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Evaluating Strategies to Reduce Mother-to-Child Transmission of HIV Infection in Resource-Limited Countries (PROMISE)

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ClinicalTrials.gov Identifier: NCT01061151
Recruitment Status : Completed
First Posted : February 2, 2010
Results First Posted : February 9, 2018
Last Update Posted : February 9, 2018
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

February 1, 2010
February 2, 2010
September 28, 2017
February 9, 2018
February 9, 2018
March 2011
September 2016   (Final data collection date for primary outcome measure)
  • Antepartum Component: Number of Confirmed Infant HIV Infections [ Time Frame: Measured at birth or Week 1 study visit ]
    Defined as HIV nucleic acid test (NAT) positivity of the specimen drawn at either the birth (Day 0-5) or Week 1 (Day 6-14) visit, confirmed by HIV NAT positivity of a second specimen collected at a different time point
  • Antepartum Component: Number of Mothers With Grade 3 or Higher Toxicities and Selected Grade 2 Hematologic, Renal, and Hepatic Adverse Events [ Time Frame: Measured through the Week 1 postpartum study visit ]
    These events were graded using the Division of AIDS (DAIDS) AE Grading Table, Version 1.0, December 2004, Clarification August 2009, which is available on the RSC website (http://rsc.tech-res.com).
  • Antepartum Component: Number of Mothers With Obstetrical Complications [ Time Frame: Measured through the Week 1 postpartum study visit ]
  • Antepartum Component: Number of Mothers With Adverse Pregnancy Outcomes (e.g.,Stillbirth, Preterm Delivery (< 37 Weeks), Low Birth Weight (< 2,500 Grams), and Congenital Anomalies) [ Time Frame: Measured at birth ]
    Composite outcome
  • Postpartum Component: Incidence of Confirmed Infant HIV Infection [ Time Frame: Measured through site recommended duration of breastfeeding, complete cessation of breastfeeding or 18 months of age, whichever comes first ]
    Defined as infant HIV NAT positivity of a specimen drawn at any post-randomization visit (i.e., any visit after the Week 1 [Day 6-14] visit), confirmed by HIV NAT positivity of a second specimen drawn at a different time point. Analyses were conducted at the Mother-Infant (M-I) pair level, hence the worst outcome for multiple births was counted as a single event.
  • Postpartum Component: Incidence of Grade 3 or Higher Adverse Events and Selected Grade 2 Hematologic, Renal, and Hepatic Adverse Events [ Time Frame: Measured through site recommended duration of breastfeeding, complete cessation of breastfeeding or 18 months of age, whichever comes first ]
    These events were graded using the Division of AIDS (DAIDS) AE Grading Table, Version 1.0, December 2004, Clarification August 2009, which is available on the RSC website (http://rsc.tech-res.com).
  • Maternal Health Component: Incidence of Progression to AIDS-defining Illness or Death [ Time Frame: From study entry until July 7, 2015, an average of 94 weeks of follow-up. ]
    AIDS-defining illness refers to the WHO Clinical Stage 4 illnesses in Appendix IV of the protocol. These events were reviewed and confirmed by an Endpoint review group.
  • Antepartum Component: Confirmed presence of infant HIV infection in infants whose mothers were a part of Arm A or Arm B, detected by HIV nucleic acid test (NAT) positivity of the specimen drawn at either the birth (Day 0-3) or Week 1 (Day 7-12) visit [ Time Frame: Measured at birth or Week 1 study visit ]
  • Antepartum Component: Grade 3 or higher toxicity, obstetrical complications, and adverse pregnancy outcomes for Arms A and B (e.g., stillbirth, preterm delivery at less than 37 weeks, low birth weight less than 2,500 g, and congenital anomalies) [ Time Frame: Measured at the end of the 5-year study period ]
  • Postpartum Component: Confirmed presence of infant HIV infection detected by HIV NAT positivity of a specimen drawn at any post-randomization visit (i.e., any visit after the Week 1 [Day 7-12] visit) [ Time Frame: Measured at the end of the 5-year study period ]
  • Postpartum Component: Grade 3 or higher toxicity [ Time Frame: Measured at the end of the 5-year study period ]
  • Maternal Health Component: Composite endpoint of progression to AIDS-defining illness or death [ Time Frame: Measured at the end of the 5-year study period ]
  • Infant Health Component: Mortality through 18 months of age [ Time Frame: Measured through 18 months of age ]
  • Infant Health Component: Grade 3 or 4 adverse events including anemia, neutropenia, elevated alanine aminotransferase (ALT), and rash through 18 months of age [ Time Frame: Measured through 18 months of age ]
Complete list of historical versions of study NCT01061151 on ClinicalTrials.gov Archive Site
  • Antepartum Component: Number of Infant HIV Infections [ Time Frame: Measured at the birth (<= 3 days postpartum) visit ]
    Detected by HIV NAT positivity
  • Antepartum Component: Overall and HIV-free Infant Survival Through 24 Months of Age (in Conjunction With Infants in the Postpartum Component) [ Time Frame: Measured through 24 months of age ]
    This secondary outcome was not included in the primary analyses and will be defined in more detail in a separate analysis plan. Results will be reported to ct.gov when available.
  • Antepartum Component: Adherence to the Maternal Antiretroviral (ARV) Regimen, as Measured by Maternal Report [ Time Frame: Measured through the Week 1 postpartum study visit ]
    This secondary outcome was not included in the primary analyses and will be defined in more detail in a separate analysis plan. Results will be reported to ct.gov when available.
  • Antepartum Component: Maternal and Infant Viral Resistance to the Maternal and Infant ARV Strategies [ Time Frame: Measured at the end of the 5-year study period ]
    This secondary outcome required additional funding for laboratory testing which was not awarded because this outcome was deemed no longer scientifically important, so this outcome is not reported.
  • Antepartum Component: Cost Effectiveness and Feasibility of the Trial ARV Regimens [ Time Frame: Measured at the end of the 5-year study period ]
    This secondary outcome was not included in the primary analyses and will be defined in more detail in a separate analysis plan. Results will be reported to ct.gov when available.
  • Antepartum Component: Maternal HIV RNA Less Than 400 Copies/mL at Delivery [ Time Frame: Measured at the time of delivery ]
    Analysis used the principle of intent to treat.
  • Antepartum Component: Antepartum Change in HBV DNA Viral Load Between Week 8 and Baseline Levels (Using Log HBV DNA) Among Women With Detectable HBV DNA Viral Loads at Baseline and Other HBV Outcome Measures [ Time Frame: Measured at Week 8 ]
    This secondary outcome required additional funding for laboratory testing. Results will be reported to ct.gov when available.
  • Postpartum Component: Proportion of Mother-Infant Pairs With no Death or HIV Diagnosis Through 24 Months Post-delivery [ Time Frame: Measured through 24 months post-delivery ]
    Defined as infant HIV NAT positivity of a specimen drawn at any post-randomization visit, confirmed by HIV NAT positivity of a second specimen drawn at a different time point, or infant death. Analyses (Kaplan-Meier probabilities) were conducted at the Mother-Infant (M-I) pair level, hence the worst outcome for multiple births was counted as a single event.
  • Postpartum Component: Proportion of Infants Alive Through 12 and 24 Months Post-delivery [ Time Frame: Measured at 12 and 24 months post-delivery ]
    Analyses (Kaplan-Meier probabilities) conducted for all individual infants (rather than M-I pair)
  • Postpartum Component: Adherence to the Maternal and/or Infant ARV Regimens, as Measured by Maternal Report and Hair Measures [ Time Frame: Measured through complete cessation of breastfeeding or 18 months of age, whichever comes first ]
    This secondary outcome was not included in the primary analyses and will be defined in more detail in a separate analysis plan. Results will be reported to ct.gov when available.
  • Postpartum Component: Rates and Patterns of Maternal and Infant Resistance to the Maternal and Infant ARV Regimens [ Time Frame: Measured at the end of the 5-year study period ]
    This secondary outcome required additional funding for laboratory testing which was not awarded because this outcome was deemed no longer scientifically important, so this outcome is not reported.
  • Postpartum Component: Cost-effectiveness and Feasibility of the Study ARV Prophylaxis Regimens [ Time Frame: Measured at the end of the 5-year study period ]
    This secondary outcome was not included in the primary analyses and will be defined in more detail in a separate analysis plan. Results will be reported to ct.gov when available.
  • Postpartum Component: Pharmacokinetic Parameters of ARV Drugs Measured in Maternal Plasma, Hair, Breast Milk, and Infant Blood (Plasma or Dried Blood Spot) Samples Collected at Birth; Weeks 1, 6, 14, and 26; and Subsequent Visits During Breastfeeding [ Time Frame: Measured through the last study visit during breastfeeding, or 18 months postpartum, whichever comes first ]
    This secondary outcome required additional funding for laboratory testing. Results will be reported to ct.gov when available.
  • Postpartum Component: Functional Maternal Antibody and HIV-envelope Binding Responses in Breast Milk and Plasma, Until Cessation of Breastfeeding or 18 Months Postpartum, Whichever Comes First [ Time Frame: Measured through the time of cessation of breastfeeding or 18 months postpartum, whichever comes first ]
    This secondary outcome required additional funding for laboratory testing. Results will be reported to ct.gov when available.
  • Maternal Health Component: Incidence of Death [ Time Frame: From study entry until July 7, 2015, an average of 94 weeks of follow-up. ]
  • Maternal Health Component: Incidence of AIDS-defining Illness [ Time Frame: From study entry until July 7, 2015, an average of 94 weeks of follow-up. ]
    "AIDS-defining illness" refers to the WHO Clinical Stage 4 illnesses listed in Appendix IV. Stage 4 illnesses were reviewed and confirmed by an Endpoint review group.
  • Maternal Health Component: Composite Endpoint of Progression to AIDS-defining Illness, Death, or a Serious Non-AIDS Cardiovascular, Hepatic, or Renal Event [ Time Frame: From study entry until July 7, 2015. ]
    This secondary outcome was not included in the primary analyses. Given the results of the primary analyses the protocol team decided that this outcome was no longer scientifically important and resources should not be spent on analyzing it.
  • Maternal Health Component: Incidence of HIV/AIDS-related Events [ Time Frame: From study entry until July 7, 2015, an average of 94 weeks of follow-up. ]
    "HIV/AIDS-related event" refers to the WHO Clinical Stage 4 illnesses, pulmonary tuberculosis, and other serious bacterial infections listed in Appendix IV of the protocol. Stage 4 illnesses were reviewed and confirmed by an Endpoint review group.
  • Maternal Health Component: Number of Cardiovascular or Other Metabolic Events [ Time Frame: From study entry until July 7, 2015. ]
    This secondary outcome was not included in the primary analyses. Given the results of the primary analyses the protocol team decided that this outcome was no longer scientifically important and resources should not be spent on analyzing it.
  • Maternal Health Component: Other Targeted Medical Conditions [ Time Frame: From study entry until July 7, 2015. ]
    This secondary outcome was not included in the primary analyses. Given the results of the primary analyses the protocol team decided that this outcome was no longer scientifically important and resources should not be spent on analyzing it.
  • Maternal Health Component: Incidence of HIV/AIDS-related Event or Death [ Time Frame: From study entry until July 7, 2015, an average of 94 weeks of follow-up. ]
    "HIV/AIDS-related event" refers to the WHO Clinical Stage 4 illnesses, pulmonary tuberculosis, and other serious bacterial infections listed in Appendix IV of the protocol. Stage 4 illnesses were reviewed and confirmed by an Endpoint review group.
  • Maternal Health Component: Incidence of HIV/AIDS-related Event or World Health Organization (WHO) Clinical Stage 2 or 3 Events [ Time Frame: From study entry until July 7, 2015, an average of 94 weeks of follow-up. ]
    "HIV/AIDS-related event" refers to the WHO Clinical Stage 4 illnesses, pulmonary tuberculosis, and other serious bacterial infections listed in Appendix IV of the protocol. Stage 4 illnesses were reviewed and confirmed by an Endpoint review group.
  • Maternal Health Component: Composite Endpoint of Any Condition Outlined in Appendix IV of the Protocol or Death [ Time Frame: From study entry until July 7, 2015. ]
    This secondary outcome was not included in the primary analyses. Given the results of the primary analyses the protocol team decided that this outcome was no longer scientifically important and resources should not be spent on analyzing it.
  • Maternal Health Component: Incidence of Tuberculosis [ Time Frame: From study entry until July 7, 2015, an average of 94 weeks of follow-up. ]
    Incidence of tuberculosis.
  • Maternal Health Component: Toxicity: Incidence of Grade 3 or Greater Laboratory Results or Signs and Symptoms and Selected Grade 2 Hematologic, Renal, and Hepatic Laboratory Results [ Time Frame: From study entry until July 7, 2015, an average of 94 weeks of follow-up. ]
    The maternal safety endpoints summarized include grade 2, 3 or 4 hematologies (hemoglobin (Hb), White Blood Cells (WBC), Absolute Neutrophil Count (ANC), platelet count), chemistries (Alanine Aminotransferase (ALT or SGPT), serum creatinine), and grade 3 or 4 signs and symptoms that occurred post-randomization. These events were graded using the Division of AIDS (DAIDS) AE Grading Table, Version 1.0, December 2004, Clarification August 2009, which is available on the RSC website (http://rsc.tech-res.com).
  • Maternal Health Component: Viral Resistance [ Time Frame: From study entry until July 7, 2015. ]
    This secondary outcome required additional funding for laboratory testing which was not awarded because this outcome was deemed no longer scientifically important, so this outcome is not reported.
  • Maternal Health Component: Self-reported Adherence [ Time Frame: From study entry until July 7, 2015. ]
    This secondary outcome was not included in the primary analyses and will be defined in more detail in a separate analysis plan. Results will be reported to ct.gov when available.
  • Maternal Health Component: Quality of Life [ Time Frame: From study entry until July 7, 2015. ]
    This secondary outcome was not included in the primary analyses and will be defined in more detail in a separate analysis plan. Results will be reported to ct.gov when available.
  • Maternal Health Component: Changes in Plasma Concentrations of Inflammatory and Thrombogenic Markers [ Time Frame: From study entry until July 7, 2015. ]
    This secondary outcome was not included in the primary analyses. Given the results of the primary analyses the protocol team decided that this outcome was no longer scientifically important and resources should not be spent on analyzing it.
  • Maternal Health Component: Cost-effectiveness [ Time Frame: From study entry until July 7, 2015. ]
    This secondary outcome was not included in the primary analyses and will be defined in more detail in a separate analysis plan. Results will be reported to ct.gov when available.
  • Antepartum Component: Infant HIV infection detected by HIV NAT positivity in the birth sample for infants in Arms A and B [ Time Frame: Measured at the end of the 5-year study period ]
  • Antepartum Component: Overall and HIV-free infant survival through 24 months of age (in conjunction with infants in the Postpartum Component) for infants in Arms A and B [ Time Frame: Measured through 24 months of age ]
  • Antepartum Component: Adherence to the maternal antiretroviral (ARV) regimen, as measured by pill count and maternal report for those in Arms A and B [ Time Frame: Measured at the end of the 5-year study period ]
  • Antepartum Component: Maternal and Infant Viral Resistance to the Maternal and Infant ARV Strategies [ Time Frame: Measured at the end of the 5-year study period ]
  • Antepartum Component: Cost effectiveness and feasibility of the trial ARV regimens for Arms A and B [ Time Frame: Measured at the end of the 5-year study period ]
  • Antepartum Component: Maternal HIV RNA less than 400 copies/mL at delivery for infants in Arms A and B [ Time Frame: Measured at the time of delivery ]
  • Antepartum Component: Antepartum change in HBV DNA viral load between Week 8 and baseline levels (using log HBV DNA) among women in Arms A and B with detectable HBV DNA viral loads at baseline and other HBV outcome measures [ Time Frame: Measured at Week 8 ]
  • Postpartum Component: Infant HIV-free survival through 24 months post-delivery [ Time Frame: Measured through 24 months post-delivery ]
  • Postpartum Component: Overall infant survival through 12 and 24 months post-delivery [ Time Frame: Measured at 12 and 24 months post-delivery ]
  • Postpartum Component: Adherence to the maternal and/or infant ARV regimens, as measured by maternal report and pill or suspension measures [ Time Frame: Measured at the end of the 5-year study period ]
  • Postpartum Component: Rates and Patterns of Maternal and Infant Resistance to the Maternal and Infant ARV Regimens [ Time Frame: Measured at the end of the 5-year study period ]
  • Postpartum Component: Cost-effectiveness and Feasibility of the Study ARV Prophylaxis Regimens [ Time Frame: Measured at the end of the 5-year study period ]
  • Maternal Health Component: Death [ Time Frame: Measured at the end of the 5-year study period ]
  • Maternal Health Component: AIDS-defining illness [ Time Frame: Measured at the end of the 5-year study period ]
  • Maternal Health Component: Composite Endpoint of Progression to AIDS-defining Illness, Death, or a Serious Non-AIDS Cardiovascular, Hepatic, or Renal Event [ Time Frame: Measured at the end of the 5-year study period ]
  • Maternal Health Component: HIV/AIDS-related events [ Time Frame: Measured at the end of the 5-year study period ]
  • Maternal Health Component: Cardiovascular or other metabolic events [ Time Frame: Measured at the end of the 5-year study period ]
  • Maternal Health Component: Other Targeted Medical Conditions [ Time Frame: Measured at the end of the 5-year study period ]
  • Maternal Health Component: Composite endpoint of HIV/AIDS-related event or death [ Time Frame: Measured at the end of the 5-year study period ]
  • Maternal Health Component: Composite endpoint of HIV/AIDS-related event or World Health Organization (WHO) Clinical Stage 2 or 3 [ Time Frame: Measured at the end of the 5-year study period ]
  • Maternal Health Component: Composite Endpoint of Any Condition Outlined in Appendix IV of the Protocol or Death [ Time Frame: Measured at the end of the 5-year study period ]
  • Maternal Health Component: Tuberculosis [ Time Frame: Measured at the end of the 5-year study period ]
  • Maternal Health Component: Toxicity: Grade 3 or greater laboratory results or signs and symptoms and selected Grade 2 renal and hepatic laboratory results [ Time Frame: Measured at the end of the 5-year study period ]
  • Maternal Health Component: Viral Resistance [ Time Frame: Measured at the end of the 5-year study period ]
  • Maternal Health Component: Self-reported Adherence [ Time Frame: Measured at the end of the 5-year study period ]
  • Maternal Health Component: Quality of Life [ Time Frame: Measured at the end of the 5-year study period ]
  • Maternal Health Component: Changes in Plasma Concentrations of Inflammatory and Thrombogenic Markers [ Time Frame: Measured at the end of the 5-year study period ]
  • Maternal Health Component: Cost-effectiveness [ Time Frame: Measured at the end of the 5-year study period ]
  • Infant Health Component: Mortality through 24 months of age [ Time Frame: Measured through 24 months ]
  • Infant Health Component: Grade 3 or 4 diarrhea, vomiting, respiratory signs and symptoms through 18 and 24 months of age [ Time Frame: Measured at 18 and 24 months ]
  • Infant Health Component: Growth faltering (categorized as prevalence of less than -2 standard deviations [SD] and less than -3 SD's of WHO centile Z scores for weight/age, height/age, and weight/height) through 18 and 24 months of age [ Time Frame: Measured at 18 and 24 months ]
  • Infant Health Component: Confirmed or probable malaria diagnoses (categorized as uncomplicated or severe per WHO definitions) through 18 and 24 months of age [ Time Frame: Measured at 18 and 24 months ]
  • Infant Health Component: Grade 3 or higher study drug-related adverse events per site attribution through 18 months of age [ Time Frame: Measured at 18 months ]
  • Infant Health Component: Cost effectiveness and feasibility of the study drug regimen [ Time Frame: Measured at the end of the 5-year study period ]
  • Infant Health Component: CTX resistance patterns of E. coli from rectal swab (or stool) specimens at 18 and 24 months of age [ Time Frame: Measured at 18 and 24 months ]
Not Provided
Not Provided
 
Evaluating Strategies to Reduce Mother-to-Child Transmission of HIV Infection in Resource-Limited Countries
Breastfeeding Version of the PROMISE Study (Promoting Maternal and Infant Survival Everywhere)

The purpose of this study was to examine, in an integrated and comprehensive fashion, three critical questions currently facing HIV-infected pregnant and postpartum women and their infants:

  1. What is the optimal intervention for the prevention of antepartum and intrapartum transmission of HIV?
  2. What is the optimal intervention for the prevention of postpartum transmission in breastfeeding (BF) infants?
  3. What is the optimal intervention for the preservation of maternal health after the risk period for prevention of mother-to-child-transmission ends (either at delivery or cessation of BF)?

The overall PROMISE protocol had three separate interventional components to address each of these three questions and was conducted at locations in Africa and other parts of the world. Due to variations in the standard of care for HIV-infected pregnant and postpartum women and their infants at different sites, not all of these questions were relevant. Therefore, two separate versions of the PROMISE protocol were developed, each containing only the relevant components. The 1077BF protocol was used at sites where the standard method of infant feeding was breastfeeding, whereas the 1077FF protocol was used at sites where the standard method of infant feeding was formula feeding. The analyses were collapsed across the two protocol versions, and therefore the summaries contain the results of the 1077BF and/or the 1077FF protocols.

The incidence of mother-to-child transmission (MTCT) of HIV has decreased in recent years in the United States, Europe, and other resource-advantaged countries. Several factors have contributed to this decrease, including the administration of HAART during pregnancy, caesarean section delivery methods, and the use of formula instead of breastfeeding to feed infants. However, in resource-limited countries, the incidence of pediatric HIV infection remains high. Many pregnant women in these countries do not receive an adequate course of HAART, and the majority breastfeed their children.

This study was divided into three components (Antepartum, Postpartum, and Maternal Health Components). The following is a description of each of the three open label sequential randomization components, each designed to address one of the following three main objectives:

  1. Antepartum Component: This PROMISE component compared the safety and efficacy of different HAART regimens for preventing the transmission of HIV during pregnancy, labor, and delivery.

    • Participants were randomly assigned to one of the following three arms:
    • Maternal Regimens:

      • Arm A : 1) Zidovudine (ZDV) from study entry through delivery, 2) single dose nevirapine (sdNVP) and emtricitabine-tenofovir disoproxil (TRV ) intrapartum, and 3) TRV postpartum for up to 14 days post-partum. Arm A is also labeled as ZDV+sdNVP+TRV tail.
      • Arm B: Lamivudine (3TC)-zidovudine (ZDV) + lopinavir (LPV)-ritonavir (RTV) from study entry up to 14 days postpartum. Arm B is also labeled as 3TC-ZDV/LPV-RTV.
      • Arm C: TRV/LPV-RTV from study entry up to 14 days postpartum. Arm C is also labeled as FTC-TDF/LPV-RTV.
    • All infants born to women enrolled in this study were to receive NVP once a day as soon as possible after birth through 42 days of age or until the Week 6 study visit, whichever was later. Women switched or initiated HAART if it was needed for their own health.
    • During pregnancy, participants attended study visits at study entry, 2 and 4 weeks after entry, and then every 4 weeks until labor and delivery. Women and infants were monitored during labor and delivery and attended a study visit 6 to 14 days after delivery. After delivery, eligibility criteria were assessed for subsequent randomizations (either Postpartum or Maternal Health). If they failed the entry criteria for the subsequent randomization, the mothers remained in follow-up for safety assessments and the infants were followed until the 104 week visit; otherwise they were followed under the subsequent component.
    • All three antepartum arms were not available to all women throughout the PROMISE study. When the trial began, there were limited safety data on tenofovir in pregnancy, and randomization to tenofovir-based ART was limited to women coinfected with HIV and HBV, because benefit was felt to outweigh risk in that group. During period 1 (PROMISE protocol version 2.0 - April 2011 through September 2012), women without HBV coinfection were randomized to either Arm A or Arm B; and Hepatitis B (HBV) co-infected women were randomized to either Arm A, Arm B, or Arm C. However, in October 2012, with increased data on tenofovir in pregnancy, the protocol was modified to allow women regardless of HBV status to be assigned to any of the three regimens during period 2 (PROMISE protocol version 3.0 - October 2012 through the end of antepartum enrollment on October 1, 2014). By arm comparisons were restricted to times in which there were contemporaneous randomizations.
    • Late Presenters: In addition the Antepartum Component, participants could enter PROMISE through the Late Presenters Registration (LP). Late presenters were identified in early or active labor or in the immediate postpartum period (up to 5 days postpartum). The Late Presenters Registration facilitated a structure to screen women and infants for randomization in the Postpartum Component. Women and infants not randomized in the Postpartum Component of PROMISE were followed through the Week 6 visit.
    • There were 3543 mothers and 3407 live born infants enrolled in the Antepartum Component. There were 204 mothers and 204 live born infants in the Late Presenters Registration.
  2. Postpartum Component: This PROMISE component compared the safety and efficacy of maternal triple ARV prophylaxis versus daily infant NVP prophylaxis for the prevention of mother-to-child transmission (PMTCT) through breastfeeding. The Postpartum Component consisted of mothers and infants from the Antepartum Component and the Late Presenters Registration who passed the Postpartum Component entry criteria.

    • Participants were randomly assigned to one of two arms:

      • Arm A: Women received LPV-RTV plus TRV from the Week 1 postpartum visit through the end of maternal follow-up (2 to 5 years). Infants received NVP once a day through 42 days of age or until the Week 6 study visit, whichever was later.
      • Arm B: Infants received NVP once a day from the Week 1 postpartum visit until the end of risk for MTCT or until 18 months postpartum (104 weeks). Women did not receive antiretroviral drugs for MTCT prophylaxis.
    • The maternal study visits were at entry, at postpartum weeks 6, 14, 26, and every 12 weeks thereafter. Infant study visits were at entry, every 4 weeks between postpartum weeks 6-26, every 12 weeks between postpartum week 38-98, and at postpartum week 104. At the end of risk for MTCT or 18 months postpartum, the mothers' eligibility criteria were assessed for a subsequent randomization in the Maternal Health Component. If they did not meet entry criteria for the Maternal Health randomization, they remained in follow-up for safety assessments; otherwise they were followed under the Maternal Health Component. Infants were followed until the 104 week visit.
    • Women switched or initiated HAART if it was needed for their own health. If a woman in Arm B initiated HAART then her infant discontinued NVP after 12 weeks of HAART or after her viral load was suppressed, whichever came first.
    • There were 2431 mothers and 2444 infants randomized as part of the Postpartum Component.
  3. Maternal Health Component: This PROMISE component randomized women to continue or discontinue HAART after the end of risk for MTCT, either after delivery or after breastfeeding. Participants included women who were receiving the triple ARV regimen in the Postpartum Component; or receiving the triple ARV regimen in the Antepartum Component and were ineligible for the Postpartum Component.

    • Participants were randomly assigned to one of two study arms:

      • Arm A: Participants continued to receive the triple ARV regimen (preferred regimen was LPV-RTV plus TRV).
      • Arm B: Participants discontinued the triple ARV regimen.
    • Study visits occurred at Weeks 4 and 12 and then every 3 months thereafter. Study visits included a medical history review, questionnaires, physical exam, and blood collection. Women switched or initiated a triple ARV regimen if it was needed for their own health.
    • There were 875 mothers randomized as part of the Maternal Health Component.
    • The analyses for the Maternal Health Component we not solely based on the Maternal Health Randomization. Instead there were four prespecified comparison groups for the Maternal Health Component. The four comparison groups used the three randomizations as appropriate to answer the following questions:

      • Question 1: What is the effect on women of using a maternal triple ARV regimen to prevent MTCT during pregnancy, relative to using ZDV + sdNVP + TRV tail to prevent MTCT during pregnancy?
      • Question 2: What is the effect on women of using a maternal triple ARV regimen to prevent MTCT during breastfeeding, relative to using infant NVP to prevent MTCT during breastfeeding?
      • Question 3: What is the effect on women of extending versus discontinuing the antepartum/intrapartum maternal triple ARV regimen at the time of birth?
      • Question 4: What is the effect on women of extending versus discontinuing the postpartum maternal triple ARV regimen after the cessation of risk for MTCT during breastfeeding?
    • There were 1602 mothers included in the analyses for Question 2.

PROMISE mothers were followed for 2 to 5 years, depending on when they enrolled. Infants were followed up to 104 weeks of age. Infant and maternal follow-up ended in September 2016. PROMISE randomizations were halted in the summer of 2014 due to slow accrual to the Later Presenters Registration and the Formula Feeding protocol. Due to the results of an external study, on July 7th 2015 the PROMISE interventions were halted and ART was offered to all participants. Per recommendation from the Data and Safety and Monitoring Board on November 4th 2014, the primary analyses for the Antepartum Component include follow-up through September 10th, 2014. Per recommendation from the Data and Safety and Monitoring Board on November 12th 2015, the primary analyses for the Postpartum Component include follow-up through July 7th, 2015. The Adverse Events in the Reported Adverse Event section include all study follow-up.

Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Investigator, Outcomes Assessor)
Masking Description:
The investigators and outcomes assessor did not receive by-arm tabulations while the study was ongoing.
Primary Purpose: Prevention
HIV Infections
  • Drug: Zidovudine (ZDV)
    300 mg twice daily
  • Drug: Nevirapine (NVP): Antepartum Mothers
    200 mg at onset of labor
  • Drug: Emtricitabine-tenofovir disoproxil fumarate (Truvada [TRV]) tail
    200 mg/300 mg x 2 tablets at onset of labor or as soon as possible thereafter; 200 mg/300 mg orally each day after delivery for 7 days or the date of the Week 1 visit (up to 14 days), whichever is later.
  • Drug: Lamivudine-Zidovudine (3TC-ZDV)
    150 mg/300 mg twice daily
  • Drug: Lopinavir-ritonavir (LPV-RTV)
    400 mg/100 mg twice daily beginning at >= 14 weeks gestation; 600 mg/150 mg twice daily beginning at >= 28 weeks gestation or at next visit (during third trimester) through delivery; 400 mg/100 mg twice daily after delivery up to 14 days postpartum.
  • Drug: Emtricitabine-tenofovir disoproxil fumarate (Truvada [TRV])
    200 mg/300 mg
  • Drug: Nevirapine (NVP): Infant short-course
    Oral suspension (dosing according to birth weight) once a day through 42 days of age or through the week 6 visit, whichever is later.
  • Drug: Nevirapine (NVP): Infant extended
    Oral suspension (dosing according to birth weight) once a day from 6 (up to 14) days of age until there was no longer any risk of MTCT or until the end of follow-up (104 weeks), whichever came first.
  • Other: No Intervention

    Women registered before/during labor received the full Antepartum Arm A regimen.

    Women registered after labor, and who received nevirapine outside of the study, received the Emtricitabine-tenofovir disoproxil fumarate (Truvada [TRV]) tail.

  • Other: Discontinue triple ARVs
    ARVs were discontinued. When protocol specified criteria were met, mothers could be prescribed any licensed antiretroviral medication, as long as the treatment met the definition of HAART (three ARV drugs from two or more drug classes).
  • Other: Continue triple ARVs
    Mothers could be prescribed any licensed antiretroviral medication, as long as the treatment met the definition of HAART (three ARV drugs from two or more drug classes).
  • Active Comparator: Antepartum Arm A
    Mothers received ZDV + sdNVP + TRV Tail
    Interventions:
    • Drug: Zidovudine (ZDV)
    • Drug: Nevirapine (NVP): Antepartum Mothers
    • Drug: Emtricitabine-tenofovir disoproxil fumarate (Truvada [TRV]) tail
    • Drug: Nevirapine (NVP): Infant short-course
  • Experimental: Antepartum Arm B
    Mothers received Triple ARV (3TC-ZDV + LPV-RTV)
    Interventions:
    • Drug: Lamivudine-Zidovudine (3TC-ZDV)
    • Drug: Lopinavir-ritonavir (LPV-RTV)
    • Drug: Nevirapine (NVP): Infant short-course
  • Experimental: Antepartum Arm C
    Mothers received Triple ARV (TRV + LPV-RTV)
    Interventions:
    • Drug: Lopinavir-ritonavir (LPV-RTV)
    • Drug: Emtricitabine-tenofovir disoproxil fumarate (Truvada [TRV])
    • Drug: Nevirapine (NVP): Infant short-course
  • Late Presenters
    Registration to facilitate a structure to screen women and infants for randomization in the Postpartum Component.
    Intervention: Other: No Intervention
  • Experimental: Postpartum Arm A (Maternal Prophylaxis)
    Mothers received prophylaxis [preferred regimen: TRV + LPV-RTV]. Infants received short-course NVP.
    Interventions:
    • Drug: Lopinavir-ritonavir (LPV-RTV)
    • Drug: Emtricitabine-tenofovir disoproxil fumarate (Truvada [TRV])
    • Drug: Nevirapine (NVP): Infant short-course
  • Experimental: Postpartum Arm B (Infant Prophylaxis)
    Infants received extended NVP.
    Intervention: Drug: Nevirapine (NVP): Infant extended
  • Experimental: Maternal Health Arm A (Continue triple ARVs)
    Mothers continued receiving triple ARV regimen [preferred regimen: TRV + LPV-RTV].
    Intervention: Other: Continue triple ARVs
  • Active Comparator: Maternal Health Arm B (Discontinue triple ARVs)
    Mothers discontinued triple ARV regimen.
    Intervention: Other: Discontinue triple ARVs

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
3747
12536
September 2016
September 2016   (Final data collection date for primary outcome measure)

Antepartum Component Inclusion Criteria:

  • Confirmed HIV-1 infection, defined as documented positive results from two samples collected at different time points prior to study entry. More information on this criterion can be found in the protocol.
  • Currently pregnant and greater than or equal to 14 weeks gestation based on clinical or other obstetrical measurements
  • CD4 count greater than or equal to 350 cells/mm^3, or greater than or equal to the country-specific threshold for initiation of treatment (if that threshold is greater than 350 cells/mm^3), on a specimen obtained within 30 days prior to study entry
  • Results of HBV screening (HBsAg testing) available from specimen obtained within 30 days prior to study entry
  • The following laboratory values from a specimen obtained within 30 days prior to study entry:

    1. Hemoglobin greater than or equal to 7.5 g/dL
    2. White blood cell count (WBC) greater than or equal to 1,500 cells/mm^3
    3. Absolute neutrophil count (ANC) greater than or equal to 750 cells/mm^3
    4. Platelets greater than or equal to 50,000 cells/mm^3
    5. Alanine aminotransferase (ALT) less than or equal to 2.5 times the upper limit of normal (ULN)
    6. Estimated creatinine clearance of greater than or equal to 60 mL/min using the Cockroft-Gault equation for women
  • Plans to deliver in the study-affiliated clinic or hospital
  • Has no plans to move outside of the study site area during the 24 months following delivery
  • Age of legal majority for the respective country and willing and able to provide written informed consent

Antepartum Component Exclusion Criteria:

  • Participation in PROMISE for a prior pregnancy
  • Ingestion of any antiretroviral (ARV) regimen with three or more drugs (regardless of duration) or more than 30 days of a single or dual ARV regimen during current pregnancy, according to self report or available medical records
  • Requires triple ARV therapy (HAART) for own health based on local standard guidelines
  • World Health Organization (WHO) stage 4 disease
  • Prior receipt of HAART for maternal treatment indications (e.g., CD4 less than 350 cells/mm^3 or clinical indications); however, could have received ARVs for the sole purpose of prevention of mother-to-child transmission (PMTCT) in previous pregnancies (prior PMTCT regimens could have included a triple ARV regimen, ZDV, 3TC-ZDV, and/or sdNVP for PMTCT, as well as use of a short dual nucleoside reverse transcriptase inhibitor [NRTI] "tail" to reduce risk of NVP resistance.)
  • In labor - at onset or beyond (may be eligible for the Late Presenter registration)
  • Clinically significant illness or condition requiring systemic treatment and/or hospitalization within 30 days prior to study entry
  • Current or history of tuberculosis (TB) disease (positive PPD without TB disease is not exclusionary)
  • Use of prohibited medications within 14 days prior to study entry (refer to the protocol for a list of prohibited medications)
  • Fetus detected to have serious congenital malformation (ultrasound not required to rule out this condition)
  • Current documented conduction heart defect (specialized assessments to rule out this condition are not required; a heart murmur alone and/or type 1 second-degree atrioventricular block [also known as Mobitz I or Wenckebach] is not considered exclusionary)
  • Known to meet the local standard criteria for treatment of HBV (Note: HBV DNA testing or other specialized assessments are not expected to be performed as part of this study. A woman would be excluded only if this information is documented from other sources and she meets the local standard criteria for HBV treatment based on those assessments.)
  • Social or other circumstances that would hinder long-term follow-up, in the opinion of the site investigator
  • Currently incarcerated

Late Presenter Inclusion Criteria:

  • Age of legal majority for the respective country
  • HIV-1 infection, defined as documented positive results from tests performed on one sample at any time prior to Late Presenter Registration
  • In labor (from onset/early labor or beyond) or within 5 days after delivery (with day of delivery considered day 0)
  • Has provided written informed consent
  • Has no plans to move outside of the study site area during the 24 months following delivery
  • If delivered, infant alive and healthy (In the case of a multiple birth, a mother-infant pair will be included in the Late Presenter registration only if both/all infants and the mother meet the eligibility criteria. If only one infant of a multiple birth is alive, the M-I pair may be registered if the infant and the mother otherwise meet all of the eligibility criteria.)

Late Presenter Exclusion Criteria:

  • Participation in PROMISE in prior pregnancy
  • Ingestion of any antiretroviral regimen during current pregnancy (including for solely for PMTCT), according to self report and available medical records (Note: Use of ARVs provided as standard of care for PMTCT during labor/delivery or postpartum prior to Late Presenter registration is not exclusionary.)
  • If known: CD4 count < 350 cells/mm3 or below the country-specific threshold for initiation of treatment, if that threshold is > 350 cells/mm3, on specimen obtained within 30 days prior to study entry (result not required prior to registration)
  • Requires triple ARV therapy (HAART) for own health according to local standard guidelines
  • WHO Stage 4 disease
  • Prior receipt of HAART for maternal treatment indications (e.g., CD4 < 350 cells/mm3 or clinical indications); however, could have received ARVs for the sole purpose of PMTCT in previous pregnancies. (Prior PMTCT regimens could have included a triple ARV regimen, ZDV, 3TCZDV and/or sdNVP for PMTCT, as well as use of a short dual NRTI "tail" to reduce risk of NVP resistance.)
  • Current or history of TB disease (positive PPD without TB disease is not exclusionary)
  • Known positive infant HIV nucleic acid test (NAT) result (result not required prior to registration)
  • Fetal demise or early neonatal death (prior to enrollment/registration)
  • Fetus detected with serious congenital malformation (ultrasound not required to rule out this condition)
  • Life threatening infant illness or birth condition incompatible with life
  • If delivered, infant birth weight < 2.0 kg
  • Social or other circumstances which would hinder long-term follow-up, in the opinion of the site investigator
  • Current documented conduction heart defect (specialized assessments to rule out this condition are not required; a heart murmur alone and/or type 1 second-degree atrioventricular block (also known as Mobitz I or Wenckebach) is not considered exclusionary)

Postpartum Component Inclusion Criteria:

  • Participation in the Antepartum Component or registered as a Late Presenter
  • Provided written informed consent
  • Has no plans to move outside of the study site area during the 24 months following delivery
  • Maternal CD4 count greater than or equal to 350 cells/mm^3, or greater than or equal to the country-specific threshold for initiation of treatment (if that threshold is greater than 350 cells/mm^3), from a specimen obtained within 30 days prior to study entry. More information on this criterion can be found in the protocol.
  • The following maternal laboratory values within 30 days prior to entry:

    1. Hemoglobin greater than or equal to 7.0 g/dL
    2. WBC greater than or equal to 1,500 cells/mm^3
    3. ANC greater than or equal to 750 cells/mm^3
    4. Platelets greater than or equal to 50,000 cells/mm^3
    5. ALT less than or equal to 2.5 times the upper limit of normal (ULN)
    6. Estimated creatinine clearance of greater than or equal to 60 mL/min using the Cockroft-Gault equation for women
  • Infant alive, healthy, less than or equal to 14 days of age, and uninfected (negative HIV NAT result on specimen drawn prior to study entry)
  • The following infant lab values on specimen obtained prior to study entry (within 14 days of birth):

    1. Hemoglobin greater than or equal to 10 g/dL
    2. WBC greater than or equal to 1,500 cells/mm^3
    3. ANC greater than or equal to 750 cells/mm^3
    4. Platelets greater than or equal to 50,000 cells/mm^3
    5. ALT less than or equal to 2.5 times the ULN
  • For Registered Late Presenters: Confirmed maternal HIV-1 infection, defined as documented positive results from two samples collected at different time points at any time prior to entry. More information on this criterion can be found in the protocol.

Postpartum Component Exclusion Criteria:

  • Positive infant HIV NAT result on specimen drawn prior to entry or no infant HIV NAT result on specimen drawn prior to entry
  • Life-threatening infant illness or birth condition incompatible with life
  • Infant birth weight less than 2.0 kg
  • Social or other circumstances that would hinder long-term follow-up, as judged by the site investigator
  • Current or history of TB disease (positive PPD without TB disease is not exclusionary)
  • Current documented conduction heart defect (specialized assessments to rule out this condition are not required; a heart murmur alone and/or type 1 second-degree atrioventricular block [also known as Mobitz I or Wenckebach] is not considered exclusionary)
  • Requires triple ARV therapy (HAART) for own health

Maternal Health Component Inclusion Criteria:

  • Randomly assigned to triple ARV prophylaxis as part of the Postpartum Component and has continued triple ARV prophylaxis until the current randomization without treatment interruption (defined as more than 14 consecutive days of missed dosing) within the previous 30 days; OR randomly assigned to triple ARV prophylaxis in the Antepartum Component but ineligible for the Postpartum Component and has continued triple ARV prophylaxis until the current randomization without treatment interruption (defined as more than 7 consecutive days of missed dosing) within the previous 30 days
  • Within two weeks after complete breastfeeding cessation is achieved (defined as completely stopping all exposure to breast milk for greater than or equal to 28 days); i.e., within 29 to 42 days of last breast milk exposure, or reached 18 months postpartum (whichever comes first). Women who reach 18 months postpartum while still breastfeeding will be eligible for entry within 2 weeks before and 4 weeks after the Week 74 visit (Week 72-78); OR if the woman was randomized to triple ARV prophylaxis in the Postpartum Component and her infant is infected and still breastfeeding, she will be eligible for the Maternal Health Component within 42 days of specimen collection for the confirmatory infant HIV NAT; OR if the woman was randomized to triple ARV prophylaxis in the Antepartum Component but mother-infant pair was ineligible for the Postpartum Component she will be eligible for the Maternal Health Component beginning at the Week 1 visit (6-14 days postpartum) through 28 days after delivery; these women should be randomized as soon as possible, ideally within 6-14 days after delivery; OR if the woman was randomized to triple ARV prophylaxis in the Postpartum Component and breastfeeding risk for MTCT ceases for other reasons (e.g., infant death or permanent removal from home through legal services or adoption) within 28 days of event. More information on this criterion can be found in the protocol.
  • Provided written informed consent
  • CD4 cell count greater than or equal to 350 cells/mm^3, or greater than or equal to the country-specific threshold for initiation of treatment (if that threshold is greater than 350 cells/mm^3), on a specimen obtained within 30 days prior to study entry
  • The following laboratory values on a specimen obtained within 30 days prior to study entry:

    1. ANC greater than or equal to 750 cells/mm^3
    2. Hemoglobin greater than or equal to 7.0 gm/dL
    3. Platelet count greater than or equal to 50,000 cells/mm^3
    4. ALT (SGPT) less than or equal to 2.5 times the ULN
    5. Estimated creatinine clearance of greater than or equal to 60 mL/min using the Cockroft-Gault equation for women
  • Intend to remain in current geographical area of residence for the duration of study

Maternal Health Component Exclusion Criteria:

  • WHO Stage 4 disease
  • Clinically significant illness or condition requiring systemic treatment and/or hospitalization within 30 days prior to study entry
  • Current or history of TB disease (positive PPD without TB disease is not exclusionary)
  • Use of prohibited medications within 14 days prior to study entry
  • Social or other circumstances that would hinder long term follow-up as judged by the site investigator
  • Current documented conduction heart defect (specialized assessments to rule out this condition are not required; a heart murmur alone and/or type 1 second-degree atrioventricular block [also known as Mobitz I or Wenckebach] is not considered exclusionary)
  • Requires a triple ARV regimen for own health
Sexes Eligible for Study: All
Child, Adult, Older Adult
No
Contact information is only displayed when the study is recruiting subjects
India,   Malawi,   South Africa,   Tanzania,   Uganda,   Zambia,   Zimbabwe
 
 
NCT01061151
1077BF (PROMISE)
10777 ( Registry Identifier: DAIDS ES )
IMPAACT 1077BF
Yes
Not Provided
Not Provided
National Institute of Allergy and Infectious Diseases (NIAID)
National Institute of Allergy and Infectious Diseases (NIAID)
Not Provided
Study Chair: Mary Glenn Fowler, MD, MPH Johns Hopkins Medical Institute, Makerere U.-JHU Research Collaboration
National Institute of Allergy and Infectious Diseases (NIAID)
September 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP