Effect of Hydroxychloroquine in COVID-19 Positive Pregnant Women (HyPreC)

• ClinicalTrials.gov Identifier: NCT04354441
• Recruitment Status: Withdrawn
• First Posted: April 21, 2020
• Last Update Posted: June 25, 2020
• Sponsor: Sir Mortimer B. Davis - Jewish General Hospital
• Information provided by (Responsible Party): Haim Abenhaim, Sir Mortimer B. Davis - Jewish General Hospital

Study Description

Brief Summary:

COVID-19 was declared a pandemic on March 11th. Efforts to save lives are essential as we will face increasing morbidity with rising demands on health care resources. Since pregnant women with COVID-19 have systematically been excluded from drug trials, potential treatment options for these high-risk individuals remain untested. The aim of our trial is to determine whether hydroxychloroquine given to COVID-19 positive pregnant women can reduce COVID-19-related hospital admissions, thereby allowing women to stay at home while limiting utilization of hospital resources and resulting exposure of health care providers.

Condition or disease	Intervention/treatment	Phase
COVID-19; SARS-CoV-2; Pregnant Women; Hydroxychloroquine	Drug: hydroxychloroquine sulfate 200 MG; Drug: Placebo oral tablet	Phase 2

Detailed Description:

Due to physiologic and immune changes, pregnant women are at high risk of severe complications and mortality from COVID-19 infections. Despite this, epidemiologic data on SARS-CoV-2 infection in pregnancy is currently limited to small case-series describing a clinical course ranging from mild to critical illness requiring extracorporeal membrane oxygenation. Chloroquine and hydroxychloroquine (HCQ) have demonstrated activity against SARS-coronaviruses in laboratory studies and are being tested in COVID-19 positive patients. HCQ appears more promising than chloroquine due to its greater effectiveness against SARS-CoV-2 in vitro and better safety profile. To date, pregnant women have been systematically excluded from trials conducted in the general outpatient population. Thus, we will carry out a randomized, placebo-controlled, double blinded trial of HCQ (considered safe in pregnancy in pregnant women with early COVID-19 infection across Canada to evaluate its effect in reducing COVID-19-related hospitalizations. This outpatient intervention is of paramount importance as its goal is to avoid overloading emergency rooms, obstetric triage, inpatient wards and critical care units. Upon completion of 6-month, our results can be directly applied to clinical care.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 0 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Participants will be randomized 1:1 to receive either the study medication (hydroxychloroquine) or an identical-looking placebo. Randomization will be in blocks of 4-6, stratified by province.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized Trial Evaluating Effect of Outpatient Hydroxychloroquine on Reducing Hospital Admissions in Pregnant Women With SARS-CoV-2 Infection: HyPreC Trial
• Estimated Study Start Date: May 2020
• Estimated Primary Completion Date: May 2020
• Estimated Study Completion Date: May 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: hydroxychloroquine; 10-day course of hydroxychloroquine 200 mg tablet twice a day. To be taken orally.	Drug: hydroxychloroquine sulfate 200 MG; Hydroxychloroquine sulfate (Plaquenil) 2MG will be taken twice a day for 10 days. Participants will be couriered the medication upon giving consent and will start taking the medication immediately.
Placebo Comparator: Placebo; An identical appearing placebo. To be taken orally twice a day for 10-days.	Drug: Placebo oral tablet; Placebo that is identical in appearance to the study medication will be taken twice a day for 10 days. It will be couriered to participants upon giving consent. They will start taking the medication immediately.

Outcome Measures

Primary Outcome Measures :

1. COVID-19-related hospital admissions [ Time Frame: Hospital Admission at any point from study enrollment to delivery ]
   COVID-19-related hospital admissions will be reported by the participants throughout pregnancy until delivery.

Secondary Outcome Measures :

1. Symptoms related to COVID-19 infection [ Time Frame: Participants will be contacted at day 3, 7, and 10 post-randomization, and every 2 weeks up to to delivery ]
   Measurement of reported symptoms using a validated questionnaire on Day 3, 7, 10, and every 2 weeks. The FLU-PRO Questionnaire instructs respondents to rate the severity of 37 influenza symptoms over the past 24 hours, including those related to the nose, throat, eye, chest, head, stomach, fatigue, and body aches/pains. For 32 of 37 items, respondents rated the severity of each symptom on 5-point Likert-type scales from 0 ("Not at all), 1 ("A little bit"), 2 ("Somewhat"), 3 ("Quite a bit"), to 4 ("Very much"). For the five remaining items, severity is expressed as frequency of occurrence: vomiting or diarrhea (0 times, 1 time, 2 times, 3 times, or 4 or more times), and sneezing, coughing, and coughed up mucus or phlegm on a scale from 0 ("Never") to 4 ("Always"), with higher scores indicating more severe symptoms.
2. Adverse Events [ Time Frame: Participants will be contacted at day 3, 7, and 10 post-randomization, and every 2 weeks up to to delivery ]
   Side effects related to hydroxychloqoruine
3. Maternal outcomes [ Time Frame: Participants will be contacted within 2 weeks after delivery to obtain information about their labor and delivery. ]
   Type of delivery (elective non-urgent cesarean, elective urgent cesarean section, non-elective cesarean within labor, instrumental vaginal, spontaneous vaginal)
4. Maternal outcomes [ Time Frame: Participants will be contacted within 2 weeks after delivery to obtain information about their labor and delivery. ]
   If had cesarean delivery, indication for cesarean section
5. Maternal outcomes [ Time Frame: Participants will be contacted within 2 weeks after delivery to obtain information about their labor and delivery. ]
   Miscarriage or stillbirth (Yes/No)
6. Maternal outcomes [ Time Frame: Participants will be contacted within 2 weeks after delivery to obtain information about their labor and delivery. ]
   Labor induction or augmentation (Yes/No) and indication
7. Maternal outcomes [ Time Frame: Participants will be contacted within 2 weeks after delivery to obtain information about their labor and delivery. ]
   Epidural use (Yes/No)
8. Newborn outcomes [ Time Frame: Participants will be contacted within 2 weeks after delivery to obtain information about their baby. ]
   Gestational age at delivery (weeks)
9. Newborn outcomes [ Time Frame: Participants will be contacted within 2 weeks after delivery to obtain information about their baby. ]
   Sex (female/male)
10. Newborn outcomes [ Time Frame: Participants will be contacted within 2 weeks after delivery to obtain information about their baby. ]

    Birth weight (kg)

    Birth weight (kg)

11. Newborn outcomes [ Time Frame: Participants will be contacted within 2 weeks after delivery to obtain information about their baby. ]
    Need for resuscitation (Yes/No)
12. Newborn outcomes [ Time Frame: Participants will be contacted within 2 weeks after delivery to obtain information about their baby. ]
    NICU admission (Yes/No)
13. Newborn outcomes [ Time Frame: Participants will be contacted within 2 weeks after delivery to obtain information about their baby. ]
    Medical conditions (jaundice, IVH, RDS, pneumothorax, PDA, NEC)
14. Newborn outcomes [ Time Frame: Participants will be contacted within 2 weeks after delivery to obtain information about their baby. ]
    Current disposition of baby (home or hospital)

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 50 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Women with a self-reported live pregnancy >14 weeks
• Presently in the outpatient setting (i.e. not admitted to the hospital)
• Tested positive for COVID-19 within last 7 days
• Must be living in Canada

Exclusion Criteria:

• Known glucose-6-phosphate dehydrogenase (G6PD) deficiency
• Known cardiac disease (or under investigation)
• Currently taking medication contraindicated as per Health Canada list for hydroxychloroquine
• Known retinopathy
• Known hypersensitivity to 4-aminoquinoline compounds
• Already taking hydroxychloroquine
• Unwilling to answer follow-up questionnaires
• Currently in labor
• Inpatient women at time of COVID-19 diagnosis.

Contacts and Locations

No Contacts or Locations Provided

More Information

Publications:

Lapinsky SE. Management of Acute Respiratory Failure in Pregnancy. Semin Respir Crit Care Med. 2017 Apr;38(2):201-207. doi: 10.1055/s-0037-1600909. Epub 2017 May 22. Review.

Callaghan WM, Creanga AA, Jamieson DJ. Pregnancy-Related Mortality Resulting From Influenza in the United States During the 2009-2010 Pandemic. Obstet Gynecol. 2015 Sep;126(3):486-490. doi: 10.1097/AOG.0000000000000996.

Mor G, Cardenas I. The immune system in pregnancy: a unique complexity. Am J Reprod Immunol. 2010 Jun;63(6):425-33. doi: 10.1111/j.1600-0897.2010.00836.x. Epub 2010 Mar 29. Review.

Chen H, Guo J, Wang C, Luo F, Yu X, Zhang W, Li J, Zhao D, Xu D, Gong Q, Liao J, Yang H, Hou W, Zhang Y. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet. 2020 Mar 7;395(10226):809-815. doi: 10.1016/S0140-6736(20)30360-3. Epub 2020 Feb 12. Erratum in: Lancet. 2020 Mar 28;395(10229):1038. Lancet. 2020 Mar 28;395(10229):1038.

Liu Y, Chen H, Tang K, Guo Y. Withdrawn: Clinical manifestations and outcome of SARS-CoV-2 infection during pregnancy. J Infect. 2020 Mar 5. pii: S0163-4453(20)30109-2. doi: 10.1016/j.jinf.2020.02.028. [Epub ahead of print]

Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, Li Y, Hu Z, Zhong W, Wang M. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020 Mar 18;6:16. doi: 10.1038/s41421-020-0156-0. eCollection 2020.

Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, Liu X, Zhao L, Dong E, Song C, Zhan S, Lu R, Li H, Tan W, Liu D. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020 Jul 28;71(15):732-739. doi: 10.1093/cid/ciaa237.

Andreoli L, Bertsias GK, Agmon-Levin N, Brown S, Cervera R, Costedoat-Chalumeau N, Doria A, Fischer-Betz R, Forger F, Moraes-Fontes MF, Khamashta M, King J, Lojacono A, Marchiori F, Meroni PL, Mosca M, Motta M, Ostensen M, Pamfil C, Raio L, Schneider M, Svenungsson E, Tektonidou M, Yavuz S, Boumpas D, Tincani A. EULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Ann Rheum Dis. 2017 Mar;76(3):476-485. doi: 10.1136/annrheumdis-2016-209770. Epub 2016 Jul 25.

Izmirly PM, Costedoat-Chalumeau N, Pisoni CN, Khamashta MA, Kim MY, Saxena A, Friedman D, Llanos C, Piette JC, Buyon JP. Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSA/Ro-antibody-associated cardiac manifestations of neonatal lupus. Circulation. 2012 Jul 3;126(1):76-82. doi: 10.1161/CIRCULATIONAHA.111.089268. Epub 2012 May 24.

Costedoat-Chalumeau N, Amoura Z, Duhaut P, Huong DL, Sebbough D, Wechsler B, Vauthier D, Denjoy I, Lupoglazoff JM, Piette JC. Safety of hydroxychloroquine in pregnant patients with connective tissue diseases: a study of one hundred thirty-three cases compared with a control group. Arthritis Rheum. 2003 Nov;48(11):3207-11.

Costedoat-Chalumeau N, Amoura Z, Huong DL, Lechat P, Piette JC. Safety of hydroxychloroquine in pregnant patients with connective tissue diseases. Review of the literature. Autoimmun Rev. 2005 Feb;4(2):111-5. Epub 2004 Dec 14. Review.

• Responsible Party: Haim Abenhaim, Obstetrician & gynecologist; Director of Perinatal Research, Sir Mortimer B. Davis - Jewish General Hospital
• ClinicalTrials.gov Identifier: NCT04354441
• Other Study ID Numbers: 1, March 30, 2020
• First Posted: April 21, 2020
• Last Update Posted: June 25, 2020
• Last Verified: June 2020

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Haim Abenhaim, Sir Mortimer B. Davis - Jewish General Hospital:

COVID-19; SARS-CoV-2; Pregnancy; hydroxychloroquine

Additional relevant MeSH terms:

COVID-19; Respiratory Tract Infections; Infections; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Hydroxychloroquine; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Anti-Infective Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents