Prevention of Malaria in HIV-uninfected Pregnant Women and Infants

NCT02793622 | Completed Phase 3 Results

• 1 other identifier: PROMOTE-BC3
• Study Type: interventional
• Target: 782
• Locations: 1 country
• Sites: 1

Brief Summary

This will be a double-blinded randomized controlled phase III trial of 782 HIV uninfected pregnant women and the children born to them. HIV uninfected women at 12-20 weeks gestation will be randomized in equal proportions to one of two intermittent preventive treatment in pregnancy (IPTp) treatment arms: 1) monthly sulfadoxine-pyrimethamine (SP), or 2) monthly dihydroartemisinin-piperaquine (DP). Both interventions arms will have either SP or DP placebo to ensure adequate blinding is achieved in the study. Follow-up for the pregnant women will end approximately 6 weeks after giving birth. All children born to mothers enrolled in the study will be followed from birth until they reach 12 months of age.

Conditions

Malaria

Keywords

Chemoprevention; Malaria; Sulfadoxine-Pyrimethamine; Dihydroartemisinin-Piperaquine

Outcome Measures

Primary Outcomes (3)

• Number of Participants Who Deliver With a Composite Adverse Birth Outcome

  Composite adverse birth outcome defined as any one of the following: 1) Low birth weight (\< 2500 gm); 2) Preterm delivery (\< 37 weeks gestational age); 3) Small for gestational age (\< 10th percentile relative to an external growth reference)

  Delivery

• Incidence of Malaria in Infants

  episodes per person year

  Time at risk will begin at birth and end when study participants reaches 12 months of age or early study termination

• Mean Gestational Age in Weeks at Birth

  Gestational age in weeks determined by ultrasound dating (gold standard) and by the metabolic profiling outcome from biological specimens including placental tissue and placental blood.

  At the time of delivery

Secondary Outcomes (11)

• Prevalence of Placental Malaria by Histology

  Delivery

• Prevalence of Placental Parasitemia

  Delivery

• Prevalence of Maternal Malaria

  Gestational age between 12-20 weeks (at study entry) up to delivery

• Number of Participants With Adverse Events

  Starting at the time of their first study drug administration, approximately gestational age between 12-20 weeks, up to one month post-delivery

• Prevalence of Anemia in Pregnant Women

  Starting at the time of their first study drug administration, approximately gestational age between 12-20 weeks, up to one month post-delivery

Study Arms (2)

Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy

ACTIVE COMPARATOR

Women will be given SP (3 full strength tabs, 500 mg/25 mg) every four weeks times during pregnancy. In addition, placebos will be used to mimic the identical dosing strategy such that every 4 weeks women will receive two drugs on day 1 (SP and placebo or DP and placebo) followed by one drug on days 2 and 3 (DP or placebo). Two placebos will be used, one that mimics the appearance of SP and one that mimics the appearance of DP.

Drug: Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy

Monthly Dihydroartemisinin-Piperaquine (DP) During 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. In addition, placebos will be used to mimic the identical dosing strategy such that every 4 weeks women will receive two drugs on day 1 (SP and placebo or DP and placebo) followed by one drug on days 2 and 3 (DP or placebo). Two placebos will be used, one that mimics the appearance of SP and one that mimics the appearance of DP.

Drug: Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy

Interventions

Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy DRUG

Also known as: Kamsidar (KPI)

Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy

Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy DRUG

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

Monthly Dihydroartemisinin-Piperaquine (DP) During 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:

• Pregnancy confirmed by positive urine pregnancy test or intrauterine pregnancy by ultrasound
• Estimated gestational age between 12-20 weeks
• Confirmed to be HIV uninfected by rapid test
• years of age or older
• Resident of Busia District, Uganda
• Provision of informed consent by the pregnant woman for herself and her unborn child
• 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 SP or DP
• Active medical problem requiring inpatient evaluation at the time of screening
• Intention of moving outside of Busia District, Uganda
• Chronic medical condition requiring frequent medical attention
• Prior SP preventive therapy or any other antimalarial therapy during this pregnancy
• Early or active labor (documented by cervical change with uterine contractions)

Sponsors & Collaborators

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

Study Sites (1)

IDRC - Tororo Research Clinic

Tororo, Uganda

Location

Related Publications (12)

• Kajubi R, Ochieng T, Kakuru A, Jagannathan P, Nakalembe M, Ruel T, Opira B, Ochokoru H, Ategeka J, Nayebare P, Clark TD, Havlir DV, Kamya MR, Dorsey G. Monthly sulfadoxine-pyrimethamine versus dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria in pregnancy: a double-blind, randomised, controlled, superiority trial. Lancet. 2019 Apr 6;393(10179):1428-1439. doi: 10.1016/S0140-6736(18)32224-4. Epub 2019 Mar 22.

  PMID: 30910321 RESULT

• Harrington WE, Kakuru A, Jagannathan P. Malaria in pregnancy shapes the development of foetal and infant immunity. Parasite Immunol. 2019 Mar;41(3):e12573. doi: 10.1111/pim.12573. Epub 2018 Aug 28.

  PMID: 30019470 RESULT

• Briggs J, Ategeka J, Kajubi R, Ochieng T, Kakuru A, Ssemanda C, Wasswa R, Jagannathan P, Greenhouse B, Rodriguez-Barraquer I, Kamya M, Dorsey G. Impact of Microscopic and Submicroscopic Parasitemia During Pregnancy on Placental Malaria in a High-Transmission Setting in Uganda. J Infect Dis. 2019 Jul 2;220(3):457-466. doi: 10.1093/infdis/jiz130.

  PMID: 30891605 RESULT

• Okiring J, Olwoch P, Kakuru A, Okou J, Ochokoru H, Ochieng TA, Kajubi R, Kamya MR, Dorsey G, Tusting LS. Household and maternal risk factors for malaria in pregnancy in a highly endemic area of Uganda: a prospective cohort study. Malar J. 2019 Apr 23;18(1):144. doi: 10.1186/s12936-019-2779-x.

  PMID: 31014336 RESULT

• Kakuru A, Jagannathan P, Kajubi R, Ochieng T, Ochokoru H, Nakalembe M, Clark TD, Ruel T, Staedke SG, Chandramohan D, Havlir DV, Kamya MR, Dorsey G. Impact of intermittent preventive treatment of malaria in pregnancy with dihydroartemisinin-piperaquine versus sulfadoxine-pyrimethamine on the incidence of malaria in infancy: a randomized controlled trial. BMC Med. 2020 Aug 10;18(1):207. doi: 10.1186/s12916-020-01675-x.

  PMID: 32772921 RESULT

• Savic RM, Jagannathan P, Kajubi R, Huang L, Zhang N, Were M, Kakuru A, Muhindo MK, Mwebaza N, Wallender E, Clark TD, Opira B, Kamya M, Havlir DV, Rosenthal PJ, Dorsey G, Aweeka FT. Intermittent Preventive Treatment for Malaria in Pregnancy: Optimization of Target Concentrations of Dihydroartemisinin-Piperaquine. Clin Infect Dis. 2018 Sep 14;67(7):1079-1088. doi: 10.1093/cid/ciy218.

  PMID: 29547881 RESULT

• Ategeka J, Kakuru A, Kajubi R, Wasswa R, Ochokoru H, Arinaitwe E, Yeka A, Jagannathan P, Kamya MR, Muehlenbachs A, Chico RM, Dorsey G. Relationships Between Measures of Malaria at Delivery and Adverse Birth Outcomes in a High-Transmission Area of Uganda. J Infect Dis. 2020 Aug 4;222(5):863-870. doi: 10.1093/infdis/jiaa156.

  PMID: 32249917 RESULT

• Roh ME, Kuile FOT, Rerolle F, Glymour MM, Shiboski S, Gosling R, Gutman J, Kakuru A, Desai M, Kajubi R, L'Ianziva A, Kamya MR, Dorsey G, Chico RM. Overall, anti-malarial, and non-malarial effect of intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine on birthweight: a mediation analysis. Lancet Glob Health. 2020 Jul;8(7):e942-e953. doi: 10.1016/S2214-109X(20)30119-4.

  PMID: 32562650 RESULT

• Vaaben AV, Levan J, Nguyen CBT, Callaway PC, Prahl M, Warrier L, Nankya F, Musinguzi K, Kakuru A, Muhindo MK, Dorsey G, Kamya MR, Feeney ME. In Utero Activation of Natural Killer Cells in Congenital Cytomegalovirus Infection. J Infect Dis. 2022 Sep 4;226(4):566-575. doi: 10.1093/infdis/jiac307.

  PMID: 35876164 DERIVED

• Hughes E, Wallender E, Kajubi R, Jagannathan P, Ochieng T, Kakuru A, Kamya MR, Clark TD, Rosenthal PJ, Dorsey G, Aweeka F, Savic RM. Piperaquine-Induced QTc Prolongation Decreases With Repeated Monthly Dihydroartemisinin-Piperaquine Dosing in Pregnant Ugandan Women. Clin Infect Dis. 2022 Aug 31;75(3):406-415. doi: 10.1093/cid/ciab965.

  PMID: 34864925 DERIVED

• Zehner N, Adrama H, Kakuru A, Andra T, Kajubi R, Conrad M, Nankya F, Clark TD, Kamya M, Rodriguez-Barraquer I, Dorsey G, Jagannathan P. Age-Related Changes in Malaria Clinical Phenotypes During Infancy Are Modified by Sickle Cell Trait. Clin Infect Dis. 2021 Nov 16;73(10):1887-1895. doi: 10.1093/cid/ciab245.

  PMID: 33738485 DERIVED

• Kakuru A, Roh ME, Kajubi R, Ochieng T, Ategeka J, Ochokoru H, Nakalembe M, Clark TD, Ruel T, Staedke SG, Chandramohan D, Havlir DV, Kamya MR, Dorsey G, Jagannathan P. Infant sex modifies associations between placental malaria and risk of malaria in infancy. Malar J. 2020 Dec 3;19(1):449. doi: 10.1186/s12936-020-03522-z.

  PMID: 33272281 DERIVED

MeSH Terms

Conditions

Malaria

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Results Point of Contact

• Title: Grant Dorsey, MD
• Organization: University of California, San Francisco

grant.dorsey@ucsf.edu

628-206-4680

Study Officials

• Grant Dorsey, MD PhD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

• Diane V Havlir, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

• Moses Kamya, MBChB MMed PhD

  Makarere Univeritys ; Infectious Disease Research Collaboration

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

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: May 20, 2016
• First Posted: June 8, 2016
• Study Start: September 1, 2016
• Primary Completion: December 4, 2018
• Study Completion: December 4, 2018
• Last Updated: April 14, 2021
• Results First Posted: April 14, 2021

Record last verified: 2021-04

Locations

UG (1)