Summary

Eligibility
for females ages 16 years and up (full criteria)
Healthy Volunteers
healthy people welcome
Dates
study started
estimated completion
Principal Investigator
Grant Dorsey, MD, PhDPhil Rosenthal, MD
Photo of Grant Dorsey
Grant Dorsey
Photo of Phil Rosenthal
Phil Rosenthal

Description

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.

Details

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.

Keywords

Malaria dihydroartemisinin-piperaquine sulfadoxine-pyrimethamine IPTp reproductive tract infection microbiome drug resistance Pyrimethamine Sulfadoxine Piperaquine Fanasil, pyrimethamine drug combination Dihydroartemisinin Sulfadoxine-pyrimethamine (SP) Dihydroartemisinin-piperaquine (DP) SP + DP given every 4 weeks

Eligibility

You can join if…

Open to females ages 16 years and up

  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

You CAN'T join if...

  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)

Lead Scientists at UCSF

  • Grant Dorsey, MD, PhD
    Since 1998, my research has primarily focused on clinical and molecular studies of malaria with a focus on antimalarial drug therapy. Our research group has completed over two dozen clinical trials involving over 10,000 patients, 9 different treatment regimens, and 9 sites in Uganda and Burkina Faso.
  • Phil Rosenthal, MD
    We have three main areas of interest, all involving malaria, one of the most important infections of humans. First, we study the basic biology of malaria parasites, including the biochemical properties and biological roles of parasite proteases and mechanisms of action of novel antimalarial agents.

Details

Status
not yet accepting patients
Start Date
Completion Date
(estimated)
Sponsor
Grant Dorsey, M.D, Ph.D.
ID
NCT04336189
Phase
Phase 3
Study Type
Interventional
Last Updated