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

Phase 3CompletedNCT02075593

ViiV Healthcare4 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Infection, Human Immunodeficiency Virus HIV Infections Arthralgia

Interventions

DTG 50 mg /ABC 600 mg /3TC 300 mg FDC tabletsDRUG

The DTG 50 mg /ABC 600 mg /3TC 300 mg FDC tablet is a purple, oval, biconvex tablets. The tablet contains 52.6 mg DTG sodium which is equivalent to 50 mg DTG free acid, 702 mg ABC sulphate which is equivalent to 600 mg ABC and 300 mg 3TC.

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (3)

GSK Investigational Site

Oryol, Russia

GSK Investigational Site

Saint Petersburg, Russia

GSK Investigational Site

Madrid, Spain

Outcomes

Primary Outcomes

Area Under the Plasma Concentration Time Curve at Steady State During a Dosing Interval (AUC [0-tau]) for Dolutegravir

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.

Time frame: 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

Maximum Observed Plasma Concentration (Cmax) for Dolutegravir

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.

Time frame: 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

Drug Concentration at the End of Dosing Interval (Ctau) for Dolutegravir

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.

Time frame: 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

Apparent Oral Clearance (CL/F) for Dolutegravir

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.

Time frame: 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

Steady State Volume of Distribution (Vss/F) After Extravascular Administration for Dolutegravir

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.

Time frame: 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

Half-life (T1/2) for Dolutegravir

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.

Time frame: 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

Number of Participants (Pregnant Women) With Maximum Severity of Post-Baseline Emergent Hematology Toxicities: Hemoglobin

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.

Time frame: Up to Week 32 of study

Absolute Values of the Chemistry Parameters: Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST)

Blood samples were collected for the analysis of chemistry parameters including ALT and AST.

Time frame: At Baseline (Day 1), Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study

Change From Baseline in Chemistry Parameters: ALT and AST

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.

Time frame: Baseline and at Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study

Absolute Values of the Chemistry Parameters: Bilirubin and Creatinine

Blood samples were collected for the analysis of chemistry parameters including Bilirubin and Creatinine.

Time frame: At Baseline (Day 1), Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study

Change From Baseline in Chemistry Parameters: Bilirubin and Creatinine

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.

Time frame: Baseline and at Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study

Absolute Values of the Hematology Parameters: Hemoglobin

Blood samples were collected for the analysis of hematology parameters including hemoglobin.

Time frame: At Baseline (Day 1), Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study

Change From Baseline in Hematology Parameters: Hemoglobin

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.

Time frame: Baseline and at Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study

Absolute Values of the Hematology Parameters: Leukocytes and Platelets

Blood samples were collected for the analysis of hematology parameters including leukocytes and platelets.

Time frame: At Baseline (Day 1), Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study

Change From Baseline in Hematology Parameters: Leukocytes and Platelets

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.

Time frame: Baseline and at Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study

Number of Participants (Pregnant Women) Who Discontinued the Treatment Due to Adverse Events (AE)

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.

Time frame: Up to Week 292

Number of Participants (Pregnant Women) Demonstrated Congenital Malformations

Data for participants (pregnant women) demonstrated congenital malformations was reported.

Time frame: At delivery (up to Week 40 of pregnancy)

Number of Participants (Pregnant Women) With Adverse Events (AE) as Per Severity Grades

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.

Time frame: Up to 292 Weeks

Secondary Outcomes

Time to Cmax (Tmax) for Dolutegravir

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.

Time frame: 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

Pre-dose Plasma Concentration (C0) for Dolutegravir

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.

Time frame: Pre-dose at Trimester 2 (Weeks 18-26 of pregnancy), Trimester 3 (Weeks 30-36 of pregnancy) and at 8-12 Weeks postpartum

Unbound DTG Concentrations in Plasma at 3 and 24 Hours Post Dose of Dolutegravir

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.

Time frame: 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

Total DTG Concentrations in Plasma From Cord Blood and Maternal Blood at the Time of Delivery

Blood samples were collected at the time of delivery for PK analysis of dolutegravir.

Time frame: At delivery (up to Week 40 of pregnancy)

Number of Participants (Pregnant Women) With Treatment-emergent Genotypic and/or Phenotypic Resistance Who Met Confirmed Virologic Withdrawal Criteria

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.

Data from ClinicalTrials.gov

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Time frame: Up to Week 32 of study

Number of Participants (Pregnant Women) With Live Birth Outcome Categories

Participants (pregnant women) with following live birth outcome categories are reported- Vaginal Birth, Planned Caesarean Section, Unscheduled Caesarean Section and Preterm Delivery.

Time frame: At delivery (up to Week 40 of pregnancy)

Gestational Age of Infants

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.

Time frame: At birth

Neonatal Length and Head Circumference at Birth

Data for neonatal length and head circumference at birth are reported.

Time frame: At birth

Neonatal Weight at Birth

Data for neonatal weight at birth has been reported.

Time frame: At birth

Number of Infants by Their Weight Categories 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.

Time frame: At birth

Number of Infants by Appearance, Pulse, Grimace, Activity, and Respiration (APGAR) Score at 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.

Time frame: 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

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.

Time frame: 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 by Visit

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.

Time frame: At Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28 and Week 32 of study

Absolute Values of Cluster of Differentiation 4 (CD4+) T Cell Counts by Visit

Blood samples were collected for the analysis of CD4+ T cell counts using cytometry.

Time frame: At Baseline (Day 1), 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

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 frame: Baseline and at 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

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.

Time frame: Up to Week 32 of study