Safety and Tolerability of Low Dose Primaquine

Sponsor

Malaria Consortium (Other)

Overall Status

Completed

CT.gov ID

NCT02434952

Collaborator

National Centre for Parasitology, Entomology and Malaria Control, Cambodia (Other), Institute Pasteur, Cambodia (Other), World Health Organization (Other), Centers for Disease Control and Prevention (U.S. Fed)

109

Enrollment

Location

Arms

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Malaria, Falciparum G6PD Deficiency	Drug: Dihydroartemisinin piperaquine (DHA PP) Drug: Primaquine	Phase 4

Study Design

Study Type:

Interventional

Actual Enrollment :

109 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

The Tolerability and Safety of Low Dose Primaquine for Transmission Blocking in Symptomatic Falciparum Infected Cambodians

Study Start Date :

Oct 1, 2014

Actual Primary Completion Date :

Jul 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: DHA PP plus primaquine, G6PD deficiency 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.	Drug: Dihydroartemisinin piperaquine (DHA PP) Other Names: Duo-Cotecxin Eurartesim Drug: Primaquine
Active Comparator: DHA PP plus primaquine, G6PD normal 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.	Drug: Dihydroartemisinin piperaquine (DHA PP) Other Names: Duo-Cotecxin Eurartesim Drug: Primaquine
Active Comparator: DHA PP alone, G6PD deficiency 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.	Drug: Dihydroartemisinin piperaquine (DHA PP) Other Names: Duo-Cotecxin Eurartesim
Active Comparator: DHA PP alone, G6PD normal 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.	Drug: Dihydroartemisinin piperaquine (DHA PP) Other Names: Duo-Cotecxin Eurartesim

Outcome Measures

Primary Outcome Measures

Haemoglobin concentration [Day 7]
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 [Day 0]
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 [Day 0]
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 [Day 0]
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 [Change from Day 0 to Day 7]
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 [Day 7]
Comparing across all 4 arms: plasma haemoglobin concentration at day 7
Urine colour change as a marker of intravascular haemolysis [Change from Day 0 to Day 7]
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 [Change from Day 0 to Day 7]
Comparing across all 4 arms: fractional change in haemoglobin on day 7 vs. day 0
Clearance rate of primaquine [Day 0-7]
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 [Day 0-7]
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 [Day 0-7]
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 [Day 0-28]
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 [Day 0-28]
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 [Day 0-28]
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 [Day 0-7]
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 [Day 0-28]
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) [Day 0-7]
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) [Day 0-28]
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 [Day 0-7]
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 [Day 0-28]
Modelled from population pharmacokinetic data from all patients receiving at least one dose of DHA PP +/- PQ

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year and Older

Sexes Eligible for Study:

All

Accepts 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