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Safety and Tolerability of Low Dose Primaquine

Primary Purpose

Malaria, Falciparum, G6PD Deficiency

Status
Completed
Phase
Phase 4
Locations
Cambodia
Study Type
Interventional
Intervention
Dihydroartemisinin piperaquine (DHA PP)
Primaquine
Sponsored by
Malaria Consortium
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malaria, Falciparum focused on measuring Malaria, Falciparum, G6PD deficiency, Primaquine, Asia

Eligibility Criteria

1 Year - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age ≥ 1 year
  • Presentation with a confirmed fever (≥ 38⁰C axilla or ≥ 37.5⁰C aural) or history of fever in previous 48 hours +/- other clinical features of uncomplicated malaria
  • Plasmodium falciparum monoinfection ≥ 1 asexual form / 500 white blood cells
  • Informed consent (written/verbal) provided by patient or relative/legal guardian
  • Signed Assent form for children aged 12 to < 18 years

Exclusion Criteria:

  • Clinical signs of severe malaria or danger signs
  • Pregnant or breast feeding
  • Unable or unwilling to take a pregnancy test (for women of child-bearing age)
  • Women intending to become pregnant in the next 3 months
  • Allergic to primaquine or DHA PP
  • Patients taking drugs known to cause acute intravascular haemolytic anaemia (AIHA) in G6PD deficiency e.g. dapsone, nalidixic acid
  • Patients on treatment for a significant illness e.g. HIV, tuberculosis (TB) treatment, steroids
  • On drugs that could interfere with anti-malarial pharmacokinetics like antiretrovirals, cimetidine, ketoconazole, antiepileptic drugs, rifampicin

Sites / Locations

  • Ratanakiri Provincial Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Active Comparator

Active Comparator

Active Comparator

Arm Label

DHA PP plus primaquine, G6PD deficiency

DHA PP plus primaquine, G6PD normal

DHA PP alone, G6PD deficiency

DHA PP alone, G6PD normal

Arm Description

Standard Dihydroartemisinin piperaquine (DHA PP) dosing according to national guidelines, oral administration of one dose per day for three consecutive days. Target dosing is 2-4 mg/kg for DHA and 20 mg/kg for PP. Children (<30kg) will receive tablets of 20mg DHA and 160mg PP, while adults will receive tablets of 40mg DHA and 320mg PP. Target dose of 0.25mg/kg primaquine given orally with first dose only of DHA PP, dosing by weight for children <18 years and standard 15mg primaquine dose for all adults ≥18 years. Small children (<25kg) will receive a primaquine suspension, adults receive 7.5mg or 15mg primaquine tablets.

Standard Dihydroartemisinin piperaquine (DHA PP) dosing according to national guidelines, oral administration of one dose per day for three consecutive days. Target dosing is 2-4 mg/kg for DHA and 20 mg/kg for PP. Children (<30kg) will receive tablets of 20mg DHA and 160mg PP, while adults will receive tablets of 40mg DHA and 320mg PP. Target dose of 0.25mg/kg primaquine given orally with first dose only of DHA PP, dosing by weight for children <18 years and standard 15mg primaquine dose for all adults ≥18 years. Small children (<25kg) will receive a primaquine suspension, adults receive 7.5mg or 15mg primaquine tablets.

Standard Dihydroartemisinin piperaquine (DHA PP) dosing according to national guidelines, oral administration of one dose per day for three consecutive days. Target dosing is 2-4 mg/kg for DHA and 20 mg/kg for PP. Children (<30kg) will receive tablets of 20mg DHA and 160mg PP, while adults will receive tablets of 40mg DHA and 320mg PP.

Standard Dihydroartemisinin piperaquine (DHA PP) dosing according to national guidelines, oral administration of one dose per day for three consecutive days. Target dosing is 2-4 mg/kg for DHA and 20 mg/kg for PP. Children (<30kg) will receive tablets of 20mg DHA and 160mg PP, while adults will receive tablets of 40mg DHA and 320mg PP.

Outcomes

Primary Outcome Measures

Haemoglobin concentration
Compare haemoglobin concentrations in g/dL between the G6PD deficient arm given DHA PP plus primaquine, and the G6PD normal arm receiving the same regimen

Secondary Outcome Measures

Determine G6PD enzyme activity
Quantitative G6PD testing among all participants using the G6PD enzyme assay from Trinity Biologicals, USA, yielding G6PD enzyme results in U/g Hb.
Assess usefulness of field adapted WHO haemoglobin colour card vs. Hemocue
Comparison of quantitative (HemoCue, g/dL HB) and qualitative (WHO haemolglobin colour card) estimates of haemoglobin concentration
Assess usefulness of rapid test for G6PDd in predicting acute intravascular haemolysis
Comparison of rapid G6PD test (AccessBio, USA) qualitative result against quantitative G6PD assay to determine predictive value for clinically significant haemolysis
Proportion patients with ≥25% change in haemoglobin as a marker of intravascular haemolysis
Comparing across all 4 arms: proportion of all patients with fractional change in haemoglobin ≥25% from day 0 to day 7
Plasma haemoglobin concentration as a marker of intravascular haemolysis
Comparing across all 4 arms: plasma haemoglobin concentration at day 7
Urine colour change as a marker of intravascular haemolysis
Change in urine colour grade from day 0 to day 7 (Hillmen, Hall et al. 2004)
Fractional change in haemoglobin as a marker of intravascular haemolysis
Comparing across all 4 arms: fractional change in haemoglobin on day 7 vs. day 0
Clearance rate of primaquine
Primaquine elimination clearance rate, modelled from population pharmacokinetic data from all patients receiving at least one dose of DHA PP + PQ
Half life of primaquine
Primaquine terminal elimination half life, modelled from population pharmacokinetic data from all patients receiving at least one dose of DHA PP + PQ
Primaquine volume of distribution
Primaquine apparent volume of distribution (Vd), modelled from population pharmacokinetic data from all patients receiving at least one dose of DHA PP + PQ
Clearance rate of piperaquine
Piperaquine elimination clearance rate, modelled from population pharmacokinetic data from all patients receiving at least one dose of DHA PP +/- PQ
Half life of piperaquine
Piperaquine terminal elimination half life, modelled from population pharmacokinetic data from all patients receiving at least one dose of DHA PP +/- PQ
Piperaquine volume of distribution
Piperaquine apparent volume of distribution (Vd), modelled from population pharmacokinetic data from all patients receiving at least one dose of DHA PP +/- PQ
Peak plasma concentration (Cmax) of primaquine
Cmax taken directly from population pharmacokinetic data from all patients receiving at least one dose of DHA PP + PQ
Peak plasma concentration (Cmax) of piperaquine
Cmax taken directly from population pharmacokinetic data from all patients receiving at least one dose of DHA PP +/- PQ
Time to primquine peak plasma concentration (Tmax)
Tmax taken directly from population pharmacokinetic data from all patients receiving at least one dose of DHA PP + PQ
Time to piperaquine peak plasma concentration (Tmax)
Tmax taken directly from population pharmacokinetic data from all patients receiving at least one dose of DHA PP +/- PQ
Area under the plasma concentration versus time curve - primaquine
Modelled from population pharmacokinetic data from all patients receiving at least one dose of DHA PP + PQ
Area under the plasma concentration versus time curve - piperaquine
Modelled from population pharmacokinetic data from all patients receiving at least one dose of DHA PP +/- PQ

Full Information

First Posted
September 11, 2014
Last Updated
August 22, 2016
Sponsor
Malaria Consortium
Collaborators
National Centre for Parasitology, Entomology and Malaria Control, Cambodia, Institute Pasteur, Cambodia, World Health Organization, Centers for Disease Control and Prevention
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1. Study Identification

Unique Protocol Identification Number
NCT02434952
Brief Title
Safety and Tolerability of Low Dose Primaquine
Official Title
The Tolerability and Safety of Low Dose Primaquine for Transmission Blocking in Symptomatic Falciparum Infected Cambodians
Study Type
Interventional

2. Study Status

Record Verification Date
August 2016
Overall Recruitment Status
Completed
Study Start Date
October 2014 (undefined)
Primary Completion Date
July 2016 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Malaria Consortium
Collaborators
National Centre for Parasitology, Entomology and Malaria Control, Cambodia, Institute Pasteur, Cambodia, World Health Organization, Centers for Disease Control and Prevention

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
In Cambodia, falciparum is becoming more difficult to treat because drugs are becoming less effective. The investigators can help to try to prevent the spread of this resistant malaria by adding a drug that will make it more difficult for the mosquito to drink up the malaria in people's blood. If the mosquito cannot drink up the malaria, then the malaria cannot develop in the mosquito so it will not be able to inject malaria back into people when it bites. The drug the investigators will use is called primaquine. Primaquine commonly causes the red cells in the blood to break apart if they are weak. Red cells need enzymes to work properly and weak red cells have low amounts of an enzyme called glucose 6 phosphate dehydrogenase (G6PD). The investigators want to know if treating malaria with primaquine will be safe for the red cells. To do this study, the investigators need to know if a subject has low G6PD or not.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malaria, Falciparum, G6PD Deficiency
Keywords
Malaria, Falciparum, G6PD deficiency, Primaquine, Asia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
109 (Actual)

8. Arms, Groups, and Interventions

Arm Title
DHA PP plus primaquine, G6PD deficiency
Arm Type
Experimental
Arm Description
Standard Dihydroartemisinin piperaquine (DHA PP) dosing according to national guidelines, oral administration of one dose per day for three consecutive days. Target dosing is 2-4 mg/kg for DHA and 20 mg/kg for PP. Children (<30kg) will receive tablets of 20mg DHA and 160mg PP, while adults will receive tablets of 40mg DHA and 320mg PP. Target dose of 0.25mg/kg primaquine given orally with first dose only of DHA PP, dosing by weight for children <18 years and standard 15mg primaquine dose for all adults ≥18 years. Small children (<25kg) will receive a primaquine suspension, adults receive 7.5mg or 15mg primaquine tablets.
Arm Title
DHA PP plus primaquine, G6PD normal
Arm Type
Active Comparator
Arm Description
Standard Dihydroartemisinin piperaquine (DHA PP) dosing according to national guidelines, oral administration of one dose per day for three consecutive days. Target dosing is 2-4 mg/kg for DHA and 20 mg/kg for PP. Children (<30kg) will receive tablets of 20mg DHA and 160mg PP, while adults will receive tablets of 40mg DHA and 320mg PP. Target dose of 0.25mg/kg primaquine given orally with first dose only of DHA PP, dosing by weight for children <18 years and standard 15mg primaquine dose for all adults ≥18 years. Small children (<25kg) will receive a primaquine suspension, adults receive 7.5mg or 15mg primaquine tablets.
Arm Title
DHA PP alone, G6PD deficiency
Arm Type
Active Comparator
Arm Description
Standard Dihydroartemisinin piperaquine (DHA PP) dosing according to national guidelines, oral administration of one dose per day for three consecutive days. Target dosing is 2-4 mg/kg for DHA and 20 mg/kg for PP. Children (<30kg) will receive tablets of 20mg DHA and 160mg PP, while adults will receive tablets of 40mg DHA and 320mg PP.
Arm Title
DHA PP alone, G6PD normal
Arm Type
Active Comparator
Arm Description
Standard Dihydroartemisinin piperaquine (DHA PP) dosing according to national guidelines, oral administration of one dose per day for three consecutive days. Target dosing is 2-4 mg/kg for DHA and 20 mg/kg for PP. Children (<30kg) will receive tablets of 20mg DHA and 160mg PP, while adults will receive tablets of 40mg DHA and 320mg PP.
Intervention Type
Drug
Intervention Name(s)
Dihydroartemisinin piperaquine (DHA PP)
Other Intervention Name(s)
Duo-Cotecxin, Eurartesim
Intervention Type
Drug
Intervention Name(s)
Primaquine
Primary Outcome Measure Information:
Title
Haemoglobin concentration
Description
Compare haemoglobin concentrations in g/dL between the G6PD deficient arm given DHA PP plus primaquine, and the G6PD normal arm receiving the same regimen
Time Frame
Day 7
Secondary Outcome Measure Information:
Title
Determine G6PD enzyme activity
Description
Quantitative G6PD testing among all participants using the G6PD enzyme assay from Trinity Biologicals, USA, yielding G6PD enzyme results in U/g Hb.
Time Frame
Day 0
Title
Assess usefulness of field adapted WHO haemoglobin colour card vs. Hemocue
Description
Comparison of quantitative (HemoCue, g/dL HB) and qualitative (WHO haemolglobin colour card) estimates of haemoglobin concentration
Time Frame
Day 0
Title
Assess usefulness of rapid test for G6PDd in predicting acute intravascular haemolysis
Description
Comparison of rapid G6PD test (AccessBio, USA) qualitative result against quantitative G6PD assay to determine predictive value for clinically significant haemolysis
Time Frame
Day 0
Title
Proportion patients with ≥25% change in haemoglobin as a marker of intravascular haemolysis
Description
Comparing across all 4 arms: proportion of all patients with fractional change in haemoglobin ≥25% from day 0 to day 7
Time Frame
Change from Day 0 to Day 7
Title
Plasma haemoglobin concentration as a marker of intravascular haemolysis
Description
Comparing across all 4 arms: plasma haemoglobin concentration at day 7
Time Frame
Day 7
Title
Urine colour change as a marker of intravascular haemolysis
Description
Change in urine colour grade from day 0 to day 7 (Hillmen, Hall et al. 2004)
Time Frame
Change from Day 0 to Day 7
Title
Fractional change in haemoglobin as a marker of intravascular haemolysis
Description
Comparing across all 4 arms: fractional change in haemoglobin on day 7 vs. day 0
Time Frame
Change from Day 0 to Day 7
Title
Clearance rate of primaquine
Description
Primaquine elimination clearance rate, modelled from population pharmacokinetic data from all patients receiving at least one dose of DHA PP + PQ
Time Frame
Day 0-7
Title
Half life of primaquine
Description
Primaquine terminal elimination half life, modelled from population pharmacokinetic data from all patients receiving at least one dose of DHA PP + PQ
Time Frame
Day 0-7
Title
Primaquine volume of distribution
Description
Primaquine apparent volume of distribution (Vd), modelled from population pharmacokinetic data from all patients receiving at least one dose of DHA PP + PQ
Time Frame
Day 0-7
Title
Clearance rate of piperaquine
Description
Piperaquine elimination clearance rate, modelled from population pharmacokinetic data from all patients receiving at least one dose of DHA PP +/- PQ
Time Frame
Day 0-28
Title
Half life of piperaquine
Description
Piperaquine terminal elimination half life, modelled from population pharmacokinetic data from all patients receiving at least one dose of DHA PP +/- PQ
Time Frame
Day 0-28
Title
Piperaquine volume of distribution
Description
Piperaquine apparent volume of distribution (Vd), modelled from population pharmacokinetic data from all patients receiving at least one dose of DHA PP +/- PQ
Time Frame
Day 0-28
Title
Peak plasma concentration (Cmax) of primaquine
Description
Cmax taken directly from population pharmacokinetic data from all patients receiving at least one dose of DHA PP + PQ
Time Frame
Day 0-7
Title
Peak plasma concentration (Cmax) of piperaquine
Description
Cmax taken directly from population pharmacokinetic data from all patients receiving at least one dose of DHA PP +/- PQ
Time Frame
Day 0-28
Title
Time to primquine peak plasma concentration (Tmax)
Description
Tmax taken directly from population pharmacokinetic data from all patients receiving at least one dose of DHA PP + PQ
Time Frame
Day 0-7
Title
Time to piperaquine peak plasma concentration (Tmax)
Description
Tmax taken directly from population pharmacokinetic data from all patients receiving at least one dose of DHA PP +/- PQ
Time Frame
Day 0-28
Title
Area under the plasma concentration versus time curve - primaquine
Description
Modelled from population pharmacokinetic data from all patients receiving at least one dose of DHA PP + PQ
Time Frame
Day 0-7
Title
Area under the plasma concentration versus time curve - piperaquine
Description
Modelled from population pharmacokinetic data from all patients receiving at least one dose of DHA PP +/- PQ
Time Frame
Day 0-28

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age ≥ 1 year Presentation with a confirmed fever (≥ 38⁰C axilla or ≥ 37.5⁰C aural) or history of fever in previous 48 hours +/- other clinical features of uncomplicated malaria Plasmodium falciparum monoinfection ≥ 1 asexual form / 500 white blood cells Informed consent (written/verbal) provided by patient or relative/legal guardian Signed Assent form for children aged 12 to < 18 years Exclusion Criteria: Clinical signs of severe malaria or danger signs Pregnant or breast feeding Unable or unwilling to take a pregnancy test (for women of child-bearing age) Women intending to become pregnant in the next 3 months Allergic to primaquine or DHA PP Patients taking drugs known to cause acute intravascular haemolytic anaemia (AIHA) in G6PD deficiency e.g. dapsone, nalidixic acid Patients on treatment for a significant illness e.g. HIV, tuberculosis (TB) treatment, steroids On drugs that could interfere with anti-malarial pharmacokinetics like antiretrovirals, cimetidine, ketoconazole, antiepileptic drugs, rifampicin
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Dysoley Lek, MD
Organizational Affiliation
National Centre for Parasitology, Entomology and Malaria Control, Cambodia
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ratanakiri Provincial Hospital
City
Ratanakiri
Country
Cambodia

12. IPD Sharing Statement

Citations:
PubMed Identifier
32179526
Citation
Vantaux A, Kim S, Piv E, Chy S, Berne L, Khim N, Lek D, Siv S, Mukaka M, Taylor WR, Menard D. Significant Efficacy of a Single Low Dose of Primaquine Compared to Stand-Alone Artemisinin Combination Therapy in Reducing Gametocyte Carriage in Cambodian Patients with Uncomplicated Multidrug-Resistant Plasmodium falciparum Malaria. Antimicrob Agents Chemother. 2020 May 21;64(6):e02108-19. doi: 10.1128/AAC.02108-19. Print 2020 May 21.
Results Reference
derived
PubMed Identifier
30871496
Citation
Dysoley L, Kim S, Lopes S, Khim N, Bjorges S, Top S, Huch C, Rekol H, Westercamp N, Fukuda MM, Hwang J, Roca-Feltrer A, Mukaka M, Menard D, Taylor WR. The tolerability of single low dose primaquine in glucose-6-phosphate deficient and normal falciparum-infected Cambodians. BMC Infect Dis. 2019 Mar 12;19(1):250. doi: 10.1186/s12879-019-3862-1.
Results Reference
derived
Links:
URL
http://www.malariaconsortium.org/
Description
Malaria Consortium
URL
http://www.cnm.gov.kh/
Description
National Centre for Parasitology, Entomology and Malaria Control Program, Cambodia

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Safety and Tolerability of Low Dose Primaquine

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