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
| NCT number | NCT01814683 |
| Other study ID # | BAKMAL 1301 |
| Secondary ID | |
| Status | Completed |
| Phase | N/A |
| First received | |
| Last updated | |
| Start date | July 2014 |
| Est. completion date | February 28, 2018 |
| Verified date | July 2018 |
| Source | University of Oxford |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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
| Status | Completed |
| Enrollment | 2388 |
| Est. completion date | February 28, 2018 |
| Est. primary completion date | February 28, 2018 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 6 Months and older |
| Eligibility |
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. |
| Country | Name | City | State |
|---|---|---|---|
| Afghanistan | Provincial Malaria & Leishmania control program (PMLCP) Nangarhar | Jalalabad | Nangarhar |
| Afghanistan | Laghman Provincial Hospital | Laghman | |
| Ethiopia | Arba Minch Hospital | Arba Minch | Snnpr |
| Ethiopia | Metahara Sugar Factory Hospital | Metahara | Oromia |
| Indonesia | Hanura Health Center | Bandar Lampung | Lampung |
| Indonesia | Tanjong Leidong District Health Center | Medan | North Sumatra |
| Vietnam | Dak O and Bu Gia Map Health Communes | Binh Phuoc | Binh Phuoc Province |
| Vietnam | Krong Pa Hospital | Krông Pa | Gia Lai |
| Lead Sponsor | Collaborator |
|---|---|
| University of Oxford | Menzies School of Health Research |
Afghanistan, Ethiopia, Indonesia, Vietnam,
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 Jul 18. pii: S0140-6736(19)31285-1. doi: 10.1016/S0140-6736(19)31285-1. [Epub ahead of print] — View Citation
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Incidence rate (per person-year) of symptomatic recurrent P. vivax | The incidence rate (i.e. per person-year) of symptomatic recurrent P. vivax parasitaemia (detected by microscopy) over 12 months of follow-up in the 7 versus 14-day primaquine groups for all sites combined and stratified by site. | 12 months | |
| Secondary | The incidence rate (per person-year) of any recurrent P. vivax malaria. | 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. | 12 months | |
| Secondary | Incidence risk of any recurrent symptomatic of P. vivax malaria compared to control arm | 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. | 12 months | |
| Secondary | The Haematological recovery in patients with vivax malaria | 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. | 12 months | |
| Secondary | Proportion of patients with Serious Adverse Drug reactions | 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. | 12 months | |
| Secondary | Primaquine tolerability | 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. | 14 days | |
| Secondary | Primaquine tolerability comparison between patients in intervention arm and control arm | 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. | 14 days | |
| Secondary | Incidence risk of severe anaemia in G6PD deficient arm | - 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. | 14 days | |
| Secondary | Cost effective analysis in the management of P. vivax with respect to the use of G6PD tests | 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. | 12 months |