Clinical Trial: IMPROV (Improving the Radical Cure of Vivax Malaria)

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Improving the Radical Cure of Vivax Malaria: A Multicentre Randomised Comparison of Short and Long Course Primaquine Regimens

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

Detailed Summary:

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.
Sponsor: University of Oxford

Current Primary Outcome: Incidence rate (per person-year) of symptomatic recurrent P. vivax [ Time Frame: 12 months ]

Original Primary Outcome: Incidence rate (per person-year) of recurrent P. vivax [ Time Frame: 12 months ]

Current Secondary Outcome:

• The incidence rate (per person-year) of any recurrent P. vivax malaria. [ Time Frame: 12 months ]
  The incidence rate (per person-year) of any recurrent (i.e. symptomatic and asymptomatic) P. vivax parasitaemia over 12 months of follow-up in the 7 and 14-day primaquine regimens for all sites combined and stratified by site.
• Incidence risk of any recurrent symptomatic of P. vivax malaria compared to control arm [ Time Frame: 12 months ]
  The incidence rate (per person-year) of any recurrent symptomatic P. vivax parasitaemia over 12 months of follow-up in either the 7 or the 14-day primaquine regimens compared with the control arm, for all sites combined and stratified by site.
• The Haematological recovery in patients with vivax malaria [ Time Frame: 12 months ]
  Haematological recovery will be assessed as the incidence risk of severe anaemia (Hb<7g/dl) and/or blood transfusion within the 12 month follow up period, and the mean fall in baseline Hb at day 7 and day 14. These outcomes will be compared between the intervention arms and also between each intervention arm and the controls.
• Proportion of patients with Serious Adverse Drug reactions [ Time Frame: 12 months ]
  The proportion of patients with one or more serious adverse drug reactions within 42 days of their primary treatment and also at 6 and 12 months.
• Primaquine tolerability [ Time Frame: 14 days ]
  Tolerability of primaquine will be assessed by comparing the proportion of patients with nausea, vomiting, abdominal pain and vomiting of a dose within 1 hour of administration between the intervention arms and also between each intervention arm and the controls.
• Primaquine tolerability comparison between patients in intervention arm and control arm [ Time Frame: 14 days ]
  Drug tolerability will be assessed also by comparing the proportion of patients completing a full course of observed primaquine therapy between the intervention arms and also between each intervention arm and the controls.
• Incidence risk of severe anaemia in G6PD deficient arm [ Time Frame: 14 days ]
  - The G6PD deficiency treatment arm will provide important data on the safety and tolerability of the WHO recommended weekly regimen. The incidence risk of severe anaemia (Hb<7g/dl) and/or requirement for blood transfusion within the 12 month follow up period and the mean fall in baseline Hb at day 7 and day 14 will be determined.
• Cost effective analysis in the management of P. vivax with respect to the use of G6PD tests [ Time Frame: 12 months ]
  The cost of illness will be compared between the intervention arms and also between each intervention arm and the controls. A cost-effectiveness analysis for the management of P. vivax with respect to the use of G6PD tests, the dosing schedule and the epidemiological context will be conducted.

Original Secondary Outcome:

• The incidence rate (per person-year) of P. vivax malaria in the control arm [ Time Frame: 12 months ]
  The incidence rate (per person-year) of P. vivax malaria over 12 months of follow-up in the 7 and 14-day primaquine regimens compared with the control arm, at each study site.
• Incidence risk of any recurrence of P. vivax malaria compared to control arm [ Time Frame: 12 months ]
  The incidence risk of any recurrence of P. vivax in the 7 and 14-day primaquine regimens compared with the control arm, at each study site.
• The Haematological recovery in patients with vivax malaria [ Time Frame: 12 months ]
  Haematological recovery will be assessed as the incidence risk of severe anaemia (Hb<7g/dl) and/or blood transfusion within the 12 month follow up period, and the mean fall in baseline Hb at day 7 and day 14. These outcomes will be compared between the intervention arms and also between each intervention arm and the controls.
• Proportion of patients with Serious Adverse Drug reactions [ Time Frame: 12 months ]
  The proportion of patients with one or more serious adverse drug reactions within 42 days of their primary treatment and also at 6 and 12 months.
• Primaquine tolerability [ Time Frame: 14 days ]
  Tolerability of primaquine will be assessed by comparing the proportion of patients with nausea, vomiting, abdominal pain and vomiting of a dose within 1 hour of administration between the intervention arms and also between each intervention arm and the controls.
• Primaquine tolerability comparison between patients in intervention arm and control arm [ Time Frame: 14 days ]
  Drug tolerability will be assessed also by comparing the proportion of patients completing a full course of observed primaquine therapy between the intervention arms and also between each intervention arm and the controls.
• Incidence risk of severe anaemia in G6PD deficient arm [ Time Frame: 14 days ]
  - The G6PD deficiency treatment arm will provide important data on the safety and tolerability of the WHO recommended weekly regimen. The incidence risk of severe anaemia (Hb<7g/dl) and/or requirement for blood transfusion within the 12 month follow up period and the mean fall in baseline Hb at day 7 and day 14 will be determined.
• Cost effective analysis in the management of P. vivax with respect to the use of G6PD tests [ Time Frame: 12 months ]
  The cost of illness will be compared between the intervention arms and also between each intervention arm and the controls. A cost-effectiveness analysis for the management of P. vivax with respect to the use of G6PD tests, the dosing schedule and the epidemiological context will be conducted.

Information By: University of Oxford

Dates:
Date Received: March 18, 2013
Date Started: July 2014
Date Completion: December 2019
Last Updated: May 3, 2017
Last Verified: May 2017