Impact of TMP-SMX Prophylaxis on Malaria Infection and Immunity in Children in Uganda

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
ClinicalTrials.gov Identifier:
NCT02094508
First received: March 20, 2014
Last updated: May 13, 2014
Last verified: February 2014
  Purpose

Background:

- Malaria is a disease that affects many children and adults in Uganda and Africa. If it is not treated, it can make some people severely ill. TMP-SMX (Trade names Bactrim, Septrin) is a drug that is given to children born to HIV-positive mothers to help prevent infection. Studies have shown that TMP-SMX also may kill malaria infection in the very early stages of infection in the body, which may positively impact the way the body can fight malaria infection. Researchers want to know if giving TMP-SMX for 6 months longer than usual helps children fight malaria better in this way.

Objective:

- To find out if taking TMP-SMX for longer than usual helps fight off malaria in infants.

Eligibility:

- Infants 0-6 weeks of age who are HIV negative.

Design:

  • Infants will be screened with a medical history and physical exam. A small amount of blood will be taken. The mothers medical records will be reviewed. Mothers will be asked about when they breastfeed.
  • Participants will take TMP-SMX according to their doctor s orders. In Uganda, mothers will get a mosquito net with insecticide on it as per standard of care.
  • Participants will come to the clinic once a month, every month, until the study ends in 2 3 years. Each visit will repeat the screening visit.
  • Participants will also visit the clinic every month for a medical history, physical exam, and different blood tests.
  • Six weeks after breastfeeding is stopped, children taking TMP-SMX will come into the clinic and will either be taken off the drug or will continue taking the drug for 6 more months.
  • If a child becomes sick, it is important that the mother bring him or her to the RHSP clinic in Rakai.

Condition Intervention Phase
Malaria
Drug: TMP-SMX
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Impact of Trimethoprim-sulfamethoxazole Prophylaxis on Malaria Infection and Immunity in Children in Uganda

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Primary outcome is to measure the incidence rate (number of new malaria parasitemia episodes) in HUE children on SOC versus EP TMP-SMX prophylaxs. [ Time Frame: Ongoing ] [ Designated as safety issue: No ]

Estimated Enrollment: 400
Study Start Date: March 2014
Estimated Study Completion Date: March 2019
Estimated Primary Completion Date: March 2019 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: TMP-SMX
    N/A
Detailed Description:

Malaria remains one of the most significant causes of morbidity and mortality throughout the world. Recent studies indicate that drugs used in HIV management can have antimalarial properties. In animal models, prophylactic doses of trimethoprim-sulfamethoxazole (TMPSMX), an antibiotic commonly used as prophylaxis against opportunistic infections in HIVexposed and HIV-infected patients, have been shown to arrest liver stage development of malaria parasites. Indeed, the liver stage of malaria parasites may be important to target since it is during this stage that clinical symptoms are absent and fewer parasites are present. TMP-SMX, used in HIV-exposed and HIV-infected subjects for opportunistic infection prophylaxis, significantly reduces clinical malaria, even in areas of moderate to high transmission intensity and high antifolate drug resistance. It is possible that reduction in liver stage parasite burden contributes to this unexpected effect. Nonetheless, the contribution of this liver-stage parasite killing to the reduction in clinical malaria observed in patients receiving TMP-SMX remains undescribed. Our primary objective aims to answer whether TMP-SMX reduces liver stage malaria infection.

For our exploratory objectives, we are interested in TMP-SMX effects on the development of anti-infection malaria immunity and effects on transmission. In mice, TMP-SMX prophylaxis during repeated malaria exposures has been shown to induce protective, anti-infection immunity against malaria (Charlotte Hobbs, unpublished data), which is distinct from naturally acquired immunity in which, after multiple infections, patients have less severe disease. TMP-SMX impact on the development of malaria-specific immunity, however, requires further investigation. Also, TMP-SMX has been shown to have sporonticidal (mosquito-oocyst killing) activity at levels achieved in patients on TMP-SMX prophylaxis in susceptible strains of P. falciparum, but the effects of TMP-SMX on transmission in the field remain undescribed.

This randomized study plans to enroll 164-220 HIV-uninfected, HIV-exposed (HUE) and 60 HIV-uninfected, HIV-unexposed (HUU) children in Kalisizo Hospital Health Center, Labor and Delivery Unit, Kalisizo, located within Rakai District, Uganda. HUE children will be randomized 1:1 into 2 arms. In the first arm (Standard of Care [SOC] arm), 82-110 children will receive TMP-SMX until 6 weeks after cessation of breast-feeding (age 12-18 months). In the second arm (Extended Prophylaxis [EP] arm), 82-110 children will receive SOC and remain on TMP-SMX for an additional 6 months after the cessation of breast-feeding. The 60 HUU children will serve as controls to establish baseline infection parameters in the community. Blood will be drawn from all subjects monthly via heel/finger stick to analyze malaria parasitemia. Additionally, venous blood will be drawn every 6 months to analyze cellular and humoral immunity. The duration of this study participation will be a minimum of 2 and up to 3 years.

Assessment of TMP-SMX impact on liver stage malaria infection and the development of protective anti-infection immunity in children will help guide decisions regarding TMP-SMX prophylaxis duration for HIV-exposed children in malaria endemic areas.

  Eligibility

Ages Eligible for Study:   up to 6 Weeks
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION CRITERIA:

    1. Infant must be 0-6 weeks of age.
    2. Parent/legal guardian must be able and willing to provide signed informed consent on behalf of the child subject, agree to bring the child to the study site for visits, and seek medical care for intercurrent illness for the child subject at the study site.
    3. Parent/legal guardian of HUE subjects must agree to be compliant with administering the daily prophylactic doses of TMP- SMX according to the schedule provided by the study team.
    4. Mothers must consent to a review of their medical records and a monthly assessment of breast-feeding status.
    5. Mother/guardian must live within 15 km of the Kaliziso District Hospital.

EXCLUSION CRITERIA:

  1. Child has a diagnosis of HIV-infection or clinical or laboratory evidence of other chronic infection or disease (including renal or hepatic insufficiency).
  2. Other condition that in the opinion of the investigator would jeopardize the safety or rights of a subject participating in the study or would render the subject unable to comply with the protocol.
  3. Other than the study described above in Subject Recruitment and Enrollment (Study #13-I-N074), study subjects should not participate in a malaria vaccine study or have a history of involvement in such a study.
  4. Contraindication to TMP-SMX (HUE subjects only) that in the judgment of the investigator contraindicates participation in this study including:

    1. Documented megaloblastic anemia due to folate deficiency.
    2. Hyperbilirubinemia
    3. Marked hepatic damage
    4. Renal insufficiency
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02094508

Contacts
Contact: Charlotte V Hobbs, M.D. (301) 402-4236 hobbsc3@mail.nih.gov

Locations
Uganda
Rakai Health Sciences Program Clinic (RHSP) Recruiting
Rakai, Uganda
Sponsors and Collaborators
Investigators
Principal Investigator: Charlotte V Hobbs, M.D. National Institute of Allergy and Infectious Diseases (NIAID)
  More Information

Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
ClinicalTrials.gov Identifier: NCT02094508     History of Changes
Other Study ID Numbers: 999914073, 14-I-N073
Study First Received: March 20, 2014
Last Updated: May 13, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Parasitemia
HIV-Exposed
HIV-Unexposed
Liver Stage
Randomized

Additional relevant MeSH terms:
Malaria
Protozoan Infections
Parasitic Diseases
Trimethoprim-Sulfamethoxazole Combination
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Anti-Infective Agents, Urinary
Renal Agents
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents

ClinicalTrials.gov processed this record on September 11, 2014