Pyronaridine-artesunate With Low Dose Primaquine for Preventing P. Falciparum Transmission

Study Overview
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Brief Summary
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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
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Protocol will be shared on request

Official Title
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The Efficacy and Safety of Pyronaridine-artesunate Combined With Low Dose Primaquine for Preventing Transmission of P. Falciparum Gametocytes in Sub-Saharan Africa

Conditions
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Malaria,Falciparum

Intervention / Treatment
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* Drug: Pyronaridine Tetraphosphate/Artesunate
* Drug: Dihydroartemisinin/Piperaquine
* Drug: Primaquine Diphosphate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pyronaridine-artesunate (PA)<br>Subjects will receive pyronaridine-artesunate (PA) once daily for 3 days. | Drug: Pyronaridine Tetraphosphate/Artesunate<br>* Adults: Tablets containing 180 mg pyronaridine-tetraphosphate/60mg artesunate (Pyramax, Shin Poong Pharmaceutical Co.), administered according to weight. Children: Granules containing 60 mg pyronaridine-tetraphosphate/20mg artesunate, administered according to weight.<br>* Other names: Pyramax;|
| Experimental: PA with single low dose primaquine (PQ)<br>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. | Drug: Pyronaridine Tetraphosphate/Artesunate<br>* Adults: Tablets containing 180 mg pyronaridine-tetraphosphate/60mg artesunate (Pyramax, Shin Poong Pharmaceutical Co.), administered according to weight. Children: Granules containing 60 mg pyronaridine-tetraphosphate/20mg artesunate, administered according to weight.<br>* Other names: Pyramax;Drug: Primaquine Diphosphate<br>* Extemporaneous preparation of 1mg/mL primaquine phosphate solution, from tablets containing 30mg primaquine (A-PQ 30®, ACE pharmaceuticals, NL) dissolved in 30mL water with a non-interacting fruit-flavoured syrup. Solution will be given at 0.25mg/kg.<br>* Other names: Primaquine;|
| Active Comparator: Dihydroartemisinin-piperaquine (DP)<br>Subjects will receive dihydroartemisinin-piperaquine (DP) once daily for 3 days. | Drug: Dihydroartemisinin/Piperaquine<br>* Tablets containing 40 mg dihydroartemisinin/320 mg piperaquine tablets (Eurartesim, Sigma Tau), administered according to weight.<br>* Other names: Euartesim;|
| Active Comparator: DP with single low dose primaquine (PQ)<br>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. | Drug: Dihydroartemisinin/Piperaquine<br>* Tablets containing 40 mg dihydroartemisinin/320 mg piperaquine tablets (Eurartesim, Sigma Tau), administered according to weight.<br>* Other names: Euartesim;Drug: Primaquine Diphosphate<br>* Extemporaneous preparation of 1mg/mL primaquine phosphate solution, from tablets containing 30mg primaquine (A-PQ 30®, ACE pharmaceuticals, NL) dissolved in 30mL water with a non-interacting fruit-flavoured syrup. Solution will be given at 0.25mg/kg.<br>* Other names: Primaquine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mosquito infectivity assessed through membrane feeding assays (day 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 | 2 days (day 0 & 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mosquito infectivity assessed through membrane feeding assays (day 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 | 2 days (day 0 & 7) | 
| Mosquito infectivity assessed through membrane feeding assays - inter arm | 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 | 3 days (day 0, 2 & 7) | 
| Duration of infectivity | 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. | 5-10 days (as described) | 
| Area under the curve (AUC) of infectivity/time | 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. | 5-10 days (as described) | 
| Haemoglobin level | 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. | 11 days | 
| Histidine rich protein 2 (HRP2) concentration | 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. | 11 days | 
| Histidine rich protein 2 (HRP2) circulation time | Histidine rich protein 2 (HRP2) protein circulation time will be compared between methods of detection | 11 days | 
| Histidine rich protein 2 (HRP2) area under the curve (AUC) | Histidine rich protein 2 (HRP2) area under the curve (AUC) will be determined from measures of HRP2 concentration | 11 days | 
| Rapid diagnostic test result | 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. | 11 days | 
| Gametocyte density | 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. | 11 days | 
| Gametocyte under the curve (AUC) | Gametocyte area under the curve (AUC) will be determined from measures of density. | 11 days | 
| Gametocyte prevalence | 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. | 11 days | 
| Gametocyte circulation time | Gametocyte circulation time (days) will be determined from measures of prevalence. | 11 days | 
| Gametocyte sex ratio | 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. | 11 days | 
| Asexual parasite density | 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. | 11 days | 
| Asexual parasite area under the curve (AUC) | Asexual parasite area under the curve (AUC) will be determined from measures of density. | 11 days | 
| Asexual parasite prevalence | 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. | 11 days | 
| Asexual parasite circulation time | Asexual parasite circulation time (days) will be determined from measures of prevalence. | 11 days | 
| Parasite genotype | 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. | 1 day | 
| Histidine rich protein gene deletion | Deletion (presence/absence) of the HRP2/3 genes will be determined from whole blood samples collected at baseline. | 1 day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Primaquine, Pyramax, Euartesim, Dihydroartemisinin-piperaquine, Pyronaridine-artesunate