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

NCT02075593 | Completed Phase 3 Results

• 1 other identifier: 200336
• Study Type: interventional
• Target: 4
• Locations: 2 countries
• Sites: 3

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.

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

Outcome Measures

Primary Outcomes (18)

• 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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  Up to Week 292

• Number of Participants (Pregnant Women) Demonstrated Congenital Malformations

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

  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.

  Up to 292 Weeks

Secondary Outcomes (16)

• 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

• 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

• 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

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

  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

  Up to Week 32 of study

Study Arms (1)

DTG/ABC/3TC

EXPERIMENTAL

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

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

Interventions

DTG 50 mg /ABC 600 mg /3TC 300 mg FDC tablets DRUG

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.

DTG/ABC/3TC

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

• ViiV Healthcare: lead
• GlaxoSmithKline: collaborator

Study Sites (3)

GSK Investigational Site

Oryol, 302040, Russia

Location

GSK Investigational Site

Saint Petersburg, 196645, Russia

Location

GSK Investigational Site

Madrid, 28046, Spain

Location

MeSH Terms

Conditions

Infections; Acquired Immunodeficiency Syndrome; HIV Infections; Arthralgia

Interventions

dolutegravir; abacavir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Joint Diseases; Musculoskeletal Diseases; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: GSK Response Center
• Organization: ViiV Healthcare

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  ViiV Healthcare

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 27, 2014
• First Posted: March 3, 2014
• Study Start: December 17, 2014
• Primary Completion: October 22, 2018
• Study Completion: September 15, 2021
• Last Updated: October 6, 2022
• Results First Posted: February 18, 2022

Record last verified: 2022-08

Locations

RU (2); ES (1)