Clinical trial NCT03009526: Efficacy and Safety of IPTp-DP Versus IPTp-SP in Malawi
Official title: A Prospective Randomized Open-Label Study on the Efficacy and Safety of Intermittent Preventive Treatment in Pregnancy (IPTp) With Dihydroartemisinin-Piperaquine (DP) Versus IPTp With Sulfadoxine-Pyrimethamine (SP) in Malawi
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Malaria
Pregnancy
Keywords: Malaria
Pregnancy
Malawi
Intermittent preventive treatment
dihydroartemisinin-piperaquine
sulfadoxine-pyrimethamine
Lead sponsor: Kamuzu University of Health Sciences
Sponsor class: OTHER
Collaborators: name: Centers for Disease Control and Prevention
First posted: 2017-01-04
Enrollment: 602
Sex: FEMALE
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This study aims to compare the efficacy of monthly IPTp-DP with monthly IPTp-SP to determine if IPTp-DP is associated with a reduction in malaria infection at delivery among HIV-negative women in an area with high levels of SP resistance in Malawi.

Detailed description: Problem to be studied Malaria in pregnancy (MiP) due to Plasmodium falciparum infection is a major cause of maternal morbidity and poor birth outcomes in malaria-endemic countries. Pregnant women are at increased risk of more frequent and severe malaria infections than non-pregnant women. Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP), which involves administration of treatment doses of SP at each antenatal visit in the second and third trimesters of pregnancy, at least one month apart, irrespective of malaria parasitemia, is currently recommended for all women, except HIV positive women taking daily cotrimoxazole prophylaxis, in areas with stable moderate to high transmission of malaria.

SP is the only drug currently used for IPTp. Due to increasing resistance to SP, it is no longer used as a treatment for symptomatic malaria, however, IPTp-SP remains effective even in areas where SP resistance in children under five (determined by in vivo efficacy studies) is up to 26%, and continues to be used for IPTp in countries where SP is no longer recommended to treat symptomatic malaria. However, IPTp-SP has become more controversial given recent data from northern Tanzania and Malawi that have demonstrated that at higher rates of resistance, IPTp-SP may no longer be effective.

Alternative drugs which could replace SP have been tested; mefloquine, azithromycin-chloroquine, and amodiaquine have been abandoned as options due to poor tolerability among pregnant women. Dihydroartemisinin-Piperaquine (DP) remains an attractive option because of the long half-life of piperaquine (PQ) and the demonstrated efficacy, safety, and tolerability in pregnancy. Recent studies in Kenya and Uganda using DP for IPTp demonstrated a significant reduction in the prevalence of malaria throughout pregnancy and at the time of delivery. However, there was not a clear benefit in terms of improved neonatal outcomes. Additional studies are therefore needed to determine the impact of switching from IPTp-SP to IPTp-DP.

Study aims Primary objectives To compare the efficacy of monthly IPTp-DP with monthly IPTp-SP to determine if IPTp-DP is associated with a reduction in malaria infection at delivery among HIV-negative women in an area with high levels of SP resistance in Malawi.

Secondary objectives

* To determine if IPTp-DP results in decreased fetal morbidity compared with IPTp-SP, where fetal morbidity is defined as the composite of any of the following: Preterm birth (\< 37 weeks gestation), low birth weight (LBW) (\< 2,500 grams), or small for gestational age (SGA).
* To evaluate the tolerability and safety of IPTp-DP in the second and third trimesters of pregnancy, including an assessment of cardiac risk, as measured by changes in QTc intervals from baseline with each successive dose.
* To compare the frequency of adverse events and fetal congenital malformations in IPTp-DP with IPTp-SP.
* To assess how SP and DP affect the maternal intestinal and vaginal microbiome.

Methodology Open-label, 2 arm randomized controlled superiority trial to compare the efficacy and safety of IPTp-DP to IPTp-SP in Malawi. The trial is designed to show a 60% decrease in malaria infection at delivery among HIV-negative women of all gravidity when IPTp-DP is used instead of IPTp-SP.

Expected findings and dissemination It is expected that in areas of high SP resistance, IPTp-DP will be superior to IPTp-SP in decreasing malaria infection at delivery. In addition, it is anticipated that DP will be well-tolerated among pregnant women and that fetal outcomes will be better than IPTp-SP.

Eligibility criteria: Inclusion Criteria:

* Viable singleton pregnancy
* Gestational age ≤28 completed weeks (28 6/7) by fundal height/ultrasound
* Maternal age ≥16 years
* No history of IPTp use during this pregnancy
* Willing to participate and complete the study schedule, including laboratory studies and delivery in the labor ward of the study clinic or hospital
* Willing to sign or thumb print informed consent
* Resident of study area and intending to stay in the area for the duration of the follow-up
* HIV-negative at enrolment

Exclusion Criteria:

* HIV-positive or unknown
* Multiple gestation
* High-risk pregnancy, including any pre-existing illness likely to cause complication of pregnancy (hypertension, diabetes, asthma, epilepsy, renal disease, liver disease, fistula repair, leg or spine deformity)
* Severe anemia requiring blood transfusion (Hb \<7.0 g/dL) at enrolment
* Known allergy or previous adverse reaction to any of the study drugs
* Previous inclusion in the same study
* Participating in other malaria intervention studies
* Known or suspected cardiac disease
* Corrected QT interval (QTcF) greater than 450 ms at baseline
* Patients taking any of the following drugs:

  * Antimicrobial agents of the following classes (systemic use only):

    * Macrolides (e.g. erythromycin, clarithromycin, azithromycin, roxithromycin)
    * Fluoroquinolones (e.g., levofloxacin, moxifloxacin, sparfloxacin)
    * Pentamidine
  * Antiarrhythmic agents (e.g. amiodarone, sotalol)
  * Antihistamines (e.g. promethazine)
  * Antifungals (systemic): ketoconazole, fluconazole, itraconazole
  * Antiretrovirals: Saquinavir
  * Diuretics (e.g. hydrochlorothiazide, furosemide)
  * Antipsychotics (neuroleptics): haloperidol, thioridazine
  * Antidepressants: imipramine, citalopram, escitalopram
  * Antiemetics: domperidone, chlorpromazine, ondansetron

Primary outcomes:
measure: Malaria infection at the time of delivery
timeFrame: delivery
measure: Fetal morbidity
timeFrame: Delivery
Secondary outcomes:
measure: Electrocardiogram changes following the receipt of DP
timeFrame: 4-6 hours after the 3rd dose with each course
measure: Microbiome changes following receipt of DP or SP
timeFrame: From date of randomization until the date of delivery or last date of follow-up, average of ~4-5 months
measure: Maternal hemoglobin at 3rd trimester
timeFrame: 3rd trimester
measure: Maternal anemia at 3rd trimester
timeFrame: 3rd trimester
measure: Fetal anemia
timeFrame: Delivery
measure: Incidence of clinical malaria episodes
timeFrame: From date of randomization until the date of delivery or last date of follow-up, average of ~4-5 months
measure: Incidence of all cause sick visits
timeFrame: From date of randomization until the date of delivery or last date of follow-up, average of ~4-5 months
measure: Serious adverse events
timeFrame: From date of randomization until the date of delivery or last date of follow-up, average of ~4-5 months
Other outcomes:
Locations:
city: Liwonde
country: Malawi
facility: Malaria Alert Center, University of Malawi College of Medicine
Study officials:
affiliation: Malawi College of Medicine
name: Don P Mathanga, MBBS PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centers for Disease Control and Prevention
name: Julie Gutman, MD MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Andronescu LR, Sharma A, Peterson I, Kachingwe M, Kachepa W, Liang Y, Gutman JR, Mathanga DP, Chinkhumba J, Laufer MK. The Effect of Intermittent Preventive Treatment of Malaria During Pregnancy and Placental Malaria on Infant Risk of Malaria. J Infect Dis. 2022 Jan 18;225(2):248-256. doi: 10.1093/infdis/jiab351.