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Completed

NCT Number: NCT04049916

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

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.

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Key information

Conditions

Malaria,Falciparum Infections Malaria Malaria, Falciparum Mosquito-Borne Diseases Parasitic Diseases Protozoan Infections Vector Borne Diseases

Age range

5 year–50 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2 / Phase 3

Primary location

Malaria Research and Training Centre, Bamako, Mali

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About this study

Protocol will be shared on request

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Pyronaridine Tetraphosphate/Artesunate

Drug

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.

Other names: Pyramax

Dihydroartemisinin/Piperaquine

Drug

Tablets containing 40 mg dihydroartemisinin/320 mg piperaquine tablets (Eurartesim, Sigma Tau), administered according to weight.

Other names: Euartesim

Primaquine Diphosphate

Drug

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.

Other names: Primaquine

Primary outcomes

  1. Change in mosquito infectivity assessed through membrane feeding assays (day 2)

    Time frame: 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 outcomes

  1. Change in mosquito infectivity assessed through membrane feeding assays (day 7)

    Time frame: 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

  2. Mosquito infectivity assessed through membrane feeding assays - inter arm

    Time frame: 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

  3. Duration of infectivity

    Time frame: 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.

  4. Area under the curve (AUC) of infectivity/time

    Time frame: 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.

  5. Haemoglobin level

    Time frame: 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.

  6. Histidine rich protein 2 (HRP2) concentration

    Time frame: 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.

  7. Histidine rich protein 2 (HRP2) circulation time

    Time frame: 11 days

    Histidine rich protein 2 (HRP2) protein circulation time will be compared between methods of detection

  8. Histidine rich protein 2 (HRP2) area under the curve (AUC)

    Time frame: 11 days

    Histidine rich protein 2 (HRP2) area under the curve (AUC) will be determined from measures of HRP2 concentration

  9. Rapid diagnostic test result

    Time frame: 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.

  10. Gametocyte density

    Time frame: 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.

  11. Gametocyte under the curve (AUC)

    Time frame: 11 days

    Gametocyte area under the curve (AUC) will be determined from measures of density.

  12. Gametocyte prevalence

    Time frame: 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.

  13. Gametocyte circulation time

    Time frame: 11 days

    Gametocyte circulation time (days) will be determined from measures of prevalence.

  14. Gametocyte sex ratio

    Time frame: 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.

  15. Asexual parasite density

    Time frame: 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.

  16. Asexual parasite area under the curve (AUC)

    Time frame: 11 days

    Asexual parasite area under the curve (AUC) will be determined from measures of density.

  17. Asexual parasite prevalence

    Time frame: 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.

  18. Asexual parasite circulation time

    Time frame: 11 days

    Asexual parasite circulation time (days) will be determined from measures of prevalence.

  19. Parasite genotype

    Time frame: 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.

  20. Histidine rich protein gene deletion

    Time frame: 1 day

    Deletion (presence/absence) of the HRP2/3 genes will be determined from whole blood samples collected at baseline.

Sponsors and collaborators

Lead sponsor

London School of Hygiene and Tropical Medicine

Other

Collaborators

  • Malaria Research and Training Center, Bamako, Mali
  • Radboud University Medical Center

Registry information

Official study title

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

Acronym: NECTAR1

Important dates

Study start
2019
Primary completion
2020
Study completion
2020
First posted
Aug 8, 2019
Registry last updated
Jan 30, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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