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Phase 2 Efficacy Study of Primaquine and Methylene Blue

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ClinicalTrials.gov Identifier: NCT02831023
Recruitment Status : Completed
First Posted : July 13, 2016
Last Update Posted : January 11, 2017
Sponsor:
Collaborators:
Malaria Research and Training Center, Bamako, Mali
Radboud University
London School of Hygiene and Tropical Medicine
Heidelberg University
Bill and Melinda Gates Foundation
Information provided by (Responsible Party):
University of California, San Francisco

Brief Summary:
The purpose of this study is to determine the most efficacious transmission blocking drug regimen for seasonal malaria chemoprophylaxis in Mali. The primary outcome measure will be the proportion of mosquitoes infected pre and post-treatment, assessed through membrane feeding and measured by oocyst prevalence in mosquitoes dissected on day 7 post feed. Primary endpoint will be a within group comparison between the mean of the pretreatment infectivity (Day 0) and infectivity at 7 days post first dose.

Condition or disease Intervention/treatment Phase
Malaria Drug: Sulphadoxine-pyrimethamine Drug: 0.25 mg/kg primaquine Drug: Dihydroartemisinin-piperaquine Drug: Methylene blue Drug: Amodiaquine Phase 2

Detailed Description:
Protocol will be shared on request.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Efficacy, Safety, and Pharmacokinetics of Sulphadoxine-pyrimethamine-amodiaquine (SP-AQ), SP-AQ Plus Primaquine, Dihydroartemisinin-piperaquine (DP), DP Plus Methylene Blue for Preventing Transmission of P. Falciparum Gametocytes in Mali
Study Start Date : July 2016
Actual Primary Completion Date : January 2017
Actual Study Completion Date : January 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria

Arm Intervention/treatment
Active Comparator: SP-AQ only
Subjects will receive sulphadoxine-pyrimethamine (SP) as single dose and administered in combination with amodiaquine (AQ), which will be given once daily for 3 days.
Drug: Sulphadoxine-pyrimethamine
Each Fansidar tablet is scored containing 500mg sulphadoxine and 25 mg pyrimethamine. Doses will be administered by weight.
Other Name: Fansidar

Drug: Amodiaquine
Amodiaquine will be administered once daily for 3 days, following weight-based dosing of 150 mg tablets.

Experimental: SP-AQ plus PQ
Participants in this arm will receive SP-AQ in combination with a single low dose of primaquine at the World Health Organization (WHO) recommended dose of 0.25 mg/kg.
Drug: Sulphadoxine-pyrimethamine
Each Fansidar tablet is scored containing 500mg sulphadoxine and 25 mg pyrimethamine. Doses will be administered by weight.
Other Name: Fansidar

Drug: 0.25 mg/kg primaquine
Primaquine will be administered in an aqueous solution according to weight-based dosing.

Drug: Amodiaquine
Amodiaquine will be administered once daily for 3 days, following weight-based dosing of 150 mg tablets.

Active Comparator: DP only
Participants in this arm will be treated with dihydroartemisinin-piperaquine (DP), which will be administered once a day for three days.
Drug: Dihydroartemisinin-piperaquine
160mg/20mg or 320mg/40mg of dihydroartemisinin/piperaquine tablets will be used to administer weight-based doses.
Other Name: Eurartesim

Experimental: DP plus MB
Study participants in this arm will receive DP as described above combined with once-daily methylene blue (MB) for 3 days, at 15 mg/kg/day (45 mg/kg total over 3 days).
Drug: Methylene blue
Methylene blue will be given as minitablets in prepackaged sachets according to weight groups.




Primary Outcome Measures :
  1. Mosquito infectivity assessed through membrane feeding assays [ Time Frame: 7 day ]
    Infectivity will be measured by oocyst prevalence in dissected mosquitoes. Primary endpoint will be a comparison between mean of pretreatment infectivity (day 0) and infectivity at days 2 and 7 post first dose.


Secondary Outcome Measures :
  1. Gametocyte prevalence, density, and sex ratio measured microscopically and by molecular methods. [ Time Frame: 42 days ]
    Outcome measured at baseline and days 1, 2, 3, 7, 14, 28, and 42 post first dose.

  2. Asexual parasite prevalence and density [ Time Frame: 42 days ]
    Asexual parasitemia will be evaluated by blood smear microscopy and confirmed by more sensitive, molecular methods. Outcome measured at baseline and days 1, 2, 3, 7, 14, 28, and 42 post first dose.

  3. Safety measurements including hemoglobin and signs of hemolysis [ Time Frame: 42 days ]
    The major safety endpoint is hemolysis. For this reason, hemoglobin and methemoglobin values will be measured before treatment, at baseline and on days 1, 2, 3, 7, 14, 28, and 42 post first dose. In addition, clinical review (including additional signs of hemolysis) will be assessed based on active and passive follow-up.

  4. Peak plasma concentration (Cmax) of primaquine [ Time Frame: 24 hours ]
    Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.

  5. Area under the concentration curve (AUC) of primaquine. [ Time Frame: 24 hours ]
    Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.

  6. Elimination half life (t1/2) of primaquine [ Time Frame: 24 hours ]
    Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.

  7. Peak plasma concentration (Cmax) of methylene blue [ Time Frame: 24 hours ]
    Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.

  8. Area under the concentration curve (AUC) of methylene blue [ Time Frame: 24 hours ]
    Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.

  9. Elimination half life (t1/2) of methylene blue [ Time Frame: 24 hours ]
    Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.

  10. Peak plasma concentration (Cmax) of sulphadoxine-pyrimethamine [ Time Frame: 24 hours ]
    Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.

  11. Area under the concentration curve (AUC) of sulphadoxine-pyrimethamine [ Time Frame: 24 hours ]
    Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.

  12. Elimination half-life (t1/2) of sulphadoxine-pyrimethamine [ Time Frame: 24 hours ]
    Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.

  13. Peak plasma concentration (Cmax) of dihydroartemisinin-piperaquine [ Time Frame: 24 hours ]
    Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.

  14. Area under the concentration curve (AUC) of dihydroartemisinin-piperaquine [ Time Frame: 24 hours ]
    Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.

  15. Elimination half-life (t1/2) of dihydroartemisinin-piperaquine [ Time Frame: 24 hours ]
    Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.

  16. Identification of cytochrome P450 (CYP) 2D6 and G6PD polymorphisms [ Time Frame: 1 hour ]
    CYP2D6 and G6PD genotyping will be performed using Thermo Fisher Scientific OpenArray Technology and Copy Number Variation (CNV) assays on the QuantStudio™ 12K Flex Real-Time PCR System.



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Ages Eligible for Study:   5 Years to 50 Years   (Child, Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Glucose-6-phosphate dehydrogenase (G6PD) normal defined by CareStart™ G6PD rapid diagnostic test (RDT) or the OSMMR2000 G6PD semi-qualitative test
  • Absence of symptomatic falciparum malaria, defined by fever upon enrollment
  • Presence of P. falciparum gametocytes on thick blood film at a density >30 gametocytes/µL (i.e. ≥2 gametocytes recorded in the thick film against 500 white blood cells)
  • No allergies to study drugs
  • No self-reported use of antimalarial drugs over the past 7 days (as reported by the participant)
  • Hemoglobin ≥ 10 g/dL
  • Individuals weighing <80 kg
  • No evidence of severe or chronic disease
  • Written, informed consent

Exclusion Criteria:

  • Age < 5 years or > 50 years
  • Female gender
  • Blood thick film negative for sexual stages of malaria
  • Previous reaction to study drugs/known allergy to study drugs
  • Signs of severe malaria, including hyperparasitemia, defined as asexual parasitemia > 100,000 parasites / µL)
  • Signs of acute or chronic illness, including hepatitis
  • Use of other medications (with the exception of paracetamol and/or aspirin)
  • Consent not given

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02831023


Locations
Mali
Malaria Research and Training Centre
Bamako, Mali
Sponsors and Collaborators
University of California, San Francisco
Malaria Research and Training Center, Bamako, Mali
Radboud University
London School of Hygiene and Tropical Medicine
Heidelberg University
Bill and Melinda Gates Foundation
Investigators
Principal Investigator: Roland Gosling, MD, PhD University of California, San Francisco
Principal Investigator: Alassane Dicko, MD Malaria Research and Training Centre
Principal Investigator: Teun Bousema, PhD Radboud University

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT02831023     History of Changes
Other Study ID Numbers: UCSF CHR # 15-16839
First Posted: July 13, 2016    Key Record Dates
Last Update Posted: January 11, 2017
Last Verified: January 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Data can be shared on request

Additional relevant MeSH terms:
Primaquine
Pyrimethamine
Piperaquine
Sulfadoxine
Amodiaquine
Dihydroartemisinin
Artemisinins
Fanasil, pyrimethamine drug combination
Methylene Blue
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Folic Acid Antagonists
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Infective Agents, Urinary
Renal Agents