Safety and Efficacy of Primaquine for P. Vivax

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Malaria

Intervention / Treatment
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* Drug: Primaquine
* Drug: delayed primaquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 12 months to 60 years Melanesian background and living in local area 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: 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. Clinical evidence of non-malarial illness (such as pneumonia or otitis media) Severe malnutrition (weight-for-age nutritional Z score [WAZ] <60th percentile) Permanent disability, which prevents or impedes study participation. Treatment with primaquine in the previous 14 days Residence or planned travel outside the study area during the follow-up period (precluding supervised treatment and follow-up procedures) Known or suspected pregnancy Currently breastfeeding 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.

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard dose<br>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<br> <br> |
| Active Comparator: High dose<br>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<br> <br> |
| Other: Control<br>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<br> <br> |

What is the study measuring?
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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 |