MalariaNCT02094508
Impact of TMP-SMX Prophylaxis on Malaria Infection and Immunity in Children in Uganda
An observational study of Malaria, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in Uganda.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 2 to 6 monthsHealthy volunteers can take part
- Conditions the study is for
- Malaria
- How many people
- 173 participants
- Where
- 1 siteUganda
- Study dates
- 7 Mar 2014to 14 Dec 2016
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 to 6 months
- All sexes
- Healthy volunteers accepted
- Child
Who may be able to join
- Infant must be born during the period beginning May 1, 2014 and ending November 30, 2014.
- Mothers of HUE subjects must be giving their child TMP-SMX prophylaxis at screening (this does not apply to HUU subjects).
- Mothers must be breastfeeding their child at screening.
- 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.
- Parent/legal guardian of HUE subjects must agree to be compliant with administering the daily prophylactic doses of TMP-SMX according to the standard guidelines.
- Mothers must consent to a review of their medical records and a monthly assessment of breastfeeding status.
- Mother/guardian must live within the Rakai District.
Who cannot join
- Child has a diagnosis of HIV-infection or clinical or laboratory evidence of other chronic infection or disease (including renal or hepatic insufficiency).
- Clinical determination of conditions that would exclude the child
- based on record review, history, and examination.
- Participation in a malaria vaccine study or have a history of
- involvement in such a study.
Trial locations and contacts
1 site in 1 country.
Uganda1 site
Rakai Health Sciences Program Uganda Virus Research Institute
Kalisizo
About this study
Official title: Impact of Trimethoprim-sulfamethoxazole Prophylaxis on Malaria Infection and Immunity in Children in Uganda
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.
Read more
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.
Read the 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.
- Conditions
- Malaria
- Keywords
- Parasitemia, HIV-Exposed, HIV-Unexposed, Liver Stage, Randomized
- Medical subject headings
- Malaria, Parasitemia
What is being measured
The primary outcome is the main question the study is designed to answer.
Malaria incidence rate (number of new malaria parasitemia episodes per time at risk) in HUE children on TMP-SMX prophylaxis compared to HUU children (not on TMP-SMX prophylaxis) between enrollment and study end. A malaria parasitemia episode is ...
Measured: At end of the study
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Mar 2014 (estimated)
- Study start7 Mar 2014
- Primary completion28 Dec 2015
- Study completion14 Dec 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for MalariaStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 173 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Steven J Reynolds, M.D., Principal investigator, National Institute of Allergy and Infectious Diseases (NIAID)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02094508
- Sponsor's protocol ID
- 999914073
- Other IDs
- 14-I-N073
- Status last verified
- 14 Dec 2016
- First submitted
- 20 Mar 2014
- Last updated
- 5 Apr 2018
- Results posted
- No
Publications
Mutanga JN, Raymond J, Towle MS, Mutembo S, Fubisha RC, Lule F, Muhe L. Institutionalizing provider-initiated HIV testing and counselling for children: an observational case study from Zambia. PLoS One. 2012;7(4):e29656. doi: 10.1371/journal.pone.0029656. Epub 2012 Apr 20.
PubMed 22536311Flateau C, Le Loup G, Pialoux G. Consequences of HIV infection on malaria and therapeutic implications: a systematic review. Lancet Infect Dis. 2011 Jul;11(7):541-56. doi: 10.1016/S1473-3099(11)70031-7.
PubMed 21700241Hobbs CV, Voza T, Coppi A, Kirmse B, Marsh K, Borkowsky W, Sinnis P. HIV protease inhibitors inhibit the development of preerythrocytic-stage plasmodium parasites. J Infect Dis. 2009 Jan 1;199(1):134-41. doi: 10.1086/594369.
PubMed 19032102Kasule J, Gabriel EE, Anok A, Neal J, Eastman RT, Penzak S, Newell K, Serwadda D, Duffy PE, Reynolds SJ, Hobbs CV. Sulfamethoxazole Levels in HIV-Exposed Uninfected Ugandan Children. Am J Trop Med Hyg. 2018 Jun;98(6):1718-1721. doi: 10.4269/ajtmh.17-0933. Epub 2018 Apr 19.
PubMed 29692311
Study at a glance
From the registry record, last updated by the sponsor on 5 Apr 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Impact of Trimethoprim-sulfamethoxazole Prophylaxis on Malaria Infection and Immunity in Children in Uganda
- ClinicalTrials.gov ID
- NCT02094508
- Acronym / sponsor ID
- 999914073
- Conditions
- Malaria
- Keywords
- Parasitemia, HIV-Exposed, HIV-Unexposed, Liver Stage, Randomized
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 173 participants (actual)
- Lead sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
- Study start
- 7 Mar 2014
- Primary completion
- 28 Dec 2015 (actual)
- Study completion
- 14 Dec 2016 (actual)
- First posted
- 21 Mar 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
Who may qualify
- Ages
- 2 to 6 months
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child
Key inclusion criteria (7 listed)
Key exclusion criteria (5 listed)
- Child has a diagnosis of HIV-infection or clinical or laboratory evidence of other chronic infection or disease (including renal or hepatic insufficiency).
- Clinical determination of conditions that would exclude the child
- based on record review, history, and examination.
- Participation in a malaria vaccine study or have a history of
- involvement in such a study.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Malaria incidence rate (number of new malaria parasitemia episodes per time at risk) in HUE children on TMP-SMX prophylaxis compared to HUU children (not on TMP-SMX prophylaxis) between enrollment and study end. A malaria parasitemia episode is ...
Time frame: At end of the study
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Apr 2018.
- Background: PubMed 22536311Mutanga JN, Raymond J, Towle MS, Mutembo S, Fubisha RC, Lule F, Muhe L. Institutionalizing provider-initiated HIV testing and counselling for children: an observational case study from Zambia. PLoS One. 2012;7(4):e29656. doi: 10.1371/journal.pone.0029656. Epub 2012 Apr 20.
- Background: PubMed 21700241Flateau C, Le Loup G, Pialoux G. Consequences of HIV infection on malaria and therapeutic implications: a systematic review. Lancet Infect Dis. 2011 Jul;11(7):541-56. doi: 10.1016/S1473-3099(11)70031-7.
- Background: PubMed 19032102Hobbs CV, Voza T, Coppi A, Kirmse B, Marsh K, Borkowsky W, Sinnis P. HIV protease inhibitors inhibit the development of preerythrocytic-stage plasmodium parasites. J Infect Dis. 2009 Jan 1;199(1):134-41. doi: 10.1086/594369.
- Derived from this study: PubMed 29692311Kasule J, Gabriel EE, Anok A, Neal J, Eastman RT, Penzak S, Newell K, Serwadda D, Duffy PE, Reynolds SJ, Hobbs CV. Sulfamethoxazole Levels in HIV-Exposed Uninfected Ugandan Children. Am J Trop Med Hyg. 2018 Jun;98(6):1718-1721. doi: 10.4269/ajtmh.17-0933. Epub 2018 Apr 19.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Steven J Reynolds, M.D. principal investigator
National Institute of Allergy and Infectious Diseases (NIAID)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Malaria, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in Uganda.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Apr 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Uganda. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Malaria incidence rate (number of new malaria parasitemia episodes per time at risk) in HUE children on TMP-SMX prophylaxis compared to HUU children (not on TMP-SMX prophylaxis) between enrollment and study end. A malaria parasitemia episode is ... (time frame: At end of the study). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02094508, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Apr 2018.