ING200336: A Prospective, Interventional Pharmacokinetic and Safety Study of DTG/ABC/3TC in Pregnant Women
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 4
- 试验地点
- 1
- 主要终点
- Steady State Volume of Distribution (Vss/F) After Extravascular Administration for Dolutegravir
研究概览
简要总结
In this study, the dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) fixed dose combination (FDC) tablet is being made available to women who become pregnant while participating in study ING117172. Continuation of antiretroviral therapy (ART) is key to both mother and the unborn fetus in order to maintain virologic suppression in the mother (thereby decreasing the risk for maternal disease progression), but also to reduce the risk of maternal-fetal transmission of human immunodeficiency virus type 1 (HIV-1) to her unborn child. This study also offers the first opportunity to investigate the impact of pregnancy on DTG pharmacokinetics (PK). This is an open-label, single arm interventional study. The number of women that will be enrolled into this study cannot be established a priori, as unintended pregnancies cannot be determined in advance. The maximum number of women would include all of those women randomized to DTG/ABC/3TC FDC (approximately 237), though unintended pregnancies in all of these women would not be anticipated.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •HIV infected females participating in ING117172 on the DTG/ABC/3TC treatment arm who became pregnant with a singleton and have not met any safety or confirmed virologic withdrawal criteria.
- •Signed and dated written informed consent is obtained from the subject or the subject's legal representative prior to screening.
- •Willingness and intent to continue pregnancy
- •Willingness to continue to receive DTG/ABC/3TC FDC.
- •Willingness to enter the Antiretroviral Pregnancy Registry.
- •Willingness to share medical information about herself and her infant for collection of delivery and infant outcomes as it relates to this study.
- •Subjects enrolled in France: a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
排除标准
- •History of allergy/sensitivity to DTG, ABC and/or 3TC.
- •History of severe pre-clampsia, eclampsia, or hemolysis, elevated liver enzymes and low platelet count (HELLP)
- •Any evidence of an active Center for Disease Control and Prevention (CDC) Category C disease, except cutaneous Kaposi's sarcoma not requiring systemic therapy or historic or current CD4+ cell levels <200 cells/millimeter^
- •Subjects with any degree of hepatic impairment.
- •Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical intraepithelial neoplasia; other localized malignancies require agreement between the investigator and the Study medical monitor for inclusion of the subject.
- •Subjects who in the investigator's judgment, poses a significant suicidality risk. Recent history of suicidal behavior and/or suicidal ideation may be considered as evidence of serious suicide risk.
- •Subjects with evidence of ongoing hepatitis B infection at screening, or anticipated need for Hepatitis C Virus therapy during the study.
- •Treatment with any of the following agents within 28 days of Baseline: radiation therapy; cytotoxic chemotherapeutic agents; any immunomodulators that alter immune responses.
- •Subjects enrolled in France: the subject has participated in any study using an investigational drug during the previous 60 days or 5 half-lives, or twice the duration of the biological effect of the experimental drug or vaccine, whichever is longer, prior to screening for the study or the subject will participate simultaneously in another clinical study.
- •Any verified Grade 4 laboratory abnormality with the exception of Grade 4 lipid abnormalities (total cholesterol, triglycerides, high density lipoprotein [HDL] cholesterol, low density lipoprotein [LDL] cholesterol). A single repeat test is allowed during the Screening period to verify a result.
- •Any acute laboratory abnormality observed in ING117172 or in any Screening laboratory assessments for ING200336, which, in the opinion of the Investigator, would preclude the subject's participation in the study.
- •Hyperbilirubinemia of unknown etiology.
- •Confirmed (with no more than 1 repeat evaluation) Grade >= 2 urine protein (dipstick), serum creatinine, total bilirubin, alanine aminotransferase or aspartate aminotransferase at the time of the screening lab.
- •Subject has Creatinine Clearance of <50 mL/minute via Cockroft-Gault method at the time of the screening visit
研究组 & 干预措施
DTG/ABC/3TC
All subjects will be administered DTG 50 milligrams (mg)/ABC 600 mg/3TC 300 mg FDC tablet once daily, with or without food.
干预措施: DTG 50 mg /ABC 600 mg /3TC 300 mg FDC tablets (Drug)
结局指标
主要结局
Steady State Volume of Distribution (Vss/F) After Extravascular Administration for Dolutegravir
时间窗: Pre-dose and at 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose at Trimester 2 (Weeks 18-26 of pregnancy), Trimester 3 (Weeks 30-36 of pregnancy) and at 8-12 Weeks postpartum
Blood samples were collected at indicated timepoints for PK analysis of dolutegravir at Trimester 2 (Weeks 18-26 of pregnancy), Trimester 3 (Weeks 30-36 of pregnancy) and at 8-12 Weeks postpartum.
Number of Participants (Pregnant Women) With Maximum Severity of Post-Baseline Emergent Hematology Toxicities: Hemoglobin
时间窗: Up to Week 32 of study
Blood samples were collected for analysis of hemoglobin. Any abnormality was graded according to Division of Acquired Immunodeficiency Syndrome (DAIDS) toxicity scales from Grade 1 to 4 (1=Mild, 2=Moderate, 3=Severe, 4=Potentially life threatening). Number of participants (Pregnant Women) with maximum severity of post-Baseline emergent toxicities with respect to hemoglobin has been presented.
Absolute Values of the Chemistry Parameters: Bilirubin and Creatinine
时间窗: At Baseline (Day 1), Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study
Blood samples were collected for the analysis of chemistry parameters including Bilirubin and Creatinine.
Area Under the Plasma Concentration Time Curve at Steady State During a Dosing Interval (AUC [0-tau]) for Dolutegravir
时间窗: Pre-dose and at 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose at Trimester 2 (Weeks 18-26 of pregnancy), Trimester 3 (Weeks 30-36 of pregnancy) and at 8-12 Weeks postpartum
Blood samples were collected at indicated timepoints for Pharmacokinetic (PK) analysis of dolutegravir at Trimester 2 (Weeks 18-26 of pregnancy), Trimester 3 (Weeks 30-36 of pregnancy) and at 8-12 Weeks postpartum.
Maximum Observed Plasma Concentration (Cmax) for Dolutegravir
时间窗: Pre-dose and at 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose at Trimester 2 (Weeks 18-26 of pregnancy), Trimester 3 (Weeks 30-36 of pregnancy) and at 8-12 Weeks postpartum
Blood samples were collected at indicated timepoints for PK analysis of dolutegravir at Trimester 2 (Weeks 18-26 of pregnancy), Trimester 3 (Weeks 30-36 of pregnancy) and at 8-12 Weeks postpartum.
Drug Concentration at the End of Dosing Interval (Ctau) for Dolutegravir
时间窗: 24 hours post dose at Trimester 2 (Weeks 18-26 of pregnancy), Trimester 3 (Weeks 30-36 of pregnancy) and at 8-12 Weeks postpartum
Blood samples were collected at indicated timepoints for PK analysis of dolutegravir at Trimester 2 (Weeks 18-26 of pregnancy), Trimester 3 (Weeks 30-36 of pregnancy) and at 8-12 Weeks postpartum.
Apparent Oral Clearance (CL/F) for Dolutegravir
时间窗: Pre-dose and at 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose at Trimester 2 (Weeks 18-26 of pregnancy), Trimester 3 (Weeks 30-36 of pregnancy) and at 8-12 Weeks postpartum
Blood samples were collected at indicated timepoints for PK analysis of dolutegravir at Trimester 2 (Weeks 18-26 of pregnancy), Trimester 3 (Weeks 30-36 of pregnancy) and at 8-12 Weeks postpartum.
Absolute Values of the Chemistry Parameters: Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST)
时间窗: At Baseline (Day 1), Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study
Blood samples were collected for the analysis of chemistry parameters including ALT and AST.
Absolute Values of the Hematology Parameters: Hemoglobin
时间窗: At Baseline (Day 1), Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study
Blood samples were collected for the analysis of hematology parameters including hemoglobin.
Number of Participants (Pregnant Women) Demonstrated Congenital Malformations
时间窗: At delivery (up to Week 40 of pregnancy)
Data for participants (pregnant women) demonstrated congenital malformations was reported.
Number of Participants (Pregnant Women) With Adverse Events (AE) as Per Severity Grades
时间窗: Up to 292 Weeks
Number of participants (pregnant women) with adverse events (AE) as per severity grades were presented. Grade 1 is mild, grade 2 is moderate, grade 3 is severe or medically significant but not immediately life-threatening and grade 4 is life-threatening consequences; urgent intervention required.
Change From Baseline in Chemistry Parameters: ALT and AST
时间窗: Baseline and at Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study
Blood samples were collected for the analysis of chemistry parameters including ALT and AST. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Number of Participants (Pregnant Women) Who Discontinued the Treatment Due to Adverse Events (AE)
时间窗: Up to Week 292
An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a study treatment. Number of participants (pregnant women) who discontinued the treatment due to adverse events have been presented.
Half-life (T1/2) for Dolutegravir
时间窗: Pre-dose and at 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose at Trimester 2 (Weeks 18-26 of pregnancy), Trimester 3 (Weeks 30-36 of pregnancy) and at 8-12 Weeks postpartum
Blood samples were collected at indicated timepoints for PK analysis of dolutegravir at Trimester 2 (Weeks 18-26 of pregnancy), Trimester 3 (Weeks 30-36 of pregnancy) and at 8-12 Weeks postpartum.
Change From Baseline in Chemistry Parameters: Bilirubin and Creatinine
时间窗: Baseline and at Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study
Blood samples were collected for the analysis of chemistry parameters including Bilirubin and Creatinine. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Change From Baseline in Hematology Parameters: Hemoglobin
时间窗: Baseline and at Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study
Blood samples were collected for the analysis of hematology parameters including hemoglobin. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Change From Baseline in Hematology Parameters: Leukocytes and Platelets
时间窗: Baseline and at Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study
Blood samples were collected for the analysis of hematology parameters including leukocytes and platelets. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Absolute Values of the Hematology Parameters: Leukocytes and Platelets
时间窗: At Baseline (Day 1), Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study
Blood samples were collected for the analysis of hematology parameters including leukocytes and platelets.
次要结局
- Gestational Age of Infants(At birth)
- Total DTG Concentrations in Plasma From Cord Blood and Maternal Blood at the Time of Delivery(At delivery (up to Week 40 of pregnancy))
- Neonatal Weight at Birth(At birth)
- Number of Infants by Appearance, Pulse, Grimace, Activity, and Respiration (APGAR) Score at 1 and 5 Minutes After Birth(1 and 5 minutes after birth)
- Percentage of Participants (Pregnant Women) With Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) <50 Copies/Milliliter (c/mL) by Visit(At Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28 and Week 32 of study)
- Pre-dose Plasma Concentration (C0) for Dolutegravir(Pre-dose at Trimester 2 (Weeks 18-26 of pregnancy), Trimester 3 (Weeks 30-36 of pregnancy) and at 8-12 Weeks postpartum)
- Number of Participants (Pregnant Women) With Treatment-emergent Genotypic and/or Phenotypic Resistance Who Met Confirmed Virologic Withdrawal Criteria(Up to Week 32 of study)
- Number of Participants (Pregnant Women) With Live Birth Outcome Categories(At delivery (up to Week 40 of pregnancy))
- Absolute Values of Cluster of Differentiation 4 (CD4+) T Cell Counts by Visit(At Baseline (Day 1), Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28 and Week 32 of study)
- Number of Participants (Pregnant Women) With Disease Progression(Up to Week 32 of study)
- Unbound DTG Concentrations in Plasma at 3 and 24 Hours Post Dose of Dolutegravir(At 3 hours and 24 hours post dose in Trimester 2 (Weeks 18-26 of pregnancy), Trimester 3 (Weeks 30-36 of pregnancy) and at 8-12 Weeks postpartum)
- Percentage of Participants (Pregnant Women) With Plasma HIV-1 RNA <400 c/mL by Visit(At Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28 and Week 32 of study)
- Change From Baseline in CD4+ T Cell Counts by Visit(Baseline and at Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28 and Week 32 of study)
- Time to Cmax (Tmax) for Dolutegravir(Pre-dose and at 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose at Trimester 2 (Weeks 18-26 of pregnancy), Trimester 3 (Weeks 30-36 of pregnancy) and at 8-12 Weeks postpartum)
- Neonatal Length and Head Circumference at Birth(At birth)
- Number of Infants by Their Weight Categories at Birth(At birth)