Clinical trial NCT01814683: IMPROV (Improving the Radical Cure of Vivax Malaria)
Official title: Improving the Radical Cure of Vivax Malaria: A Multicentre Randomised Comparison of Short and Long Course Primaquine Regimens
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Uncomplicated Vivax Malaria
Keywords: Vivax malaria
Primaquine
Placebo
Recurrence
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Menzies School of Health Research
First posted: 2013-03-20
Enrollment: 2388
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

Detailed description: Plasmodium vivax malaria is a major cause of morbidity and now recognised as an important contributor to mortality in endemic areas. Unlike P. falciparum malaria, P. vivax infections form dormant liver stages (hypnozoites) which cause relapses of the infection weeks to months after the initial attack for up to about 2 years. Relapse rates in South-East Asia commonly exceed 50%, often making relapse the main cause of vivax illness. Repeated relapse is particularly damaging to the health and development of children in vivax endemic areas. The first line treatment of vivax malaria is a combination of chloroquine (providing blood schizontocidal activity), and primaquine (providing liver hypnozoitocidal activity). However chloroquine resistance is increasing in many vivax endemic areas and adherence to 14 day primaquine regimens is very poor. This is a major threat to current malaria control and elimination initiatives. Primaquine, an 8 aminoquinoline, is currently the only licensed drug with activity against hypnozoites. An important constraint on the global deployment of primaquine is its potential to cause haemolysis in patients with glucose-6-phosphate dehydrogenase deficiency (G6PDd), which typically occurs in 2-15% (and up to 40%) of patients in endemic zones. Individuals who have less than 10% of normal enzyme activity are at risk of life-threatening haemolysis whereas those with milder variants may have negligible effects. In practice the lack of available robust diagnostics for G6PDd, concerns over drug toxicity, and the misperceived benign nature of P. vivax infection results in healthcare providers rarely prescribing primaquine even when recommended in policy.

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.

The radical cure of P. vivax in patients with known G6PDd is challenging. Current WHO guidelines recommend a weekly dose of 0.75 mg/kg for 8 weeks which mitigates primaquine-induced haemolysis whilst retaining efficacy. The weekly dosing schedule was derived from studies in the USA in a small number of healthy adults with the mildly primaquine-sensitive African A- G6PDd variant. Since host vulnerability to haemolysis varies between the over 100 different G6PDd variants, the available evidence is inadequate to ensure the universal safety of a 0.75mg/kg dose either as a single dose, as advocated for reducing the transmission of falciparum malaria, or a weekly dose for the radical cure of vivax malaria.

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.

RESULTS:

The incidence rate of symptomatic recurrent P. vivax malaria was 0.18 (95% CI, 0.15 to 0.21) episodes PPY following PQ7, 0.16 (95% CI, 0.13 to 0.18) PPY following PQ14 and 0.96 (95% CI, 0.83 to 1.08) PPY in the control arm

The incidence rate of both symptomatic and asymptomatic recurrent vivax malaria at 1 year was 0.23 (95%CI, 0.19 to 0.27) episodes PPY following PQ7 and 0.19 (95% CI: 0.16 to 0.23) episodes PPY following PQ14 (p=0.208)

In the time to first event analysis, the cumulative risk of symptomatic P. vivax at 1 year was 14.28% (95%CI, 11.75 to 17.29) after PQ7 and 12.72% (95%CI, 10.19 to 15.82) after PQ14 (p=0.197), both significantly lower than 48.73% (95%CI, 43.40 to 54.36) in the control arm (HR=0.18 \[95%CI, 0.13 to 0.26; p\<0.001\] and HR=0.14 \[95%CI, 0.09 to 0.22; p\<0.001\], respectively)

There were 27 SAEs: 18 (1.9%) in the PQ7 arm, 5 (0.5%) in the PQ14 arm and 4 (0.9%) in the control arm. Ten of these SAEs occurred within 42 days and were considered study drug related: 1.0% (9/935, PQ7), 0.1% (1/937, PQ14) (p=0.001) and none (0/464) in the control arm.

Eligibility 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.

Primary outcomes:
measure: Incidence rate (per person-year) of symptomatic recurrent P. vivax
timeFrame: 12 months
Secondary outcomes:
measure: The incidence rate (per person-year) of any recurrent P. vivax malaria.
timeFrame: 12 months
measure: Incidence risk of any recurrent symptomatic of P. vivax malaria compared to control arm
timeFrame: 12 months
measure: The Haematological recovery in patients with vivax malaria
timeFrame: 12 months
measure: Proportion of patients with Serious Adverse Drug reactions
timeFrame: 12 months
measure: Primaquine tolerability
timeFrame: 14 days
measure: Primaquine tolerability comparison between patients in intervention arm and control arm
timeFrame: 14 days
measure: Incidence risk of severe anaemia in G6PD deficient arm
timeFrame: 14 days
measure: Cost effective analysis in the management of P. vivax with respect to the use of G6PD tests
timeFrame: 12 months
Other outcomes:
Locations:
city: Jalalabad
country: Afghanistan
facility: Provincial Malaria & Leishmania control program (PMLCP) Nangarhar
state: Nangarhar
city: Laghman
country: Afghanistan
facility: Laghman Provincial Hospital
city: Metahāra
country: Ethiopia
facility: Metahara Sugar Factory Hospital
state: Oromia
city: Ārba Minch
country: Ethiopia
facility: Arba Minch Hospital
state: Snnpr
city: Bandar Lampung
country: Indonesia
facility: Hanura Health Center
state: Lampung
city: Medan
country: Indonesia
facility: Tanjong Leidong District Health Center
state: North Sumatra
city: Binh Phuoc
country: Vietnam
facility: Dak O and Bu Gia Map Health Communes
state: Binh Phuoc Province
city: Krông Pa
country: Vietnam
facility: Krong Pa Hospital
state: Gia Lai
Study officials:
affiliation: University of Oxford
name: Ric Price, FRCP
role: PRINCIPAL_INVESTIGATOR
References:
citation: Taylor WRJ, Thriemer K, von Seidlein L, Yuentrakul P, Assawariyathipat T, Assefa A, Auburn S, Chand K, Chau NH, Cheah PY, Dong LT, Dhorda M, Degaga TS, Devine A, Ekawati LL, Fahmi F, Hailu A, Hasanzai MA, Hien TT, Khu H, Ley B, Lubell Y, Marfurt J, Mohammad H, Moore KA, Naddim MN, Pasaribu AP, Pasaribu S, Promnarate C, Rahim AG, Sirithiranont P, Solomon H, Sudoyo H, Sutanto I, Thanh NV, Tuyet-Trinh NT, Waithira N, Woyessa A, Yamin FY, Dondorp A, Simpson JA, Baird JK, White NJ, Day NP, Price RN. Short-course primaquine for the radical cure of Plasmodium vivax malaria: a multicentre, randomised, placebo-controlled non-inferiority trial. Lancet. 2019 Sep 14;394(10202):929-938. doi: 10.1016/S0140-6736(19)31285-1. Epub 2019 Jul 18.
citation: IMPROV Study Group. Improving the radical cure of vivax malaria (IMPROV): a study protocol for a multicentre randomised, placebo-controlled comparison of short and long course primaquine regimens. BMC Infect Dis. 2015 Dec 7;15:558. doi: 10.1186/s12879-015-1276-2.