Pharmacokinetics and Safety of Remdesivir for Treatment of COVID-19 in Pregnant and Non-Pregnant Women in the United States
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 54
- 试验地点
- 10
- 主要终点
- PK Outcome: Geometric Mean Area Under the Plasma Concentration-time Curve (AUC) of Remdesivir (RDV) in Arm 1
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Arm 1
Pregnant women hospitalized and receiving RDV for treatment of COVID-19.
干预措施: Remdesivir (Drug)
Arm 2
Non-pregnant women of childbearing potential hospitalized and receiving RDV for treatment of COVID-19.
干预措施: Remdesivir (Drug)
结局指标
主要结局
PK Outcome: Geometric Mean Area Under the Plasma Concentration-time Curve (AUC) of Remdesivir (RDV) in Arm 1
时间窗: 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.
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.
Safety Outcome: Mean Newborn Birth Weight in Arm 1
时间窗: Delivery
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.
Safety Outcome: Mean Newborn Length in Arm 1
时间窗: Delivery
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.
PK Outcome: Geometric Mean Half-life (t1/2) of Remdesivir (RDV) in Arm 1
时间窗: 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.
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.
Safety Outcome: Proportion of Participants With Maternal Renal Adverse Event (AE) of Any Grade in Arm 1
时间窗: First infusion through 7 Days post-last infusion
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.
Safety Outcome: Proportion of Participants With Maternal Hepatic Adverse Event (AE) of Any Grade in Arm 1
时间窗: First infusion through 7 Days post-last infusion
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.
Safety Outcome: Proportion of Participants With Maternal Hematologic Adverse Event (AE) of Any Grade in Arm 1
时间窗: First infusion through 7 Days post-last infusion
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.
Safety Outcome: Proportion of Participants With Maternal Grade 3 or Higher Adverse Event (AE) in Arm 1
时间窗: First infusion through 4 Weeks post-last infusion and Delivery
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.
Safety Outcome: Proportion of Participants With Serious Adverse Event (AE) in Arm 1
时间窗: First infusion through 4 Weeks post-last infusion and Delivery
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.
PK Outcome: Geometric Mean Trough Concentration (Ctrough) of GS-441524 in Arm 1
时间窗: 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.
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.
Safety Outcome: Proportion of Participants With Small for Gestational Age, Defined as < 10th Percentile in Arm 1
时间窗: Delivery
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).
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
时间窗: First infusion through 4 Weeks post-last infusion and Delivery
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.
Safety Outcome: Proportion of Participants With Pregnancy Loss in Arm 1
时间窗: Delivery
We present the proportion of participants who had a pregnancy loss at delivery, bounded by an exact 95% confidence interval (CI).
Safety Outcome: Proportion of Participants With Congenital Anomalies in Arm 1
时间窗: Delivery
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).
Safety Outcome: Proportion of Participants With Preterm Birth, Defined as < 37 Weeks in Arm 1
时间窗: Delivery
We present the proportion of participants who had a live preterm birth defined as \< 37 weeks, bounded by an exact 95% confidence interval (CI).
Safety Outcome: Mean Newborn Head Circumference in Arm 1
时间窗: Delivery
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.
Safety Outcome: Proportion of Participants With Preterm Birth, Defined as < 34 Weeks in Arm 1
时间窗: Delivery
We present the proportion of participants who had a live preterm birth defined as \< 34 weeks, bounded by an exact 95% confidence interval (CI).
次要结局
- Safety Outcome: Proportion of Participants With Hematologic Adverse Event (AE) of Any Grade in Arm 2(First infusion through 7 Days post-last infusion)
- 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.)
- Safety Outcome: Proportion of Participants With Renal Adverse Event (AE) of Any Grade in Arm 2(First infusion through 7 Days post-last infusion)
- 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.)
- Safety Outcome: Proportion of Participants With Grade 3 or Higher Adverse Event (AE) in Arm 2(First infusion through 4 Weeks 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)
- Safety Outcome: Proportion of Participants With Serious Adverse Event (AE) in Arm 2(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(First infusion through 4 Weeks post-last infusion)
- 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.)