Plain English Summary
Background and study aims:
Malaria is an infectious disease which is common in tropical and subtropical countries, caused by a microscopic parasite which is spread from person to person by mosquitos. It can be serious disease if it is not treated quickly and effectively. One type, called vivax malaria, can hide in the liver and reenter the blood to cause repeated illness (relapse). Repeated relapse is particularly damaging to the health and development of children. The usual medicines given for vivax malaria can only kill the parasites in the blood. There is one medicine, called primaquine, which can be taken to kill the vivax malaria parasite in the liver and so will reduce the risk of relapses. Some individuals may have weak red cells. Red cells need enzymes to work properly and weak red cells have low amounts of an enzyme called glucose 6 phosphate dehydrogenase (G6PD). People with G6PD deficiency (G6PDd) can be at risk if they take primaquine because it can destroy their red cells. This study aims to find out how best to use primaquine in patients with normal or weak (G6PD deficient) red cells so that we can introduce better treatments for vivax malaria around the world.
Who can participate?
Patients presenting to a participating treatment centre with uncomplicated vivax malaria are eligible to enrol provided they are over 6 months of age, not pregnant, and not suffering from any other medical condition.
What does the study involve?
Participants are randomly allocated to one of three groups. Participants in all groups undertake standard antimalarial treatment (in pill form) as per standard practice in their country. In addition, those in the first group receive 14 days treatment of low dose primaquine ). Those in the second group receive seven days treatment of high dose primaquine followed by seven days of placebo (dummy pill). Those in the third group receive 14 days treatment with a placebo (dummy pill). Patients in all groups are followed up daily for two weeks, then weekly until week 8, and then monthly until 12 months to see if their malaria has come back.
What are the possible benefits and risks of participating?
All patients benefit from receiving treatment against vivax malaria. Patients also receive the results of their G6PD test which can be useful to them if they need malaria treatment in the future. The main potential risks are side-effects from primaquine but patients are tested for G6PDd, enrolled to a different treatment if found to have G6PDd and monitored closely.
Where is the study run from?
The study is run by Oxford University (UK) and takes place in health centres in Vietnam, Indonesia and Afghanistan
When is study starting and how long is it expected to run for?
January 2013 to December 2017
Who is funding the study?
1. Medical Research Council (UK)
2. Bill and Melinda Gates Foundation (USA)
Who is the main contact?
Professor Ric Price
rprice@menzies.edu.au
Trial website
Contact information
Type
Scientific
Primary contact
Prof Ric Price
ORCID ID
http://orcid.org/0000-0003-2000-2874
Contact details
Centre for Tropical Medicine and Global Health
Nuffield Department of Medicine
University of Oxford
Old Road Campus
Roosevelt Drive
Oxford
OX3 7FZ
United Kingdom
Additional identifiers
EudraCT number
ClinicalTrials.gov number
NCT01814683
Protocol/serial number
MR/K007424/1
Study information
Scientific title
Improving the Radical Cure of Vivax Malaria: A Multicentre Randomised Comparison of Short and Long Course Primaquine Regimen (IMPROV)
Acronym
IMPROV
Study hypothesis
Due to the long duration of standard primaquine treatment regimens, courses are difficult to supervise, are poorly adhered to and lack effectiveness. Our 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.
Ethics approval
1. Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (HREC), 16/06/2013, ref: 2013-1991
2. Oxford Tropical Research Ethics Committee (OxTREC), 04/06/2013, ref: 1014-13
Study design
Double-blind three-arm randomised controlled trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Condition
P. vivax malaria
Intervention
Patients will be randomly assigned to one of the three treatment arms below:
Intervention group 1: Standard blood schizonticidal therapy plus 14 days of supervised primaquine (7mg/kg total dose) administered once per day (0.5 mg/kg) orally
Intervention group 2: Standard blood schizonticidal 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 orally
Control group: Standard blood schizintocidal therapy plus 14 days placebo orally
The schizintocidal consists of Chloroquine in Vietnam and Afghanistan, and Dihydroartemisinin-piperaquine in Indonesia.
For all study arms, follow up is daily for 2 weeks, then weekly till week 8 and then monthly until 12 months.
Intervention type
Drug
Phase
Not Applicable
Drug names
1. Chloroquine
2. DHA-piperaquine plus primaquine
Primary outcome measure
1. Incidence rate (per person-year) of symptomatic recurrent P. vivax is measured within 12 months
2. Incidence rate (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
Secondary outcome measures
1. The incidence rate (per person-year) of any recurrent P. vivax malaria is measured at 12 months
2. 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
3. Incidence risk of any recurrent symptomatic of P. vivax malaria compared to control arm is measured at 12 months
4. 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
5. The Haematological recovery in patients with vivax malaria 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
6. Proportion of patients with Serious Adverse Drug reactions is measured within 42 days of primary treatment, 6 and 12 months
7. 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 within 12 months
8. Drug tolerability will be assessed by comparing the proportion of patients completing a full course of observed primaquine therapy within 12 months
9. Incidence risk of severe anaemia in G6PD deficient arm 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
10. Cost effective analysis in the management of P. vivax with respect to the use of G6PD tests, the dosing schedule and the epidemiological context will be conducted at 12 months
Overall trial start date
01/01/2013
Overall trial end date
31/12/2017
Reason abandoned (if study stopped)
Eligibility
Participant 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.
1. 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
2. Diagnosis based on rapid diagnostic tests
3. Over 6 months of age
4. Weight 5 kg or greater
5. Fever (axillary temperature 37.5 degrees C) or history of fever in the last 48 hours
6. Able, in the investigators opinion, and willing to comply with the study requirements and follow-up
Participant type
Patient
Age group
Mixed
Gender
Both
Target number of participants
1875
Participant exclusion criteria
1. Female participant who is pregnant, lactating or planning pregnancy during the course of the study
2. Inability to tolerate oral treatment
3. Previous episode of haemolysis or severe haemoglobinuria following primaquine
4. Signs/symptoms indicative of severe/complicated malaria or warning signs requiring parenteral treatment- Haemoglobin concentration less than 9 g/dL
5. Known hypersensitivity or allergy to the study drugs
6. Blood transfusion in last 90 days, since this can mask G6PD deficient status
7. A febrile condition due to diseases other than malaria (e.g. measles, acute lower respiratory tract infection, severe diarrhoea with dehydration)
8. 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
9. Currently taking medication known to interfere significantly with the pharmacokinetics of primaquine and the schizontocidal study drugs
10. Prior antimalarial medications in the previous 7 days
Recruitment start date
01/07/2014
Recruitment end date
31/12/2016
Locations
Countries of recruitment
Afghanistan, Ethiopia, Indonesia, Viet Nam
Trial participating centre
Health Protection and Research Organisation (HPRO)
Laghman
1001
Afghanistan
Trial participating centre
Health Care and Social Development Organization (HSDO)
Jalalabad
2601
Afghanistan
Trial participating centre
Hanura Health Center
Lampung
35451
Indonesia
Trial participating centre
Tanjong Leidong District Health Center
Medan
20231
Indonesia
Trial participating centre
Dak O Health Commune
830000
Viet Nam
Trial participating centre
Bu Gia Map Health Commune
830000
Viet Nam
Trial participating centre
Krong Pa Health Commune
600000
Viet Nam
Sponsor information
Organisation
Oxford University
Sponsor details
NDM Research Building
Nuffield Department of Medicine
University of Oxford
Old Road Campus
Roosevelt Drive
Headington
Oxford
OX3 7FZ
United Kingdom
Sponsor type
University/education
Website
Organisation
Menzies School of Health Research
Sponsor details
PO Box 41096
Casuarina NT
0811
Australia
Sponsor type
Research organisation
Website
Funders
Funder type
Research council
Funder name
Medical Research Council
Alternative name(s)
MRC
Funding Body Type
government organisation
Funding Body Subtype
Federal/National Government
Location
United Kingdom
Funder name
Bill and Melinda Gates Foundation
Alternative name(s)
Bill & Melinda Gates Foundation
Funding Body Type
private sector organisation
Funding Body Subtype
foundation
Location
United States of America
Results and Publications
Publication and dissemination plan
Primary and secondary publications will be published in peer reviewed journals from June 2018.
Intention to publish date
30/06/2018
Participant level data
Stored in repository
Basic results (scientific)
Publication list
2015 protocol in http://www.ncbi.nlm.nih.gov/pubmed/26643116