ING200336, Pharmacokinetic and Safety Study in Pregnant Women With Human Immuno Virus Infection

Phase 3

Completed

Conditions: Infection, Human Immunodeficiency Virus
HIV Infections
Arthralgia

Interventions: Drug: DTG 50 mg /ABC 600 mg /3TC 300 mg FDC tablets

Registration Number: NCT02075593

Lead Sponsor: ViiV Healthcare

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 4

Inclusion Criteria

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.

Exclusion Criteria

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^3.
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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
DTG/ABC/3TC	DTG 50 mg /ABC 600 mg /3TC 300 mg FDC tablets	All subjects will be administered DTG 50 milligrams (mg)/ABC 600 mg/3TC 300 mg FDC tablet once daily, with or without food.

Primary Outcome Measures

Name	Time	Method
Steady State Volume of Distribution (Vss/F) After Extravascular Administration 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	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	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	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	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	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	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	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)	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	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	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	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	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)	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	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	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	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	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	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.

Secondary Outcome Measures

Name	Time	Method
Gestational Age of Infants	At birth	Gestational age is defined as the number of weeks between the first day of the mother's last normal menstrual period and the day of birth. Data for gestational age of infants has been presented.
Total DTG Concentrations in Plasma From Cord Blood and Maternal Blood at the Time of Delivery	At delivery (up to Week 40 of pregnancy)	Blood samples were collected at the time of delivery for PK analysis of dolutegravir.
Neonatal Weight at Birth	At birth	Data for neonatal weight at birth has been reported.
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	APGAR is a quick test to assess the health of new born. The test is performed at 1 and 5 minutes after birth. APGAR scale is determined by evaluating the new born on five categories (appearance, pulse, grimace, activity and respiration) on a scale from zero to two with 2 being the best score, then summing up the values obtained from all five categories. APGAR score ranges from 0 to 10 (Higher score indicates better health) where a score of 7 and above is normal. Number of infants by APGAR score at 1 and 5 minutes after birth are presented.
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	Percentage of participants (pregnant women) with plasma HIV-1 RNA \<50 c/mL are presented. Plasma samples were collected for quantitative analysis of HIV-1 RNA.
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	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 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 treatment-emergent genotypic and/or phenotypic resistance who met confirmed virologic withdrawal criteria are presented. Genotypic and phenotypic analyses were carried out by Monogram Biosciences using, but not limited to, their Standard Phenosense and GenoSure testing methods for protease (PRO) and reverse transcriptase (RT), or with their GeneSeq Integrase and PhenoSense Integrase assays.
Number of Participants (Pregnant Women) With Live Birth Outcome Categories	At delivery (up to Week 40 of pregnancy)	Participants (pregnant women) with following live birth outcome categories are reported- Vaginal Birth, Planned Caesarean Section, Unscheduled Caesarean Section and Preterm Delivery.
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	Blood samples were collected for the analysis of CD4+ T cell counts using cytometry.
Number of Participants (Pregnant Women) With Disease Progression	Up to Week 32 of study	Disease progression included HIV-associated conditions, acquired immunodeficiency syndrome (AIDS) and death. Number of participants (pregnant women) with disease progression to Centers for Disease Control and Prevention (CDC) class C or death have been presented.
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	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.
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	Percentage of participants (pregnant women) with plasma HIV-1 RNA \<400 c/mL are presented. Plasma samples were collected for quantitative analysis of HIV-1 RNA.
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	Blood samples were collected for the analysis of CD4+ T cell counts using cytometry. 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.
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	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.
Neonatal Length and Head Circumference at Birth	At birth	Data for neonatal length and head circumference at birth are reported.
Number of Infants by Their Weight Categories at Birth	At birth	Weight of infants at birth were categorized as: Small for Gestational Age (SGA) defined neonates under the 10th percentile in weight, Appropriate for Gestational Age (AGA) characterized neonates between the 10th and 90th percentiles in weight and Large for Gestational Age (LGA) referred to neonates over the 90th percentile in weight.