MalariaPhase 3NCT04336189
Optimal Chemopreventive Regimens to Prevent Malaria and Improve Birth Outcomes in Uganda
A Phase 3 study testing Sulfadoxine-pyrimethamine (SP) and Dihydroartemisinin-piperaquine (DP) in people with Malaria, run by Grant Dorsey, M.D, Ph.D. at 1 site in Uganda.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 16 years and older, women onlyHealthy volunteers can take part
- Conditions the study is for
- Malaria
- What is being tested?
- Sulfadoxine-pyrimethamine (SP) and Dihydroartemisinin-piperaquine (DP)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 2,757 participants
- Where
- 1 siteUganda
- Study dates
- 28 Dec 2020to 28 Jul 2024
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 16 years and older
- Women only
- Healthy volunteers accepted
- Child, Adult, Older adult
Who may be able to join
- Viable singleton pregnancy confirmed by ultrasound
- Estimated gestational age between 12-20 weeks
- Confirmed to be HIV- uninfected by rapid test
- 16 years of age or older
- Residency within Busia District of Uganda
- 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
- Willing to deliver in the hospital
Who cannot join
- 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 chemopreventive therapy or any other antimalarial therapy during this pregnancy
- Early or active labor (documented by cervical change with uterine contractions)
- Multiple pregnancies (i.e. twins/triplets)
Trial locations and contacts
1 site in 1 country.
Uganda1 site
Infectious Diseases Research Collaboration Clinic - Masafu Hospital
Masafu, Busia
About this study
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.
Read the detailed description
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
- Malaria
- Being tested
- Sulfadoxine-pyrimethamine (SP), Dihydroartemisinin-piperaquine (DP)
- Keywords
- dihydroartemisinin-piperaquine, sulfadoxine-pyrimethamine, IPTp, reproductive tract infection, microbiome, drug resistance
- Medical subject headings
- Malaria, Reproductive Tract Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Sulfadoxine-pyrimethamine (SP)Drug
Also called Kamsidar
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)Drug
Also called Duo-Cotecxin
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.
| Study group | Role | What they receive |
|---|---|---|
| SP + DP placebo every 4 weeks | Active comparator | Not described Receives: Drug: Sulfadoxine-pyrimethamine (SP) |
| DP + SP placebo every 4 weeks | Active comparator | Not described Receives: Drug: Dihydroartemisinin-piperaquine (DP) |
| SP + DP given every 4 weeks | Active comparator | Not described Receives: Drug: Sulfadoxine-pyrimethamine (SP); Drug: Dihydroartemisinin-piperaquine (DP) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Risk of Having a Composite Adverse Birth Outcome
Composite adverse birth outcome defined as the occurrence of any of the following:
- Spontaneous abortion: Fetal loss at < 28 weeks gestational age
- Stillbirth: Infant born deceased at > 28 weeks gestational age
- Low Birth Weight (LBW): Live birth with birth weight < 2500 gm
- Preterm birth: Live birth at < 37 weeks gestational age
- Small-for-gestational age (SGA): Live birth with weight-for-gestational age < 10th percentile of reference population
- Neonatal death: Live birth with neonatal death within the first 28 days of life
Measured: Time from first dose of study drugs up to 28 days postpartum, an average of 6 months
Incidence of Serious Adverse Events (SAE) Per Time at Risk
SAEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Measured: Time from first dose of study drugs up to 28 days postpartum, an average of 6 months
Incidence of Any Grade 3 or 4 or Serious Adverse Events Per Time at Risk
Grade 3 and 4 AEs or SAEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Measured: Time from first dose of study drugs up to 28 days postpartum, an average of 6 months
Secondary outcomes (23)
Number of Participants With Spontaneous Abortion
Spontaneous abortion defined as fetal loss at < 28 weeks gestational age
Measured: Time of delivery
Incidence of Anemia Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Measured: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
Incidence of Grade 3-4 AEs Possibly Related to Study Drugs
Grade 3-4 AEs possibly or definitely related to study drug defined by the July 2017 NIH DAIDS Toxicity Tables
Measured: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
Risk of Placental Malaria
Detection of malaria parasites or pigment by histopathology
Measured: At the time of delivery
Incidence of Malaria During Pregnancy
Episodes of symptomatic malaria (incidence per person year at risk following initiation of study drugs)
Measured: Day study drugs first given until delivery, an average of 6 months
Microscopic Parasitemia During Pregnancy
Proportion of routine samples with asexual parasites detected by microscopy
Measured: Day study drugs first given until delivery, an average of 6 months
Prevalence of Anemia During Pregnancy
Proportion of routine hemoglobin measurements < 11 g/dL
Measured: Day study drugs are first given until delivery
Stillbirth
Stillbirth defined as infant born deceased at > 28 weeks gestational age
Measured: Time of delivery
Low Birth Rate
Low birth weight defined as live birth with birth weight < 2500 gm
Measured: Time of delivery
Preterm Delivery
Preterm delivery defined as live birth at < 37 weeks gestational age
Measured: Time of delivery
Small-for-gestational Age
Small-for-gestational age defined as live birth with weight-for-gestational age < 10th percentile of reference population
Measured: Time of delivery
Neonatal Death
Neonatal death defined as live birth with neonatal death within the first 28 days of life
Measured: Time of delivery
Microscopic or Sub-microscopic Parasitemia During Pregnancy
Proportion of routine samples with asexual parasites detected by microscopy or qPCR
Measured: Day study drugs first given until delivery, an average of 6 months
Prevalence of Severe Anemia During Pregnancy
Proportion of routine hemoglobin measurements < 8 g/dL
Measured: Day study drugs are first given until delivery, an average of 6 months
Incidence of Stillbirth Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Measured: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
Incidence of Congenital Anomaly Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Measured: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
Incidence of Neutropenia Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Measured: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
Incidence of Proteinuria Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Measured: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
Incidence of Thrombocytopenia Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Measured: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
Incidence of Postpartum Hemorrhage Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Measured: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
Incidence of Pre-eclampsia Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Measured: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
Incidence of Preterm Birth <28 Gestational Age Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Measured: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
Incidence of Elevated Temperature Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Measured: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Apr 2020
- Study start28 Dec 2020
- Primary completion28 Jul 2024
- Study completion28 Jul 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for MalariaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Sequential
- Model description
- Double blinded randomized controlled trial
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 2,757 participants (actual)
Sponsor and investigators
- Lead sponsor
- Grant Dorsey, M.D, Ph.D.
- Sponsor type
- University, hospital or other
- Collaborators
- National Institutes of Health (NIH), Infectious Diseases Research Collaboration, Uganda
- Responsible party
- Sponsor-investigator, Grant Dorsey, M.D, Ph.D., University of California, San Francisco
- Investigators
- Grant Dorsey, MD, PhD, Principal investigator, University of California, San FranciscoPhil Rosenthal, MD, Principal investigator, University of California, San FranciscoMoses Kamya, MBChB, MMed, PhD, Principal investigator, Makerere University; Infectious Diseases Research CollaborationAbel Kakuru, MBChB, PhD, Study director, Infectious Diseases Research Collaboration
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04336189
- Sponsor's protocol ID
- DPSP
- Status last verified
- Jun 2025
- First submitted
- 31 Mar 2020
- Last updated
- 6 Nov 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 40966190