Safety and Tolerability of Low Dose Primaquine

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

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.

Study Overview

• Status: Completed
• Conditions: Malaria, Falciparum; G6PD Deficiency
• Intervention / Treatment: Drug: Primaquine; Drug: Dihydroartemisinin piperaquine (DHA PP)

• Study Type: Interventional
• Enrollment (Actual): 109
• Phase: Phase 4

Contacts and Locations

Study Locations

• Cambodia
  • Ratanakiri, Cambodia
    • Ratanakiri Provincial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / 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: Primaquine; Drug: Dihydroartemisinin piperaquine (DHA PP); Other Names: Eurartesim; Duo-Cotecxin
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: Primaquine; Drug: Dihydroartemisinin piperaquine (DHA PP); Other Names: Eurartesim; Duo-Cotecxin
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: Eurartesim; Duo-Cotecxin
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: Eurartesim; Duo-Cotecxin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Day 0
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	Day 0
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	Day 0
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	Change 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	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)	Change from Day 0 to Day 7
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	Change from Day 0 to Day 7
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	Day 0-7
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	Day 0-7
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	Day 0-7
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	Day 0-28
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	Day 0-28
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	Day 0-28
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	Day 0-7
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	Day 0-28
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	Day 0-7
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	Day 0-28
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	Day 0-7
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	Day 0-28

Collaborators and Investigators

• Sponsor: Malaria Consortium
• Collaborators: Centers for Disease Control and Prevention; World Health Organization; National Centre for Parasitology, Entomology and Malaria Control, Cambodia; Institute Pasteur, Cambodia
• Investigators: Principal Investigator: Dysoley Lek, MD, National Centre for Parasitology, Entomology and Malaria Control, Cambodia

Publications and helpful links

General Publications

• 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.
• 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.

Helpful Links

• Malaria Consortium
• National Centre for Parasitology, Entomology and Malaria Control Program, Cambodia

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Actual): July 1, 2016

Study Registration Dates

• First Submitted: September 11, 2014
• First Submitted That Met QC Criteria: April 30, 2015
• First Posted (Estimate): May 6, 2015

Study Record Updates

• Last Update Posted (Estimate): August 23, 2016
• Last Update Submitted That Met QC Criteria: August 22, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: Asia; G6PD deficiency; Primaquine; Malaria, Falciparum
• Additional Relevant MeSH Terms: Metabolic Diseases; Infections; Hematologic Diseases; Genetic Diseases, Inborn; Vector Borne Diseases; Anemia; Parasitic Diseases; Protozoan Infections; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Malaria; Malaria, Falciparum; Glucosephosphate Dehydrogenase Deficiency; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Primaquine; Piperaquine; Artenimol
• Other Study ID Numbers: 015NECHR