Intermittent Preventive Treatment, Malaria
Conditions
Keywords
Malaria, Intermittent preventive treatment, Efficacy, Safety, Tolerability, Schoolchildren, Uganda
Brief summary
This will be a randomized, single-blinded, placebo-controlled trial to evaluate the efficacy, safety and tolerability of antimalarial regimens in healthy schoolchildren. The primary objective of the study is to compare the efficacy of different combination antimalarial regimens, including amodiaquine + sulfadoxine-pyrimethamine (AQ+SP), dihydroartemisinin-piperaquine (DP), and placebo, to SP for intermittent preventive treatment (IPT) in schoolchildren, as measured by risk of parasitaemia (unadjusted by genotyping) after 42 days of follow-up. This will assess both the efficacy for treatment of asymptomatic infections and the efficacy for prevention of new infections.
Detailed description
The study will be carried out among children aged ≥ 8 to \< 14 years (boys) and ≥ 8 to \< 12 years (girls) attending primary schools in Tororo district. Schools will be selected using convenience sampling with the assistance of the district and the education sector. The target population includes children attending primary schools in Uganda. The accessible population includes the children attending the participating primary schools in classes 3-7 in Tororo district. Children who meet the selection criteria for participation in the study will be randomized to treatment with one of the four study regimens and will be followed for 42 days. Repeat evaluations will be performed on days 1, 2, 3, 7, 14, 28, and 42 (and any unscheduled day that a student is ill) and will include assessment for the occurrence of adverse events. Treatment efficacy outcomes will be assessed using revised WHO outcome classification criteria. Acceptability of treatment regimens will be assessed using a questionnaire administered to participating students on day 7. The primary outcome measure is risk of parasitaemia (unadjusted by genotyping) after 42 days of follow-up.
Interventions
DRUGsulfadoxine-pyrimethamine
25 mg/kg po once on day 0
DRUGamodiaquine + sulfadoxine-pyrimethamine
Amodiaquine: 10 mg/kg po daily for 3 days (on days 0, 1, 2) SP: 25 mg/kg po once on day 0
DRUGdihydroartemisinin-piperaquine
2.1/17.1 mg/kg daily for three days (on days 0, 1, 2)
OTHERPlacebo
dosed as for amodiaquine (10mg/kg po daily on days 1, 2)
Sponsors
Uganda Malaria Surveillance Project
Ministry of Health, Uganda
London School of Hygiene and Tropical Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
8 Years to 13 Years
Healthy volunteers
No
Inclusion criteria
* Age ≥ 8 to \< 14 years (boys), ≥ 8 to \< 12 years (girls) * Student enrolled at participating school in classes 3-7 * Provision of informed consent from parent or guardian * Provision of assent by student
Exclusion criteria
* Known allergy or history of adverse reaction to study medications * Onset of menstruation (girls) * Fever (≥ 37.5°C axillary) or history of fever in the previous 24 hours * Evidence of severe malaria or danger signs * Haemoglobin \< 7.0 gm/dL * Parasite density \> 10,000/ul
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Risk of Parasitaemia (Unadjusted by Genotyping) | after 42 days of follow-up | Proportion of participants whose thick blood smears that are positive for asexual parasites |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Risk of New Infection (Adjusted by Genotyping) in All Participants | after 42 days of follow-up | Proportion of participants whose thick blood smears that are positive for new asexual parasites on day of failure at genotyping |
| Risk of Clinical Failure Due to Recrudescence (Adjusted by Genotyping) in Children Who Were Parasitaemic at Enrollment | Over 42 days of follow-up | Proportion of children who were parasitaemia at enrollment, with subsequent fever and a positive thick blood smear for asexual parasites on the day of failure during follow-up |
| Risk of Recrudescence (Adjusted by Genotyping) in Participants Who Were Parasitaemic at Enrollment | after 42 days of follow-up | Proportion of participants whose thick blood smears that are positive with the same asexual parasites at baseline and on the day of failure at genotyping |
| Risk of Serious Adverse Events | over 42 days of follow-up | Any untoward medical occurrence in a participant taking study medication after 14 and 42 days of follow up leading to death, disability, hospitalization or extended hospitalization |
| Acceptability of IPT Regimens | on day 7 | Perceived willingness to take study medication as routine preventive treatment |
| Mean Change in Haemoglobin | Between day 0 to day 42 | Haemoglobin measured in g/dL; Mean change in haemoglobin calculated as the difference in mean haemoglobin (g/dL) on Day 42 - Day 0, in children treated with the different antimalarial regimens |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Combination of Amodiaquine +Sulfadoxine-pyrimethamine Combination of Amodiaquine (Camoquin, Parke-Davis, 200 mg tablets, 10 mg/kg on days 0 and 1, and 5 mg/kg on day 2) + sulfadoxine-pyrimethamine (Fansidar, Roche, 500 mg/25 mg tablets, 25 mg/kg sulfadoxine and 1.25 mg/kg pyrimethamine per treatment as a single dose) given as oral tablets
amodiaquine + sulfadoxine-pyrimethamine: Amodiaquine: 10 mg/kg po daily for 3 days (on days 0, 1, 2) SP: 25 mg/kg po once on day 0 | 200 |
| Dihydroartemisinin-piperaquine Dihydroartemisinin-piperaquine (Duocotexin, Holley Pharm, 40 mg dihydroartemisinin/320 mg piperaquine tablets targeting a total dose of 6.4 and 51.2 mg/kg of dihydroartemisinin and piperaquine, respectively, given in 3 equally divided daily doses to the nearest ¼ tablet)
dihydroartemisinin-piperaquine: 2.1/17.1 mg/kg daily for three days (on days 0, 1, 2) | 198 |
| Placebo Placebo (had no active ingredients, produced by Cosmos Limited, Nairobi, Kenya)
Placebo: dosed as for amodiaquine (10mg/kg po daily on days 1, 2) | 196 |
| Sulfadoxine-pyrimethamine Alone sulfadoxine-pyrimethamine (Fansidar, Roche, 500 mg/25 mg tablets, 25 mg/kg sulfadoxine and 1.25 mg/kg pyrimethamine per treatment as a single dose) given as oral tablets
sulfadoxine-pyrimethamine: 25 mg/kg po once on day 0 | 186 |
| Total | 780 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 3 | 4 | 2 |
Baseline characteristics
| Characteristic | Combination of Amodiaquine +Sulfadoxine-pyrimethamine | Dihydroartemisinin-piperaquine | Placebo | Sulfadoxine-pyrimethamine Alone | Total |
|---|---|---|---|---|---|
| Age, Continuous | 10.7 years STANDARD_DEVIATION 1.93 | 10.3 years STANDARD_DEVIATION 1.73 | 10.6 years STANDARD_DEVIATION 1.86 | 10.6 years STANDARD_DEVIATION 1.85 | 10.6 years STANDARD_DEVIATION 1.84 |
| Bed net use | 56 Participants | 56 Participants | 57 Participants | 47 Participants | 216 Participants |
| Mean hemoglobin | 12.7 g/dL STANDARD_DEVIATION 1.33 | 12.4 g/dL STANDARD_DEVIATION 1.26 | 12.7 g/dL STANDARD_DEVIATION 1.38 | 12.7 g/dL STANDARD_DEVIATION 1.31 | 12.6 g/dL STANDARD_DEVIATION 1.32 |
| Sex: Female, Male Female | 78 Participants | 87 Participants | 78 Participants | 70 Participants | 313 Participants |
| Sex: Female, Male Male | 122 Participants | 111 Participants | 118 Participants | 116 Participants | 467 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 198 | 0 / 200 | 0 / 196 | 0 / 186 |
| other Total, other adverse events | 117 / 198 | 122 / 200 | 124 / 196 | 114 / 186 |
| serious Total, serious adverse events | 0 / 198 | 0 / 200 | 0 / 196 | 0 / 186 |
Outcome results
Primary
Risk of Parasitaemia (Unadjusted by Genotyping)
Proportion of participants whose thick blood smears that are positive for asexual parasites
Time frame: after 42 days of follow-up
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dihydroartemisinin-piperaquine | Risk of Parasitaemia (Unadjusted by Genotyping) | 23 Participants |
| Combination of Amodiaquine +Sulfadoxine-pyrimethamine | Risk of Parasitaemia (Unadjusted by Genotyping) | 87 Participants |
| Placebo | Risk of Parasitaemia (Unadjusted by Genotyping) | 164 Participants |
| Sulfadoxine-pyrimethamine Alone | Risk of Parasitaemia (Unadjusted by Genotyping) | 147 Participants |
Secondary
Acceptability of IPT Regimens
Perceived willingness to take study medication as routine preventive treatment
Time frame: on day 7
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dihydroartemisinin-piperaquine | Acceptability of IPT Regimens | 55 Participants |
| Combination of Amodiaquine +Sulfadoxine-pyrimethamine | Acceptability of IPT Regimens | 67 Participants |
| Placebo | Acceptability of IPT Regimens | 20 Participants |
| Sulfadoxine-pyrimethamine Alone | Acceptability of IPT Regimens | 23 Participants |
Secondary
Mean Change in Haemoglobin
Haemoglobin measured in g/dL; Mean change in haemoglobin calculated as the difference in mean haemoglobin (g/dL) on Day 42 - Day 0, in children treated with the different antimalarial regimens
Time frame: Between day 0 to day 42
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dihydroartemisinin-piperaquine | Mean Change in Haemoglobin | 0.34 g/dL |
| Combination of Amodiaquine +Sulfadoxine-pyrimethamine | Mean Change in Haemoglobin | 0.37 g/dL |
| Placebo | Mean Change in Haemoglobin | 0.24 g/dL |
| Sulfadoxine-pyrimethamine Alone | Mean Change in Haemoglobin | 0.18 g/dL |
Secondary
Risk of Clinical Failure Due to Recrudescence (Adjusted by Genotyping) in Children Who Were Parasitaemic at Enrollment
Proportion of children who were parasitaemia at enrollment, with subsequent fever and a positive thick blood smear for asexual parasites on the day of failure during follow-up
Time frame: Over 42 days of follow-up
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dihydroartemisinin-piperaquine | Risk of Clinical Failure Due to Recrudescence (Adjusted by Genotyping) in Children Who Were Parasitaemic at Enrollment | 2 Participants |
| Combination of Amodiaquine +Sulfadoxine-pyrimethamine | Risk of Clinical Failure Due to Recrudescence (Adjusted by Genotyping) in Children Who Were Parasitaemic at Enrollment | 6 Participants |
| Placebo | Risk of Clinical Failure Due to Recrudescence (Adjusted by Genotyping) in Children Who Were Parasitaemic at Enrollment | 64 Participants |
| Sulfadoxine-pyrimethamine Alone | Risk of Clinical Failure Due to Recrudescence (Adjusted by Genotyping) in Children Who Were Parasitaemic at Enrollment | 50 Participants |
Secondary
Risk of Clinical Failure Due to Recrudescence (Adjusted by Genotyping) in Children Who Were Parasitaemic at Enrollment
Proportion of children who were parasitaemia at enrollment, with subsequent fever and a positive thick blood smear for asexual parasites on the day of failure during follow-up
Time frame: after 42 days of follow-up
Population: Risk of recrudescence in children with parasites on day 0 (n=392). The risk of recrudescence was estimated using Kaplan-Meier survival techniques with corresponding 95% confidence intervals (CI) calculated using Greenwood variance estimates.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dihydroartemisinin-piperaquine | Risk of Clinical Failure Due to Recrudescence (Adjusted by Genotyping) in Children Who Were Parasitaemic at Enrollment | 2 Participants |
| Combination of Amodiaquine +Sulfadoxine-pyrimethamine | Risk of Clinical Failure Due to Recrudescence (Adjusted by Genotyping) in Children Who Were Parasitaemic at Enrollment | 6 Participants |
| Placebo | Risk of Clinical Failure Due to Recrudescence (Adjusted by Genotyping) in Children Who Were Parasitaemic at Enrollment | 64 Participants |
| Sulfadoxine-pyrimethamine Alone | Risk of Clinical Failure Due to Recrudescence (Adjusted by Genotyping) in Children Who Were Parasitaemic at Enrollment | 50 Participants |
Secondary
Risk of New Infection (Adjusted by Genotyping) in All Participants
Proportion of participants whose thick blood smears that are positive for new asexual parasites on day of failure at genotyping
Time frame: after 42 days of follow-up
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dihydroartemisinin-piperaquine | Risk of New Infection (Adjusted by Genotyping) in All Participants | 12 Participants |
| Combination of Amodiaquine +Sulfadoxine-pyrimethamine | Risk of New Infection (Adjusted by Genotyping) in All Participants | 55 Participants |
| Placebo | Risk of New Infection (Adjusted by Genotyping) in All Participants | 64 Participants |
| Sulfadoxine-pyrimethamine Alone | Risk of New Infection (Adjusted by Genotyping) in All Participants | 62 Participants |
Secondary
Risk of Recrudescence (Adjusted by Genotyping) in Participants Who Were Parasitaemic at Enrollment
Proportion of participants whose thick blood smears that are positive with the same asexual parasites at baseline and on the day of failure at genotyping
Time frame: after 42 days of follow-up
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dihydroartemisinin-piperaquine | Risk of Recrudescence (Adjusted by Genotyping) in Participants Who Were Parasitaemic at Enrollment | 2 Participants |
| Combination of Amodiaquine +Sulfadoxine-pyrimethamine | Risk of Recrudescence (Adjusted by Genotyping) in Participants Who Were Parasitaemic at Enrollment | 6 Participants |
| Placebo | Risk of Recrudescence (Adjusted by Genotyping) in Participants Who Were Parasitaemic at Enrollment | 64 Participants |
| Sulfadoxine-pyrimethamine Alone | Risk of Recrudescence (Adjusted by Genotyping) in Participants Who Were Parasitaemic at Enrollment | 50 Participants |
Secondary
Risk of Serious Adverse Events
Any untoward medical occurrence in a participant taking study medication after 14 and 42 days of follow up leading to death, disability, hospitalization or extended hospitalization
Time frame: over 42 days of follow-up
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dihydroartemisinin-piperaquine | Risk of Serious Adverse Events | 117 Participants |
| Combination of Amodiaquine +Sulfadoxine-pyrimethamine | Risk of Serious Adverse Events | 122 Participants |
| Placebo | Risk of Serious Adverse Events | 125 Participants |
| Sulfadoxine-pyrimethamine Alone | Risk of Serious Adverse Events | 114 Participants |