Reducing the Burden of Malaria in HIV-uninfected Pregnant Women and Infants - Full Text View

Purpose

This will be a double-blinded randomized controlled phase III trial of 300 HIV uninfected pregnant women and the children born to them. The study interventions will be divided into two phases. In the first phase, HIV uninfected women at 12-20 weeks gestation will be randomized in equal proportions to one of three intermittent preventive therapy in pregnancy (IPTp) treatment arms: 1) 3 doses of sulfadoxine-pyrimethamine (SP), 2) 3 doses of dihydroartemisinin-piperaquine (DP), or 3) monthly DP. All three interventions arms will have either SP or DP placebo to ensure adequate blinding is achieved. Follow-up for the pregnant women will end approximately 6 weeks after giving birth. In the second phase of the study, all children born to mothers enrolled in the study will be followed from birth until they reach 36 months of age. Children born to mothers randomized to receive 3 doses of SP during pregnancy will receive DP every 3 months between 2-24 months of age. Children born to mothers randomized to receive 3 doses of DP or monthly DP during pregnancy will receive either DP every 3 months or monthly DP between 2-24 months of age. To ensure adequate blinding, children who will receive DP every 3 months will be given DP placebo during the months they will not be taking DP. Children will then be followed an additional year between 24-36 months of age following the interventions. We will test the hypothesis that IPT with DP will significantly reduce the burden of malaria in pregnancy and infancy and improve the development of naturally acquired antimalarial immunity.

Condition	Intervention	Phase
Malaria	Drug: Monthly dihydroartemisinin-piperaquine (DP) for adult women during pregnancy Drug: 3 dose dihydroartemisinin-piperaquine (DP) for adult women during pregnancy Drug: 3 dose sulfadoxine-pyrimethamine (SP) for adult women during pregnancy Drug: Monthly dihydroartemisinin-piperaquine (DP) for infants Drug: 3-monthly dihydroartemisinin-piperaquine (DP) for infants	Phase 3


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Prevention
Official Title:	Reducing the Burden of Malaria in HIV-uninfected Pregnant Women and Infants (PROMOTE Birth Cohort 1)

Resource links provided by NLM:

MedlinePlus related topics: HIV/AIDS Malaria

Drug Information available for: Pyrimethamine

Genetic and Rare Diseases Information Center resources: Malaria

U.S. FDA Resources

Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:

Prevalence of placental malaria [ Time Frame: Delivery ] [ Designated as safety issue: No ]
Prevalence of placental malaria based on placental histopathology dichotomized into any evidence of placental infection (parasites or pigment) vs. no evidence and by histopathology as a categorical variable based on Rogerson et al criteria.
Incidence of malaria in pregnant women [ Time Frame: Time at risk will begin at birth and will end when study participants reaches 24 months of age, when the intervention will be stopped, or early study termination (if prior to 24 months of age). ] [ Designated as safety issue: No ]
Incidence of malaria, defined as the number of incident episodes per time at risk. Incident cases will include all treatments for malaria not proceeded by another treatment in the previous 14 days.
Incidence of malaria in infants [ Time Frame: Time at risk will begin at birth and will end when study participants reaches 24 months of age or early study termination (if prior to 24 months of age) and at 24 months of age and will end when study participants reaches 36 months of age or termination ] [ Designated as safety issue: No ]
Incident cases will include all treatments for malaria not proceeded by another treatment in the previous 14 days. The study investigators will test the hypotheses that A) infants born to mothers randomized to receive IPTp with 3 dose DP or monthly DP will have a lower incidence of malaria during the first 24 months of life compared to infants born to mothers who were randomized to receive IPTp with 3 doses of SP, and, B) infants randomized to receive monthly DP between 2-24 months of age will have a lower incidence of malaria between 24-36 months of age after the intervention is stopped compared to infants randomized q 3 monthly DP between 2-24 months of age.

Secondary Outcome Measures:

Placental parasitemia [ Time Frame: Delivery ] [ Designated as safety issue: No ]
Proportion of placental blood samples positive for parasites by microscopy or PCR
Prevalence of maternal malaria [ Time Frame: Gestational age between 12-20 weeks (at study entry) up to delivery ] [ Designated as safety issue: No ]
Any treatment for malaria while on malaria chemoprevention
Composite birth outcome [ Time Frame: Delivery ] [ Designated as safety issue: Yes ]
Congenital malformations, late spontaneous abortion, LBW (<2500g), still birth
Incidence of adverse events in pregnant women and infants [ Time Frame: For women, starting at the time of their first study drugs approximately gestational age between 12-20 weeks up to one month post-deliver; For infants: from birth up to up to 108 weeks of age ] [ Designated as safety issue: Yes ]
Adverse events stratified by type, severity score and relationship to study drugs
Prevalence of anemia in pregnant women and infants [ Time Frame: Women: Gestational age between 12-20 weeks (at study entry) up to delivery; Infants: Birth up to 24 months of age or early study termination ] [ Designated as safety issue: No ]
Proportion of routine hemoglobin measurements < 10 g/dL & < 8 g/dL
Incidence of complicated malaria in infants [ Time Frame: Birth up to 24 months of age or early study termination ] [ Designated as safety issue: No ]
Any treatment for malaria meeting criteria for severe malaria or danger signs
Incidence of hospital admissions in infants [ Time Frame: Birth up to 24 months of age or early study termination ] [ Designated as safety issue: No ]
Admission to a hospital for pediatric inpatient care for any reason
Prevalence of gametocytemia in pregnant women and infants [ Time Frame: Women: Gestational age between 12-20 weeks (at study entry) up to delivery; Infants: Birth up to 24 months of age or early study termination ] [ Designated as safety issue: No ]
Proportion of routine blood smears positive for gametocytes
Prevalence of asymptomatic parasitemia in pregnant women and infants [ Time Frame: Women: Gestational age between 12-20 weeks (at study entry) up to delivery; Infants: Birth up to 24 months of age or early study termination ] [ Designated as safety issue: No ]
Proportion of routine monthly samples positive for parasites by PCR. Proportion of routine samples (PCR or blood smears) positive for asexual parasites.


Enrollment:	300
Study Start Date:	June 2014
Estimated Study Completion Date:	June 2018
Estimated Primary Completion Date:	June 2018 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: 3 dose SP pregnancy / 3 monthly DP infancy Women will be given SP (3 full strength tabs, 500 mg/25 mg) 3 times during pregnancy at 20, 28, and 36 weeks gestational age. In addition, placebos will be used to mimic the identical dosing strategy such that every 4 weeks women will receive two pills on day 1 (SP and placebo, DP and placebo, or two placebos) followed by one pill 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. Infants will be given DP (once a day for 3 consecutive days using weight-based guidelines) every 12 weeks between 8 and 104 weeks of age. Infants randomized to receive DP every 12 weeks will receive placebo mimicking the dosing of DP every 4 weeks when they are not receiving study drug.	Drug: 3 dose sulfadoxine-pyrimethamine (SP) for adult women during pregnancy Other Name: Kamsidar (KPI) Drug: 3-monthly dihydroartemisinin-piperaquine (DP) for infants Other Name: Duo-Cotexin (Holley-Cotec)
Active Comparator: 3 dose DP pregnancy / 3 monthly DP infancy Women will be given DP (3 full strength tabs, 40 mg/320 mg, given once a day for 3 consecutive days) 3 times during pregnancy at 20, 28, and 36 weeks gestational age. In addition, placebos will be used to mimic the identical dosing strategy such that every 4 weeks women will receive two pills on day 1 (SP and placebo, DP and placebo, or two placebos) followed by one pill 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. Infants will be given DP (once a day for 3 consecutive days using weight-based guidelines) every 12 weeks between 8 and 104 weeks of age. Infants randomized to receive DP every 12 weeks will receive placebo mimicking the dosing of DP every 4 weeks when they are not receiving study drug.	Drug: 3 dose dihydroartemisinin-piperaquine (DP) for adult women during pregnancy Other Name: Duo-Cotexin (Holley-Cotec) Drug: 3-monthly dihydroartemisinin-piperaquine (DP) for infants Other Name: Duo-Cotexin (Holley-Cotec)
Active Comparator: 3 dose DP pregnancy / monthly DP infancy Women will be given DP (3 full strength tabs, 40 mg/320 mg, given once a day for 3 consecutive days) 3 times during pregnancy at 20, 28, and 36 weeks gestational age. In addition, placebos will be used to mimic the identical dosing strategy such that every 4 weeks women will receive two pills on day 1 (SP and placebo, DP and placebo, or two placebos) followed by one pill 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. Infants will be given DP (once a day for 3 consecutive days using weight-based guidelines) every 4 weeks between 8 and 104 weeks of age.	Drug: 3 dose dihydroartemisinin-piperaquine (DP) for adult women during pregnancy Other Name: Duo-Cotexin (Holley-Cotec) Drug: Monthly dihydroartemisinin-piperaquine (DP) for infants Other Name: Duo-Cotexin (Holley-Cotec)
Active Comparator: monthly DP pregnancy / 3 monthly DP infancy Women will be given DP (3 full strength tabs, 40 mg/320 mg, given once a day for 3 consecutive days) every 4 weeks during pregnancy. In addition, placebos will be used to mimic the identical dosing strategy such that every 4 weeks women will receive two pills on day 1 (SP and placebo, DP and placebo, or two placebos) followed by one pill 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. Infants will be given DP (once a day for 3 consecutive days) every 12 weeks between 8 and 104 weeks of age. Infants randomized to receive DP every 12 weeks will receive placebo mimicking the dosing of DP every 4 weeks when they are not receiving study drug.	Drug: Monthly dihydroartemisinin-piperaquine (DP) for adult women during pregnancy Other Name: Duo-Cotexin (Holley-Cotec) Drug: 3-monthly dihydroartemisinin-piperaquine (DP) for infants Other Name: Duo-Cotexin (Holley-Cotec)
Active Comparator: monthly DP pregnancy / monthly DP infancy Women will be given DP (3 full strength tabs, 40 mg/320 mg, given once a day for 3 consecutive days) every 4 weeks during pregnancy. In addition, placebos will be used to mimic the identical dosing strategy such that every 4 weeks women will receive two pills on day 1 (SP and placebo, DP and placebo, or two placebos) followed by one pill 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. Infants will be given DP (once a day for 3 consecutive days) every 4 weeks between 8 and 104 weeks of age.	Drug: Monthly dihydroartemisinin-piperaquine (DP) for adult women during pregnancy Other Name: Duo-Cotexin (Holley-Cotec) Drug: Monthly dihydroartemisinin-piperaquine (DP) for infants Other Name: Duo-Cotexin (Holley-Cotec)

Detailed Description:

Pregnant women will be scheduled to be seen in the clinic every 4 weeks during their pregnancy and 6 weeks following delivery. In addition, pregnant women will be instructed to come to the study clinic for all their medical care and avoid the use of any outside medications. Children will be scheduled to be seen in the clinic every 4 weeks and parents /guardians of children will be instructed to bring their child to the study clinic for all medical care and avoid the use of any outside medications. The study clinic will remain open 7 days a week from 8 a.m. to 5 p.m.

Each time a study participant is seen in the clinic a standardized history and physical exam will be performed. Patients who are febrile (tympanic temperature > 3 8.0˚C) or report history of fever in the past 24 hours will have blood obtained by finger prick for a thick blood smear. If the thick blood smear is positive, the patient will be diagnosed with malaria. If the thick blood smear is negative, the patient will be managed by study physicians for a non-malarial febrile illness. If the patient is afebrile and does not report a recent fever, a thick blood smear will not be obtained, except when following routine testing schedules.

Routine assessments will be done in the clinic every 4 weeks for both pregnant women and children. Pregnant women and children will receive standards of care as designated in the Uganda MOH guidelines. Routine care in children will use Integrated Management of Childhood Illness (IMCI) guidelines. During routine assessments subjects will be asked about visits to outside health facilities and the use of any medications outside the study protocol. Standardized assessment of adherence will also be done for study drugs administered at home and Insecticide Treated Net use. A routine history and physical exam will be performed using a standardized clinical assessment form. Blood will be collected by finger prick for thick smear, collection of plasma for PK studies, and filter paper samples. Phlebotomy for routine laboratory tests (CBC and ALT) to monitor for potential adverse events from study medications and for immunology studies will be performed every 8 weeks in pregnant women and every 16 weeks in children. Non malaria screening will also include stool ova and parasite examination, circulating filarial antigens (by ICT card for Wucheria), and blood smear for microfilaremia (including Mansonella perstans) using Knott's technique. For pregnant women and children 2-24 months of age, study drugs will be administered at the time of each routine visit.

Eligibility


Ages Eligible for Study:	16 Years and older (Child, Adult, Senior)
Genders Eligible for Study:	Female
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Pregnancy confirmed by positive urine pregnancy test or intrauterine pregnancy 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 30km of the study clinic
Provision of informed consent by the pregnant woman for herself and her unborn child
Agreement to come to the study clinic for any febrile episode or other illness and avoid medications given outside the study protocol
Plan to deliver in the hospital

Exclusion Criteria:

History of serious adverse event to SP or DP
Active medical problem requiring inpatient evaluation at the time of screening
Intention of moving more than 30km from the study clinic
Chronic medical condition requiring frequent medical attention
Prior SP preventive therapy or any other antimalarial therapy during this pregnancy
Early or active labor (documented by cervical change with uterine contractions)

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02163447

Locations


Uganda
IDRC Research Clinic -Tororo District Hospital
Tororo, Uganda

Sponsors and Collaborators

University of California, San Francisco

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators


Principal Investigator:	Grant Dorsey, MD, PhD	University of California, San Francisco
Principal Investigator:	Diane V Havlir, MD	University of California, San Francisco
Principal Investigator:	Moses Kamya, MBChB, MMed, PhD	Makerere University; Infectious Diseases Research Collaboration

More Information

Additional Information:

MU-UCSF Research Collaboration This link exits the ClinicalTrials.gov site

Publications:

Kakuru A, Jagannathan P, Muhindo MK, Natureeba P, Awori P, Nakalembe M, Opira B, Olwoch P, Ategeka J, Nayebare P, Clark TD, Feeney ME, Charlebois ED, Rizzuto G, Muehlenbachs A, Havlir DV, Kamya MR, Dorsey G. Dihydroartemisinin-Piperaquine for the Prevention of Malaria in Pregnancy. N Engl J Med. 2016 Mar 10;374(10):928-39. doi: 10.1056/NEJMoa1509150.


Responsible Party:	Grant Dorsey, M.D, Ph.D., Professor, University of California, San Francisco
ClinicalTrials.gov Identifier:	NCT02163447 History of Changes
Other Study ID Numbers:	PROMOTE-BC1 P01HD059454
Study First Received:	June 5, 2014
Last Updated:	April 2, 2016
Health Authority:	United States: Food and Drug Administration Uganda: Makerere University School of Biomedical Sciences Research and Ethics Committee Uganda: Uganda National Council for Science and Technology (UNCST)

Keywords provided by University of California, San Francisco:


Chemoprevention Malaria Uganda Sulfadoxine-pyrimethamine Dihydroartemisinin-piperaquine

Additional relevant MeSH terms:


Malaria Protozoan Infections Parasitic Diseases Pyrimethamine Piperaquine Sulfadoxine Dihydroartemisinin Artemisinins Fanasil, pyrimethamine drug combination	Antimalarials Antiprotozoal Agents Antiparasitic Agents Anti-Infective Agents Folic Acid Antagonists Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Anti-Infective Agents, Urinary Renal Agents

ClinicalTrials.gov processed this record on September 30, 2016

Reducing the Burden of Malaria in HIV-uninfected Pregnant Women and Infants (PROMOTE-BC1)