Pyronaridine-artesunate With Low Dose Primaquine for Preventing P. Falciparum Transmission
- Conditions
- Malaria,Falciparum
- Interventions
- Registration Number
- NCT04049916
- Lead Sponsor
- London School of Hygiene and Tropical Medicine
- Brief Summary
The purpose of this study is to assess the gametocytocidal and transmission reducing activity of pyronaridine-artesunate (PA) and dihydroartemisinin-piperaquine (DP) with and without a single low dose of primaquine (PQ; 0.25mg/kg). Outcome measures will include infectivity at 2 and 7 days after treatment, the duration of infectivity in the artemisinin combination therapy (ACT) only arms, and the production and detectability of histidine rich protein II.
- Detailed Description
Protocol will be shared on request
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 100
- Age ≥ 5 years and ≤ 50 years
- Absence of symptomatic falciparum malaria, defined by fever on enrolment
- Presence of ≥16 gametocytes/µL (i.e. ≥1 gametocytes recorded in the thick film against 500 white blood cells)
- No allergies to study drugs
- Use of antimalarial drugs over the past 7 days (as reported by the participant)
- Hemoglobin ≥ 9.5 g/dL
- Individuals weighing >< 80 kg
- No evidence of severe or chronic disease
- Written, informed consent
- Age < 5 years or > 50 years
- Pregnancy
- Previous reaction to study drugs/known allergy to study drugs
- Signs of severe malaria
- Taking drugs which may be metabolized by cytochrome enzyme CYP2D6 (e.g., flecainide, metoprolol, imipramine, amitriptyline, clomipramine)
- Blood transfusion within the last 90 days
- Patients with clinical signs or symptoms of hepatic injury (such as nausea and/or abdominal pain associated with jaundice) or known severe liver disease (i.e. decompensated cirrhosis, Child-Pugh stage B or C).
- Patients with clinical signs or symptoms of renal impairment or known renal impairment
- Family history of congenital prolongation of the QTc interval or sudden death or with any other clinical condition known to prolong the QTc interval such as history of symptomatic cardiac arrhythmias, with clinically relevant bradycardia or with severe cardiac disease.
- Taking drugs that are known to influence cardiac function and to prolong QTc interval, such as class IA and III: neuroleptics, antidepressant agents, certain antibiotics including some agents of the following classes - macrolides, fluoroquinolones, imidazole, and triazole antifungal agents, certain non-sedating antihistaminics (terfenadine, astemizole) and cisapride.
- Consent not given
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description PA with single low dose primaquine (PQ) Pyronaridine Tetraphosphate/Artesunate Subjects will receive pyronaridine-artesunate (PA) once daily for 3 days, and a low dose of primaquine (PQ) on the first dat of treatment. PQ dose is at the World Health Organization (WHO) recommended dose of 0.25 mg/kg. DP with single low dose primaquine (PQ) Primaquine Diphosphate Subjects will receive dihydroartemisinin-piperaquine (DP) once daily for 3 days., and a low dose of primaquine (PQ) on the first dat of treatment. PQ dose is at the World Health Organization (WHO) recommended dose of 0.25 mg/kg. Pyronaridine-artesunate (PA) Pyronaridine Tetraphosphate/Artesunate Subjects will receive pyronaridine-artesunate (PA) once daily for 3 days. PA with single low dose primaquine (PQ) Primaquine Diphosphate Subjects will receive pyronaridine-artesunate (PA) once daily for 3 days, and a low dose of primaquine (PQ) on the first dat of treatment. PQ dose is at the World Health Organization (WHO) recommended dose of 0.25 mg/kg. DP with single low dose primaquine (PQ) Dihydroartemisinin/Piperaquine Subjects will receive dihydroartemisinin-piperaquine (DP) once daily for 3 days., and a low dose of primaquine (PQ) on the first dat of treatment. PQ dose is at the World Health Organization (WHO) recommended dose of 0.25 mg/kg. Dihydroartemisinin-piperaquine (DP) Dihydroartemisinin/Piperaquine Subjects will receive dihydroartemisinin-piperaquine (DP) once daily for 3 days.
- Primary Outcome Measures
Name Time Method Change in mosquito infectivity assessed through membrane feeding assays (day 2) 2 days (day 0 & 2) The proportion of mosquitoes infected, assessed through membrane feeding and measured as oocyst prevalence in mosquitoes dissected on day 2 post feed, compared to baseline
- Secondary Outcome Measures
Name Time Method Histidine rich protein 2 (HRP2) area under the curve (AUC) 11 days Histidine rich protein 2 (HRP2) area under the curve (AUC) will be determined from measures of HRP2 concentration
Histidine rich protein 2 (HRP2) concentration 11 days Histidine rich protein 2 (HRP2) protein concentration in plasma will be determined in subsequent lab analysis from samples collected on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.
Duration of infectivity 5-10 days (as described) Non PQ arms only: Duration of infectivity will be determined from measures of mosquito infection prevalence, assessed through membrane feeding and measured as oocyst prevalence in mosquitoes dissected on day 0, 2, 7, 10 and 14 post treatment, and then weekly until 2 sequential negative feeds or until day 49.
Mosquito infectivity assessed through membrane feeding assays - inter arm 3 days (day 0, 2 & 7) Mosquito infection prevalence and density, assessed through membrane feeding and measured as oocyst prevalence/density in mosquitoes dissected on day 2 and 7 post feed, compared between study arms
Rapid diagnostic test result 11 days Varied rapid diagnostic tests based on the detection of HRP2 will be used on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment to determine infection prevalence, for comparison between study arms.
Gametocyte under the curve (AUC) 11 days Gametocyte area under the curve (AUC) will be determined from measures of density.
Asexual parasite area under the curve (AUC) 11 days Asexual parasite area under the curve (AUC) will be determined from measures of density.
Asexual parasite prevalence 11 days Asexual parasite prevalence (parasites/microlitre) will be measured by microscopy and by molecular methods on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.
Asexual parasite circulation time 11 days Asexual parasite circulation time (days) will be determined from measures of prevalence.
Parasite genotype 1 day Parasite merozoite surface protein 2 (MSP2) allelic diversity (presence of distinct alleles) will be determined in subsequent lab analysis from whole blood samples collected at baseline.
Change in mosquito infectivity assessed through membrane feeding assays (day 7) 2 days (day 0 & 7) The proportion of mosquitoes infected, assessed through membrane feeding and measured as oocyst prevalence in mosquitoes dissected on day 7 post feed, compared to baseline
Gametocyte density 11 days Gametocyte density (parasites/microlitre) will be measured by microscopy and by molecular methods on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.
Haemoglobin level 11 days Haemolysis will be monitored by measuring haemoglobin levels (g/dL) on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.
Histidine rich protein 2 (HRP2) circulation time 11 days Histidine rich protein 2 (HRP2) protein circulation time will be compared between methods of detection
Gametocyte sex ratio 11 days Gametocyte density will be determined by molecular methods for males and females separately, allowing analysis of sex ratio (proportion of total that is male) on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.
Histidine rich protein gene deletion 1 day Deletion (presence/absence) of the HRP2/3 genes will be determined from whole blood samples collected at baseline.
Area under the curve (AUC) of infectivity/time 5-10 days (as described) Non PQ arms only: AUC will be determined from measures of mosquito infection prevalence and density, assessed through membrane feeding and measured as oocyst prevalence/density in mosquitoes dissected on day 0, 2, 7, 10 and 14 post treatment, and then weekly until 2 sequential negative feeds or until day 49.
Gametocyte circulation time 11 days Gametocyte circulation time (days) will be determined from measures of prevalence.
Gametocyte prevalence 11 days Gametocyte prevalence (parasites/microlitre) will be measured by microscopy and by molecular methods on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.
Asexual parasite density 11 days Asexual parasite density (parasites/microlitre) will be measured by microscopy and by molecular methods on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.
Trial Locations
- Locations (2)
Malaria Research and Training Centre
🇲🇱Bamako, Mali
Radboud university medical center
🇳🇱Nijmegen, Netherlands