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

Study Overview
=================
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.

Official Title
-----------------
ING200336: A Prospective, Interventional Pharmacokinetic and Safety Study of DTG/ABC/3TC in Pregnant Women

Conditions
-----------------
Infection, Human Immunodeficiency Virus, HIV Infections, Arthralgia

Intervention / Treatment
-----------------
* Drug: DTG 50 mg /ABC 600 mg /3TC 300 mg FDC tablets


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DTG/ABC/3TC<br>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<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | At birth | 
| Neonatal Length and Head Circumference at Birth | Data for neonatal length and head circumference at birth are reported. | At birth | 
| Neonatal Weight at Birth | Data for neonatal weight at birth has been reported. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | Up to Week 32 of study | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
dolutegravir/abacavir/lamivudine fixed dose combination, pregnant women, once daily, antiretroviral therapy-naive, HIV-1 Infection, integrase inhibitor