Chemopreventive Therapy for Malaria in Ugandan Children

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized Controlled Trial of Monthly Dihydroartemisinin-piperaquine Versus Monthly Sulfadoxine-pyrimethamine Versus Daily Trimethoprim-sulfamethoxazole Versus No Therapy for the Prevention of Malaria

Conditions
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Malaria

Intervention / Treatment
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* Drug: trimethoprim-sulfamethoxazole (TS; TMP/SMX)
* Drug: sulfadoxine-pyrimethamine (SP)
* Drug: dihydroartemisinin-piperaquine (DP)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 4 -5 months Confirmed HIV status of biological mother Negative HIV DNA PCR test at time of enrollment for infants born to HIV-infected mothers Infants born to HIV-infected mothers must be breastfeeding Residency within 30km of the study clinic Agreement to come to the study clinic for any febrile episode or other illness and avoid medications given outside the study protocol Provision of informed consent by parent/guardian Exclusion Criteria: History of allergy or sensitivity to TS, SP, or DP Active medical problem requiring in-patient evaluation at the time of screening Intention of moving more that 30km from the study clinic during the follow-up period Chronic medical condition (i.e. malignancy) requiring frequent medical attention Living in the same household as a previously enrolled study participant QTc interval > 450 msec Other clinically significant ECG abnormalities such as arrhythmia, ischemia, or evidence of heart failure Family history of Long QT syndrome Current use of drugs that prolong the QT interval

Ages Eligible for Study
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Minimum Age: 4 Months
Maximum Age: 5 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: trimethoprim-sulfamethoxazole (TS; TMP/SMX)<br>* daily dosing, 20mgTMP/100mgSMX tabs, 80mgTMP/400mgSMX tabs<br>|
| Experimental: 2<br> | Drug: sulfadoxine-pyrimethamine (SP)<br>* monthly dosing given as a single dose, 500mg/25mg tabs<br>|
| Experimental: 3<br> | Drug: dihydroartemisinin-piperaquine (DP)<br>* monthly dosing given once a day for 3 consecutive days, 40mg/320mg tabs<br>|
| No Intervention: 4<br> | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incident Malaria Cases Per Person Year at Risk in HIV-unexposed Participants | The incidence of malaria, defined as the number of incident episodes per time at risk, during the period the intervention was given (6-24 mo of age). Treatments within 14d of a prior episode were not considered incident events. Time at risk was from the day following the initiation of study drugs to the last day of observation, minus 14 d after each treatment for malaria. | 6 to 24 months of age | 
| Incident Malaria Cases Per Person Year at Risk in HIV-exposed Participants | The primary outcome was the incidence of malaria, defined as the number of incident episodes per time at risk, during the period the intervention was given. Treatments within 14 days of a prior episode were not considered incident events. Time at risk was from the day following the initiation of study drugs to the last day of observation, minus 14 days after each treatment for malaria. | Randomization to 24 months of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Any Adverse Events Defined as Severity Grade 3-4 That Are Possibly, Probably, or Definitely Related to Study Drugs | NIH Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events published December, 2004 | Time from randomization until 24 months of age | 
| Rebound Incidence of Malaria Defined as the Number of Treatments for New Episodes of Malaria Per Time at Risk |  | 24 months to 36 months of age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chemoprevention, Uganda, Malaria, Trimethoprim-sulfamethoxazole, Sulfadoxine-pyrimethamine, Dihydroartemisinin-piperaquine