Reducing the Burden of Malaria in HIV-Infected Pregnant Women and Their HIV-Exposed Children (PROMOTE-BC2)

NCT02282293 | Completed Phase 3 Results DMC

• 1 other identifier: PROMOTE-BC2
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 1

Brief Summary

This is a double-blinded, randomized controlled trial of 200 HIV-infected pregnant women living in Tororo, Uganda, an area of high malaria transmission. HIV-infected pregnant women between 12 and 28 weeks gestation will be randomized to receive enhanced malaria chemoprevention with monthly dihydroartemisinin-piperaquine (DP) versus monthly DP placebo. Their HIV-exposed children will receive the same prevention regimen from 2 to 24 months of age to which the mothers were randomized. All women will receive daily trimethoprim-sulfamethoxazole (TS) throughout the study per Uganda Ministry of Health guidelines. Children will also receive daily TS from 6 weeks to 24 months of age. TS will be considered a study drug only in infants and children beginning 6 weeks after cessation of breastfeeding and upon exclusion of HIV infection. Women and their children will be followed for 36 months after delivery. In a subset of the study population, the investigators will conduct an intensive pharmacokinetic study that will evaluate pharmacokinetic exposure of DP and EFV. The investigators will also measure HIV-related outcomes among the women enrolled in the study. The investigators will test the hypothesis that for HIV-infected mothers and HIV-exposed infants, that enhanced versus standard malaria chemoprevention in HIV-infected pregnant women and their children will reduce the incidence of malaria among children from 0 to 24 months of age and improve the development of naturally acquired antimalarial immunity.

Conditions

Malaria; Human Immunodeficiency Virus

Keywords

Chemoprevention; Malaria; Uganda; Dihydroartemisinin-piperaquine; Trimethoprim-sulfamethoxazole; Human Immunodeficiency Virus

Outcome Measures

Primary Outcomes (2)

• Number of Participants With Placental Malaria

  The primary outcome will be the prevalence of placental malaria based on placental histopathology and dichotomized into any evidence of placental infection (parasites or pigment) vs. no evidence of placental infection.

  at delivery estimated to be within 10 to 30 weeks of study entry

• Incidence of Malaria, Pregnant Women

  The primary outcome will be the incidence of malaria, defined as the number of incident episodes per time at risk. Incident cases will include all treatments for malaria not proceeded by another treatment in the previous 14 days.

  Time at risk will begin following administration of first dose of study drug to delivery

Secondary Outcomes (5)

• Maternal Parasitemia at Delivery by Microscopy and LAMP

  At delivery

• Placental Parasitemia (Number of Women With Placental Blood Samples Positive for Malaria by Microscopy or PCR)

  At delivery

• Number of Monthly Routine Visits With Positive Blood Samples for Parasites

  Following administration of first dose of study drug to delivery

• Composite Adverse Birth Outcome (Proportion With Low Birth Weight (<2500 gm), Spontaneous Abortion (<28 Weeks), Stillbirth (Fetal Demise ≥28 Weeks), Congenital Anomaly, or Preterm Delivery (<37 Weeks)

  At delivery

• Number of Routine Visits Measured Every 8 Weeks During Pregnancy for Which the Participants Had Anemia

  Following administration of first dose of study drugs to delivery

Study Arms (2)

Daily TS + Monthly DP pregnancy

ACTIVE COMPARATOR

Women will be given DP (3 full strength tabs, 40 mg/320 mg, given once a day for 3 consecutive days) every 4 weeks during pregnancy. During pregancy, TS will be given to women at a dose of 960mg once daily.

Drug: Monthly dihydroartemisinin-piperaquine (DP) + daily trimethoprim/sulfamethoxazole (TS)

Daily TS + DP Placebo pregnancy

PLACEBO COMPARATOR

Women will be given DP placebo (3 tabs, given once a day for 3 consecutive days) every 4 weeks during pregnancy. During pregnancy, TS will be given to women at a dose of 960mg once daily.

Drug: Monthly placebo + daily trimethoprim/sulfamethoxazole (TS)

Interventions

Monthly dihydroartemisinin-piperaquine (DP) + daily trimethoprim/sulfamethoxazole (TS) DRUG

Also known as: Duo-Cotexin (Holley-Cotec)

Daily TS + Monthly DP pregnancy

Monthly placebo + daily trimethoprim/sulfamethoxazole (TS) DRUG

Daily TS + DP Placebo pregnancy

Eligibility Criteria

• Age: 16 Years+
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Intrauterine pregnancy confirmed by ultrasound
• Estimated gestational age between 12-28 weeks
• Confirmed to be HIV-infected by Uganda country standard rapid HIV test
• years of age or older
• Residency within 30 km of the study clinic
• Provision of informed consent
• Agreement to come to the study clinic for any febrile episode or other illness and avoid medications given outside the study protocol
• Plan to deliver in the hospital

You may not qualify if:

• History of serious adverse event to TS or DP
• Refusal to take cART during pregnancy or as part of routine HIV care
• Active medical problem requiring inpatient evaluation at the time of screening
• Intention of moving more than 30 km from the study clinic
• Active WHO stage 4 condition not stable under treatment
• Signs or symptoms of early or active labor
• Currently on ritonavir
• Currently taking drugs associated with known risk of Torsades de pointes
• Currently taking CYP3A inhibitor medications which potentially inhibit the metabolism of piperaquine
• History of cardiac problems or fainting

Sponsors & Collaborators

• University of California, San Francisco: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

IDRC Research Clinic - Tororo District Hospital

Tororo, Uganda

Location

Related Publications (11)

• Kajubi R, Huang L, Jagannathan P, Chamankhah N, Were M, Ruel T, Koss CA, Kakuru A, Mwebaza N, Kamya M, Havlir D, Dorsey G, Rosenthal PJ, Aweeka FT. Antiretroviral Therapy With Efavirenz Accentuates Pregnancy-Associated Reduction of Dihydroartemisinin-Piperaquine Exposure During Malaria Chemoprevention. Clin Pharmacol Ther. 2017 Sep;102(3):520-528. doi: 10.1002/cpt.664. Epub 2017 May 30.

  PMID: 28187497 BACKGROUND

• Sonoiki E, Nsanzabana C, Legac J, Sindhe KM, DeRisi J, Rosenthal PJ. Altered Plasmodium falciparum Sensitivity to the Antiretroviral Protease Inhibitor Lopinavir Associated with Polymorphisms in pfmdr1. Antimicrob Agents Chemother. 2016 Dec 27;61(1):e01949-16. doi: 10.1128/AAC.01949-16. Print 2017 Jan.

  PMID: 27821443 BACKGROUND

• Natureeba P, Kakuru A, Muhindo M, Ochieng T, Ategeka J, Koss CA, Plenty A, Charlebois ED, Clark TD, Nzarubara B, Nakalembe M, Cohan D, Rizzuto G, Muehlenbachs A, Ruel T, Jagannathan P, Havlir DV, Kamya MR, Dorsey G. Intermittent Preventive Treatment With Dihydroartemisinin-Piperaquine for the Prevention of Malaria Among HIV-Infected Pregnant Women. J Infect Dis. 2017 Jul 1;216(1):29-35. doi: 10.1093/infdis/jix110.

  PMID: 28329368 RESULT

• Prahl M, Jagannathan P, McIntyre TI, Auma A, Wamala S, Nalubega M, Musinguzi K, Naluwu K, Sikyoma E, Budker R, Odorizzi P, Kakuru A, Havlir DV, Kamya MR, Dorsey G, Feeney ME. Sex Disparity in Cord Blood FoxP3+ CD4 T Regulatory Cells in Infants Exposed to Malaria In Utero. Open Forum Infect Dis. 2017 Feb 11;4(1):ofx022. doi: 10.1093/ofid/ofx022. eCollection 2017 Winter.

  PMID: 28480292 RESULT

• Odorizzi PM, Feeney ME. Impact of In Utero Exposure to Malaria on Fetal T Cell Immunity. Trends Mol Med. 2016 Oct;22(10):877-888. doi: 10.1016/j.molmed.2016.08.005. Epub 2016 Sep 7.

  PMID: 27614925 RESULT

• Prahl M, Jagannathan P, McIntyre TI, Auma A, Farrington L, Wamala S, Nalubega M, Musinguzi K, Naluwu K, Sikyoma E, Budker R, Vance H, Odorizzi P, Nayebare P, Ategeka J, Kakuru A, Havlir DV, Kamya MR, Dorsey G, Feeney ME. Timing of in utero malaria exposure influences fetal CD4 T cell regulatory versus effector differentiation. Malar J. 2016 Oct 7;15(1):497. doi: 10.1186/s12936-016-1545-6.

  PMID: 27717402 RESULT

• Roh ME, Shiboski S, Natureeba P, Kakuru A, Muhindo M, Ochieng T, Plenty A, Koss CA, Clark TD, Awori P, Nakalambe M, Cohan D, Jagannathan P, Gosling R, Havlir DV, Kamya MR, Dorsey G. Protective Effect of Indoor Residual Spraying of Insecticide on Preterm Birth Among Pregnant Women With HIV Infection in Uganda: A Secondary Data Analysis. J Infect Dis. 2017 Dec 19;216(12):1541-1549. doi: 10.1093/infdis/jix533.

  PMID: 29029337 RESULT

• Pons-Duran C, Wassenaar MJ, Yovo KE, Marin-Carballo C, Briand V, Gonzalez R. Intermittent preventive treatment regimens for malaria in HIV-positive pregnant women. Cochrane Database Syst Rev. 2024 Sep 26;9(9):CD006689. doi: 10.1002/14651858.CD006689.pub3.

  PMID: 39324693 DERIVED

• Hughes E, Imperial M, Wallender E, Kajubi R, Huang L, Jagannathan P, Zhang N, Kakuru A, Natureeba P, Mwima MW, Muhindo M, Mwebaza N, Clark TD, Opira B, Nakalembe M, Havlir D, Kamya M, Rosenthal PJ, Dorsey G, Aweeka F, Savic RM. Piperaquine Exposure Is Altered by Pregnancy, HIV, and Nutritional Status in Ugandan Women. Antimicrob Agents Chemother. 2020 Nov 17;64(12):e01013-20. doi: 10.1128/AAC.01013-20. Print 2020 Nov 17.

  PMID: 33020153 DERIVED

• Wallender E, Zhang N, Conrad M, Kakuru A, Muhindo M, Tumwebaze P, Kajubi R, Mota D, Legac J, Jagannathan P, Havlir D, Kamya M, Dorsey G, Aweeka F, Rosenthal PJ, Savic RM. Modeling Prevention of Malaria and Selection of Drug Resistance with Different Dosing Schedules of Dihydroartemisinin-Piperaquine Preventive Therapy during Pregnancy in Uganda. Antimicrob Agents Chemother. 2019 Jan 29;63(2):e01393-18. doi: 10.1128/AAC.01393-18. Print 2019 Feb.

  PMID: 30530597 DERIVED

• Wallender E, Vucicevic K, Jagannathan P, Huang L, Natureeba P, Kakuru A, Muhindo M, Nakalembe M, Havlir D, Kamya M, Aweeka F, Dorsey G, Rosenthal PJ, Savic RM. Predicting Optimal Dihydroartemisinin-Piperaquine Regimens to Prevent Malaria During Pregnancy for Human Immunodeficiency Virus-Infected Women Receiving Efavirenz. J Infect Dis. 2018 Mar 5;217(6):964-972. doi: 10.1093/infdis/jix660.

  PMID: 29272443 DERIVED

MeSH Terms

Conditions

Malaria; Acquired Immunodeficiency Syndrome

Interventions

Sulfamethoxazole

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases; HIV Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Sulfanilamides; Aniline Compounds; Amines; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds

Results Point of Contact

• Title: Dr. Grant Dorsey
• Organization: UCSF

grant.dorsey@ucsf.edu

415-206-4680

Study Officials

• Diane V Havlir, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

• Grant Dorsey, MD, PhD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

• Moses R Kamya, MBChB, MMed, PhD

  Makerere University; Infectious Diseases Research Collaboration

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: October 30, 2014
• First Posted: November 4, 2014
• Study Start: December 9, 2014
• Primary Completion: May 26, 2016
• Study Completion: May 26, 2016
• Last Updated: March 5, 2019
• Results First Posted: March 5, 2019

Record last verified: 2019-02

Locations

UG (1)