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

Randomized Trial Evaluating Effect of Outpatient Hydroxychloroquine on Reducing Hospital Admissions in Pregnant Women With SARS-CoV-2 Infection: HyPreC Trial

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.

Study Overview

• Status: Withdrawn
• Conditions: COVID-19; Pregnant Women; SARS-CoV-2; Hydroxychloroquine
• Intervention / Treatment: Drug: hydroxychloroquine sulfate 200 MG; Drug: Placebo oral tablet

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 Type: Interventional
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptoms related to COVID-19 infection	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.	Participants will be contacted at day 3, 7, and 10 post-randomization, and every 2 weeks up to to delivery
Adverse Events	Side effects related to hydroxychloqoruine	Participants will be contacted at day 3, 7, and 10 post-randomization, and every 2 weeks up to to delivery
Maternal outcomes	Type of delivery (elective non-urgent cesarean, elective urgent cesarean section, non-elective cesarean within labor, instrumental vaginal, spontaneous vaginal)	Participants will be contacted within 2 weeks after delivery to obtain information about their labor and delivery.
Maternal outcomes	If had cesarean delivery, indication for cesarean section	Participants will be contacted within 2 weeks after delivery to obtain information about their labor and delivery.
Maternal outcomes	Miscarriage or stillbirth (Yes/No)	Participants will be contacted within 2 weeks after delivery to obtain information about their labor and delivery.
Maternal outcomes	Labor induction or augmentation (Yes/No) and indication	Participants will be contacted within 2 weeks after delivery to obtain information about their labor and delivery.
Maternal outcomes	Epidural use (Yes/No)	Participants will be contacted within 2 weeks after delivery to obtain information about their labor and delivery.
Newborn outcomes	Gestational age at delivery (weeks)	Participants will be contacted within 2 weeks after delivery to obtain information about their baby.
Newborn outcomes	Sex (female/male)	Participants will be contacted within 2 weeks after delivery to obtain information about their baby.
Newborn outcomes	Birth weight (kg) Birth weight (kg)	Participants will be contacted within 2 weeks after delivery to obtain information about their baby.
Newborn outcomes	Need for resuscitation (Yes/No)	Participants will be contacted within 2 weeks after delivery to obtain information about their baby.
Newborn outcomes	NICU admission (Yes/No)	Participants will be contacted within 2 weeks after delivery to obtain information about their baby.
Newborn outcomes	Medical conditions (jaundice, IVH, RDS, pneumothorax, PDA, NEC)	Participants will be contacted within 2 weeks after delivery to obtain information about their baby.
Newborn outcomes	Current disposition of baby (home or hospital)	Participants will be contacted within 2 weeks after delivery to obtain information about their baby.

Collaborators and Investigators

• Sponsor: Sir Mortimer B. Davis - Jewish General Hospital

Publications and helpful links

General Publications

• 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. No abstract available.
• 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.
• 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.
• 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.
• 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:S0163-4453(20)30109-2. doi: 10.1016/j.jinf.2020.02.028. Online ahead of print.
• 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. doi: 10.1002/art.11304.
• 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. doi: 10.1016/j.autrev.2004.11.009. Epub 2004 Dec 14.

Study record dates

Study Major Dates

• Study Start (Anticipated): May 1, 2020
• Primary Completion (Anticipated): May 1, 2020
• Study Completion (Anticipated): May 1, 2020

Study Registration Dates

• First Submitted: April 14, 2020
• First Submitted That Met QC Criteria: April 17, 2020
• First Posted (Actual): April 21, 2020

Study Record Updates

• Last Update Posted (Actual): June 25, 2020
• Last Update Submitted That Met QC Criteria: June 23, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: SARS-CoV-2; Pregnancy; COVID-19; hydroxychloroquine
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Hydroxychloroquine
• Other Study ID Numbers: 1, March 30, 2020

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No