Malaria, Falciparum
Conditions
Keywords
falciparum malaria, sub saharan, africa, elimination disorder
Brief summary
Safety of artesunate-amodiaquine combined with methylene blue or primaquine for falciparum malaria treatment in African children: A randomised controlled trial Elimination has become the goal of malaria programmes in an increasing number of endemic countries and regions. As resistance against artemisinin compounds has recently started to emerge in South-East Asia, there is a clear need to develop alternative malaria drug combinations. Adding another anti-malarial with a short half-life such as methylene blue to standard ACT (artemisinin-based combination therapy) could be a strategy to prevent artemisinin resistance development. Moreover, adding a gametocytocidal drug to ACT reduces the probability of transmission of P. falciparum parasites including drug-resistant parasites. Objectives: The primary objective of this trial is to investigate the safety of artesunate (AS) - amodiaquine (AQ) - methylene blue (MB) compared to AS - AQ - primaquine (PQ) in young children with uncomplicated falciparum malaria in Burkina Faso.
Detailed description
The overall goal of the underlying research project is to develop a MB-based first-line drug combination regimen against uncomplicated falciparum malaria in SSA. The primary objective of this study is: To study the safety of the triple combination AS-AQ-MB compared to AS-AQ-PQ in the treatment of uncomplicated falciparum malaria in young African children. The secondary objective of this study is: To study the efficacy of this MB-based triple combination in comparison with standard ACT-PQ in the treatment of uncomplicated falciparum malaria in young African children. It is a mono-center, open randomised controlled non-inferiority study in children with uncomplicated falciparum malaria in Burkina Faso. Patients will be randomised to two treatment groups (arms): 1. AS-AQ-MB 2. AS-AQ-PQ Study population: Children aged 6-59 months with uncomplicated falciparum malaria from Nouna Hospital in north-western Burkina Faso. Sample size: 100 patients (50 per study arm). Treatment: The group AS-AQ-MB will receive once daily a fixed dose AS-AQ formulation combined with once daily MB (15 mg/kg) over a three days period. The control group will receive once daily a fixed dose AS-AQ over three days combined with a single dose of PQ on day 2 (0.25 mg/kg). Endpoints: Primary endpoint is the haemoglobin value on day 7 compared to baseline. Secondary endpoints are adverse events (AE), adequate clinical and parasitological response (ACPR) rate (PCR-corrected for recrudescences), as well as gametocyte prevalence and density.
Interventions
DRUGMethylene Blue
50 patients will receive methylene blue
DRUGPrimaquine
50 patients will receive primaquine
Sponsors
Centre de Recherche en Sante de Nouna, Burkina Faso
Heidelberg University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Months to 59 Months
Healthy volunteers
No
Inclusion criteria
* Weight ≥ 6 kg * Uncomplicated malaria caused by P. falciparum * Asexual parasites ≥ 2 000/µl and ≤ 100 000/µl * Axillary temperature ≥ 37.5°C or a history of fever during the last 24 hours * Burkinabe nationality * Permanent residence in the study area with no intention of leaving during the surveillance period * Written informed consent of parents or care takers
Exclusion criteria
* Severe malaria * Mixed malaria infection * Vomiting (\>2 times within 24 hours before the visit) * Any apparent significant disease, including severe malnutrition * A history of a previous, significant adverse reaction or known allergy to one or more of the study drugs * Anaemia (haemoglobin \< 7 g/dl) * Treated in the same trial before * All modern antimalarial treatment prior to inclusion (last seven days) * Therapy with serotonin reuptake inhibitors (e.g. citalopram, escitalopram, fluoxetine, Paroxetine, Sertraline) * Simultaneous participation in another investigational study * Patients with known HIV/AIDS disease * Therapy with drugs known to inhibit the liver enzymes cytochrome 2A6 (e.g. methoxsalen, pilocarpine, tranylcypromine) and/or cytochrome 2C8 (e.g. trimethoprim, ketoconazole, ritonavir, saquinavir, lopinavir, gemfibrozil, montelukast)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Haemoglobin Compared to the Baseline | 7 days | Haemoglobin concentrations will be measured in the field using a HemoCue® (HemoCue® AB, Angelholm, Sweden) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Gametocyte Prevalence | 28 days | measured microscopically at baseline and on day 1, 2, 3, 7, 14, and 28 of follow-up |
| Adverse Events (AE) | 28 days | Reports of observed or self-reported adverse event |
| Mothers/Caretakers Questionnaire on Acceptance | 14 days | Acceptance of the different treatment regimens by mothers/caretakers |
| Gametocyte Density | 28 days | measured microscopically at baseline and on day 1, 2, 3, 7, 14, and 28 of follow-up |
Countries
Burkina Faso
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AS-AQ-MB Once daily a fixed dose artesunate-amodiaquine formulation combined with once daily methylene blue (15 mg/kg) over a three days period.
Methylene Blue: 50 patients will receive methylene blue | 50 |
| AS-AQ-PQ Once daily a fixed dose artesunate-amodiaquine over three days combined with a single dose of primaquine on day 2 (0.25 mg/kg).
Primaquine: 50 patients will receive primaquine | 50 |
| Total | 100 |
Baseline characteristics
| Characteristic | Total | AS-AQ-MB | AS-AQ-PQ |
|---|---|---|---|
| Age, Continuous | 40.27 months STANDARD_DEVIATION 13.26 | 42.34 months STANDARD_DEVIATION 12.34 | 38.2 months STANDARD_DEVIATION 13.93 |
| Any other prior illnesses within last 7 days No | 94 Participants | 46 Participants | 48 Participants |
| Any other prior illnesses within last 7 days Yes | 6 Participants | 4 Participants | 2 Participants |
| G6PD phenotype Deficient | 14 Participants | 7 Participants | 7 Participants |
| G6PD phenotype Heterozygous | 16 Participants | 11 Participants | 5 Participants |
| G6PD phenotype Normal | 70 Participants | 32 Participants | 38 Participants |
| Hemoglobin | 9.92 [g/dl] STANDARD_DEVIATION 1.53 | 10.16 [g/dl] STANDARD_DEVIATION 1.62 | 9.68 [g/dl] STANDARD_DEVIATION 1.42 |
| Length of current disease episode | 1.95 days STANDARD_DEVIATION 1.29 | 1.94 days STANDARD_DEVIATION 1.32 | 1.96 days STANDARD_DEVIATION 1.28 |
| P.falciparum gamotocytes parasite density (for those patients with gametocytes) | 181.54 parasites/µl blood STANDARD_DEVIATION 111.49 | 200.0 parasites/µl blood STANDARD_DEVIATION 123.29 | 170.0 parasites/µl blood STANDARD_DEVIATION 110.58 |
| P.falciparum merozoites paras. density | 26846.20 parasites/µl blood STANDARD_DEVIATION 29319.34 | 30373.60 parasites/µl blood STANDARD_DEVIATION 32808.1 | 23318.80 parasites/µl blood STANDARD_DEVIATION 25199.72 |
| Prior treatment of current disease episode | 29 Participants | 16 Participants | 13 Participants |
| Sex: Female, Male Female | 49 Participants | 24 Participants | 25 Participants |
| Sex: Female, Male Male | 51 Participants | 26 Participants | 25 Participants |
| Temperature | 37.80 [°C] STANDARD_DEVIATION 0.79 | 37.80 [°C] STANDARD_DEVIATION 0.81 | 37.79 [°C] STANDARD_DEVIATION 0.79 |
| Weight | 12.55 kg STANDARD_DEVIATION 3.08 | 12.91 kg STANDARD_DEVIATION 3.16 | 12.18 kg STANDARD_DEVIATION 2.98 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 33 / 50 | 28 / 50 |
| serious Total, serious adverse events | 2 / 50 | 0 / 50 |
Outcome results
Primary
Change in Haemoglobin Compared to the Baseline
Haemoglobin concentrations will be measured in the field using a HemoCue® (HemoCue® AB, Angelholm, Sweden)
Time frame: 7 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AS-AQ-MB | Change in Haemoglobin Compared to the Baseline | 0.18 g/dl | Standard Deviation 1.42 |
| AS-AQ-PQ | Change in Haemoglobin Compared to the Baseline | 0.54 g/dl | Standard Deviation 0.94 |
Secondary
Adverse Events (AE)
Reports of observed or self-reported adverse event
Time frame: 28 days
Secondary
Gametocyte Density
measured microscopically at baseline and on day 1, 2, 3, 7, 14, and 28 of follow-up
Time frame: 28 days
Secondary
Gametocyte Prevalence
measured microscopically at baseline and on day 1, 2, 3, 7, 14, and 28 of follow-up
Time frame: 28 days
Secondary
Mothers/Caretakers Questionnaire on Acceptance
Acceptance of the different treatment regimens by mothers/caretakers
Time frame: 14 days