Uncomplicated Plasmodium Falciparum Malaria
Conditions
Keywords
malaria, HIV, Children, Efavirenz, artemether, lumefantrine
Brief summary
This project determines the pharmacokinetic/pharmacodynamic (PK/PD) of an extended artemether-lumefantrine (AL) dosing regimen in HIV-infected children on efavirenz (EFV)-based antiretroviral therapy (ART) that is designed to improve the PK exposure and treatment efficacy of this artemisinins-based combination therapy (ACT) regimen. Our overarching goal is to inform the best treatment guidelines for young children in Africa. HIV-infected and HIV-uninfected children were enrolled for intensive PK studies, as well as additional children for population PK studies to enhance association analyses with clinical outcomes.
Detailed description
This is a prospective multi-site study to evaluate the PK/PD of extended duration AL in HIV-infected children on EFV-based ART and HIV-uninfected children not on ART. AL is the first-line treatment for malaria in Uganda. No change in standard of care treatment was made for the purposes of this study except for the extension of AL to 5-day dosing. This study enrolled a) HIV-infected children, and b) HIV-uninfected children. All participants may be enrolled through Tororo District Hospital (TDH) or Masafu General Hospital (MGH) in Busia, or other referral centers the area. we used a design where children were randomized to either 3-day or 5-day AL and then for subsequent episodes of malaria, should they occur. Conservatively, assuming each enrolled child participates for only a single episode of malaria, up to 60 (30 HIV-infected on 3-day and 30 HIV-infected on 5-day) and 100 (50 HIV-uninfected on 3-day and 50 HIV-uninfected on 5-day) subjects were enrolled for each of the intensive study groups. 16 (9 HIV-infected on 3-day and 7 HIV-infected on 5-day) and 120 (60 HIV-uninfected on 3-day and 60 HIV-uninfected on 5-day) subjects were enrolled for each of the population study groups. Enrollment of HIV-infected subjects for population PK study groups was not halted due to the lack of HIV-infected children in the study area. Comparisons of AL PK exposure were made among and between a) HIV-infected children with malaria receiving EFV-based ART and b) HIV-uninfected children who are not on ART. Comparisons were based on an intensive PK design for AL area under the concentration-time curve (AUC) estimations.
Interventions
DRUGArtemether-lumefantrine
Children will receive the dispersible formulation of AL which contains 20 mg artemether, 120 mg of lumefantrine (Coartem® Dispersible). Weight-based dosing will be as below: \<15kg, 1tablet; 15-25kg, 2 tablets; 25-35kg, 3 tablets; \>=35kg, 4 tablets.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Yale University
Infectious Diseases Research Collaboration, Uganda
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a prospective multi-site study accomplished through a randomized design where children will be randomized to either 3-day or 5-day AL regimen and then for subsequent episodes of malaria, should they occur..
Eligibility
Sex/Gender
ALL
Age
6 Months to 18 Years
Healthy volunteers
No
Inclusion criteria
1, All participants: 1. Residency within 60 km of the study clinics either at TDH or at MGH 2. Agreement to come to clinic for all follow-up clinical and PK evaluations 3. Provision of informed consent 4. Weight ≥6 kg 5. Presentation with uncomplicated falciparum malaria as indicated by positive smear for malaria parasites along with clinical evidence of infection (fever or history of fever in the past 24 hours) 6. Willingness to undergo intensive PK sampling and/or population PK sampling during episode(s) of malaria. 2 HIV-infected participants: 1. Confirmed HIV infection (positive rapid HIV test to be confirmed by Western Blot or HIV RNA after enrollment) 2. On stable EFV-based ART for at least 10 days prior to enrollment 3. Age 3 years to 18 years 3 HIV-uninfected participants: 1. Confirmed HIV negative test (negative rapid HIV test to be confirmed by Western Blot or HIV RNA after enrollment) 2. Age 6 months to 18 years
Exclusion criteria
1. History of significant comorbidities such as malignancy, active tuberculosis or other World Health Organization (WHO) stage 4 disease 2. Current infection with non-P. falciparum species 3. Receipt of any medications known to affect CYP450 metabolism (except ART) within 14 days of study enrollment (see 4.2.2) 4. Hemoglobin \< 7.0 g/dL 5. For the population PK study, prior treatment for malaria within 14 days of enrollment 6. For the intensive PK study, prior treatment for malaria within 28 days of enrollment 7. Signs or evidence of complicated malaria, defined as unarousable coma or any two of the following symptoms: Recent febrile convulsions, altered consciousness, lethargy, unable to drink, unable to stand/sit due to weakness, severe anemia (Hb \< 5.0 gm/dL), respiratory distress, jaundice (see Appendix D) 8. History of toxicity to AL The following medications are disallowed within 3 weeks prior to receiving study drug: * Carbamazepine * Clarithromycin * Erythromycin (oral) * Ketoconazole * Phenobarbital * Phenytoin * Rifabutin * Rifampin * Halofantrine * Any other medication known to significantly affect CYP450 metabolism. * Grapefruit juice should be avoided during the study due to its potential effects on CYP3A4.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-21d | Study day 0-day21 | Area under the plasma concentration versus time curve (AUC) from time 0 to day 21 for lumefantrine |
| Cmax for Dihydroartemisinin | 0-8hr | Maximal concentration post last dose for dihydroartimisinin (DHA) |
| Cmax for Artemether | 0-8hr | Maximal concentration post last dose for artemether |
| Cmax for Lumefantrine | 0-21 days | Maximal concentration post last dose for lumefantrine |
| AUC0-8h for Dihydroartemisinin | 0-8hr | Area under the plasma concentration versus time curve (AUC) from time 0 to 8hr post last dose for Dihydroartemisinin (DHA) |
| AUC0-8h for Artemether | 0-8hr | Area under the plasma concentration versus time curve (AUC) from 0 to 8hr post last dose for artemether (ARM) |
| Recurrent Parasitemia Following Treatment by Day 42 (Recrudescence or New Infection) | up to study day 42 | Recurrent malaria determined by microscopy (thick blood smears), loop mediated isothermal amplification (LAMP), or rapid diagnostic test (RDT). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious Adverse Events | study day 0-42 | We recorded participants tolerance of AL using the NIH Division of AIDS Adult and Pediatric Toxicity Tables. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Relationship Between Drug Resistance and Treatment Failure | study day 0-42 | drug resistance will be accessed by molecular markers. Polymorphic markers will be typed using capillary electrophoresis. |
| Prevalence of Gametocytemia | study day 0-42 | At varied time points, blood smears for the determination of parasitemia will be obtained following treatment in 3-day vs 5-day AL regimens. |
| Weight-for-age (WFA) Associations With PK | study day 0 | weight-for-age is an indicator of nutrition status and decreased weight-for-age reflects the combination of chronic and acute protein-calorie malnutrition. |
| Weight-for-height (WFH) Associations With PK | study day 0 | acute protein-calorie malnutrition resulting in weight loss or slow weight gain (decreased weight-for-height: WFH; wasting). |
| Diagnostic Sensitivity of LAMP, HS-RDT, and Microscopy for the Detection of Recurrent Parasitemia | study day 0-42 | Using Loop-mediated isothermal amplification (LAMP), highly sensitive Rapid Diagnostic Test (HS-RDT), and microscope to diagnose recurrent parasitemia. study day 0-42 |
| Height-for-age (HFA) Associations With PK | study day 0 | chronic protein-calorie malnutrition resulting in slow linear growth (decreased height-for-age: HFA; stunting). |
| Metabolomic Measurements in HIV Infected vs HIV Uninfected Children | study day 0-42 | Small-molecule metabolites, including metabolic intermediates, hormones and other signaling molecules, and secondary metabolites will be measured in plasma and reported as fold-change (e.g. infected vs uninfected). This is an exploratory study. The multiple measurements could be aggregated to fold-change. |
Countries
Uganda
Participant flow
Recruitment details
The recruitment started on 2/21/2018 and ended on 07/23/2019 and last follow up date was 09/03/2019. Study location was at Masafu General Hospital. Intensive PK recruitments were completed for all 4 arms: HIV negative 3-day and 5-day arm (n=50 each), HIV positive 3-day and 5-day arm (n=30). Population PK recruitments reached the target for HIV negative arms (n=60 each), but not for HIV-positive arms, because of the lack of HIV positive patients in the study sites.
Participants by arm
| Arm | Count |
|---|---|
| HIV-infected 3-day AL Intensive PK Standard 3-day twice daily (BID) regimen of artemether-lumefantrine for uncomplicated malaria, given over 4 days (Study Days 0, 1, 2 and 3) so that sampling will begin in the morning of day 3. These participants are HIV-infected and stabilized on EFV-based ART.
Artemether-lumefantrine: Children will receive the dispersible formulation of AL which contains 20 mg artemether, 120 mg of lumefantrine (Coartem® Dispersible). Weight-based dosing will be as below: \<15kg, 1tablet; 15-25kg, 2 tablets; 25-35kg, 3 tablets; \>=35kg, 4 tablets. | 35 |
| HIV-infected 5-day AL Intensive PK Extended 5-day BID regimen of artemether-lumefantrine, given over 6 days (Study Days 0, 1, 2, 3, 4, and 5) so that sampling will begin in the morning of day 5. These participants are HIV-infected and stabilized on EFV-based ART.
Artemether-lumefantrine: Children will receive the dispersible formulation of AL which contains 20 mg artemether, 120 mg of lumefantrine (Coartem® Dispersible). Weight-based dosing will be as below: \<15kg, 1tablet; 15-25kg, 2 tablets; 25-35kg, 3 tablets; \>=35kg, 4 tablets. | 36 |
| HIV-uninfected 3-day AL Standard 3-day BID regimen of artemether-lumefantrine for uncomplicated malaria, given over 4 days (Study Days 0, 1, 2 and 3) so that sampling will begin in the morning of day 3. These participants are HIV-uninfected.
Artemether-lumefantrine: Children will receive the dispersible formulation of AL which contains 20 mg artemether, 120 mg of lumefantrine (Coartem® Dispersible). Weight-based dosing will be as below: \<15kg, 1tablet; 15-25kg, 2 tablets; 25-35kg, 3 tablets; \>=35kg, 4 tablets. | 114 |
| HIV-uninfected 5-day AL Extended 5-day BID regimen of artemether-lumefantrine, given over 6 days (Study Days 0, 1, 2, 3, 4, and 5) so that sampling will begin in the morning of day 5. These participants are HIV-uninfected.
Artemether-lumefantrine: Children will receive the dispersible formulation of AL which contains 20 mg artemether, 120 mg of lumefantrine (Coartem® Dispersible). Weight-based dosing will be as below: \<15kg, 1tablet; 15-25kg, 2 tablets; 25-35kg, 3 tablets; \>=35kg, 4 tablets. | 113 |
| Total | 298 |
Baseline characteristics
| Characteristic | Total | HIV-uninfected 5-day AL | HIV-infected 3-day AL Intensive PK | HIV-infected 5-day AL Intensive PK | HIV-uninfected 3-day AL |
|---|---|---|---|---|---|
| Age, Continuous | 6.2 years | 5.9 years | 11.5 years | 10.4 years | 5.3 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 298 Participants | 113 Participants | 35 Participants | 36 Participants | 114 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Uganda | 298 participants | 113 participants | 35 participants | 36 participants | 114 participants |
| Sex: Female, Male Female | 160 Participants | 60 Participants | 21 Participants | 15 Participants | 64 Participants |
| Sex: Female, Male Male | 138 Participants | 53 Participants | 14 Participants | 21 Participants | 50 Participants |
| Weight | 20.2 kg | 19.1 kg | 28.4 kg | 25.8 kg | 17.3 kg |
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 / 35 | 0 / 36 | 0 / 114 | 0 / 113 |
| other Total, other adverse events | 0 / 35 | 0 / 36 | 0 / 114 | 0 / 113 |
| serious Total, serious adverse events | 0 / 35 | 0 / 36 | 2 / 114 | 0 / 113 |
Outcome results
Primary
AUC0-21d
Area under the plasma concentration versus time curve (AUC) from time 0 to day 21 for lumefantrine
Time frame: Study day 0-day21
Population: Intensive PK participants only. Population PK participants are excluded here.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| HIV-infected 3-day AL Intensive PK | AUC0-21d | 144 hr*ug/mL |
| HIV-infected 5-day AL Intensive PK | AUC0-21d | 205 hr*ug/mL |
| HIV-uninfected 3-day AL Intensive PK | AUC0-21d | 259 hr*ug/mL |
| HIV-uninfected 5-day AL Intensive PK | AUC0-21d | 318 hr*ug/mL |
Primary
AUC0-8h for Artemether
Area under the plasma concentration versus time curve (AUC) from 0 to 8hr post last dose for artemether (ARM)
Time frame: 0-8hr
Population: Intensive PK participants only, so the participant number here is different from the numbers in the participant flow module, which includes both intensive and population PK participants.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| HIV-infected 3-day AL Intensive PK | AUC0-8h for Artemether | 64.0 hr*ng/mL |
| HIV-infected 5-day AL Intensive PK | AUC0-8h for Artemether | 71.7 hr*ng/mL |
| HIV-uninfected 3-day AL Intensive PK | AUC0-8h for Artemether | 95.8 hr*ng/mL |
| HIV-uninfected 5-day AL Intensive PK | AUC0-8h for Artemether | 78.6 hr*ng/mL |
Primary
AUC0-8h for Dihydroartemisinin
Area under the plasma concentration versus time curve (AUC) from time 0 to 8hr post last dose for Dihydroartemisinin (DHA)
Time frame: 0-8hr
Population: Intensive PK participants only, so the participant number here is different from the numbers in the participant flow module, which includes both intensive and population PK participants.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| HIV-infected 3-day AL Intensive PK | AUC0-8h for Dihydroartemisinin | 109 hr.ng/mL |
| HIV-infected 5-day AL Intensive PK | AUC0-8h for Dihydroartemisinin | 95.8 hr.ng/mL |
| HIV-uninfected 3-day AL Intensive PK | AUC0-8h for Dihydroartemisinin | 241 hr.ng/mL |
| HIV-uninfected 5-day AL Intensive PK | AUC0-8h for Dihydroartemisinin | 229 hr.ng/mL |
Primary
Cmax for Artemether
Maximal concentration post last dose for artemether
Time frame: 0-8hr
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| HIV-infected 3-day AL Intensive PK | Cmax for Artemether | 22.4 ng/mL |
| HIV-infected 5-day AL Intensive PK | Cmax for Artemether | 23.0 ng/mL |
| HIV-uninfected 3-day AL Intensive PK | Cmax for Artemether | 32.5 ng/mL |
| HIV-uninfected 5-day AL Intensive PK | Cmax for Artemether | 27.3 ng/mL |
Primary
Cmax for Dihydroartemisinin
Maximal concentration post last dose for dihydroartimisinin (DHA)
Time frame: 0-8hr
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| HIV-infected 3-day AL Intensive PK | Cmax for Dihydroartemisinin | 43.8 ng/mL |
| HIV-infected 5-day AL Intensive PK | Cmax for Dihydroartemisinin | 34.9 ng/mL |
| HIV-uninfected 3-day AL Intensive PK | Cmax for Dihydroartemisinin | 89.0 ng/mL |
| HIV-uninfected 5-day AL Intensive PK | Cmax for Dihydroartemisinin | 87.9 ng/mL |
Primary
Cmax for Lumefantrine
Maximal concentration post last dose for lumefantrine
Time frame: 0-21 days
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| HIV-infected 3-day AL Intensive PK | Cmax for Lumefantrine | 5065 ng/mL |
| HIV-infected 5-day AL Intensive PK | Cmax for Lumefantrine | 6027 ng/mL |
| HIV-uninfected 3-day AL Intensive PK | Cmax for Lumefantrine | 7236 ng/mL |
| HIV-uninfected 5-day AL Intensive PK | Cmax for Lumefantrine | 8450 ng/mL |
Primary
Recurrent Parasitemia Following Treatment by Day 42 (Recrudescence or New Infection)
Recurrent malaria determined by microscopy (thick blood smears), loop mediated isothermal amplification (LAMP), or rapid diagnostic test (RDT).
Time frame: up to study day 42
Population: All participants including intensive and population PK participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HIV-infected 3-day AL Intensive PK | Recurrent Parasitemia Following Treatment by Day 42 (Recrudescence or New Infection) | 19 Participants |
| HIV-infected 5-day AL Intensive PK | Recurrent Parasitemia Following Treatment by Day 42 (Recrudescence or New Infection) | 18 Participants |
| HIV-uninfected 3-day AL Intensive PK | Recurrent Parasitemia Following Treatment by Day 42 (Recrudescence or New Infection) | 80 Participants |
| HIV-uninfected 5-day AL Intensive PK | Recurrent Parasitemia Following Treatment by Day 42 (Recrudescence or New Infection) | 66 Participants |
Secondary
Number of Participants With Serious Adverse Events
We recorded participants tolerance of AL using the NIH Division of AIDS Adult and Pediatric Toxicity Tables.
Time frame: study day 0-42
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HIV-infected 3-day AL Intensive PK | Number of Participants With Serious Adverse Events | 0 Participants |
| HIV-infected 5-day AL Intensive PK | Number of Participants With Serious Adverse Events | 0 Participants |
| HIV-uninfected 3-day AL Intensive PK | Number of Participants With Serious Adverse Events | 2 Participants |
| HIV-uninfected 5-day AL Intensive PK | Number of Participants With Serious Adverse Events | 0 Participants |
Other Pre-specified
Diagnostic Sensitivity of LAMP, HS-RDT, and Microscopy for the Detection of Recurrent Parasitemia
Using Loop-mediated isothermal amplification (LAMP), highly sensitive Rapid Diagnostic Test (HS-RDT), and microscope to diagnose recurrent parasitemia. study day 0-42
Time frame: study day 0-42
Other Pre-specified
Height-for-age (HFA) Associations With PK
chronic protein-calorie malnutrition resulting in slow linear growth (decreased height-for-age: HFA; stunting).
Time frame: study day 0
Other Pre-specified
Metabolomic Measurements in HIV Infected vs HIV Uninfected Children
Small-molecule metabolites, including metabolic intermediates, hormones and other signaling molecules, and secondary metabolites will be measured in plasma and reported as fold-change (e.g. infected vs uninfected). This is an exploratory study. The multiple measurements could be aggregated to fold-change.
Time frame: study day 0-42
Other Pre-specified
Prevalence of Gametocytemia
At varied time points, blood smears for the determination of parasitemia will be obtained following treatment in 3-day vs 5-day AL regimens.
Time frame: study day 0-42
Other Pre-specified
Relationship Between Drug Resistance and Treatment Failure
drug resistance will be accessed by molecular markers. Polymorphic markers will be typed using capillary electrophoresis.
Time frame: study day 0-42
Other Pre-specified
Weight-for-age (WFA) Associations With PK
weight-for-age is an indicator of nutrition status and decreased weight-for-age reflects the combination of chronic and acute protein-calorie malnutrition.
Time frame: study day 0
Other Pre-specified
Weight-for-height (WFH) Associations With PK
acute protein-calorie malnutrition resulting in weight loss or slow weight gain (decreased weight-for-height: WFH; wasting).
Time frame: study day 0