Clinical trial NCT02075593: ING200336, Pharmacokinetic and Safety Study in Pregnant Women With Human Immuno Virus Infection
Official title: ING200336: A Prospective, Interventional Pharmacokinetic and Safety Study of DTG/ABC/3TC in Pregnant Women
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Infection, Human Immunodeficiency Virus
HIV Infections
Arthralgia
Keywords: dolutegravir/abacavir/lamivudine fixed dose combination
pregnant women
once daily
antiretroviral therapy-naive
HIV-1 Infection
integrase inhibitor
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: GlaxoSmithKline
First posted: 2014-03-03
Enrollment: 4
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Area Under the Plasma Concentration Time Curve at Steady State During a Dosing Interval (AUC [0-tau]) for Dolutegravir
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) for Dolutegravir
timeFrame: 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
measure: Drug Concentration at the End of Dosing Interval (Ctau) for Dolutegravir
timeFrame: 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
measure: Apparent Oral Clearance (CL/F) for Dolutegravir
timeFrame: 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
measure: Steady State Volume of Distribution (Vss/F) After Extravascular Administration for Dolutegravir
timeFrame: 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
measure: Half-life (T1/2) for Dolutegravir
timeFrame: 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
measure: Number of Participants (Pregnant Women) With Maximum Severity of Post-Baseline Emergent Hematology Toxicities: Hemoglobin
timeFrame: Up to Week 32 of study
measure: Absolute Values of the Chemistry Parameters: Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST)
timeFrame: At Baseline (Day 1), Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study
measure: Change From Baseline in Chemistry Parameters: ALT and AST
timeFrame: Baseline and at Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study
measure: Absolute Values of the Chemistry Parameters: Bilirubin and Creatinine
timeFrame: At Baseline (Day 1), Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study
measure: Change From Baseline in Chemistry Parameters: Bilirubin and Creatinine
timeFrame: Baseline and at Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study
measure: Absolute Values of the Hematology Parameters: Hemoglobin
timeFrame: At Baseline (Day 1), Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study
measure: Change From Baseline in Hematology Parameters: Hemoglobin
timeFrame: Baseline and at Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study
measure: Absolute Values of the Hematology Parameters: Leukocytes and Platelets
timeFrame: At Baseline (Day 1), Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study
measure: Change From Baseline in Hematology Parameters: Leukocytes and Platelets
timeFrame: Baseline and at Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 and Week 32 of study
measure: Number of Participants (Pregnant Women) Who Discontinued the Treatment Due to Adverse Events (AE)
timeFrame: Up to Week 292
measure: Number of Participants (Pregnant Women) Demonstrated Congenital Malformations
timeFrame: At delivery (up to Week 40 of pregnancy)
measure: Number of Participants (Pregnant Women) With Adverse Events (AE) as Per Severity Grades
timeFrame: Up to 292 Weeks
Secondary outcomes:
measure: Time to Cmax (Tmax) for Dolutegravir
timeFrame: 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
measure: Pre-dose Plasma Concentration (C0) for Dolutegravir
timeFrame: Pre-dose at Trimester 2 (Weeks 18-26 of pregnancy), Trimester 3 (Weeks 30-36 of pregnancy) and at 8-12 Weeks postpartum
measure: Unbound DTG Concentrations in Plasma at 3 and 24 Hours Post Dose of Dolutegravir
timeFrame: 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
measure: Total DTG Concentrations in Plasma From Cord Blood and Maternal Blood at the Time of Delivery
timeFrame: At delivery (up to Week 40 of pregnancy)
measure: Number of Participants (Pregnant Women) With Treatment-emergent Genotypic and/or Phenotypic Resistance Who Met Confirmed Virologic Withdrawal Criteria
timeFrame: Up to Week 32 of study
measure: Number of Participants (Pregnant Women) With Live Birth Outcome Categories
timeFrame: At delivery (up to Week 40 of pregnancy)
measure: Gestational Age of Infants
timeFrame: At birth
measure: Neonatal Length and Head Circumference at Birth
timeFrame: At birth
measure: Neonatal Weight at Birth
timeFrame: At birth
measure: Number of Infants by Their Weight Categories at Birth
timeFrame: At birth
measure: Number of Infants by Appearance, Pulse, Grimace, Activity, and Respiration (APGAR) Score at 1 and 5 Minutes After Birth
timeFrame: 1 and 5 minutes after birth
measure: Percentage of Participants (Pregnant Women) With Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) <50 Copies/Milliliter (c/mL) by Visit
timeFrame: At Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28 and Week 32 of study
measure: Percentage of Participants (Pregnant Women) With Plasma HIV-1 RNA <400 c/mL by Visit
timeFrame: At Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28 and Week 32 of study
measure: Absolute Values of Cluster of Differentiation 4 (CD4+) T Cell Counts by Visit
timeFrame: At Baseline (Day 1), Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28 and Week 32 of study
measure: Change From Baseline in CD4+ T Cell Counts by Visit
timeFrame: Baseline and at Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28 and Week 32 of study
measure: Number of Participants (Pregnant Women) With Disease Progression
timeFrame: Up to Week 32 of study
Other outcomes:
Locations:
city: Orel
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: