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Efficacy and Safety of IPTp-DP Versus IPTp-SP in Malawi (STOPMIP-MW)

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ClinicalTrials.gov Identifier: NCT03009526
Recruitment Status : Recruiting
First Posted : January 4, 2017
Last Update Posted : July 14, 2017
Sponsor:
Collaborator:
Centers for Disease Control and Prevention
Information provided by (Responsible Party):
University of Malawi College of Medicine

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.

Condition or disease Intervention/treatment Phase
Malaria Pregnancy Drug: Sulfadoxine-pyrimethamine Drug: dihydroartemisinin-piperaquine Phase 3

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 602 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
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
Actual Study Start Date : January 16, 2017
Estimated Primary Completion Date : October 30, 2018
Estimated Study Completion Date : December 31, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria

Arm Intervention/treatment
Active Comparator: Sulfadoxine-pyrimethamine
Intermittent preventive treatment with Sulfadoxine-pyrimethamine: Monthly dose of 3 co-formulated tablets containing 500 mg sulfadoxine and 25 mg pyrimethamine
Drug: Sulfadoxine-pyrimethamine
Other Name: Fansidar

Experimental: dihydroartemisinin-piperaquine

Intermittent preventive treatment with dihydroartemisinin-piperaquine: Monthly course of daily doses of co-formulated DP tablets containing 40 mg dihydroartemisinin and 320 mg piperaquine, dosed based on the woman's weight, for 3 days:

  • 24-35.9 kg: Two tablets
  • 36-59.9 kg: Three tablets
  • 60-79.9 kg: Four tablets
  • ≥80 kg: Five tablets
Drug: dihydroartemisinin-piperaquine



Primary Outcome Measures :
  1. Malaria infection at the time of delivery [ Time Frame: delivery ]
    The composite of peripheral and placental parasitemia, detected by placental histology, positive peripheral blood smear at the time of delivery, or positive rapid diagnostic test at the time of delivery

  2. Fetal morbidity [ Time Frame: Delivery ]
    Composite endpoint of fetal morbidity, defined as any of the following: Preterm birth (birth before 37 weeks gestation), Low-birth-weight (birth weight under 2,500 grams), Small for gestational age (SGA)


Secondary Outcome Measures :
  1. Electrocardiogram changes following the receipt of DP [ Time Frame: 4-6 hours after the 3rd dose with each course ]
    QTc will be measured in a subset of women 4-6 hours after the 3rd dose of each course

  2. Microbiome changes following receipt of DP or SP [ Time Frame: From date of randomization until the date of delivery or last date of follow-up, average of ~4-5 months ]
    We will measure the changes in the intestinal and vaginal microbiome induced by DP and SP

  3. Maternal hemoglobin at 3rd trimester [ Time Frame: 3rd trimester ]
  4. Maternal anemia at 3rd trimester [ Time Frame: 3rd trimester ]
  5. Fetal anemia [ Time Frame: Delivery ]
    Anemia/ hemoglobin measured from cord blood

  6. Incidence of clinical malaria episodes [ Time Frame: From date of randomization until the date of delivery or last date of follow-up, average of ~4-5 months ]
  7. Incidence of all cause sick visits [ Time Frame: From date of randomization until the date of delivery or last date of follow-up, average of ~4-5 months ]
  8. Serious adverse events [ Time Frame: From date of randomization until the date of delivery or last date of follow-up, average of ~4-5 months ]


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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03009526


Contacts
Contact: Julie Gutman, MD MSc fff2@cdc.gov
Contact: Don P Mathanga, MBBS PhD dmathang@mac.medcol.mw

Locations
Malawi
Malaria Alert Center, University of Malawi College of Medicine Recruiting
Liwonde, Malawi
Contact: Don P Mathanga, MBBS PhD       dmathang@mac.medcol.mw   
Principal Investigator: Don P Mathanga, MBBS PhD         
Sub-Investigator: Jobiba Chinkhumba, MBBS PhD         
Sponsors and Collaborators
University of Malawi College of Medicine
Centers for Disease Control and Prevention
Investigators
Principal Investigator: Don P Mathanga, MBBS PhD Malawi College of Medicine
Principal Investigator: Julie Gutman, MD MSc Centers for Disease Control and Prevention

Responsible Party: University of Malawi College of Medicine
ClinicalTrials.gov Identifier: NCT03009526     History of Changes
Other Study ID Numbers: MAC-P.02/16/1872
First Posted: January 4, 2017    Key Record Dates
Last Update Posted: July 14, 2017
Last Verified: July 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by University of Malawi College of Medicine:
Malaria
Pregnancy
Malawi
Intermittent preventive treatment
dihydroartemisinin-piperaquine
sulfadoxine-pyrimethamine

Additional relevant MeSH terms:
Parasitic Diseases
Malaria
Protozoan Infections
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