IMPROV (Improving the Radical Cure of Vivax Malaria)

• Status: Completed
• Trial end date: 2018-02-28
• Target enrollment: 0
• Participant gender: All

Summary

The main determinant of primaquine efficacy is the total dose of primaquine administered, rather than the dosing schedule. Previous trials have demonstrated that the standard low dose regimen of primaquine (3.5 mg/kg total) fails to prevent relapses in many different endemic locations. For this reason the 2010 WHO antimalarial guidelines now recommend a high dose regimen of 7 mg/kg (equivalent to an adult dose of 30mg per day), although many countries still recommend lower doses for fear of causing more serious harm to unscreened G6PDd patients.

Shorter courses of higher daily doses of primaquine have the potential to improve adherence and thus effectiveness without compromising efficacy. Primaquine also has relatively weak but clinically relevant asexual stage activity against P. vivax so larger daily doses may substantially augment chloroquine's blood stage activity at low levels of resistance. In Thailand directly observed primaquine (1mg/kg/day) administered over 7 days was well tolerated and reduced relapses by day 28 to 4%. This is encouraging but not definitive since many relapses present after one month. Longer follow-up is needed to distinguish whether relapse was prevented or deferred. If the efficacy, tolerability and safety of short-course, high-dose primaquine regimens can be assured across the range of endemic settings, along with reliable point-of-care G6PDd diagnostics, then this new primaquine regimen would be a major advance in malaria treatment improving adherence to and thus the effectiveness of anti-relapse therapy.

Due to the long duration of standard primaquine treatment regimens, courses are difficult to supervise, are poorly adhered to and lack effectiveness. This proposed multicentre randomised clinical trial will provide evidence across a variety of endemic settings on the safety and efficacy of high dose-short course primaquine in G6PD normal patients. In a parallel single arm study the investigators will also gather safety data on the use of weekly primaquine in patients with G6PDd. This study aims to generate evidence that will directly inform global public health policy for the radical cure of P. vivax. A better understanding of the risks and benefits of primaquine is crucial in persuading policy makers and clinicians of the importance of the radical cure of vivax malaria that will reduce the parasite reservoir and decrease transmission.

The funder is Medical Research Council, UK. Grant number: MRC Reference: MR/K007424/1

• Phase: N/A
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Oxford
• Collaborator: Menzies School of Health Research
• Treatments: Primaquine

Criteria

Inclusion Criteria:

• Participant (or parent/guardian of children below age of consent) is willing and able to give written informed consent to participate in the trial; verbal consent in the presence of a literate witness is required for illiterate patients. In addition, written assent (or verbal assent in the presence of a literate witness for illiterates) from children 12 to 17 years as per local practice.

• Monoinfection with P. vivax of any parasitaemia in countries which use Chloroquine (CQ) as blood schizontocidal therapy. Mixed infections with P. vivax and P. falciparum can be enrolled in countries which use an artemisinin combination therapy.

• Diagnosis based on rapid diagnostic tests.

• Over 6 months of age.

• Weight 5 kg or greater.

• Fever (axillary temperature 37.5 degrees C) or history of fever in the last 48 hours.

• Able, in the investigators opinion, and willing to comply with the study requirements and follow-up.

Exclusion Criteria:

• Female participant who is pregnant, lactating or planning pregnancy during the course of the study.

• Inability to tolerate oral treatment.

• Previous episode of haemolysis or severe haemoglobinuria following primaquine

• Signs/symptoms indicative of severe/complicated malaria or warning signs requiring parenteral treatment- Haemoglobin concentration less than 9 g/dL

• Known hypersensitivity or allergy to the study drugs

• Blood transfusion in last 90 days, since this can mask G6PD deficient status

• A febrile condition due to diseases other than malaria (e.g. measles, acute lower respiratory tract infection, severe diarrhoea with dehydration)

• Presence of any condition which in the judgment of the investigator would place the participant at undue risk or interfere with the results of the study (e.g. serious underlying cardiac, renal or hepatic disease; severe malnutrition; HIV/AIDS; or severe febrile condition other than malaria); coadministration of other medication known to cause haemolysis or that could interfere with the assessment of antimalarial regimens.

• Currently taking medication known to interfere significantly with the pharmacokinetics of primaquine and the schizontocidal study drugs.

• Prior antimalarial medications in the previous 7 days.