Chemopreventive Therapy for Malaria in Ugandan Children

NCT00948896 | Completed Phase 3 Results DMC

• 6 other identifiers: H9926-33953NIH P01HD0594542009-077HS-580686/ESR/NDA/DID-11/2009H9926-33953 and 10-01489
• Study Type: interventional
• Target: 600
• Locations: 1 country
• Sites: 1

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.

Conditions

Malaria

Keywords

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

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (2)

• Incidence of Any Adverse Events Defined as Severity Grade 3-4 That Are Possibly, Probably, or Definitely Related to Study Drugs

  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

Study Arms (4)

1

EXPERIMENTAL

Drug: trimethoprim-sulfamethoxazole (TS; TMP/SMX)

2

EXPERIMENTAL

Drug: sulfadoxine-pyrimethamine (SP)

3

EXPERIMENTAL

Drug: dihydroartemisinin-piperaquine (DP)

4

NO INTERVENTION

Interventions

trimethoprim-sulfamethoxazole (TS; TMP/SMX) DRUG

daily dosing, 20mgTMP/100mgSMX tabs, 80mgTMP/400mgSMX tabs

1

sulfadoxine-pyrimethamine (SP) DRUG

monthly dosing given as a single dose, 500mg/25mg tabs

2

dihydroartemisinin-piperaquine (DP) DRUG

monthly dosing given once a day for 3 consecutive days, 40mg/320mg tabs

3

Eligibility Criteria

• Age: 4 Months - 5 Months
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of California, San Francisco: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

IDRC Research Clinic -Tororo District Hospital

Tororo, Uganda

Location

Related Publications (9)

• 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.

  PMID: 23270614 RESULT

• 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.

  PMID: 23796921 RESULT

• 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.

  PMID: 25145704 RESULT

• 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.

  PMID: 25493596 RESULT

• 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.

  PMID: 25652127 RESULT

• 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.

  PMID: 25870429 RESULT

• 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.

  PMID: 25093754 RESULT

• 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.

  PMID: 26403465 RESULT

• 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.

  PMID: 25753626 RESULT

Related Links

• MU-UCSF Research Collaboration

MeSH Terms

Conditions

Malaria

Interventions

Trimethoprim, Sulfamethoxazole Drug Combination; fanasil, pyrimethamine drug combination

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Sulfamethoxazole; Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Sulfanilamides; Aniline Compounds; Amines; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Trimethoprim; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Results Point of Contact

• Title: Dr. Grant Dorsey
• Organization: University of California, San Francisco

grant.dorsey@ucsf.edu

415-206-4680

Study Officials

• Diane V. Havlir, MD

  University of California, San Francisco

  STUDY DIRECTOR

• M. Grant Dorsey, MD, PhD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

• Moses R Kamya MBChB, MMed, MPH

  Makerere University; IDRC

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: July 27, 2009
• First Posted: July 29, 2009
• Study Start: June 1, 2010
• Primary Completion: April 1, 2014
• Study Completion: April 1, 2014
• Last Updated: November 24, 2015
• Results First Posted: August 4, 2015

Record last verified: 2015-10

Locations

UG (1)