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Optimal Chemopreventive Regimens to Prevent Malaria and Improve Birth Outcomes in Uganda

NCT ID: NCT04336189

Last Updated: 2025-11-06

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

2757 participants

Study Classification

INTERVENTIONAL

Study Start Date

2020-12-28

Study Completion Date

2024-07-28

Brief Summary

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This trial tests the hypothesis that intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) + dihydroartemisin-piperaquine (DP) will significantly reduce the risk of adverse birth outcomes compared to IPTp with SP alone or DP alone. This double-blinded randomized controlled phase III trial of 2757 HIV uninfected pregnant women enrolled at 12-20 weeks gestation will be randomized in equal proportions to one of three IPTp treatment arms: 1) SP given every 4 weeks, or 2) DP given every 4 weeks, or 3) SP+DP given every 4 weeks. SP or DP placebos will be used to ensure adequate blinding is achieved in the study and follow-up will end 28 days after giving birth.

Detailed Description

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Malaria in pregnancy remains a major challenge in Africa, where approximately 50 million women are at risk for P. falciparum infection during pregnancy each year. Among pregnant women living in malaria endemic areas symptomatic disease is uncommon, but infection with malaria parasites is associated with maternal anemia and adverse birth outcomes including abortions, stillbirth, preterm birth, low birth weight (LBW), and infant mortality. The World Health Organization (WHO) recommends the use of long-lasting insecticidal nets (LLINs) and intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) for the prevention of malaria in pregnancy in endemic areas of Africa. However, there is concern for diminishing efficacy of these interventions due to the spread of vector resistance to the pyrethroid insecticides used in LLINs and parasite resistance to SP. Thus, there is an urgent need for new strategies for the prevention of malaria in pregnancy and improving birth outcomes. Artemisinin-based combination therapies (ACTs) are now the standard treatment for malaria in Africa. Dihydroartemisin-piperaquine (DP) is a fixed-dose ACT and an attractive alternative to SP for IPTp. DP is highly efficacious, and the long half-life of piperaquine provides at least 4 weeks of post-treatment prophylaxis. Recent randomized controlled trials showed that, compared to IPTp with SP, IPTp with DP dramatically reduced risks of malaria-specific outcomes but there were minimal differences between the SP and DP groups in risks of adverse birth outcomes. The key question for this study is why IPTp with either SP or DP is associated with similar risks of adverse birth outcomes despite the far superior antimalarial activity of DP. The likely explanation is that SP, a broad-spectrum antibiotic, protects against non-malarial causes of LBW and preterm birth. The central hypothesis is that SP improves birth outcomes independent of its antimalarial activity and that IPTp with a combination of SP+DP will offer antimalarial and non-antimalarial benefits, thus providing superior prevention of adverse birth outcomes compared to either drug used alone. To test this hypothesis, a double-blinded randomized clinical trial will conducted in a rural area of Uganda with very high malaria transmission intensity, where there is already an established infrastructure for clinical research. Specific aims will be (1) to compare the risk of adverse birth outcomes among pregnant women randomized to receive monthly IPTp with SP vs. DP vs. SP+DP, (2) To compare safety and tolerability of IPTp regimens among pregnant women randomized to receive monthly IPTp with SP vs. DP vs. SP+DP, and (3) to compare risks of malaria-specific and non-malarial outcomes among pregnant women randomized to receive monthly IPTp with SP vs. DP vs. SP+DP. This study will be the first to evaluate the efficacy and safety of a novel combination of well-studied drugs for improving birth outcomes and findings may well have important policy implications, with a change in standard practice for millions of pregnant women in Africa.

Conditions

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Malaria

Keywords

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dihydroartemisinin-piperaquine sulfadoxine-pyrimethamine IPTp reproductive tract infection microbiome drug resistance

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

SEQUENTIAL

Double blinded randomized controlled trial
Primary Study Purpose

PREVENTION

Blinding Strategy

TRIPLE

Participants Caregivers Investigators
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 or SP and DP) 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. A randomization list will be computer generated by a member of the project who will not be directly involved in the conduct of the study. The randomization list will include consecutive treatment numbers with corresponding random treatment assignments. Randomized codes will correspond to the 3 treatment arms using permuted variable sized blocks of 6 and 9.

Study Groups

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SP + DP placebo every 4 weeks

Group Type ACTIVE_COMPARATOR

Sulfadoxine-pyrimethamine (SP)

Intervention Type DRUG

SP (Kamsidar) will be supplied by Kampala Pharmaceutical Industries (KPI), Uganda. SP will be given as a single dose consisting of 3 full strength tablets.

DP + SP placebo every 4 weeks

Group Type ACTIVE_COMPARATOR

Dihydroartemisinin-piperaquine (DP)

Intervention Type DRUG

DP (Duo-Cotecxin) will be supplied by Holley-Cotec, Beijing, China. DP will consist of 3 full strength tablets given once a day for 3 consecutive days.

SP + DP given every 4 weeks

Group Type ACTIVE_COMPARATOR

Sulfadoxine-pyrimethamine (SP)

Intervention Type DRUG

SP (Kamsidar) will be supplied by Kampala Pharmaceutical Industries (KPI), Uganda. SP will be given as a single dose consisting of 3 full strength tablets.

Dihydroartemisinin-piperaquine (DP)

Intervention Type DRUG

DP (Duo-Cotecxin) will be supplied by Holley-Cotec, Beijing, China. DP will consist of 3 full strength tablets given once a day for 3 consecutive days.

Interventions

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Sulfadoxine-pyrimethamine (SP)

SP (Kamsidar) will be supplied by Kampala Pharmaceutical Industries (KPI), Uganda. SP will be given as a single dose consisting of 3 full strength tablets.

Intervention Type DRUG

Dihydroartemisinin-piperaquine (DP)

DP (Duo-Cotecxin) will be supplied by Holley-Cotec, Beijing, China. DP will consist of 3 full strength tablets given once a day for 3 consecutive days.

Intervention Type DRUG

Other Intervention Names

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Kamsidar Duo-Cotecxin

Eligibility Criteria

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Inclusion Criteria

1. Viable singleton pregnancy confirmed by ultrasound
2. Estimated gestational age between 12-20 weeks
3. Confirmed to be HIV- uninfected by rapid test
4. 16 years of age or older
5. Residency within Busia District of Uganda
6. Provision of informed consent
7. Agreement to come to the study clinic for any febrile episode or other illness and avoid medications given outside the study protocol
8. Willing to deliver in the hospital

Exclusion Criteria

1. History of serious adverse event to SP or DP
2. Active medical problem requiring inpatient evaluation at the time of screening
3. Intention of moving outside of Busia District Uganda
4. Chronic medical condition requiring frequent medical attention
5. Prior chemopreventive therapy or any other antimalarial therapy during this pregnancy
6. Early or active labor (documented by cervical change with uterine contractions)
7. Multiple pregnancies (i.e. twins/triplets)
Minimum Eligible Age

16 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

Yes

Sponsors

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National Institutes of Health (NIH)

NIH

Sponsor Role collaborator

Infectious Diseases Research Collaboration, Uganda

OTHER

Sponsor Role collaborator

Grant Dorsey, M.D, Ph.D.

OTHER

Sponsor Role lead

Responsible Party

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Grant Dorsey, M.D, Ph.D.

Principle Investigator

Responsibility Role SPONSOR_INVESTIGATOR

Principal Investigators

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Grant Dorsey, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Phil Rosenthal, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Moses Kamya, MBChB, MMed, PhD

Role: PRINCIPAL_INVESTIGATOR

Makerere University; Infectious Diseases Research Collaboration

Abel Kakuru, MBChB, PhD

Role: STUDY_DIRECTOR

Infectious Diseases Research Collaboration

Locations

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Infectious Diseases Research Collaboration Clinic - Masafu Hospital

Masafu, Busia, Uganda

Site Status

Countries

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Uganda

References

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Kakuru A, Kizza J, Aguti M, Adrama H, Ategeka J, Olwoch P, Nakalembe M, Nankabirwa JI, Opira B, Ozarslan N, Ranjit A, Dela Cruz E, Clark TD, Roh ME, Gaw SL, Jagannathan P, Rosenthal PJ, Kamya MR, Dorsey G. Dihydroartemisinin-piperaquine plus sulfadoxine-pyrimethamine versus either drug alone for intermittent preventive treatment of malaria in pregnancy: A double-blind, randomized, controlled phase 3 trial from Uganda. PLoS Med. 2025 Sep 18;22(9):e1004582. doi: 10.1371/journal.pmed.1004582. eCollection 2025 Sep.

Reference Type DERIVED
PMID: 40966190 (View on PubMed)

Provided Documents

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Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

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DPSP

Identifier Type: -

Identifier Source: org_study_id