Back to resultsPhase 2 Efficacy Study of Primaquine and Methylene Blue
Primary Purpose
Malaria
Status
Completed
Phase
Phase 2
Locations
Mali
Study Type
Interventional
Intervention
Sulphadoxine-pyrimethamine
0.25 mg/kg primaquine
Dihydroartemisinin-piperaquine
Methylene blue
Amodiaquine
Sponsored by
About this trial
This is an interventional treatment trial for Malaria
Eligibility 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
Sites / Locations
- Malaria Research and Training Centre
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Active Comparator
Experimental
Active Comparator
Experimental
Arm Label
SP-AQ only
SP-AQ plus PQ
DP only
DP plus MB
Arm Description
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.
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.
Participants in this arm will be treated with dihydroartemisinin-piperaquine (DP), which will be administered once a day for three days.
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).
Outcomes
Primary Outcome Measures
Mosquito infectivity assessed through membrane feeding assays
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
Gametocyte prevalence, density, and sex ratio measured microscopically and by molecular methods.
Outcome measured at baseline and days 1, 2, 3, 7, 14, 28, and 42 post first dose.
Asexual parasite prevalence and density
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.
Safety measurements including hemoglobin and signs of hemolysis
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.
Peak plasma concentration (Cmax) of primaquine
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Area under the concentration curve (AUC) of primaquine.
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Elimination half life (t1/2) of primaquine
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Peak plasma concentration (Cmax) of methylene blue
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Area under the concentration curve (AUC) of methylene blue
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Elimination half life (t1/2) of methylene blue
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Peak plasma concentration (Cmax) of sulphadoxine-pyrimethamine
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Area under the concentration curve (AUC) of sulphadoxine-pyrimethamine
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Elimination half-life (t1/2) of sulphadoxine-pyrimethamine
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Peak plasma concentration (Cmax) of dihydroartemisinin-piperaquine
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Area under the concentration curve (AUC) of dihydroartemisinin-piperaquine
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Elimination half-life (t1/2) of dihydroartemisinin-piperaquine
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Identification of cytochrome P450 (CYP) 2D6 and G6PD polymorphisms
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.
Full Information
NCT ID
NCT02831023
First Posted
July 6, 2016
Last Updated
January 9, 2017
Sponsor
University of California, San Francisco
Collaborators
Malaria Research and Training Center, Bamako, Mali, Radboud University Medical Center, London School of Hygiene and Tropical Medicine, Heidelberg University, Bill and Melinda Gates Foundation
1. Study Identification
Unique Protocol Identification Number
NCT02831023
Brief Title
Phase 2 Efficacy Study of Primaquine and Methylene Blue
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 Type
Interventional
2. Study Status
Record Verification Date
January 2017
Overall Recruitment Status
Completed
Study Start Date
July 2016 (undefined)
Primary Completion Date
January 2017 (Actual)
Study Completion Date
January 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of California, San Francisco
Collaborators
Malaria Research and Training Center, Bamako, Mali, Radboud University Medical Center, London School of Hygiene and Tropical Medicine, Heidelberg University, Bill and Melinda Gates Foundation
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
Detailed Description
Protocol will be shared on request.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malaria
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
80 (Actual)
8. Arms, Groups, and Interventions
Arm Title
SP-AQ only
Arm Type
Active Comparator
Arm Description
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.
Arm Title
SP-AQ plus PQ
Arm Type
Experimental
Arm Description
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.
Arm Title
DP only
Arm Type
Active Comparator
Arm Description
Participants in this arm will be treated with dihydroartemisinin-piperaquine (DP), which will be administered once a day for three days.
Arm Title
DP plus MB
Arm Type
Experimental
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
Sulphadoxine-pyrimethamine
Other Intervention Name(s)
Fansidar
Intervention Description
Each Fansidar tablet is scored containing 500mg sulphadoxine and 25 mg pyrimethamine. Doses will be administered by weight.
Intervention Type
Drug
Intervention Name(s)
0.25 mg/kg primaquine
Intervention Description
Primaquine will be administered in an aqueous solution according to weight-based dosing.
Intervention Type
Drug
Intervention Name(s)
Dihydroartemisinin-piperaquine
Other Intervention Name(s)
Eurartesim
Intervention Description
160mg/20mg or 320mg/40mg of dihydroartemisinin/piperaquine tablets will be used to administer weight-based doses.
Intervention Type
Drug
Intervention Name(s)
Methylene blue
Intervention Description
Methylene blue will be given as minitablets in prepackaged sachets according to weight groups.
Intervention Type
Drug
Intervention Name(s)
Amodiaquine
Intervention Description
Amodiaquine will be administered once daily for 3 days, following weight-based dosing of 150 mg tablets.
Primary Outcome Measure Information:
Title
Mosquito infectivity assessed through membrane feeding assays
Description
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.
Time Frame
7 day
Secondary Outcome Measure Information:
Title
Gametocyte prevalence, density, and sex ratio measured microscopically and by molecular methods.
Description
Outcome measured at baseline and days 1, 2, 3, 7, 14, 28, and 42 post first dose.
Time Frame
42 days
Title
Asexual parasite prevalence and density
Description
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.
Time Frame
42 days
Title
Safety measurements including hemoglobin and signs of hemolysis
Description
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.
Time Frame
42 days
Title
Peak plasma concentration (Cmax) of primaquine
Description
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Time Frame
24 hours
Title
Area under the concentration curve (AUC) of primaquine.
Description
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Time Frame
24 hours
Title
Elimination half life (t1/2) of primaquine
Description
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Time Frame
24 hours
Title
Peak plasma concentration (Cmax) of methylene blue
Description
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Time Frame
24 hours
Title
Area under the concentration curve (AUC) of methylene blue
Description
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Time Frame
24 hours
Title
Elimination half life (t1/2) of methylene blue
Description
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Time Frame
24 hours
Title
Peak plasma concentration (Cmax) of sulphadoxine-pyrimethamine
Description
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Time Frame
24 hours
Title
Area under the concentration curve (AUC) of sulphadoxine-pyrimethamine
Description
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Time Frame
24 hours
Title
Elimination half-life (t1/2) of sulphadoxine-pyrimethamine
Description
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Time Frame
24 hours
Title
Peak plasma concentration (Cmax) of dihydroartemisinin-piperaquine
Description
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Time Frame
24 hours
Title
Area under the concentration curve (AUC) of dihydroartemisinin-piperaquine
Description
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Time Frame
24 hours
Title
Elimination half-life (t1/2) of dihydroartemisinin-piperaquine
Description
Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose.
Time Frame
24 hours
Title
Identification of cytochrome P450 (CYP) 2D6 and G6PD polymorphisms
Description
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.
Time Frame
1 hour
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
5 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Roland Gosling, MD, PhD
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Alassane Dicko, MD
Organizational Affiliation
Malaria Research and Training Centre
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Teun Bousema, PhD
Organizational Affiliation
Radboud University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Malaria Research and Training Centre
City
Bamako
Country
Mali
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Data can be shared on request
Citations:
PubMed Identifier
29422384
Citation
Dicko A, Roh ME, Diawara H, Mahamar A, Soumare HM, Lanke K, Bradley J, Sanogo K, Kone DT, Diarra K, Keita S, Issiaka D, Traore SF, McCulloch C, Stone WJR, Hwang J, Muller O, Brown JM, Srinivasan V, Drakeley C, Gosling R, Chen I, Bousema T. Efficacy and safety of primaquine and methylene blue for prevention of Plasmodium falciparum transmission in Mali: a phase 2, single-blind, randomised controlled trial. Lancet Infect Dis. 2018 Jun;18(6):627-639. doi: 10.1016/S1473-3099(18)30044-6. Epub 2018 Feb 6.
Results Reference
derived
Learn more about this trial
Phase 2 Efficacy Study of Primaquine and Methylene Blue
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