Chemopreventive Therapy for Malaria in Ugandan Children
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 3

Summary: 
      Young African children living in high transmission areas suffer the greatest burden of
      malaria. In most African countries, such as Uganda, the only current preventive measure
      against malaria in high transmission settings is the use of insecticide treated bednets
      (ITNs). Preliminary data show that even in the setting of ITN use, young children living in a
      high transmission setting suffer almost 4 episodes of clinical malaria per year, highlighting
      the need for new preventive strategies. Chemopreventive strategies offer a potential means of
      reducing the burden of malaria among young children living in a high transmission setting.
      This study will compare the efficacy and safety of 3 promising chemopreventive strategies
      (monthly dihydroartemisinin-piperaquine, monthly sulfadoxine-pyrimethamine, daily
      trimethoprim-sulfamethoxazole) with the current standard of no chemoprevention and will be
      conducted in two distinct patient populations: 1) HIV-unexposed children (HIV-uninfected
      children born to HIV-uninfected mothers) and 2) HIV-exposed children (HIV-uninfected children
      born to HIV-infected mothers). The intervention will begin in HIV-unexposed children when
      they reach 6 months of age, the time at which the incidence of malaria begins to increase,
      and will be continued until the children reach 24 months of age, which prior data suggest is
      when the incidence of malaria begins to decline due to the development of semi-immunity. In
      addition, study participants will be followed for one additional year following
      chemopreventive therapy to examine for "rebound" in the incidence of malaria following our
      intervention. HIV-exposed children will begin the intervention when they have completed
      breastfeeding and have been confirmed to remain HIV-uninfected. The intervention will
      continue until study participants reach 24 months of age and then the study participants will
      be followed for an additional year to examine for rebound in the incidence of malaria. It is
      anticipated that the results of this study will provide valuable comparative data on the
      effect of different chemopreventive strategies on malaria incidence in two distinct patient
      populations at high risk for malaria. In addition it is anticipated the results of this study
      will provide insight into the development of naturally acquired antimalarial immunity in the
      setting of chemopreventive therapy that will differ in terms of the drug regimens, the age at
      which the intervention is started, and the HIV status of the mothers.
    

Detailed description: 
      Convenience sampling will be used to enroll a cohort of 600 HIV-uninfected infants between
      the ages of 4-5 months of age according to the following strata based on the mother's HIV
      status: 1) 200 HIV-exposed infants born to HIV-infected mothers, and 2) 400 HIV-unexposed
      infants born to HIV-uninfected mothers. Potential study participants will be identified from
      the Tororo District Hospital Antenatal Clinic and surrounding clinics providing routine
      pediatric care. Potential study participants less than 6 months of age and their
      parents/guardians will be referred to our study clinic for screening. Eligible children will
      be enrolled when they reach 4-5 months of age and followed until the age of 36 months for all
      their routine medical care at our designated study clinic. All mother-child pairs will
      receive 2 long lasting ITNs at enrollment and, as available, a basic care package including a
      safe water vessel, multivitamins and condoms. HIV-unexposed children will be randomized to
      one of four chemoprevention arms when they reach 6 months of age. All HIV-exposed children
      born to HIV-infected mothers will be given TS prophylaxis and mothers will be encouraged to
      introduce food at 6 months of life and continue breastfeeding until 1 year of life, in
      accordance with Ugandan Ministry of Health (MOH) guidelines. HIV-exposed children will
      retested for HIV approximately every 60 days during breastfeeding and 6 weeks following
      cessation of breastfeeding. HIV-exposed children who remain HIV-uninfected following
      cessation of breastfeeding will be randomized to one of four chemoprevention arms.
      HIV-exposed children who test positive for HIV during the course of the study (those who
      seroconvert during breastfeeding) will be excluded from the study and referred for
      appropriate care.

      During the follow-up period, all patients presenting to the clinic with a new episode of
      fever will undergo standard evaluation (history, physical examination and Giemsa-stained
      blood smear) for the diagnosis of malaria. Children diagnosed with uncomplicated malaria will
      be treated with AL and children diagnosed with complicated malaria will be treated with
      quinine in accordance with national guidelines. Response to antimalarial therapy will be
      assessed using standardized guidelines. All AL treatment failures occurring within 14 days of
      diagnosis will be treated with quinine in accordance with national guidelines. In the event
      that a patient fails quinine therapy, therapy will be repeated with quinine plus clindamycin.
      Patients with complicated malaria who have contraindications to giving quinine will be
      treated with parenteral artesunate. All episodes diagnosed more than 14 days after a previous
      episode will be considered new episodes for treatment purposes. After two years of age,
      patients with uncomplicated malaria will have follow up visits on the days Antimalarial drugs
      are administered only (Day 0, 1, and 2). Routine assessments will be performed in the study
      clinic approximately every 30 days. Routine assessments will include review of study protocol
      with parents/guardians of study participants, assessment for any outside medical care,
      assessment for adherence to assigned chemopreventive therapy, a focused history and physical
      examination and routine blood smears for the detection of asymptomatic parasitemia. Routine
      phlebotomy will be performed approximately every 120 days for all study participants for CBC,
      glucose and ALT measurements.
    

Intervention name(s): trimethoprim-sulfamethoxazole (TS; TMP/SMX); sulfadoxine-pyrimethamine (SP); dihydroartemisinin-piperaquine (DP)
Intervention type(s): Drug; Drug; Drug
Intervention description(s): daily dosing, 20mgTMP/100mgSMX tabs, 80mgTMP/400mgSMX tabs; monthly dosing given as a single dose, 500mg/25mg tabs; monthly dosing given once a day for 3 consecutive days, 40mg/320mg tabs
Intervention MeSH terms: Pyrimethamine; Piperaquine; Sulfadoxine; Trimethoprim; Fanasil, pyrimethamine drug combination; Artenimol; Trimethoprim, Sulfamethoxazole Drug Combination; Sulfamethoxazole
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Chemoprevention; Uganda; Malaria; Trimethoprim-sulfamethoxazole; Sulfadoxine-pyrimethamine; Dihydroartemisinin-piperaquine