, NCT04361318, clinicaltrials.gov/study/NCT04361318clinicaltrials.gov.

22. Levi et al., Open Label Study to Compare Efficacy, Safety and Tolerability of Hydroxychloroquine Combined With Azithromycin Compared to Hydroxychloroquine Combined With Camostat Mesylate and to "no Treatment" in SARS CoV 2 Virus (COSTA), NCT04355052, clinicaltrials.gov/study/NCT04355052clinicaltrials.gov.

23. WellStar, Hydroxychloroquine Use in Hospitalized Patients With COVID-19: Impact on Progression to Severe or Critical Disease, NCT04429867, clinicaltrials.gov/study/NCT04429867clinicaltrials.gov.

24. Burney et al., Hydroxychloroquine Chemoprophylaxis for COVID-19 Infection in High-risk Healthcare Workers, NCT04370015, clinicaltrials.gov/study/NCT04370015clinicaltrials.gov.

25. Sow et al., Phytomedicines Versus Hydroxychloroquine as an Add on Therapy to Azithromycin in Asymptomatic Covid-19 Patients (PHYTCOVID-19), NCT04501965, clinicaltrials.gov/study/NCT04501965clinicaltrials.gov.

26. Pellegrini et al., Effectiveness of Prophylactic Hydroxychloroquine on incidence of COVID-19 infection in Front-line Health and Allied Health Care Workers: The COVID-SHIELD Trial, COVID-SHIELD, ACTRN12620000501943, www.anzctr.org.au/TrialSearch.aspx#&&conditionCode=&dateOfRegistrationFrom=&interventionDescription=&interventionCodeOperator=OR&primarySponsorType=&gender=&distance=&postcode=&pageSize=20&ageGroup=&recruitmentCountryOperator=OR&recruitmentRegion=ðicsReview=&countryOfRecruitment=Australia%7cNew+Zealand®istry=&searchTxt=ACTRN12620000501943org.au.

27. Sarwar et al., Post-Exposure Prophylaxis for Asymptomatic SARS-CoV-2 COVID-19 Patients With Choloroquine Compounds (PEACE), NCT04346667, clinicaltrials.gov/study/NCT04346667clinicaltrials.gov.

28. Sarwar (B) et al., Prophylaxis of Exposed COVID-19 Individuals With Mild Symptoms Using Choloroquine Compounds (PRECISE), NCT04351191, clinicaltrials.gov/study/NCT04351191clinicaltrials.gov.

29. Connor et al., HEalth Care Worker pROphylaxis Against COVID-19: The HERO Trial (HERO), NCT04352946, clinicaltrials.gov/study/NCT04352946clinicaltrials.gov.

30. El-Sherbiny et al., Development and Validation of "Ready-to-Use" Inhalable Forms of Hydroxychloroquine for Treatment of COVID-19, NCT04477083, clinicaltrials.gov/study/NCT04477083clinicaltrials.gov.

31. Ajili et al., A Study of Hydroxychloroquine and Zinc in the Prevention of COVID-19 Infection in Military Healthcare Workers (COVID-Milit), NCT04377646, clinicaltrials.gov/study/NCT04377646clinicaltrials.gov.

32. Mežnar et al., Use of Bromhexine and Hydroxychloroquine for Treatment of COVID-19 Pneumonia, NCT04355026, clinicaltrials.gov/study/NCT04355026clinicaltrials.gov.

33. Niriella et al., Hydroxychloroquine for post-exposure prophylaxis of COVID-19 among naval personnel in Sri Lanka: study protocol for a randomized, controlled trial, Trials, doi:10.1186/s13063-020-04659-7.biomedcentral.com, doi.org.

34. Farooq et al., Effectiveness of Hydroxychloroquine in Covid-19 Patients (Covid), NCT04328272, clinicaltrials.gov/study/NCT04328272clinicaltrials.gov.

35. Butler et al., PRINCIPLE: A clinical trial evaluating treatments for suspected and confirmed COVID-19 for recovery at home, PRINCIPLE, www.isrctn.com/ISRCTN86534580isrctn.com.

36. Treluyer et al., Prevention of SARS-CoV-2 in Hospital Workers s Exposed to the Virus (PREP-COVID), PREP-COVID, NCT04344379, clinicaltrials.gov/study/NCT04344379clinicaltrials.gov.

37. Kim et al., Comparison of Lopinavir/Ritonavir or Hydroxychloroquine in Patients With Mild Coronavirus Disease (COVID-19), NCT04307693, clinicaltrials.gov/study/NCT04438837clinicaltrials.gov.

González et al., 31 Oct 2021, Double Blind Randomized Controlled Trial, placebo-controlled, Spain, peer-reviewed, trial NCT04410562 (history). Contact: raquel.gonzalez@isglobal.org (corresponding author).

Hydroxychloroquine efficacy and safety in preventing SARS-CoV-2 infection and COVID-19 disease severity during pregnancy (COVID-Preg): a structured summary of a study protocol for a randomised placebo controlled trial

Raquel González, Laura García-Otero, Clara Pons-Duran, Elena Marbán-Castro, Anna Goncé, Elisa Llurba, Maria Del Mar Gil, Miguel Ángel Rodríguez-Zambrano, Haily Chen, Máximo Ramírez, Azucena Bardají, Clara Menendez

Trials, doi:10.1186/s13063-020-04557-y

Objectives: The primary objectives of the study are: 1. To assess the effect of hydroxychloroquine (HCQ) in reducing SARS-CoV-2 viral shedding by PCR in infected pregnant women with mild symptoms. 2. To assess the efficacy of HCQ to prevent SARS-CoV-2 infection in pregnant women in contact with an infected or suspected case. 3. To evaluate the effect of HCQ in preventing the development of the COVID-19 disease in asymptomatic SARS-CoV-2-infected pregnant women. The secondary objectives are: 1. To determine the effect of HCQ on the clinical course and duration of the COVID-19 disease in SARS-CoV-2-infected pregnant women. 2. To determine the impact of HCQ on the risk of hospitalization and mortality of SARS-CoV-2-infected pregnant women. 3. To assess the safety and tolerability of HCQ in pregnant women. 4. To describe the clinical presentation of SARS-CoV-2 infection during pregnancy. 5. To describe the effects of maternal SARS-CoV-2 infection on pregnancy and perinatal outcomes by treatment group.

Numbers to be randomised (sample size): This study requires 200 SARS-CoV-2 infected and 514 contact pregnant women, randomised 1:1 with 100 and 227 respectively in each study arm. Trial Status: Protocol version 1.0, from May 8 th , 2020. Recruitment is ongoing (first patient recruited the 19 th May 2020 and recruitment end anticipated by December 2020). Trial registration: EudraCT number: 2020-001587-29, registered 2 April 2020. Clinicaltrials.gov identifier: NCT04410562, retrospectively registered 1 June 2020. Full protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. Keywords: COVID-19, Randomised controlled trial, Protocol, Hydroxychloroquine, Pregnant, Women Supplementary information Supplementary information accompanies this paper at https://doi.org/10. 1186/s13063-020-04557-y. Ethics approval and consent to participate On April 2 nd , 2020, a short trial proposal was approved by the Comité de Ética en Investigación of the Hospital Clínic of Barcelona to allow the start of the clinical trial procedures in the COVID-19 emergency situation (trial code HCB/2020/0382, meeting reference 9/2020_Extraordinària). The full trial protocol was approved as an amendment by the same committee on the ordinary meeting of May 14 th , 2020...

DOI record: { "DOI": "10.1186/s13063-020-04557-y", "ISSN": [ "1745-6215" ], "URL": "http://dx.doi.org/10.1186/s13063-020-04557-y", "alternative-id": [ "4557" ], "article-number": "607", "assertion": [ { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Received", "name": "received", "order": 1, "value": "23 June 2020" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Accepted", "name": "accepted", "order": 2, "value": "25 June 2020" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "First Online", "name": "first_online", "order": 3, "value": "2 July 2020" }, { "group": { "label": "Ethics approval and consent to participate", "name": "EthicsHeading" }, "name": "Ethics", "order": 1, "value": "On April 2nd, 2020, a short trial proposal was approved by the Comité de Ética en Investigación of the Hospital Clínic of Barcelona to allow the start of the clinical trial procedures in the COVID-19 emergency situation (trial code HCB/2020/0382, meeting reference 9/2020_Extraordinària). The full trial protocol was approved as an amendment by the same committee on the ordinary meeting of May 14th, 2020.The clinical trial was authorized by the Spanish Agency of Drugs and Medical Products (AEMPS) on April 8th, 2020 (authorization tracking code FEPZKWTD4D), and the agency approved the full protocol on May 22nd, 2020 (authorization tracking code FBVJZBZ766).Informed consent will be obtained from all participants." }, { "group": { "label": "Consent for publication", "name": "EthicsHeading" }, "name": "Ethics", "order": 2, "value": "Not applicable." }, { "group": { "label": "Competing interests", "name": "EthicsHeading" }, "name": "Ethics", "order": 3, "value": "The authors declare that they have no competing interests." } ], "author": [ { "ORCID": "http://orcid.org/0000-0001-5487-801X", "affiliation": [], "authenticated-orcid": false, "family": "González", "given": "Raquel", "sequence": "first" }, { "affiliation": [], "family": "García-Otero", "given": "Laura", "sequence": "additional" }, { "affiliation": [], "family": "Pons-Duran", "given": "Clara", "sequence": "additional" }, { "affiliation": [], "family": "Marbán-Castro", "given": "Elena", "sequence": "additional" }, { "affiliation": [], "family": "Goncé", "given": "Anna", "sequence": "additional" }, { "affiliation": [], "family": "Llurba", "given": "Elisa", "sequence": "additional" }, { "affiliation": [], "family": "Gil", "given": "Maria del Mar", "sequence": "additional" }, { "affiliation": [], "family": "Rodríguez-Zambrano", "given": "Miguel Ángel", "sequence": "additional" }, { "affiliation": [], "family": "Chen", "given": "Haily", "sequence": "additional" }, { "affiliation": [], "family": "Ramírez", "given": "Máximo", "sequence": "additional" }, { "affiliation": [], "family": "Bardají", "given": "Azucena", "sequence": "additional" }, { "affiliation": [], "family": "Menendez", "given": "Clara", "sequence": "additional" } ], "container-title": "Trials", "container-title-short": "Trials", "content-domain": { "crossmark-restriction": false, "domain": [ "link.springer.com" ] }, "created": { "date-parts": [ [ 2020, 7, 2 ] ], "date-time": "2020-07-02T09:25:31Z", "timestamp": 1593681931000 }, "deposited": { "date-parts": [ [ 2020, 8, 3 ] ], "date-time": "2020-08-03T07:07:46Z", "timestamp": 1596438466000 }, "funder": [ { "DOI": "10.13039/501100004587", "award": [ "COV20/00286" ], "doi-asserted-by": "publisher", "name": "Instituto de Salud Carlos III" } ], "indexed": { "date-parts": [ [ 2023, 7, 7 ] ], "date-time": "2023-07-07T08:55:18Z", "timestamp": 1688720118644 }, "is-referenced-by-count": 9, "issue": "1", "issued": { "date-parts": [ [ 2020, 7, 2 ] ] }, "journal-issue": { "issue": "1", "published-print": { "date-parts": [ [ 2020, 12 ] ] } }, "language": "en", "license": [ { "URL": "http://creativecommons.org/licenses/by/4.0/", "content-version": "tdm", "delay-in-days": 0, "start": { "date-parts": [ [ 2020, 7, 2 ] ], "date-time": "2020-07-02T00:00:00Z", "timestamp": 1593648000000 } }, { "URL": "http://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2020, 7, 2 ] ], "date-time": "2020-07-02T00:00:00Z", "timestamp": 1593648000000 } } ], "link": [ { "URL": "http://link.springer.com/content/pdf/10.1186/s13063-020-04557-y.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "http://link.springer.com/article/10.1186/s13063-020-04557-y/fulltext.html", "content-type": "text/html", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "http://link.springer.com/content/pdf/10.1186/s13063-020-04557-y.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "297", "original-title": [], "prefix": "10.1186", "published": { "date-parts": [ [ 2020, 7, 2 ] ] }, "published-online": { "date-parts": [ [ 2020, 7, 2 ] ] }, "published-print": { "date-parts": [ [ 2020, 12 ] ] }, "publisher": "Springer Science and Business Media LLC", "reference-count": 0, "references-count": 0, "relation": {}, "resource": { "primary": { "URL": "https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-020-04557-y" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [ "Pharmacology (medical)", "Medicine (miscellaneous)" ], "subtitle": [], "title": "Hydroxychloroquine efficacy and safety in preventing SARS-CoV-2 infection and COVID-19 disease severity during pregnancy (COVID-Preg): a structured summary of a study protocol for a randomised placebo controlled trial", "type": "journal-article", "update-policy": "http://dx.doi.org/10.1007/springer_crossmark_policy", "volume": "21" }