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

HIV Clinical Trial

— PROMISE  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01253538
• Other study ID #: 1077FF (PROMISE)
• Secondary ID: 10778IMPAACT 107
• Status: Completed
• Phase: N/A
• First received: December 1, 2010
• Last updated: October 11, 2016
• Start date: April 2011
• Est. completion date: September 2016

Study information

• Verified date: October 2016
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

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 74 to 104 weeks of age. Follow-up for all women and infants will be completed by the end of September 2016.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 284
• Est. completion date: September 2016
• Est. primary completion date: September 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A and older

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• HIV

Intervention

Drug:
• Zidovudine (ZDV)
Antepartum Arm A: 300 mg orally twice daily beginning at greater than or equal to 14 weeks gestation (at study entry) through delivery
• Nevirapine (NVP)
For women, 200 mg orally (one single dose) at onset of labor; for infants with birth weight greater than or equal to 2,500 gm: 1.5 mL suspension orally once a day beginning as soon as possible after birth through 42 days of age or through the Week 6 study visit, whichever is later; for infants with a birth weight of 2,000 to 2, 499 gm: 1.0 mL suspension orally once a day beginning as soon as possible after birth through 42 days of age or until the Week 6 study visit, whichever is later; for infants with a birth weight of less than 2,000 gm: 2 mg/kg based on birth weight orally once a day beginning as soon as possible after birth through 3 weeks of age and 4 mg/kg based on weight at 3 weeks of age orally once a day beginning at 3 weeks of age through 42 days of age or through the Week 6 visit, whichever is later.
• Emtricitabine-tenofovir disoproxil fumarate (Truvada [TRV])
Antepartum Arm A: 200 mg/300 mg x 2 tablets for a total dose of 400 mg/600 mg orally once ideally at onset of labor or as soon as possible thereafter; 200 mg/300 mg (1 tablet) orally each day after delivery for 7 days or the date of the Week 1 visit (up to 14 days), whichever is later. Antepartum Arm C: 200 mg/300 mg orally once daily beginning at greater than or equal to 14 weeks gestation (at study entry) until Week 1 postpartum visit (up to 14 days)
• Lamivudine-Zidovudine (3TC-ZDV)
Antepartum Arm B: 150 mg/300 mg orally twice daily beginning at greater than or equal to 14 weeks gestation (at study entry) through delivery and until 1 week postpartum visit (up to 14 days)
• Lopinavir-ritonavir (LPV-RTV)
Antepartum Arm B: 200 mg/50 mg x 2 tablets for a dose of 400 mg/100 mg orally twice daily beginning at >/= 14 weeks gestation (at study entry) through 28 weeks gestation (through second trimester); 200 mg/50 mg x 3 tablets for a dose of 600 mg/150 mg orally twice daily beginning at >/= 28 weeks gestation or at next visit (during third trimester) through delivery; 200 mg/50 mg x 2 tablets for a dose of 400 mg/100 mg orally twice daily after delivery until Week 1 postpartum visit (up to 14 days). Antepartum Arm C: 200 mg/50 mg x 2 tablets for a dose of 400 mg/100 mg orally twice daily beginning at > 14 weeks gestation (at study entry) through 28 weeks gestation (through second trimester); 200 mg/50 mg x 3 tablets for a dose of 600 mg/150 mg orally twice daily beginning > 28 weeks gestation, or at the next visit (during third trimester) through delivery; 200 mg/50 mg x 2 tablets for a dose of 400 mg/100 mg orally twice daily after delivery until week 1 postpartum visit (up to 14 days).

Locations

Country	Name	City	State
India	Byramjee Jeejeebhoy Medical College (BJMC) CRS	Pune	Maharashtra
South Africa	Durban Paediatric HIV CRS	Durban	KwaZulu-Natal
South Africa	Soweto IMPAACT CRS	Johannesburg	Gauteng
South Africa	Family Clinical Research Unit (FAM-CRU) CRS	Tygerberg	Western Cape Province

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Countries where clinical trial is conducted

India,  South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maternal Health Component: Composite endpoint of progression to AIDS-defining illness or death		Measured at the end of the 5-year study period	Yes
Primary	Antepartum Component: Confirmed presence of infant HIV infection	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	Measured at birth or Week 1	No
Primary	Antepartum Component: Grade 3 or higher toxicity (for women, also selected Grade 2 hematologic, renal, and hepatic adverse events)		Measured through the Week 1 postpartum study visit	Yes
Primary	Antepartum Component: Obstetrical complications		Measured through the Week 1 postpartum study visit	Yes
Primary	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)		Measured through the Week 1 postpartum study visit	Yes
Secondary	Maternal Health Component: Death		Measured at the end of the 5-year study period	Yes
Secondary	Maternal Health Component: AIDS-defining illness		Measured at the end of the 5-year study period	Yes
Secondary	Maternal Health Component: Composite endpoint of progression to AIDS-defining illness, death, or a serious non-AIDS cardiovascular, hepatic, or renal event		Measured at the end of the 5-year study period	Yes
Secondary	Maternal Health Component: HIV/AIDS-related events		Measured at the end of the 5-year study period	Yes
Secondary	Maternal Health Component: Cardiovascular or other metabolic events		Measured at the end of the 5-year study period	Yes
Secondary	Maternal Health Component: Other targeted medical conditions		Measured at the end of the 5-year study period	Yes
Secondary	Maternal Health Component: Composite endpoint of HIV/AIDS-related event or death		Measured at the end of the 5-year study period	Yes
Secondary	Maternal Health Component: Composite endpoint of HIV/AIDS-related event or World Health Organization (WHO) Clinical Stage 2 or 3 event		Measured at the end of the 5-year study period	Yes
Secondary	Maternal Health Component: Composite endpoint of any condition outlined in Appendix IV of the protocol or death		Measured at the end of the 5-year study period	Yes
Secondary	Maternal Health Component: Tuberculosis		Measured at the end of the 5-year study period	No
Secondary	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		Measured at the end of the 5-year study period	Yes
Secondary	Maternal Health Component: Viral resistance		Measured at the end of the 5-year study period	No
Secondary	Maternal Health Component: Self-reported adherence		Measured at the end of the 5-year study period	No
Secondary	Maternal Health Component: Quality of life		Measured at the end of the 5-year study period	No
Secondary	Maternal Health Component: Changes in plasma concentrations of inflammatory and thrombogenic markers		Measured at the end of the 5-year study period	No
Secondary	Maternal Health Component: Cost-effectiveness		Measured at the end of the 5-year study period	No
Secondary	Antepartum Component: Infant HIV infection detected by HIV NAT positivity in the birth sample		Measured at the birth (Day 0-5) visit	No
Secondary	Antepartum Component: Overall and HIV-free infant survival		Measured through 24 months post-delivery	Yes
Secondary	Antepartum Component: Adherence to the maternal ARV regimen, measured by maternal report		Measured through the Week 1 postpartum study visit	No
Secondary	Antepartum Component: Cost-effectiveness and feasibility of the trial ARV regimens		Measured at study completion	No
Secondary	Antepartum Component: Maternal and infant viral resistance to the maternal and infant ARV strategies		Measured throughout study	No
Secondary	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		Measured at Week 8	No
Secondary	Antepartum Component: Maternal HIV RNA less than 400 copies/mL at delivery		Measured at the time of delivery	No