Assessing how good a single and low dose of primaquine is at stopping the transmission of falciparum malaria between children and mosquitoes and how primaquine is handled by the body
| ISRCTN | ISRCTN16297951 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN16297951 |
| Secondary identifying numbers | MAL21003, Grant reference: RIA2019PD-2893 |
- Submission date
- 09/07/2021
- Registration date
- 26/07/2021
- Last edited
- 04/09/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Infections and Infestations
Plain English Summary
Background and study aims
Plasmodium falciparum malaria is a parasitic infection transmitted by mosquitoes that causes 400,000 deaths per year, mostly in African children. To complete its life cycle, mosquitoes take up mature male and female forms (gametocytes) from human blood, which mate to produce oocysts. Primaquine is the only drug that kills mature gametocytes. The aim of this study is to assess the effectiveness of a single low dose of pediatric primaquine in children with acute uncomplicated falciparum malaria, adapting the WHO-recommended adult dose (0.25 mg/kg).
Who can participate?
Young children aged 6 months to 5 years with acute uncomplicated Plasmodium falciparum malaria
What does the study involve?
Participants are randomly allocated to receive the standard treatment (artesunate pyronaridine) alone or with primaquine. How well primaquine blocks transmission is assessed by feeding mosquitoes on blood samples and seeing if oocysts are present (failure) or absent (success). By measuring primaquine concentrations, the researchers will see if primaquine is affected by standard treatment.
What are the possible benefits and risks of participating?
Primaquine is generally well tolerated. The main side effects are abdominal pain which is dose-related and improved by taking PQ with food.
The most important side effect is acute hemolytic anaemia (destruction of red blood cells) in individuals with G6PD deficiency (a genetic disorder). Its severity is related to the degree of G6PD deficiency and the primaquine dose. Haemolysis is less severe in the African (A-) G6PD variant compared to the Asian and Mediterranean variants and lower doses of primaquine are used in this study.
Artesunate pyronaridine is usually well tolerated with few patients needing to be withdrawn because of gastrointestinal (digestive system) toxicity. Raised alanine aminotransferase (ALT) and raised bilirubin have been reported but repeat dose studies have not been associated with clinically significant toxicity. The repeated treatments with pyronaridine-artesunate did not increase the specific risks of liver injury. This led to the lifting of the registration label that restricted its use to once only. Hepatotoxicity events (liver damage) with pyronaridine–artesunate were more common in adults than in children younger than 5 years or aged 5 to younger than 18 years, and more common in patients weighing at least 20 kg than in patients less than 20 kg. In a repeated treatment study conducted in Burkina Faso, Mali and Guinea, none of the hepatotoxicity events were associated with any signs or symptoms, required any intervention, or resulted in any consequences. The researchers will monitor patients to detect possible early drug-induced hepatotoxicity.
Blood taking causes discomfort but this tends to be brief. Rarely, a venepuncture or finger stick site may become infected. Full aseptic techniques will be used when taking blood to minimise the infection risk.
Patients who enrol into this study will benefit from the close follow-up by the study doctors of their malaria episode and any other minor illnesses that occur during the follow-up period. Adding primaquine to treatment of malaria and the information obtained will benefit the wider community because if scaled up, primaquine should result in a further reduction in malaria transmission. The patient will be fully taken in charge of by the study for the period of admission in the health centre and money will provided to pay for transport for the follow-up visits. No other payments will be made. The researchers will compensate legal guardians for their time; this will be 5000 FCFA/day (about 7 pounds sterling). Reasonable transport costs will also be reimbursed for caregivers attending follow-up visits.
Where is the study run from?
Groupe de Recherche Action en Santé (GRAS) (Burkina Faso)
When is the study starting and how long is it expected to run for?
September 2020 to October 2025
Who is funding the study?
European & Developing Countries Clinical Trials Partnership (EDCTP)
Who is the main contact?
Bob Taylor
bob@tropmedres.ac
Contact information
Scientific
Groupe de Recherche Action en Santé (GRAS)
Ouagadougou
06 BP 10248
Burkina Faso
| Phone | +226 (0)25355690 |
|---|---|
| a.ouedraogo@gras.bf |
Scientific
Mahidol Oxford Tropical Medicine Research Unit (MORU)
Mahidol University
420/6 Rajvithi Road
Rajthevee
Bangkok
10400
Thailand
 ORCID ID |
0000-0001-8293-6926 |
|---|---|
| Phone | +66 (0)2 203 6333 |
| bob@tropmedres.ac |
Study information
| Study design | Randomized open-label study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | See study outputs table |
| Scientific title | The anti-infectivity efficacy and pharmacokinetics of WHO-recommended single low dose primaquine in children with acute Plasmodium falciparum |
| Study acronym | SLDPQ-BF |
| Study hypothesis | The key hypothesis to be tested is whether single low dose primaquine will enhance transmission blocking in children <5 years. |
| Ethics approval(s) | 1. Approved 29/07/2021, Oxford Tropical Research Ethics Committee (University of Oxford, Research Services, University Offices, Wellington Square, Oxford OX1 2JD, UK; +44 (0)1865 (2)82106; oxtrec@admin.ox.ac.uk), ref: 13-21 2. Approved 01/07/2022, Ethics Committee for Health Research (03 BP 7009, Ouagadougou 03, Burkina Faso, West Africa; +226 70 26 89 98; email not provided), ref: 2022-06-149 |
| Condition | Acute uncomplicated Plasmodium falciparum malaria |
| Intervention | Current intervention as of 28/06/2022: Anti-infectivity study This is an open, randomised, parallel, phase IIb trial assessing the anti-infectivity efficacy, tolerability and PK of single low-dose primaquine (SLDPQ) in paediatric patients from Burkina Faso with acute uncomplicated Plasmodium falciparum malaria. Infectivity will be assessed by direct membrane feeding assays (D0, D1, D2, and D7). A computer-generated randomisation list will be provided. The treatment allocation will be placed in a sealed opaque envelope which will be opened after a study (randomisation) number is given. The treatment allocation will describe the treatment arm. There will be two arms and patients will be randomised to receive either: 1. Artesunate pyronaridine (ASPYR), dosed by weight. ASPYR granules will be used for patients weighing between 5-20 kg; thereafter, tablets will be used 2. ASPYR + SLDPQ (allometrically scaled weight-based regimen) Acceptability study This will be done using the ClinSearch Acceptability Score Test (CAST®) and then calculating the score. Qualitative studies KAP survey A knowledge, attitudes and practice (KAP) survey on malaria and health-seeking behaviour will be conducted. This will consist of a list of mostly simple yes/no questions about malaria, like how commonly affected people are, its dangers, what families do when there is a fever in the family, do they take all the prescribed drugs, are drugs kept for other children. The researchers will also collect basic economic data, including willingness to pay, household income, cost of visiting the clinic, loss of work days. Focus group discussions Focus group discussions on broader issues will include e.g. drug adherence, how to improve it, monitoring side effects in the community, using a drug like primaquine that aims to improve health in the community rather than the individual benefit. There is no fixed sample size but the researchers plan for between 8 to 12 mothers/legal guardians. The process will be explained to mothers/legal guardians when informed consent is taken. The researchers will aim for sessions lasting 60 minutes but mothers can leave early if they feel they have had enough. The discussion will be focused on the following topics: 1. General knowledge about malaria 2. Home management of fevers/treatment-seeking behaviour 3. Practice against malaria assessment questions 4. Drug (primaquine) adherence and ways to improve this 5. Perceptions on the use of tablets vs. granules 6. Improving health in the community with the use of drugs that have community rather than an individual benefit 7. Willingness to pay All conversations are regarded as confidential and any note-taking will not include names and only first names will be used. The discussions will be recorded. Both will be kept securely locked with limited access to the original notes/recordings and the data in the database. At the study end, notes and recordings will be destroyed. Participants will be told that anonymised data may be shared with other researchers and some of their quotes used in presentations. Previous intervention: Anti-infectivity study This is an open, randomised, parallel, phase IIb trial assessing the anti-infectivity efficacy, tolerability and PK of single low-dose primaquine (SLDPQ) in paediatric patients from Burkina Faso with acute uncomplicated Plasmodium falciparum malaria. Infectivity will be assessed by direct membrane feeding assays (D0, D2, D3, D7 & 14). A computer-generated randomisation list will be provided. The treatment allocation will be placed in a sealed opaque envelope which will be opened after a study (randomisation) number is given. The treatment allocation will describe the treatment arm. There will be two arms and patients will be randomised to receive either: 1. Artesunate pyronaridine (ASPYR), dosed by weight. ASPYR granules will be used for patients weighing between 5-20 kg; thereafter, tablets will be used 2. ASPYR + SLDPQ (allometrically scaled weight-based regimen) Acceptability study This will be done using the ClinSearch Acceptability Score Test (CAST®) and then calculating the score. Qualitative studies KAP survey A knowledge, attitudes and practice (KAP) survey on malaria and health-seeking behaviour will be conducted. This will consist of a list of mostly simple yes/no questions about malaria, like how commonly affected people are, its dangers, what families do when there is a fever in the family, do they take all the prescribed drugs, are drugs kept for other children. The researchers will also collect basic economic data, including willingness to pay, household income, cost of visiting the clinic, loss of work days. Focus group discussions Focus group discussions on broader issues will include e.g. drug adherence, how to improve it, monitoring side effects in the community, using a drug like primaquine that aims to improve health in the community rather than the individual benefit. There is no fixed sample size but the researchers plan for between 8 to 12 mothers/legal guardians. The process will be explained to mothers/legal guardians when informed consent is taken. The researchers will aim for sessions lasting 60 minutes but mothers can leave early if they feel they have had enough. The discussion will be focused on the following topics: 1. General knowledge about malaria 2. Home management of fevers/treatment-seeking behaviour 3. Practice against malaria assessment questions 4. Drug (primaquine) adherence and ways to improve this 5. Perceptions on the use of tablets vs. granules 6. Improving health in the community with the use of drugs that have community rather than an individual benefit 7. Willingness to pay All conversations are regarded as confidential and any note-taking will not include names and only first names will be used. The discussions will be recorded. Both will be kept securely locked with limited access to the original notes/recordings and the data in the database. At the study end, notes and recordings will be destroyed. Participants will be told that anonymised data may be shared with other researchers and some of their quotes used in presentations. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Artesunate pyronaridine, primaquine |
| Primary outcome measure | Current primary outcome measure as of 28/06/2022: 1. Proportions of patients infecting ≥1 mosquito in the ASPYR arm vs ASPYR+SLDPQ arm assessed by direct membrane feeding on days 0, 1, 2, and 7 2. Mean within-person percentage change in mosquito infectivity assessed by direct membrane feeding at baseline and on days 1, 2, 7, and 14 Previous primary outcome measure: 1. Proportions of patients infecting ≥1 mosquito in the ASPYR arm vs ASPYR+SLDPQ arm assessed by direct membrane feeding at days 2, 3, 7 and 14 2. Mean within-person percentage change in mosquito infectivity assessed by direct membrane feeding on days 2, 3, 7 and 14 vs baseline |
| Secondary outcome measures | Current secondary outcome measures as of 28/06/2022: 1. Determine mosquito infectivity by measuring proportion of mosquitoes with detected oocysts and sporozoites, oocyst intensity & sporozoite index on days 0, 1, 2, and 7 2. Gametocyte carriage assessed by quantitative nucleic acid sequence-based amplification and microscopy on days 0, 1, 2, 7, and 14 3. Primaquine exposure and anti-infectivity efficacy measured using pharmacokinetics (PK) on days 0 and 1 and direct membrane feeding assay (DMFA) on days 0, 1, 2, and 7 4. Haemoglobin (Hb) dynamics & recovery by Day 28 measured using a HemoCue® machine on days 0, 1, 2, 3, 7, 14, 21, 28, 35, and 42 5. Presence of sickle cell trait/disease, thalassemia and G6PD variants measured using PCR on day 0 6. Cure rate measured using microscopy of a Giemsa stained thick blood film on day 42 7. Parasite and fever clearance times measured using microscopy and a thermometer respectively on days 0, 1, 2, 3, 7, 14, 21, 28, 35 and 42 8. Tolerability measured using adverse events, methaemoglobin oximeter on day 0, 1, 2, 3, 7, 14, 21, 28, 35, and 42 and biochemistry on days 0 and 7 9. CYP 2D6 polymorphisms measured using PCR on day 0 10. PQ and carboxyPQ PK parameters measured using PK on days 0 and 1 11. Covariates explaining variability in PQ and carboxyPQ PK parameters measured using nonlinear mixed-effects modelling on days 0 and 1 12. Acceptability score measured using the ClinSearch Acceptability Score Test (CAST) on day 0 13. Proportions of patients/careers responding to specific questions on a Knowledge, Attitude and Practices (KAP) questionnaire and the mean values of household income on day 0 Previous secondary outcome measures: 1. Gametocyte carriage assessed by quantitative nucleic acid sequence-based amplification and microscopy at days 0, 3, 7, 14, 28, 35 and 42 2. Primaquine exposure and anti-infectivity efficacy measured using pharmacokinetics (PK) and direct membrane feeding assay (DMFA) at days 0, 1 and days 0, 2, 3, 7 and 14, respectively 3. Haemoglobin (Hb) dynamics & recovery by Day 28 measured using a HemoCue® machine at days 0, 1, 2, 3, 7, 14, 21, 28, 35 and 42 4. Presence of sickle cell trait/disease, thalassemia and G6PD variants measured using PCR at day 0 5. Cure rate measured using microscopy of a Giemsa stained thick blood film at day 42 6. Parasite and fever clearance times measured using microscopy and a thermometer respectively at days 0, 1, 2, 3, 7, 14, 21, 28, 35 and 42 7. Tolerability measured using adverse events, methaemoglobin oximeter at day 0, 1, 2, 3, 7, 14, 21, 28, 35, 42 and biochemistry at days 0 and 7 8. CYP 2D6 polymorphisms measured using PCR at day 0 9. PQ and carboxyPQ PK parameters measured using PK at days 0 and 1 10. Covariates explaining variability in PQ and carboxyPQ PK parameters measured using nonlinear mixed-effects modelling at days 0 and 1 11. Acceptability score measured using the ClinSearch Acceptability Score Test (CAST) at day 0 12. Proportions of patients/careers responding to specific questions on a Knowledge, Attitude and Practices (KAP) questionnaire and the mean values of household income at day 0 |
| Overall study start date | 01/09/2020 |
| Overall study end date | 31/10/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Child |
| Lower age limit | 6 Months |
| Upper age limit | 5 Years |
| Sex | Both |
| Target number of participants | 56 patients i.e. 28 patients per arm |
| Participant inclusion criteria | 1. Participant parent/legal guardian is willing and able to give informed consent for participation in the study 2. Aged ≥6 months and <5 years 3. Weight ≥5 kg 4. Presentation with fever (axillary ≥37.5°C, tympanic ≥38°C) or fever history ≤24 h and clinically uncomplicated disease 5. P. falciparum parasitaemia 1,000 – 250,000/μl (mono-/mixed Plasmodium species) detected by light microscopy 6. Ability and willingness to comply with the protocol for the duration of the study and to comply with the study visit schedule |
| Participant exclusion criteria | 1. General danger signs in children under 5 years or signs of severe falciparum malaria according to the definitions of WHO (2000) e.g. prostration, respiratory distress, reduced consciousness 2. Persistent vomiting as given in the history of the current illness 3. P. falciparum (Pf) parasitaemia >250,000/μl (>5% parasitaemia) 4. Haemoglobin (Hb) <5 g/dl 5. Patients on treatment for a significant illness e.g. HIV/AIDS, TB, leprosy or currently taking a drug known to cause haemolysis in G6PDd 6. Known to be allergic to PQ or ASPYR 7. On regular medication, which might interfere with antimalarial pharmacokinetics 8. Antimalarials taken within the last 2 weeks 9. Having taken a herbal medicine within the last 4 weeks 10. Previous participation in a malaria vaccine trial 11. Previous enrolment in the current trial or current enrolment in another trial 12. Severe malnutrition – defined as a mid-upper arm circumference (MUAC) <115 mm 13. Febrile condition due to diseases other than malaria (e.g. measles, acute lower respiratory tract infection, severe diarrhoea with dehydration) or other known underlying chronic or severe diseases (e.g. cardiac, renal or hepatic diseases, HIV/AIDS) |
| Recruitment start date | 15/07/2024 |
| Recruitment end date | 30/11/2024 |
Locations
Countries of recruitment
- Burkina Faso
Study participating centre
Secteur 19, Somgandé
Ouagadougou
-
Burkina Faso
Sponsor information
University/education
University Offices
Wellington Square
Oxford
OX1 2JD
England
United Kingdom
| Phone | +44 (0)1865 270000 |
|---|---|
| research.services@admin.ox.ac.uk | |
| Website | http://www.ox.ac.uk/ |
"ROR" |
https://ror.org/052gg0110 |
Funders
Funder type
Research organisation
Private sector organisation / International organizations
- Alternative name(s)
- Le partenariat Europe-Pays en développement pour les essais cliniques, A Parceria entre a Europa e os Países em Desenvolvimento para a Realização de Ensaios Clínicos, The European & Developing Countries Clinical Trials Partnership, European and Developing Countries Clinical Trials, EDCTP
- Location
- Netherlands
Results and Publications
| Intention to publish date | 31/12/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | The researchers plan to publish the protocol and statistical analysis plan in a peer-reviewed, open-access journal. |
| IPD sharing plan | Data will be made available upon reasonable request and in accordance with the data-sharing policies of GRAS and Mahidol Oxford Tropical Medicine Research Unit (MORU). |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | 03/09/2024 | 04/09/2024 | Yes | No |
Editorial Notes
04/09/2024: Publication reference added.
04/06/2024: The recruitment start date was changed from 01/06/2024 to 15/07/2024.
12/07/2023: The following changes have been made:
1. The overall trial end date has been changed from 31/12/2025 to 31/10/2025 and the plain English summary has been updated to reflect this change.
2. The recruitment end date has been changed from 15/08/2025 to 30/11/2024.
04/07/2023: The following changes have been made:
1. The recruitment start date has been changed from 01/07/2023 to 01/06/2024.
2. The recruitment end date has been changed from 15/09/2024 to 15/08/2025.
3. The overall trial end date has been changed from 31/12/2024 to 31/12/2025 and the plain English summary has been updated to reflect this change.
4. The intention to publish date has been changed from 01/01/2025 to 31/12/2026.
14/09/2022: Ethics approval added.
28/06/2022: The following changes have been made:
1. The intervention has been updated.
2. The primary outcome measure has been updated.
3. The secondary outcome measures have been updated.
4. The trial website has been added.
5. The grant reference has been added to the protocol /serial number.
09/06/2022: The following changes have been made:
1. The recruitment start date has been changed from 06/06/2022 to 01/07/2023.
2. The recruitment end date has been changed from 15/01/2023 to 15/09/2024.
3. The overall trial end date has been changed from 28/02/2023 to 31/12/2024 and the plain English summary has been updated to reflect this change.
02/08/2021: Contact details updated.
19/07/2021: Trial's existence confirmed by Oxford Tropical Research Ethics Committee.
