Neurobehavioral ManifestationsPROTECTNCT02557425
Prophylaxis Against Malaria to Enhance Child Development (PROTECT Study)
An observational study of Neurobehavioral Manifestations, run by Indiana University at 1 site in Uganda.
Trial summary
Each year, ~85.3 million pregnant women are at risk of becoming infected with Plasmodium falciparum(1). Among women in sub-Saharan Africa, most of whom have some degree of clinical immunity to malaria, malaria infection in pregnancy leads to placental malaria (PM), often without clinical symptoms in the mother. Read more about this study
- Who is it for?
- Ages 10 to 38 months
- Conditions the study is for
- Neurobehavioral Manifestations
- How many people
- 272 participants
- Where
- 1 siteUganda
- Study dates
- Oct 2015to 5 Aug 2021
- 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 10 to 38 months
- All sexes
- No healthy volunteers
- Child
Study population: 300 Ugandan Children already enrolled in PROMOTE II study
Who may be able to join
- Enrolled in Makerere University-UCSF PROMOTE II study
- HIV-uninfected
- 12 months of age at the time of enrollment
- Within 30 km of the clinic
Who cannot join
- Serious adverse event to the study drugs requiring cessation of study drug
- Active illness at enrollment (child can be enrolled once active illness has been treated and they are back to baseline health)
- Previous history of head trauma or coma in the child
- Cerebral palsy or other severe neurologic disease
- Known chronic illness requiring medical care
- Major medical abnormalities on screening history of past health
- Known developmental delay
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Prophylaxis Against Malaria to Enhance Child Development
Each year, ~85.3 million pregnant women are at risk of becoming infected with Plasmodium falciparum(1). Among women in sub-Saharan Africa, most of whom have some degree of clinical immunity to malaria, malaria infection in pregnancy leads to placental malaria (PM), often without clinical symptoms in the mother. The systemic and placental changes that occur with malaria in pregnancy can adversely affect the developing fetal brain, an fetal brain injury strongly affects long-term childhood neurodevelopmental (ND) and behavior but there are no published studies to date on the impact of malaria in pregnancy on childhood ND. This study, conducted in Uganda, will address the effects of malaria in pregnancy and childhood ND and define mechanisms by which malaria may lead to ND impairment including micronutrient deficiencies. ND outcomes will be measured by the following neuropsychological and behavioral tests: Mullen Scales of Early Learning, the Color Object Association Test, the Early Childhood Vigilance Test, the Behavior Rating Scales, the Behavior Related inventory of Executive Function and the Child Behavior Checklist. These tests will be given at 12, 24, 36, and 60 months of age. This study will be nested in an ongoing Ugandan IRB approved interventional trial (PROMOTE-II) (NCT02163447). Blood sampling is being conducted in the PROMOTE-II protocol for research purposes. Some of that blood will be used to test for micronutrient deficiencies as well as other immune responses to malaria.
Read the detailed description
The PROMOTE-II randomized clinical trial in Tororo, Uganda, led by investigators from Makerere University in Uganda and the University of California-San Francisco (UCSF), provides an ideal setting to assess the effects of malaria prevention in pregnant women and their children on childhood ND. In PROMOTE-II Project 1,300 pregnant HIV-uninfected women will be randomized at 12-20 weeks of gestation to malaria prophylaxis with 3 doses of sulfadoxine-pyrimethamine (current standard of care), 3 doses of dihydroartemisinin-piperaquine (DP), or monthly DP. Their children will be randomized to receive DP prophylaxis monthly or every 3 months from 2 to 24 months age. The children will be followed for malaria episodes from birth to age 36 months. The proposed prospective study of child ND, the Prophylaxis against malaria To Enhance Child developmenT (PROTECT) study, will be nested within the PROMOTE-II Project 1 cohort. It is hypothesized that mothers on SP and mothers and children on less frequent prophylaxis will have more malaria episodes. The investigators predict that child ND will improve with more effective prophylaxis.
The central hypotheses of this study are that malaria prevention in pregnant women and their children improves child ND through 1) prevention of placental sequestration and inflammation and of consequent micronutrient deficiency in the fetus, and 2) reduction of systemic inflammation and endothelial activation that can lead to micronutrient deficiency and anemia during pregnancy and in early childhood and thus to alteration of brain structures particularly sensitive to such deficiencies (e.g., the hippocampus, myelin and the frontal lobe). The collaborative team, which has expertise in malaria in pregnant women and children, malaria pathogenesis, micronutrient deficiency, fetal and child neurodevelopment, and modeling of complex disease pathways, is well qualified to undertake the proposed research.
The specific aims of the study are:
Aim 1. Determine the effect of malaria prevention in pregnant women and their children on child ND. Hypotheses: 1) Long-term child ND improves with more effective chemoprevention in pregnant women and in their children. 2) The effect of malaria prevention on child ND persists through 36 months of age. Child ND will be assessed with a testing battery validated in previous studies by this group in Ugandan children. The investigators will test these hypotheses by comparing child ND at 12, 24, 36 and 60 months of age between treatment groups.
Aim 2. Identify the major mechanisms by which malaria prevention in pregnant women and children affects child ND. Hypotheses: 1) Malaria prevention in pregnant women affects child ND through prevention of placental sequestration and inflammation, with consequent prevention of prematurity, intrauterine growth retardation and fetal micronutrient deficiency. 2) Malaria prevention in pregnant women and in their children after birth improves child ND through reduction of systemic inflammation, endothelial activation, micronutrient deficiency and anemia, but the relative contributions of the factors differ in pregnant women compared to children. The investigators will test these hypotheses by conducting path analysis to determine if networks that include these paths explain a significant proportion of the difference in child ND between treatment groups.
- Conditions
- Neurobehavioral Manifestations
- Being tested
- No intervention in PROTECT
- Keywords
- malaria, infant, pregnancy, prophylaxis, dihyroartemisinin-piperaquine, sulfadoxine-pyrimethamine, behavior, neurodevelopment, cognitive
- Medical subject headings
- Neurobehavioral Manifestations, Malaria, Behavior
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
No intervention in PROTECTOther
| Study group | Role | What they receive |
|---|---|---|
| Maternal SP/Child 3mo DP | In this group in the PROMOTE-II study, mothers receive 3 doses of sulfadoxine-pyrimethamine (SP), and children receive every 3 month dihydroartemisinin-piperaquine (DP). No intervention is given in the observational PROTECT study. Receives: Other: No intervention in PROTECT | |
| Maternal 3 dose DP/Child 3mo DP | In this group in the PROMOTE-II study, mothers receive 3 doses of DP, and children receive every 3 month DP.No intervention is given in the observational PROTECT study. Receives: Other: No intervention in PROTECT | |
| Maternal 3 dose DP/Child monthly DP | In this group in the PROMOTE-II study, mothers receive 3 doses of DP, and children receive monthly DP. No intervention is given in the observational PROTECT study. Receives: Other: No intervention in PROTECT | |
| Maternal monthly DP/Child 3mo DP | In this group in the PROMOTE-II study, mothers receive monthly DP, and children receive every 3 month DP. No intervention is given in the observational PROTECT study. Receives: Other: No intervention in PROTECT | |
| Maternal monthly DP/child monthly DP | In this group in the PROMOTE-II study, mothers receive monthly DP, and children receive every monthly DP. No intervention is given in the observational PROTECT study. Receives: Other: No intervention in PROTECT |
What is being measured
The primary outcome is the main question the study is designed to answer.
Z-scores for Overall cognitive ability
Measured: 12 months of age
Z-scores for Overall cognitive ability
Measured: 24 months of age
Z-scores for Overall cognitive ability
Measured: 36 months of age
Z scores for Elicited Imitation
Measured: 12 months of age
Z scores for Elicited Imitation
Measured: 24 months of age
Z scores for Elicited Imitation
Measured: 36 months of age
Z scores of Overal Cognitive ability
Measured: 60 months of age
Z scores of Elicited Imitation
Measured: 60 months of age
Secondary outcomes (3)
Z scores for Behavioral Rating Scale
Measured: 24, 36, and 60 months of age
Z scores for Behavior Related Inventory of Executive Function (BRIEF)
Measured: 24, 36, and 60 months of age
Z scores for Child Behavior Checklist (CBCL)
Measured: 24, 36, and 60 months of age
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Sep 2015 (estimated)
- Study startOct 2015
- Primary completion5 Aug 2021
- Study completion5 Aug 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Neurobehavioral ManifestationsStudies of the same condition, open and under way.
- 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
- Cohort
- Time perspective
- Prospective
- Enrolment
- 272 participants (actual)
Sponsor and investigators
- Lead sponsor
- Indiana University
- Sponsor type
- University, hospital or other
- Collaborators
- Makerere University
- Responsible party
- Principal investigator, Chandy John, Indiana University
- Investigators
- Chandy C John, MD, Principal investigator, Indiana University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02557425
- Sponsor's protocol ID
- 1506994146
- Acronym
- PROTECT
- Status last verified
- Aug 2021
- First submitted
- 21 Sep 2015
- Last updated
- 25 Aug 2021
- Results posted
- No
- Data monitoring committee
- No
Publications
Bangirana P, Conroy AL, Opoka RO, Semrud-Clikeman M, Jang JH, Apayi C, Kakuru A, Muhindo MK, Georgieff MK, Dorsey GM, Kamya MR, Havlir D, John CC. Effect of Malaria and Malaria Chemoprevention Regimens in Pregnancy and Childhood on Neurodevelopmental and Behavioral Outcomes in Children at 12, 24, and 36 Months: A Randomized Clinical Trial. Clin Infect Dis. 2023 Feb 18;76(4):600-608. doi: 10.1093/cid/ciac815.
PubMed 36219705
Study at a glance
From the registry record, last updated by the sponsor on 25 Aug 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prophylaxis Against Malaria to Enhance Child Development
- ClinicalTrials.gov ID
- NCT02557425
- Acronym / sponsor ID
- PROTECT / 1506994146
- Conditions
- Neurobehavioral Manifestations
- Keywords
- malaria, infant, pregnancy, prophylaxis, dihyroartemisinin-piperaquine, sulfadoxine-pyrimethamine, behavior, neurodevelopment
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 272 participants (actual)
- Lead sponsor
- Indiana UniversityUniversity, hospital or other
- Collaborators
- Makerere University
- Study start
- Oct 2015
- Primary completion
- 5 Aug 2021 (actual)
- Study completion
- 5 Aug 2021 (actual)
- First posted
- 23 Sep 2015 (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.
Each year, ~85.3 million pregnant women are at risk of becoming infected with Plasmodium falciparum(1). Among women in sub-Saharan Africa, most of whom have some degree of clinical immunity to malaria, malaria infection in pregnancy leads to placental malaria (PM), often without clinical symptoms in the mother. The systemic and placental changes that occur with malaria in pregnancy can adversely affect the developing fetal brain, an fetal brain injury strongly affects long-term childhood neurodevelopmental (ND) and behavior but there are no published studies to date on the impact of malaria in pregnancy on childhood ND. This study, conducted in Uganda, will address the effects of malaria in pregnancy and childhood ND and define mechanisms by which malaria may lead to ND impairment including micronutrient deficiencies. ND outcomes will be measured by the following neuropsychological and behavioral tests: Mullen Scales of Early Learning, the Color Object Association Test, the Early Childhood Vigilance Test, the Behavior Rating Scales, the Behavior Related inventory of Executive Function and the Child Behavior Checklist. These tests will be given at 12, 24, 36, and 60 months of age. This study will be nested in an ongoing Ugandan IRB approved interventional trial (PROMOTE-II) (NCT02163447). Blood sampling is being conducted in the PROMOTE-II protocol for research purposes. Some of that blood will be used to test for micronutrient deficiencies as well as other immune responses to malaria.
Detailed description
The PROMOTE-II randomized clinical trial in Tororo, Uganda, led by investigators from Makerere University in Uganda and the University of California-San Francisco (UCSF), provides an ideal setting to assess the effects of malaria prevention in pregnant women and their children on childhood ND. In PROMOTE-II Project 1,300 pregnant HIV-uninfected women will be randomized at 12-20 weeks of gestation to malaria prophylaxis with 3 doses of sulfadoxine-pyrimethamine (current standard of care), 3 doses of dihydroartemisinin-piperaquine (DP), or monthly DP. Their children will be randomized to receive DP prophylaxis monthly or every 3 months from 2 to 24 months age. The children will be followed for malaria episodes from birth to age 36 months. The proposed prospective study of child ND, the Prophylaxis against malaria To Enhance Child developmenT (PROTECT) study, will be nested within the PROMOTE-II Project 1 cohort. It is hypothesized that mothers on SP and mothers and children on less frequent prophylaxis will have more malaria episodes. The investigators predict that child ND will improve with more effective prophylaxis.
The central hypotheses of this study are that malaria prevention in pregnant women and their children improves child ND through 1) prevention of placental sequestration and inflammation and of consequent micronutrient deficiency in the fetus, and 2) reduction of systemic inflammation and endothelial activation that can lead to micronutrient deficiency and anemia during pregnancy and in early childhood and thus to alteration of brain structures particularly sensitive to such deficiencies (e.g., the hippocampus, myelin and the frontal lobe). The collaborative team, which has expertise in malaria in pregnant women and children, malaria pathogenesis, micronutrient deficiency, fetal and child neurodevelopment, and modeling of complex disease pathways, is well qualified to undertake the proposed research.
The specific aims of the study are:
Aim 1. Determine the effect of malaria prevention in pregnant women and their children on child ND. Hypotheses: 1) Long-term child ND improves with more effective chemoprevention in pregnant women and in their children. 2) The effect of malaria prevention on child ND persists through 36 months of age. Child ND will be assessed with a testing battery validated in previous studies by this group in Ugandan children. The investigators will test these hypotheses by comparing child ND at 12, 24, 36 and 60 months of age between treatment groups.
Aim 2. Identify the major mechanisms by which malaria prevention in pregnant women and children affects child ND. Hypotheses: 1) Malaria prevention in pregnant women affects child ND through prevention of placental sequestration and inflammation, with consequent prevention of prematurity, intrauterine growth retardation and fetal micronutrient deficiency. 2) Malaria prevention in pregnant women and in their children after birth improves child ND through reduction of systemic inflammation, endothelial activation, micronutrient deficiency and anemia, but the relative contributions of the factors differ in pregnant women compared to children. The investigators will test these hypotheses by conducting path analysis to determine if networks that include these paths explain a significant proportion of the difference in child ND between treatment groups.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| Maternal SP/Child 3mo DP | – | Other: No intervention in PROTECTIn this group in the PROMOTE-II study, mothers receive 3 doses of sulfadoxine-pyrimethamine (SP), and children receive every 3 month dihydroartemisinin-piperaquine (DP). No intervention is given in the observational PROTECT study. |
| Maternal 3 dose DP/Child 3mo DP | – | Other: No intervention in PROTECTIn this group in the PROMOTE-II study, mothers receive 3 doses of DP, and children receive every 3 month DP.No intervention is given in the observational PROTECT study. |
| Maternal 3 dose DP/Child monthly DP | – | Other: No intervention in PROTECTIn this group in the PROMOTE-II study, mothers receive 3 doses of DP, and children receive monthly DP. No intervention is given in the observational PROTECT study. |
| Maternal monthly DP/Child 3mo DP | – | Other: No intervention in PROTECTIn this group in the PROMOTE-II study, mothers receive monthly DP, and children receive every 3 month DP. No intervention is given in the observational PROTECT study. |
| Maternal monthly DP/child monthly DP | – | Other: No intervention in PROTECTIn this group in the PROMOTE-II study, mothers receive monthly DP, and children receive every monthly DP. No intervention is given in the observational PROTECT study. |
Who may qualify
- Ages
- 10 to 38 months
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
- Study population
- 300 Ugandan Children already enrolled in PROMOTE II study
Key inclusion criteria (4 listed)
- Enrolled in Makerere University-UCSF PROMOTE II study
- HIV-uninfected
- 12 months of age at the time of enrollment
- Within 30 km of the clinic
Key exclusion criteria (7 listed)
- Serious adverse event to the study drugs requiring cessation of study drug
- Active illness at enrollment (child can be enrolled once active illness has been treated and they are back to baseline health)
- Previous history of head trauma or coma in the child
- Cerebral palsy or other severe neurologic disease
- Known chronic illness requiring medical care
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| No intervention in PROTECT | Other | Maternal 3 dose DP/Child 3mo DP, Maternal 3 dose DP/Child monthly DP, Maternal SP/Child 3mo DP, Maternal monthly DP/Child 3mo DP, Maternal monthly DP/child monthly DP |
Primary outcome
Z-scores for Overall cognitive ability
Time frame: 12 months of age
Z-scores for Overall cognitive ability
Time frame: 24 months of age
Z-scores for Overall cognitive ability
Time frame: 36 months of age
Z scores for Elicited Imitation
Time frame: 12 months of age
Z scores for Elicited Imitation
Time frame: 24 months of age
Z scores for Elicited Imitation
Time frame: 36 months of age
Z scores of Overal Cognitive ability
Time frame: 60 months of age
Z scores of Elicited Imitation
Time frame: 60 months of age
3 secondary outcomes
Z scores for Behavioral Rating Scale
Time frame: 24, 36, and 60 months of age
Z scores for Behavior Related Inventory of Executive Function (BRIEF)
Time frame: 24, 36, and 60 months of age
Z scores for Child Behavior Checklist (CBCL)
Time frame: 24, 36, and 60 months of age
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 25 Aug 2021.
- Derived from this study: PubMed 36219705Bangirana P, Conroy AL, Opoka RO, Semrud-Clikeman M, Jang JH, Apayi C, Kakuru A, Muhindo MK, Georgieff MK, Dorsey GM, Kamya MR, Havlir D, John CC. Effect of Malaria and Malaria Chemoprevention Regimens in Pregnancy and Childhood on Neurodevelopmental and Behavioral Outcomes in Children at 12, 24, and 36 Months: A Randomized Clinical Trial. Clin Infect Dis. 2023 Feb 18;76(4):600-608. doi: 10.1093/cid/ciac815.
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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.
Chandy C John, MD principal investigator
Indiana University
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 Neurobehavioral Manifestations, run by Indiana University 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 4 inclusion and 7 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 25 Aug 2021. 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?
Z-scores for Overall cognitive ability (time frame: 12 months of age). The study lists 8 primary outcomes in all. 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 NCT02557425, which also lists 1 linked publication.
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 25 Aug 2021; AzTrials last refreshed its copy on 29 Oct 2026.