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MainTitle

Evaluating the Efficacy and Safety of Dolutegravir-Containing Versus Efavirenz-Containing Antiretroviral Therapy Regimens in HIV-1-Infected Pregnant Women and Their Infants (VESTED)

This study is not yet open for participant recruitment. (see Contacts and Locations)

Verified October 2017 by National Institute of Allergy and Infectious Diseases (NIAID)

Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)


Information provided by (Responsible Party)
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier
NCT03048422

First received: February 7, 2017
Last updated: October 16, 2017
Last Verified: October 2017
History of Changes
Purpose

Purpose

The purpose of this study is to compare the virologic efficacy and safety of three antiretroviral (ARV) regimens in HIV-1-infected pregnant women and to compare the safety of these regimens for their infants.

Condition Intervention Phase
HIV Infections

Drug : Dolutegravir
Drug : Emtricitabine/tenofovir alafenamide
Drug : Emtricitabine/tenofovir disoproxil fumarate
Drug : Efavirenz/emtricitabine/tenofovir disoproxil fumarate
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase III Study of the Virologic Efficacy and Safety of Dolutegravir-Containing Versus Efavirenz-Containing Antiretroviral Therapy Regimens in HIV-1-Infected Pregnant Women and Their Infants

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures

  • Proportion of mothers with HIV-1 RNA less than 200 copies/mL at delivery [ Time Frame: Measured at delivery and up to day 14 postpartum ]
    Determined using real-time test results obtained at site laboratories (testing superiority)
  • Proportion of mothers with an adverse pregnancy outcome of spontaneous abortion (at <20 weeks gestation), fetal death (at ≥20 weeks gestation), preterm delivery (<37 completed weeks), or small for gestational age (<10th percentile using WHO norms) [ Time Frame: Measured at delivery (approximately through 40 weeks gestation) ]
    Based on clinical evaluations/observations
  • Cumulative proportion of mothers with grade 3 or higher adverse events, including events resulting in death due to any cause [ Time Frame: Measured through approximately 50 weeks on study ]
    The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 2.0, will be used in this study.
  • Cumulative proportion of infants with grade 3 or higher adverse events, including events resulting in death due to any cause [ Time Frame: Measured from birth through Week 50 postpartum ]
    The DAIDS AE Grading Table, Version 2.0, will be used in this study.
Secondary Outcome Measures:
  • Proportion of mothers with HIV-1 RNA less than 200 copies/mL [ Time Frame: Measured at delivery and up to day 14 postpartum ]
    Determined using real-time test results obtained at site laboratories (testing non-inferiority)
  • Proportion of mothers with HIV-1 RNA less than 50 copies/mL at delivery [ Time Frame: Measured at delivery and up to day 14 postpartum ]
    Determined using batched test results obtained from central laboratory
  • Proportion of mothers with HIV-1 RNA less than 200 copies/mL at delivery [ Time Frame: Measured at delivery and up to day 14 postpartum ]
    Determined using real-time test results obtained from site laboratories and Food and Drug Administration (FDA) snapshot algorithm
  • Proportion of mothers with HIV-1 RNA less than 200 copies/mL [ Time Frame: Measured at Week 50 postpartum ]
    Determined using real-time results obtained from site laboratories and FDA snapshot algorithm
  • Proportion of pregnancies resulting in a spontaneous abortion (at <20 weeks gestation), fetal death (at ≥20 weeks gestation), preterm delivery (<37 completed weeks), small for gestational age (<10th percentile using WHO norms) or major congenital anomaly [ Time Frame: Measured at delivery (approximately through Week 40) ]
    Major congenital anomaly will be defined for this study consistent with the definition of malformation provided by Holmes and Westgate (i.e., a structural abnormality with surgical, medical, or cosmetic importance)
  • Proportion of participants in each classified ranked composite infant safety outcome [ Time Frame: Measured through Week 50 postpartum ]
    Infants and pregnancy outcomes will be classified on a scale of 1 to 10: 1) Infant death; 2) Spontaneous abortion (<20 weeks gestation) or fetal death (≥20 weeks gestation); 3) Infant HIV infection; 4) Extremely and very early preterm (<32 completed weeks); 5) Major congenital anomaly; 6) Preterm delivery (<37 completed weeks); 7) Small for gestational age (<10th percentile using WHO norms); 8) Hospitalization; 9) Grade 3 or 4 adverse event; 10) None of the above
  • Proportion of infants with HIV infection at delivery and after delivery [ Time Frame: Measured through Week 50 postpartum ]
    Based on positive confirmatory HIV nucleic acid test (NAT) test results
  • Proportion of infant deaths due to any cause [ Time Frame: Measured through Week 50 postpartum ]
    The DAIDS AE Grading Table, Version 2.0, will be used in this study.
  • Proportion of infants with bone toxicity [ Time Frame: Measured at Week 26 postpartum ]
    Assessed based on whole body and lumbar spine bone mineral content (BMC) Z-scores from DXA scan
  • Proportion of mothers with bone toxicity [ Time Frame: Measured at Week 50 postpartum ]
    Assessed based on lumbar spine and hip bone mineral density (BMD) Z-scores from DXA scan
  • Proportion of mothers with renal toxicity [ Time Frame: Measured through Week 50 postpartum ]
    Assessed based on maternal serum creatinine and creatinine clearance rate (Cockcroft-Gault formula), urine protein creatinine ratio, beta 2 microglobulin, and retinol binding protein
  • Proportion of infants with renal toxicity [ Time Frame: Measured through Week 26 postpartum ]
    Assessed based on serum creatinine and creatinine clearance rate (Schwartz formula)
  • Proportion of mothers with HIV-1 ARV drug resistance mutations at the time of maternal virologic failure [ Time Frame: Measured through Week 50 postpartum ]
    Drug resistance mutations will be assessed at study entry for mothers with resistance detected at the time of virologic failure to determine if the resistance was present at enrollment or occurred post-enrollment. Drug resistance mutations will be assessed using the Stanford algorithm.
  • Proportion of infants with HIV-1 antiretroviral drug resistance mutations at the time HIV diagnosis for HIV-infected infants [ Time Frame: Measured through Week 50 postpartum ]
    Based on laboratory blood test results
  • Proportion of preterm deliveries [ Time Frame: Measured through 37 weeks gestation ]
    Assessed as <37 completed weeks
  • Proportion of infants born small for gestational age [ Time Frame: Measured at delivery (approximately through Week 40) ]
    Assessed as <10th percentile using WHO norms

Estimated Enrollment: 549
Anticipated Study Start Date: November 2017
Estimated Study Completion Date: May 2020
Estimated Primary Completion Date: May 2020 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
Experimental: Arm 1: Maternal DTG+FTC/TAF
Mothers will receive dolutegravir (DTG) plus emtricitabine/tenofovir alafenamide (FTC/TAF) during pregnancy, through delivery, and for 50 weeks postpartum.
Drug: Dolutegravir

One 50 mg DTG tablet will be administered orally once daily

Other Name: DTG
Drug: Emtricitabine/tenofovir alafenamide

One fixed-dose combination tablet (FTC 200 mg/TAF 25 mg) will be administered orally once daily

Other Name: FTC/TAF
Experimental: Arm 2: Maternal DTG+FTC/TDF
Mothers will receive DTG plus emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) during pregnancy, through delivery, and for 50 weeks postpartum.
Drug: Dolutegravir

One 50 mg DTG tablet will be administered orally once daily

Other Name: DTG
Drug: Emtricitabine/tenofovir disoproxil fumarate

One fixed-dose combination tablet (FTC 200 mg/TDF 300 mg) will be administered orally once daily

Other Name: FTC/TDF
Active Comparator: Arm 3: Maternal EFV/FTC/TDF
Mothers will receive efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) during pregnancy, through delivery, and for 50 weeks postpartum.
Drug: Efavirenz/emtricitabine/tenofovir disoproxil fumarate

One fixed-dose combination tablet (EFV 600 mg/FTC 200 mg/TDF 300 mg) will be administered orally once daily

Other Name: EFV/FTC/TDF

Detailed Description:

This study will compare the virologic efficacy and safety of three ARV regimens in HIV-1-infected pregnant women: dolutegravir (DTG) plus emtricitabine/tenofovir alafenamide (FTC/TAF), DTG plus emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), and efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF). The study will also compare the safety of these regimens for their infants.
At study entry, mothers will be randomly assigned to either receive DTG plus FTC/TAF (Arm 1), DTG plus FTC/TDF (Arm 2), or EFV/FTC/TDF (Arm 3) during pregnancy, through delivery, and for 50 weeks postpartum.
Mothers will complete study visits at study entry and every four weeks during pregnancy. Study visits for mothers and their infants will occur at delivery and at 6, 14, 26, 38, and 50 weeks postpartum. Visits for mothers and infants will include physical examinations and blood collection. Select study visits may include breast milk collection from mothers who breast feed, hair and urine collection, ultrasound scans, and, for a subset of participants, dual energy x-ray absorptiometry (DXA) scans for mothers and their infants.

Eligibility

Eligibility

Ages Eligible for Study: 18 Years and older  
Sexes Eligible for Study: Female  
Accepts Healthy Volunteers: No  

Criteria

Inclusion Criteria:

  • Mother is at least 18 years of age and willing and able to provide written informed consent for her and her infant's participation in this study
  • Mother has confirmed HIV-1 infection based on documented testing of two samples collected at different time points:
    • Sample #1 may be tested using any of the following:
    • Two rapid antibody tests from different manufacturers or based on different principles and epitopes
    • One enzyme immunoassay (EIA) OR Western blot OR immunofluorescence assay OR chemiluminescence assay
    • One HIV DNA polymerase chain reaction (PCR)
    • One quantitative HIV RNA PCR (above the limit of detection of the assay)
    • One qualitative HIV RNA PCR
    • One total HIV nucleic acid test
    • Sample #2 may be tested using any of the following:
    • One rapid antibody test. If this option is used in combination with two rapid tests for Sample #1, at least one of the three rapid tests must be FDA-approved and the third rapid test must be from a third manufacturer or based on a third principle or epitope.
    • One EIA OR Western blot OR immunofluorescence assay OR chemiluminescence assay
    • One HIV DNA PCR
    • One quantitative HIV RNA PCR (above the limit of detection of the assay)
    • One qualitative HIV RNA PCR
    • One total HIV nucleic acid test.
    • See the protocol for more information on this inclusion criterion.
  • At screening, mother is ART-naive, defined as having not received prior ART other than ARVs received during prior pregnancies or prior periods of breastfeeding (i.e., receipt of any single, dual, or triple ARV regimen during prior time-limited periods of pregnancy and breastfeeding is permitted). Receipt of up to 14 days of ARVs during the current pregnancy is permitted prior to study entry so that initiation of ARVs during the current pregnancy is not delayed during the study screening period. Note: Non-study ART may be initiated in the current pregnancy prior to initiation of the study screening process. For eligible participants, enrollment must occur within 14 days of non-study ART initiation. Receipt of ARVs during a prior pregnancy or prior period of breastfeeding must have concluded at least six months prior to study entry. See the protocol for more information on this inclusion criterion.
  • At screening, mother has the following laboratory test results (based on testing of samples collected within 14 days prior to study entry):
    • Grade 1 or lower (less than 2.5 times upper limit of normal [ULN]) alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
    • Grade 2 or lower (less than or equal to 1.8 times ULN) creatinine
    • Grade 2 or lower (greater than or equal to 60 mL/min) estimated creatinine clearance (CrCl; Cockcroft-Gault formula). See the protocol for more information on this inclusion criteria.
  • At screening and at study entry, no evidence of multiple gestation or fetal anomalies, as assessed by best available method
  • At study entry, gestational age of 14-28 weeks, defined as greater than 13 weeks plus six days and less than 28 completed weeks gestation, estimated by best available method. Note: For this inclusion criterion and the previous inclusion criterion, fetal ultrasound is preferred but not required for purposes of eligibility determination. If ultrasound cannot be performed during the study screening period (prior to study entry), it must be performed within 14 days after study entry. As further explained in the protocol, enrolled participants will not be withdrawn from the study based on ultrasound findings obtained after study entry.
  • At study entry, mother expects to remain in the geographic area of the study site during pregnancy and for 50 weeks postpartum


Exclusion Criteria:
  • Mother is currently incarcerated or involuntarily confined in a medical facility
  • Mother is currently receiving:
    • A psychoactive medication for treatment of a psychiatric illness
    • Treatment for active tuberculosis
    • Treatment for active hepatitis C infection
  • Mother is expected to require treatment with interferon and/or ribavirin for hepatitis C infection during the study follow-up period
  • Mother has a history of any of the following, as determined by the site investigator or designee based on maternal report and available medical records:
    • Hypersensitivity or clinically significant adverse reaction to any of the ARVs included in the three study drug regimens (ever)
    • Clinically significant heart disease and/or known prolonged corrected QT (QTc) interval (ever)
    • Suicidal ideation or attempt (ever)
    • Zika virus infection, diagnosed or suspected, during the current pregnancy
    • Receipt of any antiretroviral medication within six months prior to study entry, with the exception of receipt of up 14 days of ARVs during the current pregnancy
    • Receipt of any prohibited medication within 14 days prior to study entry (see the protocol for more information)
    • Clinically significant acute illness requiring systemic treatment and/or hospitalization within 14 days prior to study entry
    • Unstable liver disease (defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice) or known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) within 14 days prior to study entry
  • Mother or fetus has any other condition that, in the opinion of the site investigator
or designee, would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives

contacts and locations

Contacts and Locations

Choosing to participate in a study is an important personal decision.Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT03048422

Contacts

Contact:   Anne Coletti 919-544-7040 ext 11238 acoletti@fhi360.org
Contact:   Katie McCarthy 919-544-7040 ext 11439 kmccarthy@fhi360.org

Locations

United States, Florida
Univ. of Florida Jacksonville NICHD CRS Not yet recruiting
Jacksonville, Florida, United States, 32209
Contact: Saniyyah Mahmoudi, A.R.N.P.    904-244-5331    saniyyah.mahmoudi@jax.ufl.edu
Pediatric Perinatal HIV Clinical Trials Unit CRS Not yet recruiting
Miami, Florida, United States, 33136
Contact: Grace Alvarez    305-243-4447    galvarez2@miami.edu
Botswana
Gaborone CRS Not yet recruiting
Gaborone, South-East District, Botswana
Contact: Tebogo J. Kakhu    267-3931353    tkakhu@bhp.org.bw
Molepolole CRS Not yet recruiting
Gaborone, Botswana
Contact: Unoda A. Chakalisa, MBBCh    267-3910388    uchakalisa@bhp.org.bw
South Africa
Wits RHI Shandukani Research Centre CRS Not yet recruiting
Johannesburg, Gauteng, South Africa, 2001
Contact: Hermien Gous, Pharm.D.    27-11-3585500 ext 5502    hgous@wrhi.ac.za
Tanzania
Kilimanjaro Christian Medical Centre (KCMC) Not yet recruiting
Moshi, Tanzania
Contact: Cynthia A. Asiyo    255-753698484    cynthia.asiyo@duke.edu
Thailand
Siriraj Hospital, Mahidol University NICHD CRS Not yet recruiting
Bangkok, Bangkoknoi, Thailand, 10700
Contact: Watcharee Lermankul    66-2-4197000 ext 5695    watchareeped@gmail.com
Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS Not yet recruiting
Chiang Mai, Thailand, 50200
Contact: Daralak Tavornprasit, R.N., M.Sc.    66-898507866    daralak@rihes-cmu.org
Zimbabwe
Seke North CRS Not yet recruiting
Chitungwiza, Zimbabwe
Contact: Suzen Maonera, M.Sc., B.Sc., R.N.    263-772-268521    smaonera@uzchs-ctu.org
St Mary's CRS Not yet recruiting
Chitungwiza, Zimbabwe
Contact: Emmie Marote, R.N., B.A.    263-772-268519    emarote@uzchs-ctu.org
Harare Family Care CRS Not yet recruiting
Harare, Zimbabwe
Contact: Sukunena J. Maturure, RGN    263-712437682    sjmaturure@uzcrc.co.zw

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

Study Chair: Shahin Lockman, MD, MSc Harvard T.H. Chan School of Public Health
Study Chair: Lameck Chinula, MBBS, MMED, FCOG Kamuzu Central Hospital
More Information

More Information

Additional Information:

Related Info

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)  
ClinicalTrials.gov Identifier: NCT03048422   History of Changes  
Other Study ID Numbers: IMPAACT 2010  
  30129  
Study First Received: February 7, 2017  
Last Updated: October 16, 2017  

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

Additional relevant MeSH terms:
HIV Infections
Tenofovir
Emtricitabine
Efavirenz
Dolutegravir
Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination

ClinicalTrials.gov processed this data on October 23, 2017
This information is provided by ClinicalTrials.gov.