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

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ClinicalTrials.gov Identifier: NCT03386578
Recruitment Status : Not yet recruiting
First Posted : December 29, 2017
Last Update Posted : July 10, 2018
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
HIV Infections Drug: Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) Behavioral: Behavioral HIV risk reduction package Phase 2

Detailed Description:

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 390 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: 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
Estimated Study Start Date : July 2018
Estimated Primary Completion Date : July 2021
Estimated Study Completion Date : July 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Pharmacokinetics Component: Group 1
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)
200 mg/300 mg of FTC/TDF administered orally as a fixed-dose combination tablet once daily
Other Name: Truvada

Experimental: Pharmacokinetics Component: Group 2
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)
200 mg/300 mg of FTC/TDF administered orally as a fixed-dose combination tablet once daily
Other Name: Truvada

Experimental: PrEP Comparison Component: Cohort 1
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)
200 mg/300 mg of FTC/TDF administered orally as a fixed-dose combination tablet once daily
Other Name: Truvada

Behavioral: Behavioral HIV risk reduction package
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.

Active Comparator: PrEP Comparison Component: Cohort 2
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
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.




Primary Outcome Measures :
  1. Number of participants with steady state TFV-DP concentrations in the PK Component [ Time Frame: Measured at Week 12 ]
    Determined from PK data

  2. TFV-DP drug concentration levels in participants in the PrEP Comparison Component [ Time Frame: Measured through Week 26 ]
    Measured by dried blood spot testing (DBS)

  3. Frequency of maternal Grade 3 or higher adverse events in participants in the PrEP Comparison Component [ Time Frame: Measured through Week 26 ]
    Based on signs, symptoms, labs, and diagnoses

  4. Frequency of maternal Grade 2 or higher chemistry abnormalities in participants in the PrEP Comparison Component [ Time Frame: Measured through Week 26 ]
    Based on laboratory evaluations

  5. Composite outcome of adverse pregnancy outcomes in the PrEP Comparison Component [ Time Frame: Measured at delivery (approximately through 40 weeks gestation) ]
    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)

  6. Frequency of infant death in the PrEP Comparison Component [ Time Frame: Measured through Week 26 ]
    Based on safety-related data recorded on electronic case report forms (eCRFs) and complete expedited adverse event (EAE) reporting by site investigators

  7. Frequency of infant Grade 3 or higher adverse events in the PrEP Comparison Component [ Time Frame: Measured through Week 26 ]
    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

  8. Infant bone mineral content in the PrEP Comparison Component [ Time Frame: Measured through Week 26 ]
    Based on dual-energy x-ray absorptiometry (DXA) scan of the whole body (WB-BMC) and lumbar spine (LS-BMC)

  9. Infant creatinine levels in the PrEP Comparison Component [ Time Frame: Measured through Week 26 ]
    Based on laboratory evaluations

  10. Infant creatinine clearance (CrCl) rate in the PrEP Comparison Component [ Time Frame: Measured through Week 26 ]
    CrCl measured by Schwartz equation

  11. Infant length for age z-score in the PrEP Comparison Component [ Time Frame: Measured through Week 26 ]
    Determined by statistical analysis


Secondary Outcome Measures :
  1. Number of participants with steady state TFV-DP concentrations in the PK Component [ Time Frame: Measured at Week 12 ]
    Determined by statistical analysis of PK data



Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years to 24 Years   (Child, Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

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)
    • Grade 1 or 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 as diagnosed by calculated creatinine clearance (CrCl) with a value less than 60 mL/min, accounting for age and pregnancy, 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, qualifying laboratory test results as follows:

    • 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
    • Grade 1 or 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03386578


Contacts
Contact: Kathryn Lypen, MPH 919-544-7040 ext 11684 klypen@fhi360.org
Contact: Emily Brown, MA 919-544-7040 ext 11123 EmBrown@fhi360.org

Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
Study Chair: Benjamin Chi, MD, MSc University of North Carolina, Chapel Hill
Study Chair: Lynda Stranix-Chibanda, MBChB, MMED University of Zimbabwe College of Health Sciences

Additional Information:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT03386578     History of Changes
Other Study ID Numbers: IMPAACT 2009
30020 ( Registry Identifier: DAIDS-ES Registry Number )
First Posted: December 29, 2017    Key Record Dates
Last Update Posted: July 10, 2018
Last Verified: July 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
HIV Infections
Anti-HIV Agents
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Tenofovir
Emtricitabine
Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents