Study to Improve Survival Among HIV-Exposed Infants in Botswana (Mpepu)

Study Description

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Brief Summary:

The purpose of this study is to find ways to improve infant health and survival among infants whose mothers are HIV-infected but who do not themselves have HIV.

Condition or disease	Intervention/treatment	Phase
HIV Infections; Neutropenia; Anemia	Drug: cotrimoxazole prophylaxis; Drug: cotrimoxazole placebo; Behavioral: exclusive breastfeeding until 6 months of age; Behavioral: breastfeeding for 12 months	Phase 2

Detailed Description:

As improved MTCT prevention interventions reduce the number of HIV-infected infants in the antepartum and peripartum periods, interventions to improve HIV-free survival among HIV-uninfected infants are needed. Morbidity and mortality are increased among HIV-uninfected infants born to HIV-infected mothers, and reduced infant survival among HIV-exposed infants may lead to as many deaths as HIV infection itself. In Botswana, the use of formula feeding or shorter breastfeeding may worsen the problem of early infant mortality among HIV-exposed infants.

The study will enroll pregnant or postpartum HIV-1-infected women, and their HIV-uninfected infants in Botswana. At 2-4 weeks of age, live HIV-uninfected infants will be randomized to receive either double-blinded cotrimoxazole (CTX) or placebo from 2-4 weeks through 15 months. In addition, breastfeeding (BF) infants will be randomized to BF until either 6 or 12 months of age. Children will be followed prospectively until 18 months of age. The primary endpoint will be survival at 18 months comparing all infants in the CTX vs. placebo arms, and by randomized duration of BF among those BF at randomization. Secondary endpoints will evaluate survival and morbidity/mortality at 12 and 15 months; HIV-free survival to 18 months; and the safety of CTX prophylaxis. Secondary observational objectives include comparing MTCT and mortality by initial feeding method (formula feeding or any BF > 1 month), and an analysis of maternal characteristics as predictors for initial feeding choice and HIV-free survival. All women and infants will receive standard antenatal and peripartum prophylaxis from the Botswana government for MTCT prevention (PMTCT), and will choose a feeding method with counseling. Breastfeeding infants will receive infant nevirapine (NVP) prophylaxis or will be protected from MTCT by the use of maternal HAART.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	3724 participants
Allocation:	Randomized
Intervention Model:	Factorial Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Prevention
Official Title:	A Randomized Study of Cotrimoxazole Prophylaxis and Longer Breastfeeding Duration to Improve Survival Among HIV-Exposed Infants in Botswana
Study Start Date :	May 2011
Actual Primary Completion Date :	March 2015
Estimated Study Completion Date :	October 2018

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: infant cotrimoxazole	Drug: cotrimoxazole prophylaxis; 100mg/20mg per day (or 2.5 mL of syrup from a 200mg/40mg per 5mL suspension) from 1-6 months, followed by 200mg/40mg per day (or 5 mL of syrup from a 200mg/40mg per 5 mL suspension) from 6 to 12 months; Other Name: Trimethoprim-Sulfamethoxazole Combination
Placebo Comparator: infant placebo	Drug: cotrimoxazole placebo; 100mg/20mg per day (or 2.5 mL of syrup from a 200mg/40mg per 5mL suspension) from 1-6 months, followed by 200mg/40mg per day (or 5 mL of syrup from a 200mg/40mg per 5 mL suspension) from 6 to 12 months
Active Comparator: exclusive breastfeeding for 6 months	Behavioral: exclusive breastfeeding until 6 months of age; Breastfeeding for 6 months, followed by formula feeding for 6 month. Breastfeeding infants will be prophylaxed with maternal highly active antiretroviral therapy (HAART) (if available) or with infant nevirapine.
Active Comparator: exclusive breastfeeding for 12 months	Behavioral: breastfeeding for 12 months; Breastfeeding infants will be prophylaxed with maternal HAART (if available) or with infant nevirapine.

Outcome Measures

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Primary Outcome Measures :

1. Survival [ Time Frame: 18 months of age ]
   The primary outcome measure is survival at 18 months comparing all infants in the CTX vs. placebo arms, and by randomized duration of breastfeeding among those breastfeeding at randomization.

Secondary Outcome Measures :

1. HIV-free Survival [ Time Frame: 18 months of age ]
   Secondary outcome measures will evaluate HIV-free survival between 4 weeks and 18 months among infants randomized to either 6 months or 12 months of breastfeeding.
2. Safety of CTX prophylaxis [ Time Frame: 18 months ]
   Secondary outcome measures will evaluate the safety of CTX prophylaxis through 18 months
3. Morbidity and mortality [ Time Frame: 18 months of age ]
   Secondary outcome measures will evaluate morbidity and mortality to 18 months.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• HIV-infected women, > 26 weeks gestation and < 34 days postpartum.
• Women must be ¬> 18 years of age and willing/able to sign informed consent.
• Women and infants must be able to follow up regularly at a study clinic through 18 months postpartum.
• For Feeding Randomization Only: Women must be willing to breastfeed for up to 12 months, and to stop at 6 months, depending upon their feeding assignment.

Exclusion Criteria:

• Antepartum women: Known infant anomalies resulting in a high probability that the infant will not survive to 18 months.
• Postpartum women: Known HIV-infected infant, or infant medical condition making survival to 18 months unlikely.

Contacts and Locations

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Locations

Botswana
Princess Marina Hospital
Gaborone, Botswana
Athlone Hospital
Lobatse, Botswana
Scottish Livingstone Hospital
Molepolole, Botswana

Sponsors and Collaborators

Harvard School of Public Health

Harvard Medical School

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

Principal Investigator:	Shahin Lockman, MD, MS	Harvard School of Public Health
Principal Investigator:	Roger L Shapiro, MD, MPH	Harvard School of Public Health

More Information

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Additional Information:

Shapiro RL et al. Similar mortality with cotrimoxazole vs. placebo in HIV-exposed uninfected children, Conference on Retroviruses and Opportunistic Infections (CROI 2016), Boston, abstract 37. 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Lockman S, Hughes M, Powis K, Ajibola G, Bennett K, Moyo S, van Widenfelt E, Leidner J, McIntosh K, Mazhani L, Makhema J, Essex M, Shapiro R. Effect of co-trimoxazole on mortality in HIV-exposed but uninfected children in Botswana (the Mpepu Study): a double-blind, randomised, placebo-controlled trial. Lancet Glob Health. 2017 May;5(5):e491-e500. doi: 10.1016/S2214-109X(17)30143-2.

Ajibola G, Zash R, Shapiro RL, Batlang O, Botebele K, Bennett K, Chilisa F, Widenfelt EV, Makhema J, Lockman S, Holmes LB, Powis KM. Detecting congenital malformations - Lessons learned from the Mpepu study, Botswana. PLoS One. 2017 Mar 24;12(3):e0173800. doi: 10.1371/journal.pone.0173800. eCollection 2017.

Responsible Party:	Roger Shapiro, Principal Investigator, Harvard School of Public Health
ClinicalTrials.gov Identifier:	NCT01229761 History of Changes
Other Study ID Numbers:	18677; R01HD061265 ( U.S. NIH Grant/Contract )
First Posted:	October 28, 2010
Last Update Posted:	March 10, 2017
Last Verified:	March 2017

Keywords provided by Roger Shapiro, Harvard School of Public Health:

HIV; Trimethoprim-Sulfamethoxazole Combination; Breast Feeding; Infant Mortality; Morbidity	Botswana; Africa; Infectious disease transmission, vertical; adverse drug event

Additional relevant MeSH terms:

HIV Infections; Neutropenia; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Agranulocytosis; Leukopenia; Leukocyte Disorders; Hematologic Diseases; Trimethoprim	Trimethoprim, Sulfamethoxazole Drug Combination; Sulfamethoxazole; Anti-Infective Agents, Urinary; Anti-Infective Agents; Renal Agents; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Folic Acid Antagonists; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Cytochrome P-450 CYP2C8 Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Anti-Bacterial Agents