Radical cure for vivax malaria in Indonesia 2
| ISRCTN | ISRCTN82366390 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN82366390 |
| Secondary identifying numbers | Vivax-primaquine-ACT-AS/EOCRU.2012.002 |
- Submission date
- 09/03/2013
- Registration date
- 20/03/2013
- Last edited
- 16/12/2015
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Infections and Infestations
Plain English summary of protocol
Background and study aims
This study aims to measure the efficacy of primaquine against relapse when administered with one of two ACT therapies likely to replace chloroquine as the companion blood schizontocide with primaquine for radical cure of vivax malaria. The study also examines safety and tolerability of these therapies.
The findings will assess current first line therapy, will guide rational decisions about new first-line therapies and will inform strategy concerning the development of new pairs of therapies for radical cure of vivax malaria in Indonesia.
Who can participate?
180 participants from Indonesian Army Batallion 408 Sragen, East Java, Indonesia, returning from 6 months deployment at Papua, who have vivax malaria based on microscopic examination, will participate
What does the study involve?
All study participants are asked to stay on the base for at least 28 days. They are randomly allocated to one of three treatments: (i) artesunate first followed by primaquine (AS+PQ), (ii) Pyronaridine Tetraphosphate-Artesunate combined with primaquine (PYR-AS) or (iii) Dihydroartemisinin-Piperaquine Phosphate (DHA-PQP) plus primaquine. The follow up will be for one year. The participants will be closely observed by routine clinical and laboratory investigations including the measurement and recording of vital signs, complete blood counts, and blood chemistries, along with measurement of peripheral blood methaemoglobin level and also ECG examinations. The total amount of blood taken is about 150 ml from 9 blood draws and 20 finger pricks.
What are the possible benefits and risks of participating?
There are two main risks in this study: drug toxicity and the risk of a recurrent bout of malaria. In general, these drugs are well tolerated, although in some cases adverse reaction could occur. This study will provide on-site clinic for 24 hours and 7 days a week. If participants have recurrent malaria, they will receive immediate standard therapy. The main benefit is that all participants will be given safe and effective drugs and will be closely monitored for safety until completely recovered and well beyond.
Where is the study run from?
This study is run by the Faculty of Medicine University of Indonesia, Eijkman Institute for Molecular Biology in Jakarta, the Eijkman Oxford Clinical Research Unit and the Indonesian Army Medical Corps.
When is the study starting and how long is it expected to run for?
March 2013 to July 2014.
Who is funding the study?
This study is sponsored by the ALERTAsia Foundation (Indonesia) and funded by Medicines for Malaria Venture (Switzerland)
Who is the main contact?
Dr Erni Juwita Nelwan
erni.juwita@ui.ac.id
Contact information
Scientific
Department of Internal Medicine
Faculty of Medicine
University of Indonesia
Jl. Salemba No. 6
Jakarta
10430
Indonesia
| erni.juwita@ui.ac.id |
Study information
| Study design | Single-center randomized open-label clinical trial of primaquine efficacy against relapse |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Other |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details below to request a patient information sheet |
| Scientific title | Randomized, open-label trial of the safety, tolerability and efficacy of primaquine against relapse when combined with pyronaridine tetraphosphate-artesunate or dihydroartemisinin-piperquine phosphate for radical cure of acute Plasmodium vivax malaria in soldiers |
| Study objectives | The first treatment arm, AS+PQ administered consecutively, will test the hypothesis that primaquine administered after a rapidly excreted blood schizontocide may offer protection against relapse. |
| Ethics approval(s) | 1. Medical Research Ethics Committee of Faculty of Medicine, University of Indonesia, 14/01/2013, ref: 13/H2.F1/ETIK/2013 2. Medical Research Ethics Committee of Faculty of Medicine, University of Indonesia, Amendment Approval of Protocol v3 dated 11/03/2013, No. 247/H2.F1/ETIK/III/2013 2. OXTREC Approval of Protocol v3 dated 15/03/2013 |
| Health condition(s) or problem(s) studied | Malaria |
| Intervention | 1. AS+PQ= One tablet of artesunate contains 50 mg base. Artesunate alone will use the same artesunate tablet from co-blister of Arsuamoon™ used by Ind MoH for malaria therapy. Arsuamoon™ manufactured by Guilin Pharmaceutical, China. This will be administered on days 0-6 (200 mg day 0; 100 mg days 1-6). After a 48hr pause, 0.5 mg/kg primaquine in tablets containing 26.3 mg of primaquine phosphate (15 mg base) daily for days 8 to 21. Primaquine manufactured by Sanofi, France. 2. PYR-AS+PQ=One tablet of PYR-AS contains 180 mg of pyronaridine tetraphosphate & 60 mg artesunate. Dosing is daily for 3 days and by weight per EMA recommendations: - 24 kg to <45 kg - 2 tablets - > 45 kg to <65 kg - 3 tablets - >65 kg - 4 tablets The target doses are 7.2 to 13.8 mg/kg PYR and 2.4 to 4.6 mg/kg AS. These tablets (Pyramax™) will be supplied by the manufacturer, Shin Poong Pharmaceuticals (South Korea). This will be administered on days 0-2 concurrently with 0.5 mg/kg primaquine in tablets containing 26.3 mg of primaquine phosphate (15 mg base) daily for days 0 to 13. Primaquine manufactured by Sanofi, France. 3. DHA-PQP+PQ=One tablet of DHA-PQP contains 40 mg of DHA and 320 mg of PQP. Dosing is daily and by weight: - < 75 kg - 3 tablets - ≥ 75 kg - 4 tablets These tablets ((Eurartesim™) will be supplied by the manufacturer, Sigma Tau (Italy). This will be administered on days 0-2 concurrently with 0.5 mg/kg primaquine in tablets containing 26.3 mg of primaquine phosphate (15 mg base) daily for days 0 to 13. Primaquine manufactured by Sanofi, France. Follow up was for 365 days, counting the first day of study drug administration as Day 0. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Primaquine, Pyronaridine Tetraphosphate-Artesunate, Dihydroartemisinin-Piperquine Phosphate |
| Primary outcome measure | To obtain independent, high precision estimates of the efficacy of standard primaquine therapy when combined with PYR-AS or DHA-PQP for radical cure of acute malaria caused by P. vivax. Efficacy of relapse is calculated as: (natural relapse rate - relapse rate post-PQ) / natural relapse rate x 100% Measured by following up for 365 days, counting the first day of study drug administration as Day 0 |
| Secondary outcome measures | Measure the efficacy of the blood schizontocides against acute vivax malaria, documenting safety and pharmacokinetic characteristics of the drug regimens, and their tolerability through monitoring adverse events. Measured by following up for 365 days, counting the first day of study drug administration as Day 0 |
| Overall study start date | 28/03/2013 |
| Completion date | 01/07/2014 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Male |
| Target number of participants | 60 participants per arm, total 180 participants. |
| Key inclusion criteria | 1. Age 18 years or older, but younger than 65 years 2. Travelled for >1 month to northeastern Papua within the past 12 months 3. Body weight >40 kg and ≤ 90 kg 4. A diagnosis of P. vivax parasitemia, mono- or mixed-species infection of any density and confirmed by a second microscopist 5. Written informed consent provided by participants 6. Glucose-6-phosphate dehydrogenase (G6PD) normal using the NADPH qualitative fluorescent spot test (Trinity Biologicals, USA) 7. Able to swallow oral medication |
| Key exclusion criteria | 1. Patient confirmed as having Plasmodium falciparum mono infection 2. Patient requires hospitalization for any reasons 3. Haemoglobin <7 g/dL. 4. G6PD deficient according to NADPH spot test 5. Definite plans for an absence of 5 consecutive days or more from the base within 28 days of being enrolled, if the destination of travel exceeds 100km from the study site. 6. Known history of clinically significant disorders, such as: 6.1. Cardiovascular 6.2. Respiratory including active tuberculosis 6.3. Hepatic 6.4. Renal 6.5. Gastrointestinal 6.6. Immunological 6.7. Neurological, including hearing impairment 6.8. Endocrine 6.9. Infectious 6.10. Malignancy 6.11. Psychiatric 6.12. Recent head trauma 6.13. Any other clinically significant finding that the investigator judges will place the patient at risk or interfere with the study results. 7. Laboratory evidence of clinically significant disorders, such as: 7.1. A corrected QT interval (QTc) >450 ms*. 7.2. Active Hepatitis A, e.g. by detection of anti HAV-IgM. 7.3. Hepatitis B surface antigen (HBsAg) carrier. 7.4. Hepatitis C antibody (HCV Ab). 7.5. Liver function tests (AST/ALT levels) more than 2.5 times the upper limit of normal range. 7.6. Renal impairment as indicated by abnormal creatinine clearance of <60 ml/min, measured using Cockcroft-Gault formula. 8. Known history of hypersensitivity, allergy or adverse reactions to primaquine, artesunate, dihydroartemisinin (DHA), pyronaridine or other artemisinins. 9. Previous participation in the present clinical trial, i.e., subjects experiencing relapse may not be enrolled and randomized as a new subject. 10. Have received any investigational drug within the past 4 weeks. 11. Anyone of the following contra indications of DHA-PQP, such as: 11.1. Family history of sudden unexplained death. 11.2. Known congenital QTc prolongation. 11.3. Known presence of a medical condition known to prolong the QT interval: myxoedema, cardiomyopathies, recent myocardial infarction. 11.4. History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia. 11.5. Cardiac illnesses predisposing to arrythmias e.g. hypertension, left ventricular hypertrophy, cardiomyopathies, cardiac failure with reduced ejection fraction. 11.6. Presence of an electrolyte disturbance particularly hypokalaemia, hypocalcaemia, hypomagnesaemia. 11.7. On any drug known to prolong the QTc interval, including: 11.7.1. Antiarrhythmics (e.g. amiodarone, disopyramide, dofetilide, ibutilide, procainamide, quinidine, hydroquinidine, sotalol). 11.7.2. Neuroleptics (e.g. phenothiazines, sertindole, sultopride, chlorpromazine, haloperidol, mesoridazine, pimozide, or thioridazine) and antidepressive agents. 11.7.3. Certain antimicrobial agents, including agents of the following classes: macrolides (e.g. erythromycin, clarithromycin), fluoroquinolones (e.g. moxifloxacin, sparfloxacin), imidazole and triazole antifungal agents and also pentamidine and saquinavir. 12. Recent treatment with medicinal products known to prolong the QTc interval that may still be circulating at the time that Eurartesim is commenced (e.g. mefloquine, halofantrine, lumefantrine, chloroquine, quinine and other antimalarial agents) taking into account their elimination half-life. * We will use the Fridericia formula (QTcF=QR/(RR)0.3 or Bazetts formula (QTcF=QR/(RR)0.5 whichever is lower. |
| Date of first enrolment | 28/03/2013 |
| Date of final enrolment | 01/07/2013 |
Locations
Countries of recruitment
- Indonesia
Study participating centre
10430
Indonesia
Sponsor information
Research organisation
c/o Dr. Claudia Surjadjaja
Jl. Diponegoro No. 69
Jakarta
10430
Indonesia
| claudia@alertasia.org | |
"ROR" |
https://ror.org/04fhhgs91 |
Funders
Funder type
Research organisation
Private sector organisation / Other non-profit organizations
- Alternative name(s)
- MMV
- Location
- Switzerland
Results and Publications
| Intention to publish date | |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not provided at time of registration |
| Publication and dissemination plan | Not provided at time of registration |
| IPD sharing plan |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | results | 11/12/2015 | Yes | No |
Editorial Notes
On 12/01/2015 the following changes were made to the trial record:
1. The overall trial start date was changed from 18/03/2013 to 28/03/2013.
2. The overall trial end date was changed from 30/08/2014 to 01/07/2014.
