Evaluating the Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral Pre-Exposure Prophylaxis for HIV Prevention During Pregnancy and Postpartum

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the pharmacokinetics, feasibility, acceptability, and safety of a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) as oral daily pre-exposure prophylaxis (PrEP) to prevent HIV during pregnancy and postpartum in adolescents and young women and their infants.

Detailed Description
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This study will evaluate the pharmacokinetics, feasibility, acceptability, and safety of FTC/TDF as oral daily PrEP to prevent HIV during pregnancy and postpartum in adolescents and young women and their infants. The study will be conducted in two consecutive components: 1) Pharmacokinetics (PK) Component and 2) PrEP Comparison Component. In the PK Component, women will be enrolled in one of two groups. Group 1 will include antepartum women at 14 to 24 weeks' gestation and Group 2 will include postpartum women who delivered 6 to 12 weeks prior to enrollment. Both groups will receive a fixed-dose combination of FTC/TDF administered once daily from Day 0 through Week 12. In the PrEP Comparison Component, women will be enrolled in one of two cohorts. Participants in both Cohorts 1 and 2 will receive a behavioral HIV risk reduction package, including cohort-appropriate short message service (SMS) messages from Day 0 through Week 26. Cohort 1 will also receive daily oral FTC/TDF as PrEP from Day 0 through Week 26 and enhanced adherence support, including SMS messaging and feedback of drug levels with tailored counseling. Mothers in the PK Component will have weekly study visits through Week 12 to be evaluated for drug levels and monitored for adverse effects, with their infants. Mothers in the PrEP Comparison Component will have several study visits through Week 26 (post-partum). Infants in the PrEP Comparison Component will have four study visits from birth through week 26 of life. For mothers, study visits may include physical examinations, blood and urine collection, vaginal and rectal swab collection, vaginal secretions collection, ultrasounds, and dual-energy x-ray absorptiometry (DXA) scans. For infants, study visits may include physical examinations, rectal swab and blood collection, and DXA scans.

Official Title
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Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral Pre-Exposure Prophylaxis for Primary HIV Prevention During Pregnancy and Postpartum in Adolescents and Young Women and Their Infants

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF)
* Behavioral: Behavioral HIV risk reduction package


Participation Criteria
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Eligibility Criteria
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PK Component (Groups 1 and 2) Inclusion Criteria: At study entry, mother is 16-24 years of age. For mothers who are of legal age to provide independent informed consent as determined by site standard operating procedures (SOPs) and consistent with site institutional review board (IRB)/ethics committee (EC) policies and procedures: The mother is willing and able to provide written informed consent for her and her infant's study participation. For mothers who are not of legal age to provide independent informed consent. The parent/guardian or other legally authorized representative of the mother and her infant is willing and able to provide written informed consent for the mother and her infant's study participation; in addition, when applicable the mother is willing and able to provide written assent for her and her infant's study participation. At screening, evidence of a viable singleton pregnancy (Group 1 only) with sonographic confirmation. Note: If adequate sonographic results are not available from medical records at screening, an ultrasound must be performed so that the result is available at study entry. At study entry, pregnant or recently delivered, in one of the following two enrollment windows: Group 1: Gestational age of 14 to 24 weeks, defined as greater than 13 weeks plus six days and less than 24 completed weeks of gestation with sonographic confirmation*, or Group 2: 6 to 12 weeks postpartum, defined as between 42 and 84 days after the date of delivery. *Note: If adequate sonographic results are not available from medical records at screening, an ultrasound must be performed so that the result is available at study entry. At study entry, willing to initiate once-daily oral PrEP and continue use for at least 12 weeks under directly observed therapy and support for adherence. Within 14 days prior to study entry, HIV negative by HIV RNA test. At study entry, rapid test negative and absence of symptoms of acute HIV infection (i.e. acute viral illness). At screening, Hepatitis B negative by Hepatitis B surface antigen test. At screening, has the following laboratory test results: Grade 1 or normal (less than 2.5 x upper limit of normal [ULN]) alanine transaminase (ALT) Grade 1 or normal (greater than or equal to 9.5 g/dL) hemoglobin Grade 1 or normal (greater than or equal to 800 cells/mm^3) absolute neutrophil count (ANC) Normal (greater than or equal to 90 mL/min) estimated creatinine clearance (CrCl; Cockcroft-Gault formula) At screening, mother has negative or trace proteinuria (less than Grade 1). At screening, mother has normal dipstick urine for glucose (less than Grade 1). At study entry, mother weighs greater than 35 kg. Intention to stay within the study site's catchment area for at least 12 weeks (or through delivery). Exclusion Criteria (PK Component and PrEP Comparison Component): Mother has any current significant uncontrolled, active or chronic disease process that, in the judgment of the site investigator, would make participation in the study inappropriate. Mother has a known history of any of the following, as determined by the site investigator or designee based on maternal report and available medical records: Sickle cell anemia (excluding sickle cell trait), chronic bleeding, blood transfusion within the past 120 days (excluding for chronic illness) or other blood dyscrasias Bone fracture not explained by trauma Allergy/sensitivity to FTC/TDF or its components Fetus has a known or suspected major congenital anomaly, from chart review of prior data, defined as a structural malformation with surgical, medical, or cosmetic importance Mother has confirmed renal insufficiency, a history of known renal parenchymal disease, or known single kidney at screening Current use of prohibited medications listed in the protocol Concurrent participation in a study of any biomedical HIV prevention intervention or investigational drug in an HIV vaccine study or microbicide study Past participation in an HIV vaccine study Currently taking a PrEP regimen from non-study sources Any other condition or adverse social situation that, in the opinion of the site investigator, would preclude informed consent, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives Past participation in IMPAACT 2009 PrEP Comparison Component (Cohorts 1 and 2) Inclusion Criteria: At study entry, mother is 16-24 years of age. For mothers who are of legal age to provide independent informed consent as determined by site SOPs and consistent with site IRB/EC policies and procedures: The mother is willing and able to provide written informed consent for her and her infant's study participation. For mothers who are not of legal age to provide independent informed consent. The parent/guardian or other legally authorized representative of the mother and her infant is willing and able to provide written informed consent for the mother and her infant's study participation; in addition, when applicable the mother is willing and able to provide written assent for her and her infant's study participation. At screening, evidence of a viable singleton pregnancy with gestational age of 32 weeks or less, defined as 224 days or less after the date of conception with sonographic confirmation. Note: if adequate sonographic results are not available from medical records at screening, an ultrasound must be performed in the interim so that the result is available at study entry. Within 14 days prior to study entry, negative by HIV RNA test. At study entry, HIV rapid test negative and absence of symptoms of acute HIV infection (i.e. acute viral illness). At screening, Hepatitis B negative by Hepatitis B surface antigen test performed. At screening, has the following laboratory test results: Grade 1 or normal (less than 2.5 x ULN) ALT Grade 1 or normal (greater than or equal to 9.5 g/dL) HB Grade 1 or normal (greater than or equal to 800 cells/mm^3) ANC Normal (greater than or equal to 90 mL/min) for estimated creatinine clearance (CrCl; Cockcroft-Gault formula) At screening, mother has negative or trace proteinuria (less than Grade 1). At screening, mother has normal dipstick urine for glucose (less than Grade 1). Intention to stay within the study site's catchment area through 26 weeks postpartum Regular access to a cellular phone that is able to receive short message service (SMS) messages, and for Cohort 1 only, is also able to send SMS messages. Cohort 1 only: At study entry, expresses willingness to take PrEP from pregnancy up to 26 weeks postpartum Cohort 2 only: At study entry, expresses unwillingness to take PrEP from pregnancy up to 26 weeks postpartum At study entry, mother weighs greater than 35 kg Based on site investigator assessment at screening, mother is literate in one or more of the study languages

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 24 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pharmacokinetics Component: Group 1<br>Participants will be enrolled during singleton pregnancy at 14-24 weeks' gestation. Participants will receive a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) once daily under direct observation from Day 0 through Week 12. | Drug: Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF)<br>* 200 mg/300 mg of FTC/TDF administered orally as a fixed-dose combination tablet once daily<br>* Other names: Truvada;|
| Experimental: Pharmacokinetics Component: Group 2<br>Participants will be enrolled postpartum within 6-12 weeks after delivery. Participants will receive a fixed-dose combination of FTC/TDF once daily under direct observation from Day 0 through Week 12. | Drug: Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF)<br>* 200 mg/300 mg of FTC/TDF administered orally as a fixed-dose combination tablet once daily<br>* Other names: Truvada;|
| Experimental: PrEP Comparison Component: Cohort 1<br>Participants will receive daily oral PrEP (FTC/TDF) from Day 0 through Week 26. Participants will also receive behavioral HIV risk reduction package, including cohort-appropriate SMS messages, from Day 0 through Week 26. | Drug: Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF)<br>* 200 mg/300 mg of FTC/TDF administered orally as a fixed-dose combination tablet once daily<br>* Other names: Truvada;Behavioral: Behavioral HIV risk reduction package<br>* HIV risk reduction package, including cohort-appropriate SMS messages. Participants in the PrEP Comparison Component: Cohort 1 will also receive enhanced adherence support, including two-way SMS messaging and tailored counseling with near-real time drug level feedback.<br>|
| Active Comparator: PrEP Comparison Component: Cohort 2<br>Participants will receive a behavioral HIV risk reduction package, including cohort-appropriate SMS messages, from Day 0 through Week 26. | Behavioral: Behavioral HIV risk reduction package<br>* HIV risk reduction package, including cohort-appropriate SMS messages. Participants in the PrEP Comparison Component: Cohort 1 will also receive enhanced adherence support, including two-way SMS messaging and tailored counseling with near-real time drug level feedback.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with steady state TFV-DP concentrations in the PK Component | Determined from PK data | Measured at Week 12 | 
| TFV-DP drug concentration levels in participants in the PrEP Comparison Component | Measured by dried blood spot testing (DBS) | Measured through Week 26 | 
| Frequency of maternal Grade 3 or higher adverse events in participants in the PrEP Comparison Component | Based on signs, symptoms, labs, and diagnoses | Measured through Week 26 | 
| Frequency of maternal Grade 2 or higher chemistry abnormalities in participants in the PrEP Comparison Component | Based on laboratory evaluations | Measured through Week 26 | 
| Composite outcome of adverse pregnancy outcomes in the PrEP Comparison Component | Univariable and multivariable logistic regression methods will be used to evaluate associations of PrEP use and the composite outcome indicating presence vs. absence of any adverse pregnancy outcomes. Adverse outcomes are defined as at least one of the following: spontaneous abortion (less than 20 weeks gestation), stillbirth (greater than or equal to 20 weeks gestation), preterm delivery (less than 37 weeks), or small for gestational age (less than 10th percentile using WHO norms) | Measured at delivery (approximately through 40 weeks gestation) | 
| Frequency of infant death in the PrEP Comparison Component | Based on safety-related data recorded on electronic case report forms (eCRFs) and complete expedited adverse event (EAE) reporting by site investigators | Measured through Week 26 | 
| Frequency of infant Grade 3 or higher adverse events in the PrEP Comparison Component | Assessed according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017 | Measured through Week 26 | 
| Infant bone mineral content in the PrEP Comparison Component | Based on dual-energy x-ray absorptiometry (DXA) scan of the whole body (WB-BMC) and lumbar spine (LS-BMC) | Measured through Week 26 | 
| Infant creatinine levels in the PrEP Comparison Component | Based on laboratory evaluations | Measured through Week 26 | 
| Infant creatinine clearance (CrCl) rate in the PrEP Comparison Component | CrCl measured by Schwartz equation | Measured through Week 26 | 
| Infant length for age z-score in the PrEP Comparison Component | Determined by statistical analysis | Measured through Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with steady state TFV-DP concentrations in the PK Component | Determined by statistical analysis of PK data | Measured at Week 12 |