Clinical trial NCT04336189: Optimal Chemopreventive Regimens to Prevent Malaria and Improve Birth Outcomes in Uganda
Official title: Optimal Chemopreventive Regimens to Prevent Malaria and Improve Birth Outcomes in Uganda
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Malaria
Keywords: dihydroartemisinin-piperaquine
sulfadoxine-pyrimethamine
IPTp
reproductive tract infection
microbiome
drug resistance
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: Infectious Diseases Research Collaboration, Uganda
First posted: 2020-04-07
Enrollment: 2757
Sex: FEMALE
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Double blinded randomized controlled trial
Primary purpose: PREVENTION

Brief 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. 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: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Risk of having a composite adverse birth outcome
timeFrame: Time of delivery up to 28 days postpartum
measure: Incidence of any grade 3-4 Adverse Events (AE) or Serious Adverse Events (SAE) per time at risk
timeFrame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination
Secondary outcomes:
measure: Prevalence of individual composite adverse birth outcome
timeFrame: Time of delivery up to 28 days postpartum
measure: Incidence of individual grade 3-4 AE or SAE per time at risk
timeFrame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination
measure: Incidence of grade 3-4 AEs related to study drugs
timeFrame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination
measure: Vomiting following administration of study drugs
timeFrame: Total time receiving study drugs, an average of 20 weeks
measure: Measure of non-adherence with study drugs
timeFrame: Total time receiving study drugs, an average of 20 weeks
measure: Risk of placental malaria
timeFrame: At the time of delivery
measure: Incidence of malaria during pregnancy
timeFrame: Day study drugs are first given until delivery
measure: Prevalence of parasitemia during pregnancy
timeFrame: Day study drugs are first given until delivery
measure: Prevalence of anemia during pregnancy
timeFrame: Day study drugs are first given until delivery
measure: Prevalence of markers of DP resistance
timeFrame: Day study drugs are first given until delivery
measure: Prevalence of Reproductive tract infections (RTIs) at delivery
timeFrame: At time of delivery
measure: Relative changes in vaginal microbiota
timeFrame: Day of study enrollment until 32 weeks gestational age
measure: Absolute changes vaginal microbiota
timeFrame: Day of study enrollment until 32 weeks gestational age
measure: Relative changes intestinal microbiota
timeFrame: Day of study enrollment until 32 weeks gestational age
measure: Absolute changes intestinal microbiota
timeFrame: Day of study enrollment until 32 weeks gestational age
measure: Prevalence of markers of SP resistance
timeFrame: Day study drugs are first given until delivery
Other outcomes:
Locations:
city: Masafu
country: Uganda
facility: Infectious Diseases Research Collaboration Clinic - Masafu Hospital
state: Busia
Study officials:
affiliation: University of California, San Francisco
name: Grant Dorsey, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Phil Rosenthal, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Makerere University; Infectious Diseases Research Collaboration
name: Moses Kamya, MBChB, MMed, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Infectious Diseases Research Collaboration
name: Abel Kakuru, MBChB, PhD
role: STUDY_DIRECTOR
References: