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

NCT04582266 | Completed Results DMC FDA Drug

• 2 other identifiers: IMPAACT 2032DAIDS Study ID 38746
• Study Type: observational
• Target: 54
• Locations: 1 country
• Sites: 10

Brief Summary

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.

Conditions

COVID-19

Keywords

COVID-19, Pregnancy

Outcome Measures

Primary Outcomes (17)

• 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 Outcomes (9)

• PK Outcome: Geometric Mean Area Under the Plasma Concentration-time Curve (AUC) of Remdesivir (RDV) in Arm 2

  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

  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

  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

  First infusion through 7 Days post-last infusion

• Safety Outcome: Proportion of Participants With Hepatic Adverse Event (AE) of Any Grade in Arm 2

  First infusion through 7 Days post-last infusion

Other Outcomes (2)

• PK Outcome: Ratio of Cord Blood/Maternal Plasma Remdisivir (RDV) Concentrations

  Delivery

• PK Outcome: Ratio of Cord Blood/Maternal Plasma GS-441524 Concentrations

  Delivery

Study Arms (2)

Arm 1

Pregnant women hospitalized and receiving RDV for treatment of COVID-19.

Drug: Remdesivir

Arm 2

Non-pregnant women of childbearing potential hospitalized and receiving RDV for treatment of COVID-19.

Drug: Remdesivir

Interventions

Remdesivir DRUG

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 1; Arm 2

Eligibility Criteria

• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Gilead Sciences: collaborator

Study Sites (10)

David Geffen School of Medicine at UCLA (Site #: 5112)

Los Angeles, California, 90095, United States

Location

Childrens Hospital (U. Colorado, Denver) NICHD CRS (Site #: 5052)

Denver, Colorado, 80218-1088, United States

Location

Pediatric Perinatal HIV Clinical Trials Unit (Site #: 5127)

Miami, Florida, 33136, United States

Location

Emory University School of Medicine (Site #: 5030)

Atlanta, Georgia, 30308, United States

Location

Rush University Cook County Hospital NICHD CRS (Site #: 5083)

Chicago, Illinois, 60612, United States

Location

Lurie Children's Hospital of Chicago (LCH) CRS (Site #: 4001)

Chicago, Illinois, 60614, United States

Location

Johns Hopkins University NICHD CRS (Site #: 5092)

Baltimore, Maryland, 21287, United States

Location

Stony Brook University Medical Center (Site #: 5040)

Stony Brook, New York, 11794, United States

Location

Bronx-Lebanon Hospital Center (Site #: 5114)

The Bronx, New York, 10457, United States

Location

Texas Children's Hospital (Site #: 5128)

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Brooks KM, Baltrusaitis K, Clarke DF, Nachman S, Jao J, Purswani MU, Agwu A, Beneri C, Deville JG, Powis KM, Stek AM, Eke AC, Shapiro DE, Capparelli E, Greene E, George K, Yin DE, Jean-Philippe P, Chakhtoura N, Bone F, Bacon K, Johnston B, Reding C, Kersey K, Humeniuk R, Best BM, Mirochnick M, Momper JD; IMPAACT 2032 Study Team. Pharmacokinetics and Safety of Remdesivir in Pregnant and Nonpregnant Women With COVID-19: Results From IMPAACT 2032. J Infect Dis. 2024 Oct 16;230(4):878-888. doi: 10.1093/infdis/jiae298.

  PMID: 38839047 DERIVED

Related Links

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

MeSH Terms

Conditions

COVID-19

Interventions

remdesivir

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Limitations and Caveats

Because the study population might not include women who started RDV and discontinued it before the fourth infusion, this study may not identify PK, safety, or tolerance issues that occur after drug initiation and estimates of the frequency of adverse outcomes might be optimistic. Due to the way the data was collected, some AEs may not have been detected following hospital discharge.

Results Point of Contact

• Title: IMPAACT Clinicaltrials.gov Coordinator
• Organization: Family Health International (FHI 360)

IMPAACT.ctgov@fstrf.org

(919) 405-1429

Study Officials

• Mark Mirochnick, MD

  Department of Pediatrics, Boston University Chobanian and Avedisian School of Medicine

  STUDY CHAIR

• Diana Clarke, PharmD

  Pediatric Infectious Diseases, Boston Medical Center

  STUDY CHAIR

• Brookie Best, PharmD, MAS

  University of California, San Diego

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 8, 2020
• First Posted: October 9, 2020
• Study Start: March 31, 2021
• Primary Completion: April 13, 2022
• Study Completion: April 13, 2022
• Last Updated: June 9, 2023
• Results First Posted: June 9, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• 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.
• 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.

Locations

US (10)