Evaluating Strategies to Reduce Mother-to-Child Transmission of HIV Infection in Populations Using Formula Feeding (PROMISE)

Condition(s) targeted: HIV

Intervention: Zidovudine (ZDV) (Drug); Nevirapine (NVP) (Drug); Emtricitabine-tenofovir disoproxil fumarate (Truvada [TRV]) (Drug); Lamivudine-Zidovudine (3TC-ZDV) (Drug); Lopinavir-ritonavir (LPV-RTV) (Drug)

Phase: N/A

Status: Recruiting

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

Official(s) and/or principal investigator(s):
Mary Glenn Fowler, MD, MPH, Study Chair, Affiliation: Johns Hopkins Medical Institute

The purpose of this study is to examine effective methods of preventing the transmission of HIV from mother to child during pregnancy, labor, and delivery. This is one part of the three-part PROMISE study. This study will be conducted at resource-limited locations in Africa and other parts of the world where women typically receive a short course of highly active antiretroviral therapy (HAART) during pregnancy and where formula feeding (FF) is standard.

Official title: Formula Feeding Version of the PROMISE Study (Promoting Maternal and Infant Survival Everywhere)

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Primary outcome:

Maternal Health Component: Composite endpoint of progression to AIDS-defining illness or death

Antepartum Component: Confirmed presence of infant HIV infection

Antepartum Component: Grade 3 or higher toxicity (for women, also selected Grade 2 hematologic, renal, and hepatic adverse events)

Antepartum Component: Obstetrical complications

Antepartum Component: Adverse pregnancy outcomes (e.g., stillbirth, preterm delivery at less than 37 weeks gestation, low birth weight less than 2,500 grams, and congenital anomalies)

Secondary outcome:

Maternal Health Component: Death

Maternal Health Component: AIDS-defining illness

Maternal Health Component: Composite endpoint of progression to AIDS-defining illness, death, or a serious non-AIDS cardiovascular, hepatic, or renal event

Maternal Health Component: HIV/AIDS-related events

Maternal Health Component: Cardiovascular or other metabolic events

Maternal Health Component: Other targeted medical conditions

Maternal Health Component: Composite endpoint of HIV/AIDS-related event or death

Maternal Health Component: Composite endpoint of HIV/AIDS-related event or World Health Organization (WHO) Clinical Stage 2 or 3 event

Maternal Health Component: Composite endpoint of any condition outlined in Appendix IV of the protocol or death

Maternal Health Component: Tuberculosis

Maternal Health Component: Toxicity, defined as Grade 3 or greater laboratory results or signs and symptoms and selected Grade 2 renal and hepatic laboratory results

Maternal Health Component: Viral resistance

Maternal Health Component: Self-reported adherence

Maternal Health Component: Quality of life

Maternal Health Component: Changes in plasma concentrations of inflammatory and thrombogenic markers

Maternal Health Component: Cost-effectiveness

Antepartum Component: Infant HIV infection detected by HIV NAT positivity in the birth sample

Antepartum Component: Overall and HIV-free infant survival

Antepartum Component: Adherence to the maternal ARV regimen, measured by maternal report

Antepartum Component: Cost-effectiveness and feasibility of the trial ARV regimens

Antepartum Component: Maternal and infant viral resistance to the maternal and infant ARV strategies

Antepartum Component: Antepartum change in HBV DNA viral load (using log HBV DNA) among women with detectable HBV DNA viral loads at baseline and other HBV outcome measures

Antepartum Component: Maternal HIV RNA less than 400 copies/mL at delivery

Detailed description: The incidence of mother-to-child transmission 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, these improvements have mostly been seen in the United States, Europe, and other resource-advantaged areas. In resource-limited countries, barriers to the implementation of effective interventions for the prevention of mother-to-child transmission (PMTCT) still remain.

The PROMISE study is evaluating effective methods of preventing the transmission of HIV from a mother to her baby during pregnancy, labor and delivery, and breastfeeding. This version of the PROMISE study will be conducted at research sites in Africa and other parts of the world where formula feeding is standard.

This study is divided into two parts:

1. Antepartum Component:

This part of the study will compare the safety and effectiveness of different HAART regimens at preventing the transmission of HIV during pregnancy, labor, and delivery.

Pregnant HIV-infected women will be randomly assigned to one of the following three groups:

Arm A: Participants will receive zidovudine (ZDV) + single dose nevirapine (sdNVP) + emtricitabine-tenofovir disoproxil fumarate (Truvada [TRV]) tail. Participants will receive ZDV from 14 weeks gestation through delivery, sdNVP and TRV at onset of labor, and TRV postpartum for 7 days or through the Week 1 visit (6-14 days postpartum), whichever is later.

Arm B: Participants will receive lamivudine (3TC)-zidovudine (ZDV) + lopinavir (LPV)-ritonavir (RTV). Participants will receive the triple antiretroviral (ARV) study drug regimen from 14 weeks gestation through the Week 1 visit (6-14 days postpartum).

Arm C: Participants will receive TRV/LPV-RTV. Participants will receive the triple ARV study drug regimen from 14 weeks gestation through the Week 1 visit (6-14 days postpartum).

Fixed-dose FTC-TDF-RPV (Complera) may be used as an alternative first-line regimen for mothers who are not able to tolerate or adhere to LPV-RTV or ATV-RTV. The FTC-TDF-RPV regimen is not defined in the protocol and should be determined at the discretion of staff at the study sites.

All infants born to women enrolled in this study will receive NVP once a day through 42 days of age or until the Week 6 study visit, whichever is later, regardless of which study arm their mother is enrolled in. Should women need HAART or to switch HAART regimens for their own health, they will be moved into Step 2 or Step 3 of this part of the study.

During pregnancy, participants will attend study visits at study entry, 2 and 4 weeks after entry, and then every 4 weeks until labor and delivery. Women and infants will be monitored during labor and delivery and will attend a study visit 6 to 14 days after delivery. Follow-up visits will occur at Weeks 1, 6, and 14. Thereafter, they will be once a month for infants and every 3 months for women. Study visits may include a medical history review, questionnaires, interviews, physical exam, and blood collection.

2. Maternal Health Component:

This part of the study will examine if women who received a triple ARV regimen during pregnancy have better health outcomes than women who discontinue a triple ARV regimen.

Participants will include women who were receiving the triple ARV regimen in the Antepartum Component.

Participants will be randomly assigned to one of two study arms:

Arm A: Participants will continue to receive the triple ARV regimen (TRV and LPV-RTV).

Arm B: Participants will discontinue the triple ARV regimen.

Study visits will occur at Weeks 4 and 12, then every 3 months thereafter. Women who are infected with hepatitis B virus (HBV) will have an additional visit at Week 8. Study visits may include a medical history review, questionnaires, physical exam, and blood collection. Should women need a triple ARV regimen or to switch triple ARV regimens for their own health, they will be moved into Step 2 or Step 3 of this part of the study.

The total duration of the two study components is 5 years. Women will remain in the study for follow-up for 2 to 5 years, depending on when they enroll. Infants will remain in the study through 104 weeks of age.

Minimum age: N/A. Maximum age: N/A. Gender(s): Both.

Criteria:

Antepartum Component Inclusion Criteria (Step 1):

- Confirmed HIV-1 infection, documented by the results of testing performed on two

separate specimens at any time prior to study entry. More information on this criterion can be found in the protocol.

- Currently pregnant and at greater than 14 weeks gestation based on clinical or other

obstetrical measurements

- CD4 count greater than or equal 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 (hepatitis B surface antigen [HBsAg] testing) available from

specimen obtained within 30 days prior to entry

- Certain laboratory values from a specimen obtained within 30 days prior to study

entry. More information on this criterion can be found in the protocol.

- 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

- Intends to formula feed

Antepartum Component Exclusion Criteria (Step 1):

- Participation in PROMISE for a prior pregnancy

- Ingestion of any 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

- WHO Stage 4 disease

- Prior receipt of HAART for maternal treatment indications (e. g., CD4 count less than

350 cells/mm^3 or clinical indications); however, could have received prior ARVs for the sole purpose of PMTCT in previous pregnancies; prior PMTCT regimens could have included a triple-ARV regimen, ZDV, 3TC-ZDV, and/or single-dose NVP for PMTCT as well as use of a short dual-nucleoside reverse transcriptase inhibitor (NRTI) "tail" to reduce risk of NVP resistance

- In labor, onset or beyond

- 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 purified protein derivative

[PPD] without TB disease is not exclusionary)

- Use of prohibited medications within 14 days prior to study entry (refer to protocol

for list of prohibited medications)

- Fetus detected with 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. More information on

this criterion can be found in the protocol.

- Social or other circumstances that would hinder long-term follow-up, in the opinion

of the site investigator

- Currently incarcerated

Antepartum Component Inclusion Criteria (Step 2):

- On Antepartum Step 1 Arm A (ZDV + single dose NVP + TRV tail); OR

- On Antepartum Step 1 Arm B or C (maternal triple-ARV prophylaxis) and currently

receiving triple-ARV prophylaxis but does not meet the criteria for switching to a second line regimen (has not failed HAART) and Step 3 entry; OR

- On Step 1 Arm B or C (maternal triple-ARV prophylaxis) and not enrolled in the

Maternal Health Component but remains in observational follow-up and is not currently receiving a triple-ARV regimen (stopped the regimen)

- Reached an indication for triple-ARV therapy (HAART) for own health, as specified in

protocol

- Willing and able to initiate HAART

Antepartum Component Exclusion Criteria (Step 2):

No exclusion criteria for this step.

Antepartum Component Inclusion Criteria (Step 3):

- On Step 1 Arm B or C or on Step 2

- Met the criteria for switching to a second-line regimen (as specified in the

protocol) while on a triple-ARV regimen

- Willing and able to continue a triple-ARV regimen

Antepartum Component Exclusion Criteria (Step 3):

- Women on 1077FA Step 1 Arm B or C who were not enrolled in the Maternal Health

Component but remain in observational follow-up and are not currently receiving a triple-ARV regimen

Maternal Health Component Inclusion Criteria (Step 1):

- Randomized to triple-ARV prophylaxis as part of the Antepartum Component and has

continued triple-ARV prophylaxis until the current randomization (7 to 12 days postpartum) without treatment interruption (defined as more than 7 consecutive days of missed dosing) within the previous 30 days

- 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 specimen obtained within 30 days prior to study entry. More information on this criterion can be found in the protocol.

- Certain laboratory values on a specimen obtained within 30 days prior to study entry.

More information on this criterion can be found in the protocol.

- Intend to remain in current geographical area of residence for the duration of study

Maternal Health Component Exclusion Criteria (Step 1):

- WHO Stage 4 disease

- Clinically significant illness or condition requiring systemic treatment and/or

hospitalization within 30 days prior to entry in Maternal Health Component

- Current or history of TB disease (positive PPD without TB disease is not

exclusionary)

- Use of prohibited medications within 14 days prior to entry in Maternal Health

Component

- 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 triple-ARV therapy for own health (includes women who are on Step 2 of the

Antepartum Component and women who are on Step 3 of the Antepartum Component who entered Step 3 for immunologic/clinical disease progression requiring a change in their triple-ARV regimen (HAART). More information on this criterion can be found in the protocol.

Maternal Health Component Inclusion Criteria (Step 2):

- On Step 1 Arm B (discontinue the study triple-ARV regimen arm); OR

- On Step 1 Arm A (triple-ARV regimen) and currently on the triple-ARV regimen but does

not meet the criteria for switching to a second-line regimen and entry into Step 3

- Reached an indication for triple-ARV treatment for her own health, as specified in

the protocol

- Willing and able to reinitiate or continue triple-ARV therapy

Maternal Health Component Exclusion Criteria (Step 2):

No exclusion criteria for this step.

Maternal Health Component Inclusion Criteria (Step 3):

- On Step 1 Arm A or Step 2

- Meets the criteria for switching to a second-line regimen as specified in protocol

while on a triple-ARV regimen

- Willing and able to continue an alternative triple-ARV regimen (HAART)

Maternal Health Component Exclusion Criteria (Step 3):

- On Step 1 Arm B

Stellenbosch Univ. CRS, Cape Town 7505, South Africa; Recruiting
Joan Coetzee, Phone: 27-21-9384157, Email: joan@sun.ac.za

Soweto IMPAACT CRS, Johannesburg, Gauteng, South Africa; Recruiting
Nasreen Abrahams, Phone: 27-11-9899742, Email: abrahamsn@phru.co.za

Shandukani Research CRS, Johannesburg, Gauteng 2001, South Africa; Not yet recruiting
Hermien Gous, PharmD, Phone: 27-11-3585500, Ext: 5930, Email: hgous@wrhi.ac.za

Durban Paediatric HIV CRS, Durban, KwaZulu-Natal 4001, South Africa; Recruiting
Rosie Mngqibisa, MBBS, Phone: 27-31-2604669, Email: mngqibisa@ukzn.ac.za

BJ Medical College CRS, Pune, Maharashtra 411001, India; Recruiting
Nishi Suryavanshi, Ph.D., Phone: 91-20-26052419, Email: nishi@jhumitpune.com

Starting date: April 2011
Last updated: November 19, 2012