PK and Safety of Remdesivir for Treatment of COVID-19 in Pregnant and Non-Pregnant Women in the US

Pharmacokinetics and Safety of Remdesivir for Treatment of COVID-19 in Pregnant and Non-Pregnant Women in the United States

IMPAACT 2032 was a Phase IV prospective, open label, non-randomized opportunistic study. The objectives of this study were to describe the pharmacokinetic (PK) properties and safety of remdesivir (RDV) administered intravenously as part of clinical care among hospitalized pregnant and non-pregnant women of childbearing potential with coronavirus disease of 2019 (COVID-19). RDV was provided and managed by the participant's treating physician and was not provided as part of this study.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Drug: Remdesivir

Detailed Description

IMPAACT 2032 was a Phase IV prospective, open label, non-randomized opportunistic study to evaluate the PK and safety of RDV when administered to pregnant and non-pregnant women of childbearing potential for treatment of COVID-19. Participants were pregnant and non-pregnant women hospitalized for COVID-19 who received daily RDV infusions, typically for 5 days but in some cases for up to 10 days, as part of their clinical care. RDV was provided and managed by the participants' treating physician and was not provided as a part of this study.

This study was comprised of two population-based arms: Arm 1 included pregnant women of any gestational age (GA) and Arm 2 included non-pregnant women of childbearing potential, who were between 18 and 45 years of age. The target sample size was 20 PK-evaluable participants per arm. Study sites were located in the United States.

Study procedures for this study were limited to data collection and blood specimens for PK. Except for PK sampling, study procedures were largely done via medical chart abstraction or remote contact/telemedicine visit. Collection of clinical and laboratory data started at 48 hours before the first infusion and continued through 4 weeks after the last infusion. In addition, data were collected at the time of delivery for participants in Arm 1, and limited data were also collected from the birth and newborn exam records of their infants. All participants were followed for safety through 4 weeks after the last infusion; Arm 1 participants who were still pregnant at that time had an additional follow-up at the time of delivery. If there was a gap in time between 4 weeks after the last infusion and delivery, no data were collected during that interval.

No formal statistical comparisons were made between Arm 1 and Arm 2 for primary and secondary objectives. Therefore, all analyses for primary and secondary outcome measures represent single arm evaluations.

• Study Type: Observational
• Enrollment (Actual): 54

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • David Geffen School of Medicine at UCLA (Site #: 5112)
  • Colorado
    • Denver, Colorado, United States, 80218-1088
      • Childrens Hospital (U. Colorado, Denver) NICHD CRS (Site #: 5052)
  • Florida
    • Miami, Florida, United States, 33136
      • Pediatric Perinatal HIV Clinical Trials Unit (Site #: 5127)
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Emory University School of Medicine (Site #: 5030)
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Cook County Hospital NICHD CRS (Site #: 5083)
    • Chicago, Illinois, United States, 60614
      • Lurie Children's Hospital of Chicago (LCH) CRS (Site #: 4001)
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University NICHD CRS (Site #: 5092)
  • New York
    • Bronx, New York, United States, 10457
      • Bronx-Lebanon Hospital Center (Site #: 5114)
    • Stony Brook, New York, United States, 11794
      • Stony Brook University Medical Center (Site #: 5040)
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital (Site #: 5128)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

This study was conducted among hospitalized pregnant and non-pregnant women receiving RDV for treatment of COVID-19 as part of their clinical care.

Description

Inclusion Criteria: Arm 1 (Pregnant Women)

• Of legal age or otherwise able to provide independent informed consent or is unable to provide informed consent (e.g., impaired capacity) and a Legally Authorized Representative (LAR) is willing and able to provide written informed consent on behalf of the participant
• At study entry, viable intra-uterine pregnancy of any gestational age, based on medical records.
• At study entry, hospitalized AND has confirmed or suspected COVID-19, based on medical records.
• At study entry, receiving or expected to receive RDV for COVID-19 clinical care, as prescribed by the clinical care provider and documented in medical records.

Inclusion Criteria - Arm 2 (Non-Pregnant Women)

• Of legal age or otherwise able to provide independent informed consent or is unable to provide informed consent (e.g., impaired capacity) and a Legally Authorized Representative (LAR) is willing and able to provide written informed consent on behalf of the participant
• At study entry, between 18 and 45 years of age, based on medical records and participant report.
• Assigned female at birth and at study entry not taking cross-sex hormone therapy.
• At study entry, not suspected to be pregnant, based on participant report and/or investigator or designee determination.
• At study entry, hospitalized AND has confirmed or suspected COVID-19, based on medical records.
• At study entry, receiving or expected to receive RDV for COVID-19 clinical care, as prescribed by the clinical care provider and documented in medical records.

Exclusion Criteria:

• At study entry, has started or received the 4th RDV infusion.
• At study entry, evidence of post-menopausal status (medical or surgical), based on medical records and/or participant report.
• At study entry, any contraindications to RDV treatment for COVID-19, based on investigator or designee determination.
• Received or administered any disallowed medications within 48 hours prior to study entry.
• At study entry, has any other condition, that, in the opinion of the site investigator or designee, would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving study objectives.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Arm 1; Pregnant women hospitalized and receiving RDV for treatment of COVID-19.	Drug: Remdesivir; RDV was not provided as part of the study. Participants were administered RDV intravenously once daily for up to 10 days per clinical care.
Arm 2; Non-pregnant women of childbearing potential hospitalized and receiving RDV for treatment of COVID-19.	Drug: Remdesivir; RDV was not provided as part of the study. Participants were administered RDV intravenously once daily for up to 10 days per clinical care.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK Outcome: Geometric Mean Area Under the Plasma Concentration-time Curve (AUC) of Remdesivir (RDV) in Arm 1	AUC calculated using non-compartmental methods with linear up-log down trapezoidal rule (Phoenix WinNonlin v 8.3, Certara®). Intensive PK sampling occurred once, on the day of the 3rd, 4th, or 5th infusion.	At 3rd, 4th, or 5th infusion. Collection timepoints included: pre-dose, end of infusion (EOI), EOI + 0.75 hours, EOI + 1.5 hours, EOI + 3 hours, EOI + 5 hours, EOI + 7 hours, EOI + 23 hours.
PK Outcome: Geometric Mean Half-life (t1/2) of Remdesivir (RDV) in Arm 1	t1/2 calculated using non-compartmental methods with linear up-log down trapezoidal rule (Phoenix WinNonlin v 8.3, Certara®). Intensive PK sampling occurred once, on the day of the 3rd, 4th, or 5th infusion.	At 3rd, 4th, or 5th infusion. Collection timepoints included: pre-dose, end of infusion (EOI), EOI + 0.75 hours, EOI + 1.5 hours, EOI + 3 hours, EOI + 5 hours, EOI + 7 hours, EOI + 23 hours.
PK Outcome: Geometric Mean Trough Concentration (Ctrough) of GS-441524 in Arm 1	GS-441524 is a metabolite of remdesivir (RDV). Ctrough calculated using non-compartmental methods with linear up-log down trapezoidal rule (Phoenix WinNonlin v 8.3, Certara®). Intensive PK sampling occurred once, on the day of the 3rd, 4th, or 5th infusion.	At 3rd, 4th, or 5th infusion. Collection timepoints included: pre-dose, end of infusion (EOI), EOI + 0.75 hours, EOI + 1.5 hours, EOI + 3 hours, EOI + 5 hours, EOI + 7 hours, EOI + 23 hours.
Safety Outcome: Proportion of Participants With Maternal Renal Adverse Event (AE) of Any Grade in Arm 1	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. We present the proportion of participants with at least one maternal renal AE through 7 days post last infusion, bounded by an exact 95% confidence interval (CI). Renal AEs were defined using the MedDRA system organ class term "Renal and urinary disorders" and high level grouping term "Renal and urinary tract investigations and urinalyses". The number of RDV infusions varied by participant.	First infusion through 7 Days post-last infusion
Safety Outcome: Proportion of Participants With Maternal Hepatic Adverse Event (AE) of Any Grade in Arm 1	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. We present the proportion of participants with at least one maternal hepatic AE through 7 days post last infusion, bounded by an exact 95% confidence interval (CI). Hepatic AEs were defined using the MedDRA system organ class term "Hepatobiliary disorders" and high level grouping term "Hepatobiliary investigations". The number of RDV infusions varied by participant.	First infusion through 7 Days post-last infusion
Safety Outcome: Proportion of Participants With Maternal Hematologic Adverse Event (AE) of Any Grade in Arm 1	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. We present the proportion of participants with at least one maternal hematologic AE through 7 days post last infusion, bounded by an exact 95% confidence interval (CI). Hematologic AEs were defined using the MedDRA system organ class term "Blood and lymphatic system disorders" and high level grouping term "Haematology investigations (incl blood groups)". The number of RDV infusions varied by participant.	First infusion through 7 Days post-last infusion
Safety Outcome: Proportion of Participants With Maternal Grade 3 or Higher Adverse Event (AE) in Arm 1	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. The DAIDS grading table provides an AE severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one maternal grade 3 or higher adverse event through 4 weeks post last infusion and delivery, bounded by an exact 95% confidence interval (CI). The number of RDV infusions varied by participant.	First infusion through 4 Weeks post-last infusion and Delivery
Safety Outcome: Proportion of Participants With Serious Adverse Event (AE) in Arm 1	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. We present the proportion of participants with at least one maternal serious AE through 4 weeks post last infusion and delivery, bounded by an exact 95% confidence interval (CI). The number of RDV infusions varied by participant.	First infusion through 4 Weeks post-last infusion and Delivery
Safety Outcome: Proportion of Participants With Maternal Grade 3 or Higher Adverse Event (AE) Assessed as Related to Remdesivir (RDV) by the Clinical Management Committee (CMC) in Arm 1	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. The DAIDS grading table provides an AE severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one maternal grade 3 or higher AE assessed as related to RDV by the CMC through 4 weeks post last infusion and delivery, bounded by an exact 95% confidence interval (CI). The number of RDV infusions varied by participant.	First infusion through 4 Weeks post-last infusion and Delivery
Safety Outcome: Proportion of Participants With Pregnancy Loss in Arm 1	We present the proportion of participants who had a pregnancy loss at delivery, bounded by an exact 95% confidence interval (CI).	Delivery
Safety Outcome: Proportion of Participants With Congenital Anomalies in Arm 1	We present the proportion of participants who had a live infant born with congenital anomalies at delivery, bounded by an exact 95% confidence interval (CI).	Delivery
Safety Outcome: Proportion of Participants With Preterm Birth, Defined as < 37 Weeks in Arm 1	We present the proportion of participants who had a live preterm birth defined as < 37 weeks, bounded by an exact 95% confidence interval (CI).	Delivery
Safety Outcome: Proportion of Participants With Preterm Birth, Defined as < 34 Weeks in Arm 1	We present the proportion of participants who had a live preterm birth defined as < 34 weeks, bounded by an exact 95% confidence interval (CI).	Delivery
Safety Outcome: Proportion of Participants With Small for Gestational Age, Defined as < 10th Percentile in Arm 1	We present the proportion of participants who a live born infant who was small for gestational age defined as < 10th percentile, bounded by an exact 95% confidence interval (CI).	Delivery
Safety Outcome: Mean Newborn Birth Weight in Arm 1	We present the newborn mean weight among the participants who had live born infant, bounded by a 95% confidence interval (CI) calculated using the t distribution.	Delivery
Safety Outcome: Mean Newborn Length in Arm 1	We present the newborn mean length among the participants who had a live born infant, bounded by a 95% confidence interval (CI) calculated using the t distribution.	Delivery
Safety Outcome: Mean Newborn Head Circumference in Arm 1	We present the newborn mean head circumference among the participants who had a live born infant, bounded by a 95% confidence interval (CI) calculated using the t distribution.	Delivery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK Outcome: Geometric Mean Area Under the Plasma Concentration-time Curve (AUC) of Remdesivir (RDV) in Arm 2	AUC calculated using non-compartmental methods with linear up-log down trapezoidal rule (Phoenix WinNonlin v 8.3, Certara®). Intensive PK sampling occurred once, on the day of the 3rd, 4th, or 5th infusion.	At 3rd, 4th, or 5th infusion. Collection timepoints included: pre-dose, end of infusion (EOI), EOI + 0.75 hours, EOI + 1.5 hours, EOI + 3 hours, EOI + 5 hours, EOI + 7 hours, EOI + 23 hours.
PK Outcome: Geometric Mean Half-life (t1/2) of Remdesivir (RDV) in Arm 2	t1/2 calculated using non-compartmental methods with linear up-log down trapezoidal rule (Phoenix WinNonlin v 8.3, Certara®). Intensive PK sampling occurred once, on the day of the 3rd, 4th, or 5th infusion.	At 3rd, 4th, or 5th infusion. Collection timepoints included: pre-dose, end of infusion (EOI), EOI + 0.75 hours, EOI + 1.5 hours, EOI + 3 hours, EOI + 5 hours, EOI + 7 hours, EOI + 23 hours.
PK Outcome: Geometric Mean Trough Concentration (Ctrough) of GS-441524 in Arm 2	GS-441524 is a metabolite of remdesivir (RDV). Ctrough calculated using non-compartmental methods with linear up-log down trapezoidal rule (Phoenix WinNonlin v 8.3, Certara®). Intensive PK sampling occurred once, on the day of the 3rd, 4th, or 5th infusion.	At 3rd, 4th, or 5th infusion. Collection timepoints included: pre-dose, end of infusion (EOI), EOI + 0.75 hours, EOI + 1.5 hours, EOI + 3 hours, EOI + 5 hours, EOI + 7 hours, EOI + 23 hours.
Safety Outcome: Proportion of Participants With Renal Adverse Event (AE) of Any Grade in Arm 2	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. We present the proportion of participants with at least one renal AE through 7 days post last infusion, bounded by an exact 95% confidence interval (CI). Renal AEs were defined using the MedDRA system organ class term "Renal and urinary disorders" and high level grouping term "Renal and urinary tract investigations and urinalyses". The number of RDV infusions varied by participant.	First infusion through 7 Days post-last infusion
Safety Outcome: Proportion of Participants With Hepatic Adverse Event (AE) of Any Grade in Arm 2	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. We present the proportion of participants with at least one hepatic AE through 7 days post last infusion, bounded by an exact 95% confidence interval (CI). Hepatic AEs were defined using the MedDRA system organ class term "Hepatobiliary disorders" and high level grouping term "Hepatobiliary investigations". The number of RDV infusions varied by participant.	First infusion through 7 Days post-last infusion
Safety Outcome: Proportion of Participants With Hematologic Adverse Event (AE) of Any Grade in Arm 2	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. We present the proportion of participants with at least one hematologic AE through 7 days post last infusion, bounded by an exact 95% confidence interval (CI). Hematologic AEs were defined using the MedDRA system organ class term "Blood and lymphatic system disorders" and high level grouping term "Haematology investigations (incl blood groups)". The number of RDV infusions varied by participant.	First infusion through 7 Days post-last infusion
Safety Outcome: Proportion of Participants With Grade 3 or Higher Adverse Event (AE) in Arm 2	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. The DAIDS grading table provides an AE severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one grade 3 or higher AE through 4 weeks post last infusion, bounded by an exact 95% confidence interval (CI).	First infusion through 4 Weeks post-last infusion
Safety Outcome: Proportion of Participants With Serious Adverse Event (AE) in Arm 2	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. We present the proportion of participants with at least one serious AE through 4 weeks post last infusion, bounded by an exact 95% confidence interval (CI). The number of RDV infusions varied by participant.	First infusion through 4 Weeks post-last infusion
Safety Outcome: Proportion of Participants With Grade 3 or Higher Adverse Event (AE) Assessed as Related to Remdesivir (RDV) by the Clinical Management Committee (CMC) in Arm 2	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. The DAIDS grading table provides an AE severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one grade 3 or higher AE as related to RDV by the CMC through 4 weeks post last infusion, bounded by an exact 95% confidence interval (CI). The number of RDV infusions varied by participant.	First infusion through 4 Weeks post-last infusion

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK Outcome: Ratio of Cord Blood/Maternal Plasma Remdisivir (RDV) Concentrations	Ratio of cord blood/maternal plasma is calculated for women in Arm 1 who received RDV within 5 days of delivery only.	Delivery
PK Outcome: Ratio of Cord Blood/Maternal Plasma GS-441524 Concentrations	GS-441524 is a metabolite of remdesivir (RDV). Ratio of cord blood/maternal plasma is calculated for women in Arm 1 who received RDV within 5 days of delivery only.	Delivery

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Gilead Sciences
• Investigators: Study Chair: Diana Clarke, PharmD, Pediatric Infectious Diseases, Boston Medical Center; Study Chair: Brookie Best, PharmD, MAS, University of California, San Diego; Study Chair: Mark Mirochnick, MD, Department of Pediatrics, Boston University Chobanian and Avedisian School of Medicine

Publications and helpful links

Helpful Links

• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010
• DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, dated July 2017

Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2021
• Primary Completion (Actual): April 13, 2022
• Study Completion (Actual): April 13, 2022

Study Registration Dates

• First Submitted: October 8, 2020
• First Submitted That Met QC Criteria: October 8, 2020
• First Posted (Actual): October 9, 2020

Study Record Updates

• Last Update Posted (Actual): June 9, 2023
• Last Update Submitted That Met QC Criteria: May 16, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: COVID-19, Pregnancy
• 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; Antiviral Agents; Antimetabolites; Remdesivir
• Other Study ID Numbers: IMPAACT 2032; DAIDS Study ID 38746 (Other Identifier: DAIDS CRMS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie results in the publication, after deidentification.
• IPD Sharing Time Frame: Beginning 3 months following publication and available throughout period of funding of the International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) Network by NIH.
• IPD Sharing Access Criteria: With whom? Researchers who provide a methodologically sound proposal for use of the data that is approved by the IMPAACT Network.; For what types of analyses? To achieve aims in the proposal approved by the IMPAACT Network.; By what mechanism will data be made available? Researchers may submit a request for access to data using the IMPAACT "Data Request" form at: https://www.impaactnetwork.org/resources/study-proposals.htm. Researchers of approved proposals will need to sign an IMPAACT Data Use Agreement before receiving the data.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No