Investigation of Short Course, High Dose Primaquine Treatment for Liver Stages of Plasmodium Vivax Infection

Safety, Tolerability and Pilot Efficacy of Short Course, High Dose Primaquine Treatment for Liver Stages of Plasmodium Vivax Infection

This study specifically seeks to provide data on the safety, tolerability and pilot efficacy of short course, high dose primaquine treatment in Papua New Guinean children aged 5-10 years, in a cross-sectional study design. Community screened asymptomatic cases and/or cases of clinically diagnosed malaria admitted to the out-patient units of the health center, will be screened for Glucose-6-phosphate dehydrogenase deficiency (G6PD) and malaria illness by rapid diagnostic test and P. vivax infection confirmed by light microscopy. Following treatment with artemether-lumefantrine (Coartem), G6PD normal children will be enrolled into the study and followed for 2 months. Primaquine treatment will be allocated to study participants in a step-wise design; firstly receiving the current 14 day treatment regimen of 0.5 mg/kg total dose (n=40); secondly, a 7 day treatment regimen receiving a total dose of 1.0 mg/kg/day; then thirdly, receive 1.0 mg/kg twice daily dose (bd) for a total of 3.5 days, should the 7 day treatment prove to be safe and well tolerated. In addition to this dose-escalation study, the pharmacokinetic profiles of single doses of 0.5 mg/kg and 1.0 mg/kg will be determined using an intensive sampling protocol, in children aged 5-10 years. The pharmacokinetic profiles obtained by this sub-study will be essential for modeling the population pharmacokinetic data obtained from the dose-escalation study. As there is currently no data on the safety, tolerability and efficacy of primaquine in children, the present study will validate previous observation and contribute to the knowledge of primaquine as a treatment for liver stages of Plasmodium vivax infection.

Study Overview

• Status: Unknown
• Conditions: Plasmodium Vivax
• Intervention / Treatment: Drug: Primaquine

• Study Type: Interventional
• Enrollment (Anticipated): 150
• Phase: Phase 4

Contacts and Locations

Study Locations

• Papua New Guinea
  • Madang Province
    • Madang, Madang Province, Papua New Guinea
      • Recruiting
      • PNG Institute of Medical Research
      • Contact: Brioni R Moore, PhD; Phone Number: +61466266334; Email: brioni.moore@uwa.edu.au
      • Principal Investigator: Inoni Betuela, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 10 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Permanent resident in study area
• Absence of history of hypersensitivity reactions to pre-treatment drugs
• Positive for P. vivax infections on blood smear or PCR
• Normal G6PD enzyme activity

Exclusion Criteria:

• Features of severe malaria
• Clinical evidence of nonmalarial illness
• Severe malnutrition (weight for age nutritional Z score <60th percentile)
• Moderate to severe anemia (Hb <8g/dL)
• Permanent disability which prevents or impedes study participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 14 day dose regimen; 0.5 mg/kg oral Primaquine administered daily for 14 days	Drug: Primaquine; Primaquine treatment given in a step-wise manner; (a) 0.5 mg/kg total dose daily for 14 days (n=40), (b) 1.0 mg/kg total dose daily for 7 days (n=40), (c) 1.0 mg/kg twice daily for 3.5 days (n=40); Other Names: Primaquine phosphate
Active Comparator: 7 day dose regimen; 1.0 mg/kg oral Primaquine administered daily for 7 days	Drug: Primaquine; Primaquine treatment given in a step-wise manner; (a) 0.5 mg/kg total dose daily for 14 days (n=40), (b) 1.0 mg/kg total dose daily for 7 days (n=40), (c) 1.0 mg/kg twice daily for 3.5 days (n=40); Other Names: Primaquine phosphate
Active Comparator: 3.5 day dose regimen; 1.0 mg/kg oral Primaquine administered twice daily (bd) for 3.5 days	Drug: Primaquine; Primaquine treatment given in a step-wise manner; (a) 0.5 mg/kg total dose daily for 14 days (n=40), (b) 1.0 mg/kg total dose daily for 7 days (n=40), (c) 1.0 mg/kg twice daily for 3.5 days (n=40); Other Names: Primaquine phosphate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety and tolerability as measured by hemoglobin	2 months post baseline
Safety and tolerability as measured by methemoglobin	2 months post baseline
Safety and tolerability as measured by liver biochemistry	2 months post baseline
Safety and tolerability as measured by symptom questionnaire	2 months post baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to first or only Plasmodium vivax infection by light microscopy and polymerase chain reaction (PCR)	Thick and thin blood films, along with PCR samples, will be collected at time of recruitment and then at any time the participant develops fever within the study period.	2 months from baseline
Time to first or only clinical Plasmodium vivax episode		2 months from baseline
Comparison of the rate of incidence of P. vivax relapses in 3.5 or 7 day treatment arm compared to standard 14 day regimen		2 months from baseline
Pharmacokinetics - elimination half-life (t1/2)		42 days
Pharmacokinetics - clearance (CL)		42 days
Pharmacokinetics - volume of distribution (Vd)		42 days
Pharmacokinetics - maximal concentration (Cmax)		42 days
Pharmacokinetics - area under the curve (AUC)		42 days

Collaborators and Investigators

• Sponsor: Papua New Guinea Institute of Medical Research
• Collaborators: University of Oxford; Curtin University; The University of Western Australia; Walter and Eliza Hall Institute of Medical Research
• Investigators: Principal Investigator: Ivo Mueller, PhD, Walter and Eliza Hall Institute of Medical Research; Centre de Recerca en Salut Internacional de Barcelona (CRESIB); Principal Investigator: Inoni Betuela, MD, PhD, PNG Institute of Medical Research; Principal Investigator: J Kevin Baird, PhD, Eijkman-Oxford Clinical Research Unit, Oxford University; Principal Investigator: Timothy ME Davis, FRAC, PhD, The University of Western Australia

Study record dates

Study Major Dates

• Study Start: June 1, 2010
• Primary Completion (Anticipated): June 1, 2016
• Study Completion (Anticipated): December 1, 2016

Study Registration Dates

• First Submitted: November 13, 2014
• First Submitted That Met QC Criteria: February 10, 2015
• First Posted (Estimate): February 18, 2015

Study Record Updates

• Last Update Posted (Estimate): October 14, 2015
• Last Update Submitted That Met QC Criteria: October 12, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Primaquine
• Other Study ID Numbers: MRAC10.14