Chemopreventive Therapy for Malaria in Ugandan Children (PROMOTE-Chemop)

• Sponsor: University of California, San Francisco
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Information provided by (Responsible Party): Grant Dorsey, M.D, Ph.D., University of California, San Francisco

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Malaria	Drug: trimethoprim-sulfamethoxazole (TS; TMP/SMX); Drug: sulfadoxine-pyrimethamine (SP); Drug: dihydroartemisinin-piperaquine (DP)	Phase 3

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	600 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Prevention
Official Title:	A Randomized Controlled Trial of Monthly Dihydroartemisinin-piperaquine Versus Monthly Sulfadoxine-pyrimethamine Versus Daily Trimethoprim-sulfamethoxazole Versus No Therapy for the Prevention of Malaria
Study Start Date :	June 2010
Actual Primary Completion Date :	April 2014
Actual Study Completion Date :	April 2014

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Incident Malaria Cases Per Person Year at Risk in HIV-unexposed Participants [ Time Frame: 6 to 24 months of age ]
   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.
2. Incident Malaria Cases Per Person Year at Risk in HIV-exposed Participants [ Time Frame: Randomization to 24 months of age ]
   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.

Secondary Outcome Measures :

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

Eligibility Criteria

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Ages Eligible for Study:	4 Months to 5 Months (Child)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

1. Age 4 -5 months
2. Confirmed HIV status of biological mother
3. Negative HIV DNA PCR test at time of enrollment for infants born to HIV-infected mothers
4. Infants born to HIV-infected mothers must be breastfeeding
5. Residency within 30km of the study clinic
6. Agreement to come to the study clinic for any febrile episode or other illness and avoid medications given outside the study protocol
7. Provision of informed consent by parent/guardian

Exclusion Criteria:

1. History of allergy or sensitivity to TS, SP, or DP
2. Active medical problem requiring in-patient evaluation at the time of screening
3. Intention of moving more that 30km from the study clinic during the follow-up period
4. Chronic medical condition (i.e. malignancy) requiring frequent medical attention
5. Living in the same household as a previously enrolled study participant
6. QTc interval > 450 msec
7. Other clinically significant ECG abnormalities such as arrhythmia, ischemia, or evidence of heart failure
8. Family history of Long QT syndrome
9. Current use of drugs that prolong the QT interval

Contacts and Locations

Locations

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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

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Study Director:	Diane V. Havlir, MD	University of California, San Francisco
Principal Investigator:	M. Grant Dorsey, MD, PhD	University of California, San Francisco
Principal Investigator:	Moses R Kamya MBChB, MMed, MPH	Makerere University; IDRC

More Information

Publications of Results:

Osterbauer B, Kapisi J, Bigira V, Mwangwa F, Kinara S, Kamya MR, Dorsey G. Factors associated with malaria parasitaemia, malnutrition, and anaemia among HIV-exposed and unexposed Ugandan infants: a cross-sectional survey. Malar J. 2012 Dec 27;11:432. doi: 10.1186/1475-2875-11-432.

Ochong E, Tumwebaze PK, Byaruhanga O, Greenhouse B, Rosenthal PJ. Fitness Consequences of Plasmodium falciparum pfmdr1 Polymorphisms Inferred from Ex Vivo Culture of Ugandan Parasites. Antimicrob Agents Chemother. 2013 Sep;57(9):4245-4251. doi: 10.1128/AAC.00161-13. Epub 2013 Jun 24.

Marquez C, Okiring J, Chamie G, Ruel TD, Achan J, Kakuru A, Kamya MR, Charlebois ED, Havlir DV, Dorsey G. Increased morbidity in early childhood among HIV-exposed uninfected children in Uganda is associated with breastfeeding duration. J Trop Pediatr. 2014 Dec;60(6):434-41. doi: 10.1093/tropej/fmu045. Epub 2014 Aug 21.

Kamya MR, Kapisi J, Bigira V, Clark TD, Kinara S, Mwangwa F, Muhindo MK, Kakuru A, Aweeka FT, Huang L, Jagannathan P, Achan J, Havlir DV, Rosenthal PJ, Dorsey G. Efficacy and safety of three regimens for the prevention of malaria in young HIV-exposed Ugandan children: a randomized controlled trial. AIDS. 2014 Nov 28;28(18):2701-9. doi: 10.1097/QAD.0000000000000497.

Kapisi J, Bigira V, Clark T, Kinara S, Mwangwa F, Achan J, Kamya M, Soremekun S, Dorsey G. Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated malaria in the setting of three different chemopreventive regimens. Malar J. 2015 Feb 5;14:53. doi: 10.1186/s12936-015-0583-9.

Snyman K, Mwangwa F, Bigira V, Kapisi J, Clark TD, Osterbauer B, Greenhouse B, Sturrock H, Gosling R, Liu J, Dorsey G. Poor housing construction associated with increased malaria incidence in a cohort of young Ugandan children. Am J Trop Med Hyg. 2015 Jun;92(6):1207-13. doi: 10.4269/ajtmh.14-0828. Epub 2015 Apr 13.

Bigira V, Kapisi J, Clark TD, Kinara S, Mwangwa F, Muhindo MK, Osterbauer B, Aweeka FT, Huang L, Achan J, Havlir DV, Rosenthal PJ, Kamya MR, Dorsey G. Protective efficacy and safety of three antimalarial regimens for the prevention of malaria in young Ugandan children: a randomized controlled trial. PLoS Med. 2014 Aug 5;11(8):e1001689. doi: 10.1371/journal.pmed.1001689. eCollection 2014 Aug.

Sundell K, Jagannathan P, Huang L, Bigira V, Kapisi J, Kakuru MM, Savic R, Kamya MR, Dorsey G, Aweeka F. Variable piperaquine exposure significantly impacts protective efficacy of monthly dihydroartemisinin-piperaquine for the prevention of malaria in Ugandan children. Malar J. 2015 Sep 24;14:368. doi: 10.1186/s12936-015-0908-8.

Tumwebaze P, Conrad MD, Walakira A, LeClair N, Byaruhanga O, Nakazibwe C, Kozak B, Bloome J, Okiring J, Kakuru A, Bigira V, Kapisi J, Legac J, Gut J, Cooper RA, Kamya MR, Havlir DV, Dorsey G, Greenhouse B, Nsobya SL, Rosenthal PJ. Impact of antimalarial treatment and chemoprevention on the drug sensitivity of malaria parasites isolated from ugandan children. Antimicrob Agents Chemother. 2015;59(6):3018-30. doi: 10.1128/AAC.05141-14. Epub 2015 Mar 9.

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Responsible Party:	Grant Dorsey, M.D, Ph.D., Associate Professor, University of California, San Francisco
ClinicalTrials.gov Identifier:	NCT00948896 History of Changes
Other Study ID Numbers:	H9926-33953; NIH P01HD059454; 2009-077 ( Other Identifier: Makerere Univ Fac of Med Research and Ethics Committee ); HS-580 ( Other Identifier: Uganda National Council for Science and Tech ); 686/ESR/NDA/DID-11/2009 ( Other Identifier: Uganda National Drug Authority ); H9926-33953 and 10-01489 ( Other Identifier: UCSF Committee on Human Research )
First Posted:	July 29, 2009
Results First Posted:	August 4, 2015
Last Update Posted:	November 24, 2015
Last Verified:	October 2015

Keywords provided by Grant Dorsey, M.D, Ph.D., University of California, San Francisco:

Chemoprevention; Uganda; Malaria	Trimethoprim-sulfamethoxazole; Sulfadoxine-pyrimethamine; Dihydroartemisinin-piperaquine

Additional relevant MeSH terms:

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Malaria; Protozoan Infections; Parasitic Diseases; Pyrimethamine; Piperaquine; Trimethoprim; Sulfadoxine; Dihydroartemisinin; Artemisinins; Fanasil, pyrimethamine drug combination; Trimethoprim, Sulfamethoxazole Drug Combination; Sulfamethoxazole; Antimalarials	Antiprotozoal Agents; Antiparasitic Agents; Anti-Infective Agents; Folic Acid Antagonists; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents, Urinary; Renal Agents; Anti-Dyskinesia Agents; Cytochrome P-450 CYP2C8 Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Anti-Bacterial Agents