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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Malaria
• Intervention / Treatment: Drug: Sulfadoxine-pyrimethamine (SP); Drug: Dihydroartemisinin-piperaquine (DP)

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.

• Study Type: Interventional
• Enrollment (Actual): 2757
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Grant Dorsey, MD, PhD; Phone Number: 628-206-4680; Email: grant.dorsey@ucsf.edu
• Study Contact Backup: Name: Abel Kakuru, MBChB, PhD; Phone Number: +256 (0) 312 281 479; Email: akakuru@idrc-uganda.org

Study Locations

• Uganda
  • Busia
    • Masafu, Busia, Uganda
      • Infectious Diseases Research Collaboration Clinic - Masafu Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: SP + DP placebo every 4 weeks	Drug: 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.; Other Names: Kamsidar
Active Comparator: DP + SP placebo every 4 weeks	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.; Other Names: Duo-Cotecxin
Active Comparator: SP + DP given every 4 weeks	Drug: 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.; Other Names: Kamsidar; 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.; Other Names: Duo-Cotecxin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Time of delivery up to 28 days postpartum
Incidence of any grade 3-4 Adverse Events (AE) or Serious Adverse Events (SAE) per time at risk	Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables	Day study drugs are first given until when study participants reach 28 days postpartum or early study termination

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevalence of individual 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; LBW: Live birth with birth weight < 2500 gm; Preterm birth: Live birth at < 37 weeks 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	Time of delivery up to 28 days postpartum
Incidence of individual grade 3-4 AE or SAE per time at risk	Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables	Day study drugs are first given until when study participants reach 28 days postpartum or early study termination
Incidence of grade 3-4 AEs related to study drugs	Grade 3-4 AEs possibly or definitely related to study drug defined by the July 2017 NIH DAIDS Toxicity Tables	Day study drugs are first given until when study participants reach 28 days postpartum or early study termination
Vomiting following administration of study drugs	Every 28 days study participants will receive one course of study drugs consisting of once a day dosing for 3 consecutive days. Day 1 of study drug administration will be directly observed in the study clinic where vomiting will be assessed. Vomiting of days 2 of 3 of study drugs administered at home will be done at the time of each subsequent routine clinic visit using a standardized assessment.	Total time receiving study drugs, an average of 20 weeks
Measure of non-adherence with study drugs	Every 28 days study participants will receive one course of study drugs consisting of once a day dosing for 3 consecutive days. Day 1 of study drug administration will be directly observed in the study clinic. Adherence to days 2 of 3 of study drugs administered at home will be done at the time of each subsequent routine clinic visit using a standardized assessment.	Total time receiving study drugs, an average of 20 weeks
Risk of placental malaria	Detection of malaria parasites or pigment by histopathology	At the time of delivery
Incidence of malaria during pregnancy	New episodes of fever plus positive blood smear per person time	Day study drugs are first given until delivery
Prevalence of parasitemia during pregnancy	Proportion of routine samples with asexual parasites detected by microscopy or qPCR	Day study drugs are first given until delivery
Prevalence of anemia during pregnancy	Proportion of routine hemoglobin measurements < 11 g/dL	Day study drugs are first given until delivery
Prevalence of markers of DP resistance	Proportion of parasite positive samples with molecular markers of DP resistance	Day study drugs are first given until delivery
Prevalence of Reproductive tract infections (RTIs) at delivery	Proportion of vaginal samples collected as the time of delivery positive for RTIs	At time of delivery
Relative changes in vaginal microbiota	Measures of relative abundance of microorganisms	Day of study enrollment until 32 weeks gestational age
Absolute changes vaginal microbiota	Measures of absolute abundance of microorganisms	Day of study enrollment until 32 weeks gestational age
Relative changes intestinal microbiota	Measures of relative abundance of microorganisms	Day of study enrollment until 32 weeks gestational age
Absolute changes intestinal microbiota	Measures of absolute abundance of microorganisms	Day of study enrollment until 32 weeks gestational age
Prevalence of markers of SP resistance	Proportion of parasite positive samples with molecular markers of SP resistance	Day study drugs are first given until delivery

Collaborators and Investigators

• Sponsor: Grant Dorsey, M.D, Ph.D.
• Collaborators: National Institutes of Health (NIH); Infectious Diseases Research Collaboration, Uganda
• Investigators: Principal Investigator: Grant Dorsey, MD, PhD, University of California, San Francisco; Principal Investigator: Phil Rosenthal, MD, University of California, San Francisco; Principal Investigator: Moses Kamya, MBChB, MMed, PhD, Makerere University; Infectious Diseases Research Collaboration; Study Director: Abel Kakuru, MBChB, PhD, Infectious Diseases Research Collaboration

Study record dates

Study Major Dates

• Study Start (Actual): December 28, 2020
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): June 1, 2024

Study Registration Dates

• First Submitted: March 31, 2020
• First Submitted That Met QC Criteria: April 2, 2020
• First Posted (Actual): April 7, 2020

Study Record Updates

• Last Update Posted (Actual): March 19, 2024
• Last Update Submitted That Met QC Criteria: March 15, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: microbiome; drug resistance; IPTp; dihydroartemisinin-piperaquine; sulfadoxine-pyrimethamine; reproductive tract infection
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Mosquito-Borne Diseases; Malaria; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Folic Acid Antagonists; Anti-Infective Agents, Urinary; Pyrimethamine; Piperaquine; Sulfadoxine; Fanasil, pyrimethamine drug combination; Artenimol
• Other Study ID Numbers: DPSP

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No