Malaria, Falciparum
Conditions
Keywords
Malaria, Falciparum, Malaria, Protozoan Infections, Lumefantrine, Artemether, Amodiaquine, Piperaquine, Artemether-lumefantrine combination, Artemisinins, Dihydroartemisinin, Mefloquine, Artemisinin, Antimalarials, Antiparasitic Agents, Anti-Infective Agents, ACT, TACT, Triple ACT(s), Resistance, Antimalarial resistance, Cardiotoxicity, Safety, Tolerability, Efficacy
Brief summary
This study is a multi-centre, open-label randomised trial to assess the efficacy, safety and tolerability of the Triple ACT artemether-lumefantrine+amodiaquine (AL+AQ) compared to the ACT artemether-lumefantrine (AL) in uncomplicated falciparum malaria in Cambodia and Vietnam. The estimated total sample size is 600 patients from 2 sites in Cambodia and 2 sites in Vietnam. There are 2 treatment arms Arm 1: Artemether-lumefantrine for 3 days Arm 2: Artemether-lumefantrine for 3 days plus Amodiaquine for 3 days. According to the World Health Organization guideline, all patients except children under 10 kilograms will also be treated with a single dose of primaquine as a gametocytocidal treatment. Funder :Bill & Melinda Gates Foundation (BMGF) Grant reference number: OPP1132628
Detailed description
The study of artemether-lumefantrine or artemether-lumefantrine combined with amodiaquine will be a two-arm randomized open label comparative study. The main activity proposed is a series of detailed in vivo clinical, parasitological and pharmacological assessments in 600 subjects across 2 sites in Cambodian (400 subjects) and 2 sites in Vietnam (200 subjects). The subjects will be randomized between the ACT artemether-lumefantrine and the TACT artemether-lumefantrine+amodiaquine. Parasite clearance rates will be assessed by repeated assessments of the parasite counts after the start of the antimalarial treatments. Efficacy, safety and tolerability of ACTs and TACTs will be assessed through weekly follow up visits where vital signs, symptom questionnaires, physical examinations, blood smears, biochemistry assays and full blood counts will be performed. Ex vivo assessments of parasite susceptibility to artemisinins and partner drugs will be measured and compared to historical data, clinical phenotype and other sites in an effort to identify artemisinin and partner drug resistance. This study will obtain data on the effect of antimalarials on the corrected QT intervals. In addition, the effects of antimalarials on factors such as post-treatment haematocrit and haemoglobin levels will be assessed. Extensive pharmacokinetic analysis will allow for an assessment of drug-drug interactions. Plasma histidine-rich protein 2 (HRP2) levels (a marker of parasite biomass) that could potentially serve for the estimation of parasitaemia dynamics before and after treatment will be measured and subsequently modelled.
Interventions
DRUGACT
Artemether-lumefantrine (20/120 mg) as a fixed dose combination twice daily for 3 days according to weight plus low dose primaquine at hour 24
DRUGTACT
Artemether-lumefantrine (20/120 mg) as a fixed dose combination twice daily for 3 days according to weight plus Amodiaquine (150mg) twice daily for 3 days according to weight plus low dose primaquine at hour 24
Sponsors
University of Oxford
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
open-label randomised trial
Eligibility
Sex/Gender
ALL
Age
2 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male or female, aged from 2 years to 65 years old * Acute uncomplicated P. falciparum malaria, confirmed by positive blood smear with asexual forms of P. falciparum (or mixed with non-falciparum species) * Asexual P. falciparum parasitaemia: 16 to 200,000/microlitre, determined on a thin or thick blood film * Fever defined as \> 37.5°C tympanic temperature or a history of fever within the last 24 hours * Written informed consent (by parent/guardian in case of children) * Willingness and ability of the patients or parents/guardians to comply with the study protocol for the duration of the study
Exclusion criteria
* Signs of severe/complicated malaria * Haematocrit \< 25% or Hb \< 8 g/dL at screening * Acute illness other than malaria requiring treatment * For females: pregnancy, breast feeding * Patients who have received artemisinin or a derivative or an artemisinin-containing combination therapy (ACT) within the previous 7 days * History of allergy or known contraindication to artemisinins, lumefantrine or amodiaquine * Previous splenectomy * corrected QT interval \> 450 milliseconds at moment of presentation * Documented or claimed history of cardiac conduction problems * Previous participation in the current study or another study in the previous 3 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Polymerase Chain Reaction Corrected Efficacy Defined as Adequate Clinical and Parasitological Response (ACPR) by Study Arm | 42 days | Efficacy is defined as participants, following initial parasite and fever clearance, not having a recrudescence of the original plasmodium infection and fever, up to 42 days of follow up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Parasite Clearance Half-life | 42 day | Parasite clearance half-life assessed by microscopy as primary parameter to determine parasite clearance |
| Fever Clearance Time | 42 day | The time taken for the tympanic temperature to fall below 37.5˚C and remain there for at least 24 hours |
| Number of Severe Adverse Events by Study Arm | 42 days | All numerators in AE tables mean that the AE was reported as present according to the definitions defined in the US government DAIDS 2017 grading tables for reporting of adverse events. The AEs are reported without grading in this table, but are graded in the paper reporting this clinical trial. All Primary analyses are reported (also in the accepted manuscript) along with the secondary outcomes needed to support the primary analysis. Secondary outcomes not involving the randomised comparison will be updated when the analyses are available. Please note that analyses of these Secondary outcomes will take time. |
| Incidence of Adverse Events Concerning Markers of Hepatic or Renal Toxicity | 42 day | Total bilirubin, Alanine transaminase, Aspartate transaminase, Alkaline phosphatase and creatinine will be measured |
| Incidence of Prolongation of the Corrected QT Interval | 28 day | We record the number of events where the QT interval exceeds 500ms or increases by 60ms or greater. |
| Prolongation of the Corrected QT Interval | Hour 4, Hour 24, Hour 28, Hour 48, Hour 52, Hour 60, Hour 64, Day 7 and Day 28 and between these time points | We record the number of events where the QT interval exceeds 500ms or increases by 60ms or greater. There were zero events of this at any time point in either study arm. So no further analyses are possible. |
| Parasite Reduction Rates | 24 and 48 hours | Parasite reduction rates and ratios at 24 and 48 hours assessed by microscopy The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. |
| Parasite Count to Fall 50% | 42 days | Time for parasite count to fall 50% of initial parasite density The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. |
| Parasite Count to Fall 90% | 42 days | Time for parasite count to fall 90% of initial parasite density The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. |
| Parasite Count to Fall 99% | 42 days | Time for parasite count to fall 99% of initial parasite density The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. |
| Change in Haematocrit | Day 1 to 7, 14, 21, 28, 35, 42 | Change in haematocrit at specified time points according to geographical location and study arm, stratified for G6PD status The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. |
| Correlation Between the Host Genotype and the Pharmacokinetics and Pharmacodynamics of Antimalarials | 42 day | Correlation between the host genotype and the pharmacokinetics and pharmacodynamics of antimalarials The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. |
| Proportion of Patients That Reports Completing a Full Course of Observed TACT or ACT | 42 day | Proportion of patients that reports completing a full course of observed TACT or ACT without withdrawal of consent or exclusion from study because of drug related serious adverse event The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. |
| 42-day Polymerase Chain Reaction Corrected Efficacy According to Site/Geographic Region | 42 day | 42-day polymerase chain reaction corrected efficacy defined as adequate clinical and parasitological response (ACPR) according to site/geographic region. |
| Prevalence/Incidence of Other Genetic Markers of Antimalarial Drug Resistance Such as Multidrug Resistance Gene 1 Copy Number and Multidrug Resistance Gene 1 Mutations | 48 hours | Prevalence/incidence of other genetic markers of antimalarial drug resistance such as multidrug resistance gene 1 copy number and multidrug resistance gene 1 mutations The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. |
| Genome Wide Association With in Vivo/in Vitro Sensitivity Parasite Phenotype | 42 day | Genome wide association with in vivo/in vitro sensitivity parasite phenotype The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. |
| Correlation Between Single Nucleotide Polymorphisms and Whole Genome Sequencing | 42 day | Correlation between single nucleotide polymorphisms measured in dry blood spots and whole genome sequencing in leukocyte depleted blood samples The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. |
| A Comparison of Transcriptomic Patterns Between Sensitive and Resistant Parasites | baseline and t = 6 hours | Transcriptomic patterns measure at baseline and at specified time points after the start of treatment comparing sensitive and resistant parasites. The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. |
| Correlation Between Quantitative Polymerase Chain Reaction Based Versus Microscopy Based Assessments of Parasite Clearance Dynamics | 14 days | Correlation between qPCR based versus microscopy based assessments of parasite clearance dynamics The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. |
| Proportion of Patients With Gametocytaemia Before, During and After Treatment With TACT or ACT | At admission and up to day 14 | Proportion of patients with gametocytaemia before, during and after treatment with TACT or ACT stratified by the presence of gametocytes at enrolment The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. |
| Levels of RNA Transcription Coding for Male or Female Specific Gametocytes | 14 days | Levels of RNA transcription coding for male or female specific gametocytes at admission up to day 14, stratified by the presence of gametocytes at enrolment The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. |
| In Vitro Sensitivity of P. Falciparum to Artemisinins and Partner Drugs | At admission & subjects with recurrent parasitaemia, up to 42 days | In vitro sensitivity of P. falciparum to artemisinins and partner drugs according to study sites and genotype The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. |
| Pharmacokinetic Profiles and Interactions (Cmax) of Artemisinin-derivatives and Partner Drugs | 42 days | Pharmacokinetic profiles and interactions (Cmax) of artemisinin-derivatives and partner drugs in 20 ACT treated and 20 TACT treated patients of both study arms in Vietnam The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. |
| Pharmacokinetic Profiles and Interactions (AUC) of Artemisinin-derivatives and Partner Drugs | 42 days | Pharmacokinetic profiles and interactions (AUC) of artemisinin-derivatives and partner drugs in 20 ACT treated and 20 TACT treated patients of both study arms in Vietnam The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. |
| Day 7 Drug Levels of Partner Drugs in Association With Treatment Efficacy and Treatment Arm | 7 days | Day 7 drug levels of partner drugs in association with treatment efficacy and treatment arm The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. |
| Correlation Between Histidine-rich Protein 2 (HRP2) Based Versus Microscopy Based Assessments of Parasite Clearance Dynamics | 42 days | Correlation between histidine-rich protein 2 (HRP2) based versus microscopy based assessments of parasite clearance dynamics The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. |
| Prevalence of Kelch13 Mutations of Known Significance | 42 day | Prevalence of Kelch13 mutations of known significance The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study. |
Countries
Cambodia, Vietnam
Participant flow
Recruitment details
Enrolled at hospitals and health centres 18 March 2018 to 30 January 2020
Pre-assignment details
Actual number randomised was 312, however, an exclusion criterion was an ECG-measured QTc interval of ≥450ms. After randomisation the ECG was routinely repeated before drug administration, and in 2 participants (1 in each arm) the repeat ECG was ≥450 therefore no study drug was administered and the participants were treated with standard of care and recovered fully. There is no further data on these participants and the denominator for all subsequent tables is the 310 who received study drugs.
Participants by arm
| Arm | Count |
|---|---|
| Artemether-lumefantrine for 3 Days Plus Primaquine at Hour 24 ACT: Artemether-lumefantrine (20/120 mg) as a fixed dose combination twice daily for 3 days according to weight plus low dose primaquine at hour 24 | 154 |
| Artemether-lumefantrine for 3 Days Plus Amodiaquine for 3 Days Plus Primaquine at Hour 24 TACT: Artemether-lumefantrine (20/120 mg) as a fixed dose combination twice daily for 3 days according to weight plus Amodiaquine (150mg) twice daily for 3 days according to weight plus low dose primaquine at hour 24 | 156 |
| Total | 310 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Lost to Follow-up | 11 | 7 |
| Overall Study | Protocol Violation | 1 | 2 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Artemether-lumefantrine for 3 Days Plus Amodiaquine for 3 Days Plus Primaquine at Hour 24 | Total | Artemether-lumefantrine for 3 Days Plus Primaquine at Hour 24 |
|---|---|---|---|
| Age, Continuous | 25 years | 25 years | 24 years |
| Co-infection with P. vivax | 29 Participants | 51 Participants | 22 Participants |
| Diastolic blood pressure | 68 millimeters of mercury (mmHg) STANDARD_DEVIATION 8 | 69 millimeters of mercury (mmHg) STANDARD_DEVIATION 8 | 69 millimeters of mercury (mmHg) STANDARD_DEVIATION 8 |
| Gametocytaemia | 16 Participants | 30 Participants | 14 Participants |
| Heart rate | 90 beats per minute (bpm) | 90 beats per minute (bpm) | 89 beats per minute (bpm) |
| Heart rate-corrected QT interval (QTcB) | 415 millisecond (ms) STANDARD_DEVIATION 17 | 414 millisecond (ms) STANDARD_DEVIATION 17 | 413 millisecond (ms) STANDARD_DEVIATION 18 |
| Height | 157 centimeters (cm) STANDARD_DEVIATION 14 | 158 centimeters (cm) STANDARD_DEVIATION 13 | 158 centimeters (cm) STANDARD_DEVIATION 12 |
| Hemoglobin (Hb) | 12.7 grams per decilitre (g/dL) STANDARD_DEVIATION 1.8 | 12.7 grams per decilitre (g/dL) STANDARD_DEVIATION 1.7 | 12.8 grams per decilitre (g/dL) STANDARD_DEVIATION 1.7 |
| Parasitaemia | 11647 Parasitaemias per µL | 9464 Parasitaemias per µL | 7670 Parasitaemias per µL |
| P. falciparum, not genotyped | 1 Participants | 5 Participants | 4 Participants |
| Pfkelch13 mutant | 93 Participants | 174 Participants | 81 Participants |
| Pfkelch13 wild-type | 62 Participants | 131 Participants | 69 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Cambodia | 130 Participants | 259 Participants | 129 Participants |
| Region of Enrollment Vietnam | 26 Participants | 51 Participants | 25 Participants |
| Respiratory rate | 26 breaths per minute (bpm) | 25 breaths per minute (bpm) | 25 breaths per minute (bpm) |
| Sex: Female, Male Female | 24 Participants | 36 Participants | 12 Participants |
| Sex: Female, Male Male | 132 Participants | 274 Participants | 142 Participants |
| Systolic blood pressure | 113 millimeters of mercury (mmHg) STANDARD_DEVIATION 12 | 113 millimeters of mercury (mmHg) STANDARD_DEVIATION 11 | 113 millimeters of mercury (mmHg) STANDARD_DEVIATION 11 |
| Tympanic temperature ≥37·5°C | 83 Participants | 164 Participants | 81 Participants |
| Weight | 51 kilograms (kg) STANDARD_DEVIATION 12 | 51 kilograms (kg) STANDARD_DEVIATION 12 | 51 kilograms (kg) STANDARD_DEVIATION 11 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 154 | 0 / 156 |
| other Total, other adverse events | 122 / 154 | 141 / 156 |
| serious Total, serious adverse events | 2 / 154 | 5 / 156 |
Outcome results
Primary
Polymerase Chain Reaction Corrected Efficacy Defined as Adequate Clinical and Parasitological Response (ACPR) by Study Arm
Efficacy is defined as participants, following initial parasite and fever clearance, not having a recrudescence of the original plasmodium infection and fever, up to 42 days of follow up.
Time frame: 42 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Artemether-lumefantrine for 3 Days Plus Primaquine at Hour 24 | Polymerase Chain Reaction Corrected Efficacy Defined as Adequate Clinical and Parasitological Response (ACPR) by Study Arm | 146 Participants |
| Artemether-lumefantrine for 3 Days Plus Amodiaquine for 3 Days Plus Primaquine at Hour 24 | Polymerase Chain Reaction Corrected Efficacy Defined as Adequate Clinical and Parasitological Response (ACPR) by Study Arm | 151 Participants |
p-value: 0.3895% CI: [0.2, 1.9]Regression, Cox
Secondary
42-day Polymerase Chain Reaction Corrected Efficacy According to Site/Geographic Region
42-day polymerase chain reaction corrected efficacy defined as adequate clinical and parasitological response (ACPR) according to site/geographic region.
Time frame: 42 day
Population: The numbers analysed differ from the overall total as for this secondary analysis we report efficacy stratified by each of the 3 study sites.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Artemether-lumefantrine for 3 Days Plus Primaquine at Hour 24 | 42-day Polymerase Chain Reaction Corrected Efficacy According to Site/Geographic Region | West Cambodia | 32 Participants |
| Artemether-lumefantrine for 3 Days Plus Primaquine at Hour 24 | 42-day Polymerase Chain Reaction Corrected Efficacy According to Site/Geographic Region | East Cambodia | 91 Participants |
| Artemether-lumefantrine for 3 Days Plus Primaquine at Hour 24 | 42-day Polymerase Chain Reaction Corrected Efficacy According to Site/Geographic Region | Vietnam | 23 Participants |
| Artemether-lumefantrine for 3 Days Plus Amodiaquine for 3 Days Plus Primaquine at Hour 24 | 42-day Polymerase Chain Reaction Corrected Efficacy According to Site/Geographic Region | West Cambodia | 35 Participants |
| Artemether-lumefantrine for 3 Days Plus Amodiaquine for 3 Days Plus Primaquine at Hour 24 | 42-day Polymerase Chain Reaction Corrected Efficacy According to Site/Geographic Region | East Cambodia | 90 Participants |
| Artemether-lumefantrine for 3 Days Plus Amodiaquine for 3 Days Plus Primaquine at Hour 24 | 42-day Polymerase Chain Reaction Corrected Efficacy According to Site/Geographic Region | Vietnam | 26 Participants |
Secondary
A Comparison of Transcriptomic Patterns Between Sensitive and Resistant Parasites
Transcriptomic patterns measure at baseline and at specified time points after the start of treatment comparing sensitive and resistant parasites. The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study.
Time frame: baseline and t = 6 hours
Secondary
Change in Haematocrit
Change in haematocrit at specified time points according to geographical location and study arm, stratified for G6PD status The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study.
Time frame: Day 1 to 7, 14, 21, 28, 35, 42
Secondary
Correlation Between Histidine-rich Protein 2 (HRP2) Based Versus Microscopy Based Assessments of Parasite Clearance Dynamics
Correlation between histidine-rich protein 2 (HRP2) based versus microscopy based assessments of parasite clearance dynamics The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study.
Time frame: 42 days
Secondary
Correlation Between Quantitative Polymerase Chain Reaction Based Versus Microscopy Based Assessments of Parasite Clearance Dynamics
Correlation between qPCR based versus microscopy based assessments of parasite clearance dynamics The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study.
Time frame: 14 days
Secondary
Correlation Between Single Nucleotide Polymorphisms and Whole Genome Sequencing
Correlation between single nucleotide polymorphisms measured in dry blood spots and whole genome sequencing in leukocyte depleted blood samples The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study.
Time frame: 42 day
Secondary
Correlation Between the Host Genotype and the Pharmacokinetics and Pharmacodynamics of Antimalarials
Correlation between the host genotype and the pharmacokinetics and pharmacodynamics of antimalarials The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study.
Time frame: 42 day
Secondary
Day 7 Drug Levels of Partner Drugs in Association With Treatment Efficacy and Treatment Arm
Day 7 drug levels of partner drugs in association with treatment efficacy and treatment arm The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study.
Time frame: 7 days
Secondary
Fever Clearance Time
The time taken for the tympanic temperature to fall below 37.5˚C and remain there for at least 24 hours
Time frame: 42 day
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Artemether-lumefantrine for 3 Days Plus Primaquine at Hour 24 | Fever Clearance Time | 18.3 Hours to fever clearance | Standard Deviation 12.6 |
| Artemether-lumefantrine for 3 Days Plus Amodiaquine for 3 Days Plus Primaquine at Hour 24 | Fever Clearance Time | 14.9 Hours to fever clearance | Standard Deviation 9.9 |
Secondary
Genome Wide Association With in Vivo/in Vitro Sensitivity Parasite Phenotype
Genome wide association with in vivo/in vitro sensitivity parasite phenotype The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study.
Time frame: 42 day
Secondary
Incidence of Adverse Events Concerning Markers of Hepatic or Renal Toxicity
Total bilirubin, Alanine transaminase, Aspartate transaminase, Alkaline phosphatase and creatinine will be measured
Time frame: 42 day
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Artemether-lumefantrine for 3 Days Plus Primaquine at Hour 24 | Incidence of Adverse Events Concerning Markers of Hepatic or Renal Toxicity | 53 Events |
| Artemether-lumefantrine for 3 Days Plus Amodiaquine for 3 Days Plus Primaquine at Hour 24 | Incidence of Adverse Events Concerning Markers of Hepatic or Renal Toxicity | 63 Events |
Secondary
Incidence of Prolongation of the Corrected QT Interval
We record the number of events where the QT interval exceeds 500ms or increases by 60ms or greater.
Time frame: 28 day
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Artemether-lumefantrine for 3 Days Plus Primaquine at Hour 24 | Incidence of Prolongation of the Corrected QT Interval | 0 Events |
| Artemether-lumefantrine for 3 Days Plus Amodiaquine for 3 Days Plus Primaquine at Hour 24 | Incidence of Prolongation of the Corrected QT Interval | 0 Events |
Secondary
In Vitro Sensitivity of P. Falciparum to Artemisinins and Partner Drugs
In vitro sensitivity of P. falciparum to artemisinins and partner drugs according to study sites and genotype The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study.
Time frame: At admission & subjects with recurrent parasitaemia, up to 42 days
Secondary
Levels of RNA Transcription Coding for Male or Female Specific Gametocytes
Levels of RNA transcription coding for male or female specific gametocytes at admission up to day 14, stratified by the presence of gametocytes at enrolment The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study.
Time frame: 14 days
Secondary
Number of Severe Adverse Events by Study Arm
All numerators in AE tables mean that the AE was reported as present according to the definitions defined in the US government DAIDS 2017 grading tables for reporting of adverse events. The AEs are reported without grading in this table, but are graded in the paper reporting this clinical trial. All Primary analyses are reported (also in the accepted manuscript) along with the secondary outcomes needed to support the primary analysis. Secondary outcomes not involving the randomised comparison will be updated when the analyses are available. Please note that analyses of these Secondary outcomes will take time.
Time frame: 42 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Artemether-lumefantrine for 3 Days Plus Primaquine at Hour 24 | Number of Severe Adverse Events by Study Arm | 2 Participants |
| Artemether-lumefantrine for 3 Days Plus Amodiaquine for 3 Days Plus Primaquine at Hour 24 | Number of Severe Adverse Events by Study Arm | 5 Participants |
Secondary
Parasite Clearance Half-life
Parasite clearance half-life assessed by microscopy as primary parameter to determine parasite clearance
Time frame: 42 day
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Artemether-lumefantrine for 3 Days Plus Primaquine at Hour 24 | Parasite Clearance Half-life | 5 Hours | Standard Deviation 2.5 |
| Artemether-lumefantrine for 3 Days Plus Amodiaquine for 3 Days Plus Primaquine at Hour 24 | Parasite Clearance Half-life | 5.5 Hours | Standard Deviation 2.6 |
Secondary
Parasite Count to Fall 50%
Time for parasite count to fall 50% of initial parasite density The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study.
Time frame: 42 days
Secondary
Parasite Count to Fall 90%
Time for parasite count to fall 90% of initial parasite density The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study.
Time frame: 42 days
Secondary
Parasite Count to Fall 99%
Time for parasite count to fall 99% of initial parasite density The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study.
Time frame: 42 days
Secondary
Parasite Reduction Rates
Parasite reduction rates and ratios at 24 and 48 hours assessed by microscopy The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study.
Time frame: 24 and 48 hours
Secondary
Pharmacokinetic Profiles and Interactions (AUC) of Artemisinin-derivatives and Partner Drugs
Pharmacokinetic profiles and interactions (AUC) of artemisinin-derivatives and partner drugs in 20 ACT treated and 20 TACT treated patients of both study arms in Vietnam The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study.
Time frame: 42 days
Secondary
Pharmacokinetic Profiles and Interactions (Cmax) of Artemisinin-derivatives and Partner Drugs
Pharmacokinetic profiles and interactions (Cmax) of artemisinin-derivatives and partner drugs in 20 ACT treated and 20 TACT treated patients of both study arms in Vietnam The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study.
Time frame: 42 days
Secondary
Prevalence/Incidence of Other Genetic Markers of Antimalarial Drug Resistance Such as Multidrug Resistance Gene 1 Copy Number and Multidrug Resistance Gene 1 Mutations
Prevalence/incidence of other genetic markers of antimalarial drug resistance such as multidrug resistance gene 1 copy number and multidrug resistance gene 1 mutations The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study.
Time frame: 48 hours
Secondary
Prevalence of Kelch13 Mutations of Known Significance
Prevalence of Kelch13 mutations of known significance The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study.
Time frame: 42 day
Secondary
Prolongation of the Corrected QT Interval
We record the number of events where the QT interval exceeds 500ms or increases by 60ms or greater. There were zero events of this at any time point in either study arm. So no further analyses are possible.
Time frame: Hour 4, Hour 24, Hour 28, Hour 48, Hour 52, Hour 60, Hour 64, Day 7 and Day 28 and between these time points
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Artemether-lumefantrine for 3 Days Plus Primaquine at Hour 24 | Prolongation of the Corrected QT Interval | 0 Events |
| Artemether-lumefantrine for 3 Days Plus Amodiaquine for 3 Days Plus Primaquine at Hour 24 | Prolongation of the Corrected QT Interval | 0 Events |
Secondary
Proportion of Patients That Reports Completing a Full Course of Observed TACT or ACT
Proportion of patients that reports completing a full course of observed TACT or ACT without withdrawal of consent or exclusion from study because of drug related serious adverse event The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study.
Time frame: 42 day
Secondary
Proportion of Patients With Gametocytaemia Before, During and After Treatment With TACT or ACT
Proportion of patients with gametocytaemia before, during and after treatment with TACT or ACT stratified by the presence of gametocytes at enrolment The data are collected, but this secondary outcome will come from analyses done by specialist researchers and the results will not affect the the presently reported primary outcomes of efficacy, safety and tolerability. These fields will be updated once results become available. We will also provide a link to the paper reporting the trial when it is published online as this will provide additional detail about the study.
Time frame: At admission and up to day 14