Uncomplicated Vivax Malaria Clinical Trial
Official title:
Improving the Radical Cure of Vivax Malaria: A Multicentre Randomised Comparison of Short and Long Course Primaquine Regimens
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
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.
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