Breastfeeding Version of the PROMISE Study (Promoting Maternal and Infant Survival Everywhere)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 3,747
- 试验地点
- 14
- 主要终点
- Maternal Health Component: Incidence of Progression to AIDS-defining Illness or Death
研究概览
简要总结
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:
- What is the optimal intervention for the prevention of antepartum and intrapartum transmission of HIV?
- What is the optimal intervention for the prevention of postpartum transmission in breastfeeding (BF) infants?
- 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.
详细描述
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:
- 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.
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Participants were randomly assigned to one of the following three arms:
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Maternal Regimens:
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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.
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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.
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Arm C: TRV/LPV-RTV from study entry up to 14 days postpartum. Arm C is also labeled as FTC-TDF/LPV-RTV.
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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.
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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.
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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.
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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.
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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.
- 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Double (Investigator, Outcomes Assessor)
盲法说明
The investigators and outcomes assessor did not receive by-arm tabulations while the study was ongoing.
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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:
- •Hemoglobin greater than or equal to 7.5 g/dL
- •White blood cell count (WBC) greater than or equal to 1,500 cells/mm^3
- •Absolute neutrophil count (ANC) greater than or equal to 750 cells/mm^3
- •Platelets greater than or equal to 50,000 cells/mm^3
- •Alanine aminotransferase (ALT) less than or equal to 2.5 times the upper limit of normal (ULN)
- •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
排除标准
- •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:
- •Hemoglobin greater than or equal to 7.0 g/dL
- •WBC greater than or equal to 1,500 cells/mm^3
- •ANC greater than or equal to 750 cells/mm^3
- •Platelets greater than or equal to 50,000 cells/mm^3
- •ALT less than or equal to 2.5 times the upper limit of normal (ULN)
- •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):
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研究组 & 干预措施
Antepartum Arm B
Mothers received Triple ARV (3TC-ZDV + LPV-RTV)
干预措施: Lamivudine-Zidovudine (3TC-ZDV) (Drug)
Antepartum Arm A
Mothers received ZDV + sdNVP + TRV Tail
干预措施: Zidovudine (ZDV) (Drug)
Antepartum Arm A
Mothers received ZDV + sdNVP + TRV Tail
干预措施: Emtricitabine-tenofovir disoproxil fumarate (Truvada [TRV]) tail (Drug)
Antepartum Arm B
Mothers received Triple ARV (3TC-ZDV + LPV-RTV)
干预措施: Lopinavir-ritonavir (LPV-RTV) (Drug)
Antepartum Arm C
Mothers received Triple ARV (TRV + LPV-RTV)
干预措施: Lopinavir-ritonavir (LPV-RTV) (Drug)
Antepartum Arm C
Mothers received Triple ARV (TRV + LPV-RTV)
干预措施: Emtricitabine-tenofovir disoproxil fumarate (Truvada [TRV]) (Drug)
Late Presenters
Registration to facilitate a structure to screen women and infants for randomization in the Postpartum Component.
干预措施: No Intervention (Other)
Postpartum Arm A (Maternal Prophylaxis)
Mothers received prophylaxis [preferred regimen: TRV + LPV-RTV]. Infants received short-course NVP.
干预措施: Lopinavir-ritonavir (LPV-RTV) (Drug)
Postpartum Arm A (Maternal Prophylaxis)
Mothers received prophylaxis [preferred regimen: TRV + LPV-RTV]. Infants received short-course NVP.
干预措施: Emtricitabine-tenofovir disoproxil fumarate (Truvada [TRV]) (Drug)
Maternal Health Arm A (Continue triple ARVs)
Mothers continued receiving triple ARV regimen [preferred regimen: TRV + LPV-RTV].
干预措施: Continue triple ARVs (Other)
Maternal Health Arm B (Discontinue triple ARVs)
Mothers discontinued triple ARV regimen.
干预措施: Discontinue triple ARVs (Other)
结局指标
主要结局
Maternal Health Component: Incidence of Progression to AIDS-defining Illness or Death
时间窗: 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: Number of Mothers With Grade 3 or Higher Toxicities and Selected Grade 2 Hematologic, Renal, and Hepatic Adverse Events
时间窗: 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 Confirmed Infant HIV Infections
时间窗: 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 Adverse Pregnancy Outcomes (e.g.,Stillbirth, Preterm Delivery (< 37 Weeks), Low Birth Weight (< 2,500 Grams), and Congenital Anomalies)
时间窗: Measured at birth
Composite outcome
Postpartum Component: Incidence of Confirmed Infant HIV Infection
时间窗: 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.
Antepartum Component: Number of Mothers With Obstetrical Complications
时间窗: Measured through the Week 1 postpartum study visit
Complications included deaths, diagnoses, signs/symptoms, chemistry lab tests, or hematological lab tests, with grades of 3 (Severe) or worse. Obstetrical complications were those classified by the MedDra coding system as "Pregnancy, puerperium and perinatal conditions", except if the condition was the death of the fetus: "Abortions not specified as induced or spontaneous", "Abortions spontaneous", or "Stillbirth and foetal death."
Postpartum Component: Incidence of Grade 3 or Higher Adverse Events and Selected Grade 2 Hematologic, Renal, and Hepatic Adverse Events
时间窗: 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).
次要结局
- Antepartum Component: Probability of Overall and HIV-free Infant Survival Until 104 Weeks of Age, by Antepartum Arm (in Conjunction With Infants in the Postpartum Component)(Measured from birth through 104 weeks of age)
- Postpartum Component: Proportion of Mother-Infant Pairs With no Death or HIV Diagnosis Through 24 Months Post-delivery(Measured through 24 months post-delivery)
- Postpartum Component: Proportion of Infants Alive Through 12 and 24 Months Post-delivery(Measured at 12 and 24 months post-delivery)
- Antepartum Component: Number of Infant HIV Infections(Measured at the birth (<= 3 days postpartum) visit)
- Antepartum Component: Maternal HIV RNA Less Than 400 Copies/mL at Delivery(Measured at the time of delivery)
- Maternal Health Component: Incidence of AIDS-defining Illness(From study entry until July 7, 2015, an average of 94 weeks of follow-up.)
- Maternal Health Component: Incidence of Tuberculosis(From study entry until July 7, 2015, an average of 94 weeks of follow-up.)
- 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(From study entry until July 7, 2015, an average of 94 weeks of follow-up.)
- Maternal Health Component: Incidence of Death(From study entry until July 7, 2015, an average of 94 weeks of follow-up.)
- Maternal Health Component: Incidence Rate of Cardiovascular or Other Metabolic Events(From study entry until July 7, 2015, an average of 94 weeks of follow-up.)
- Maternal Health Component: Incidence of HIV/AIDS-related Events(From study entry until July 7, 2015, an average of 94 weeks of follow-up.)
- Maternal Health Component: Incidence Rate of Progression to AIDS-defining Illness, Death, or a Serious Non-AIDS Cardiovascular, Hepatic, or Renal Event(From study entry until July 7, 2015, an average of 94 weeks of follow-up.)
- Maternal Health Component: Other Targeted Medical Conditions(From study entry until July 7, 2015, an average of 94 weeks of follow-up.)
- Maternal Health Component: Incidence of HIV/AIDS-related Event or World Health Organization (WHO) Clinical Stage 2 or 3 Events(From study entry until July 7, 2015, an average of 94 weeks of follow-up.)
- Maternal Health Component: Incidence Rate of Death or Any Condition of Particular Concern(From study entry until July 7, 2015, an average of 94 weeks of follow-up.)
- Maternal Health Component: Incidence of HIV/AIDS-related Event or Death(From study entry until July 7, 2015, an average of 94 weeks of follow-up.)