Safety and Efficacy of Primaquine for P. Vivax

Evaluation of Safety and Efficacy of Two Primaquine Dosing Regimens for the Radical Treatment of Plasmodium Vivax Malaria in Vanuatu and Solomon Islands

The Melanesian states of the Western Pacific (Papua New Guinea, Solomon Islands and Vanuatu) represent a unique and especially prescient challenge to malaria control and elimination.

While the use of bed nets and other vector control and case management measures have achieved major advances in overall malaria control, the P. vivax and P. ovale species account for an ever-increasing burden of clinical disease.

The lack of effective treatment of the hypnozoite stages of infection with these species result in ongoing relapses and a continuing reservoir of infection.

The only known drug effective for treatment of the hypnozoite stage is primaquine; however the safe and effective dose of this drug in malaria treatment is still unclear.

A recent study evaluated the safety and efficacy of two primaquine dosing regimens (0.25mg/kg and 0.5mg/kg) in a population in New Ireland province, PNG. This study aims to replicate this methodology in Vanuatu and Solomon Islands, to provide a more complete picture of primaquine efficacy and safety in each of the three countries of this region.

Study Overview

• Status: Unknown
• Conditions: Malaria
• Intervention / Treatment: Drug: Primaquine; Drug: delayed primaquine

Detailed Description

Study Aims

Primary To define and compare the efficacy of standard (0.25mg/kg/day for 14 days) and high-dose (0.5mg/kg/day for 14 days) primaquine in preventing early relapses from P. vivax in Solomon Islands and Vanuatu.

Secondary To measure safety and toxicity of primaquine when administered as a standard or high-dose regimen in Melanesian adults and children in Solomon Islands and Vanuatu.

• Study Type: Interventional
• Enrollment (Anticipated): 180
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ivo Mueller, PhD; Phone Number: +61 3 9345 2555; Email: mueller@wehi.edu.au

Study Locations

• Solomon Islands
  • Guadalcanal Province
    • Honiara, Guadalcanal Province, Solomon Islands
      • Tetere Hospital, Guadalcanal Province
      • Contact: Lyndes Wini
      • Contact: Albino Bobogare
  • Malaita Province
    • Auki, Malaita Province, Solomon Islands
      • Aoki Hospital, Malaita Province
      • Contact: Lyndes Wini
      • Contact: Albino Bobogare
• Vanuatu
  • Sanma Province
    • Luganville, Sanma Province, Vanuatu
      • Northern Provincial Hospital, Nambauk Aid Post, V.F.H.A Dispensary and Fanafo Dispensary
      • Contact: George Taleo
      • Contact: Edward Tambisari
  • Shefa Province
    • Port Vila, Shefa Province, Vanuatu
      • Toroa Dispensary, NTM Health Centre and Vila Central Hospital
      • Contact: George Taleo
      • Contact: Edward Tambisari, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months to 58 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 12 months to 60 years
2. Melanesian background and living in local area
3. Microscopically (based on field microscopy) or RDT confirmed P.vivax regardless of parasite density. Mixed infections (P.falciparum-P.vivax and P.malariae-P.vivax) can be included.

Exclusion Criteria:

1. Any signs of severe malaria (see WHO definitions) including: impaired consciousness, respiratory distress, severe anaemia (Hb<5), multiple seizures, frequent vomiting/ inability to swallow tablets, prostration, jaundice, hypotension, abnormal bleeding or hypoglycaemia.
2. Clinical evidence of non-malarial illness (such as pneumonia or otitis media)
3. Severe malnutrition (weight-for-age nutritional Z score [WAZ] <60th percentile)
4. Permanent disability, which prevents or impedes study participation.
5. Treatment with primaquine in the previous 14 days
6. Residence or planned travel outside the study area during the follow-up period (precluding supervised treatment and follow-up procedures)
7. Known or suspected pregnancy
8. Currently breastfeeding
9. A positive rapid test for G6PD deficiency (Binax or Carestart RDT)

Following later PCR-based confirmation of malaria speciation, there may be some post-hoc exclusion of subjects in whom it is thought the initial field-based microscopic diagnosis may have been incorrect.

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard dose; Participants will receive a standard 3-day treatment course of artemether-lumefantrine at the standard age-based dosage, and will be administered the standard recommended primaquine dose of 0.25mg/kg for 14 consecutive days.	Drug: Primaquine
Active Comparator: High dose; Participants will receive a standard 3-day treatment course of artemether-lumefantrine at the standard age-based dosage, and will be administered a primaquine dose of 0.5mg/kg/day for 14 consecutive days.	Drug: Primaquine
Other: Control; Participants will receive a standard 3-day treatment course of artemether-lumefantrine at the standard age-based dosage, but will not receive primaquine until the time of confirmed recurrent parasitaemia or completion of 3 months follow up.	Drug: delayed primaquine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy: Numbers of Plasmodium vivax relapses per person-years of follow-	Total number of microscopically diagnosed (including both symptomatic and asymptomatic infections), PCR-confirmed relapses with Plasmodium vivax in participants in each treatment arm over the 3-month follow-up period, expressed as number of relapses per person-years of follow-up.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and toxicity (1): Numbers with mild adverse events	Numbers in each treatment arm experiencing any documented adverse event defined as "mild" (not severe enough to interfere with daily activities).	12 months
Safety and toxicity (2) Numbers with moderate adverse events	Numbers in each treatment arm experiencing any documented adverse event defined as "moderate" (severe enough to interfere with daily activities but not severe enough to warrant admission to hospital).	12 months
Safety and toxicity (3) Numbers with severe adverse events	Numbers in each treatment arm experiencing any documented adverse event defined as "severe" (severe to warrant admission to hospital or to be considered a risk for death or disability arising from the event).	12 months
Safety and toxicity (4) Numbers with any adverse events	Numbers in each treatment arm experiencing any documented event (defined as either mild, moderate or severe as above).	12 months
Safety and toxicity (5) Numbers with assumed significant haemolysis	Numbers in each treatment arm experiencing any of the following: Haemoglobinuria on dipstick examination; Scleral icterus; Haemoglobin concentration fall by more than 25% of baseline or absolute concentration <5g/dL	12 months
Safety and toxicity (6) Numbers with significant methaemoglobinaemia	Numbers in each treatment arm experiencing any of the following: Cyanosis (blue tongue, lips and peripheries); Measured methaemoglobin saturation (using Masimo Rad-57 plus oximeter) >15%; Measured oxygen saturation <85%	12 months

Collaborators and Investigators

• Sponsor: Menzies School of Health Research
• Collaborators: World Health Organization; Walter and Eliza Hall Institute of Medical Research; Ministry of Health, Vanuatu; Ministry of Health, Solomon Islands

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Anticipated): May 1, 2014
• Study Completion (Anticipated): May 1, 2015

Study Registration Dates

• First Submitted: March 25, 2013
• First Submitted That Met QC Criteria: April 18, 2013
• First Posted (Estimate): April 23, 2013

Study Record Updates

• Last Update Posted (Estimate): November 8, 2013
• Last Update Submitted That Met QC Criteria: November 7, 2013
• Last Verified: November 1, 2013

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: VanSI_2013