IMPROV (Improving the Radical Cure of Vivax Malaria)

NCT01814683 | Completed DMC

• 1 other identifier: BAKMAL 1301
• Study Type: interventional
• Target: 2,388
• Locations: 4 countries
• Sites: 8

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

Conditions

Uncomplicated Vivax Malaria

Keywords

Vivax malaria; Primaquine; Placebo; Recurrence

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• The incidence rate (per person-year) of any recurrent P. vivax malaria.

  12 months

• Incidence risk of any recurrent symptomatic of P. vivax malaria compared to control arm

  12 months

• The Haematological recovery in patients with vivax malaria

  12 months

• Proportion of patients with Serious Adverse Drug reactions

  12 months

• Primaquine tolerability

  14 days

Study Arms (3)

Primaquine 7 day

EXPERIMENTAL

Standard blood schizontocidal therapy plus 7 days of supervised primaquine (7mg/kg total dose) administered once per day (1.0 mg/kg OD) followed by 7 days of placebo.

Drug: Primaquine

Placebo controlled arm

PLACEBO COMPARATOR

Standard blood schizontocidal therapy plus 14 days placebo.

Drug: Placebo

Primaquine 14 day

ACTIVE COMPARATOR

Standard blood schizontocidal therapy plus 14 days of supervised primaquine (7mg/kg total dose) administered once per day (0.5 mg/kg).

Drug: Primaquine

Interventions

Primaquine DRUG

14 days of supervised primaquine (7mg/kg total dose) administered once per day (0.5 mg/kg).

Primaquine 14 day

Placebo DRUG

14 days placebo.

Placebo controlled arm

Eligibility Criteria

• Age: 6 Months+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Oxford: lead
• Menzies School of Health Research: collaborator

Study Sites (8)

Provincial Malaria & Leishmania control program (PMLCP) Nangarhar

Jalalabad, Nangarhar, Afghanistan

Location

Laghman Provincial Hospital

Laghmān, Afghanistan

Location

Metahara Sugar Factory Hospital

Metehara, Oromiya, Ethiopia

Location

Arba Minch Hospital

Ārba Minch, Snnpr, Ethiopia

Location

Hanura Health Center

Bandar Lampung, Lampung, Indonesia

Location

Tanjong Leidong District Health Center

Medan, North Sumatra, 20156, Indonesia

Location

Dak O and Bu Gia Map Health Communes

Bình Phước, Binh Phuoc Province, Vietnam

Location

Krong Pa Hospital

Krông Pa, Gia Lai, Vietnam

Location

Related Publications (4)

• 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.

  PMID: 31327563 BACKGROUND

• Taylor WRJ, Meagher N, Ley B, Thriemer K, Bancone G, Satyagraha A, Assefa A, Chand K, Chau NH, Dhorda M, Degaga TS, Ekawati LL, Hailu A, Hasanzai MA, Naddim MN, Pasaribu AP, Rahim AG, Sutanto I, Thanh NV, Tuyet-Trinh NT, Waithira N, Woyessa A, Dondorp A, von Seidlein L, Simpson JA, White NJ, Baird JK, Day NP, Price RN. Weekly primaquine for radical cure of patients with Plasmodium vivax malaria and glucose-6-phosphate dehydrogenase deficiency. PLoS Negl Trop Dis. 2023 Sep 6;17(9):e0011522. doi: 10.1371/journal.pntd.0011522. eCollection 2023 Sep.

  PMID: 37672548 DERIVED

• Thriemer K, Commons RJ, Rajasekhar M, Degaga TS, Chand K, Chau NH, Assefa A, Naddim MN, Pasaribu AP, Rahim AG, Sutanto I, Hien TT, Hailu A, Hasanzai MA, Ekawati LL, Woyessa A, Teferi T, Waithira N, Taylor WRJ, Ley B, Dondorp A, Baird JK, White NJ, Day NP, Price RN, Simpson JA, von Seidlein L. The heterogeneity of symptom reporting across study sites: a secondary analysis of a randomised placebo-controlled multicentre antimalarial trial. BMC Med Res Methodol. 2023 Sep 4;23(1):198. doi: 10.1186/s12874-023-02022-3.

  PMID: 37667204 DERIVED

• 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.

  PMID: 26643116 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Malaria, Vivax; Recurrence

Interventions

Primaquine

Condition Hierarchy (Ancestors)

Malaria; Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Ric Price, FRCP

  University of Oxford

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 18, 2013
• First Posted: March 20, 2013
• Study Start: July 1, 2014
• Primary Completion: February 28, 2018
• Study Completion: February 28, 2018
• Last Updated: September 17, 2019

Record last verified: 2018-07

Locations

AF (2); VN (2); ID (2); ET (2)