Plain English Summary
Background and study aims
Malaria is a disease that is spread by mosquito bites. It causes flu-like symptoms but can also cause serious illness and death. Malaria is a major problem in tropical areas like Africa. Research has shown that a drug called primaquine can reduce the malaria offspring in mosquitos which can then reduce malaria transmission. However, primaquine has a major disadvantage as it changes to act like bleach in the body. This is problematic to people who have naturally weak red blood cells and are lacking an enzyme that makes the chemicals that counteract bleach and drug metabolites called glucose 6 phosphate dehydrogenase (G6PD). The less G6PD in the red cells, the more damaging primaquine's is. It can cause red cells may burst open (haemolysis) which creates many health problems. Many malaria control programmes are unwilling to use primaquine because they think it is too dangerous and they cannot afford the cost, training or equipment to test for G6PD levels. Although the World Health Organisation (WHO) recommends using low dose primaquine even in malaria patients with G6PD deficiency, primaquine is not being used due to a lack of research, concerns about tests for G6PD and issues providing the medication to children. The aim of this study is to provide evidence that a low dose of primaquine is safe in G6PD deficient kids in order to reduce malaria rates and benefit communities.
Who can participate?
Children aged six months to 11 years old who have malaria.
What does the study involve?
Participants are allocated to one of two groups. Those in the first group have a deficiency in G6PD and those in the second group have normal G6PD levels. Participants in each group are then randomly allocated to one of four dosing treatments which include primaquine and combination treatments and two placebo primaquine treatment. The doses vary with each participant’s age and weight and are given daily for three days. The placebo group only receives the medication once. Participants are followed up for 42 days to measure their iron deficiency level in their blood.
What are the possible benefits and risks of participating?
Participants may benefit from knowing the status of their G6PD levels and from receiving information and counseling. There are risks with primaquine as it can cause anaemia (low blood iron).
Where is the study run from?
1. Kinshasa Mahidol Oxford Tropical Medicine Research Unit (Democratic Republic of Congo)
2. The Mbale Regional Referral Hospital (Uganda)
When is the study starting and how long is it expected to run for?
Feburary 2017 to November 2020
Who is funding the study?
DFID/MRC/Wellcome Trust (UK), grant reference number: MR/P006973/1
Who is the main contact?
Dr Bob Taylor
Study website
Additional identifiers
EudraCT/CTIS number
IRAS number
ClinicalTrials.gov number
Protocol/serial number
BAKMAL1606, 106698/Z/14/Z
Study information
Scientific title
Assessing the tolerability and safety of single low dose primaquine in African children with acute uncomplicated falciparum malaria and glucose 6 phosphate dehydrogenase deficiency in Africa
Acronym
PAC study
Study hypothesis
The aim of this study is to provide evidence for drug policy on the safety of the WHO recommended SLDPQ regimen when used under close to routine conditions to G6PDd African children with acute uncomplicated P. falciparum.
Ethics approval(s)
Oxford Tropical Research Ethics Committee, 01/03/2017, ref: 53-16
Study design
Multi-centre double blind open randomised parallel safety trial
Primary study design
Interventional
Secondary study design
Randomised parallel trial
Study setting(s)
Hospital
Study type
Treatment
Patient information sheet
See additional files
Condition
Uncomplicated falciparum Malaria, G6PD deficiency, Single low dose primaquine (SLDPQ)
Intervention
Participants are allocated to either the G6PDd group or the G6PD normal group based on their the results of a G6PD rapid diagnostic test (RDT).
Participants are then randomly allocated as to which dosing group they receive using a computer generated randomisation list generated for each site. Treatment allocation is placed in a sealed envelope which is opened once participants receive their study number. The treatment allocation described the Artemisinin based combination treatment (ACT) to be given and the number of PQ/placebo pack.
The four dosing groups are the following:
1. Artemether Lumefantrine (AL) + single low-dose primaquine (SLDPQ)
2. Artemether Lumefantrine (AL) + single low-dose primaquine (SLDPQ) placebo
3. Dihydroartemisinin-piperaquine (DHAPP) + single low-dose primaquine (SLDPQ)
4. Dihydroartemisinin-piperaquine (DHAPP) + single low-dose primaquine (SLDPQ) placebo
The dosages for primaquine depends vary with age and the dosing for AL vary with weight (in kg). DHAPP+SLDPQ dosages are given daily for three days and vary with body weight (in kg). Those who receive the primaquine/placebo receive it once only at baseline. Follow up continues until day 42.
Intervention type
Drug
Pharmaceutical study type(s)
Phase
Phase III/IV
Drug/device/biological/vaccine name(s)
Artemether, lumefantrine, dihydroartemisinin, piperaquine, primaquine
Primary outcome measure
1. Profound anaemia (Hb concentration < 4g/dL) is measured using the HemoCue machine during the first days 21 days of follow up
2. Severe anaemia (Hb <5g/dL) with clinical features of severe malaria is measured using the HemoCue machine during the first 21 days of follow up
Secondary outcome measures
1. Fractional change in haemoglobin on day seven vs. baseline, measured by HemoCue® at baseline and day seven
2. Proportion of patients with a fractional change of ≥ 25% measured by HemoCue® over the follow up period of 42 days
3. Determinants of changes in HemoCue® measured haemoglobin over the follow up period of 42 days
4. G6PD genotype (hemizygous male, homo-, heterozygous female, normal) and selected G6PD variants (e.g. G6PD A- 202 mutations) are assessed by polymerase chain reaction (PCR) at baseline
5. G6PD enzyme activity is measured using a quantitative spectrophotometric method at baseline
6. Genotypes of other inherited blood disorders are assessed by polymerase chain reaction (PCR) at baseline
7. Incidence of adverse events are measured using clinical and laboratory records over the follow up period of 42 days
8. Pharmacokinetic characteristics of PQ and carboxyPQ by measuring drug concentrations at baseline and at hours one, one and a half, two, three, four, six, eight, ten, 12, 24 hours
9. Pharmacokinetic characteristics of lumefantrine and piperaquine are measured using their drug concentrations at baseline, day three, seven and 28
10. CYP 2D6 genotypes are assessed by polymerase chain reaction (PCR) at baseline
11. Asexual parasitaemia clearance time and half life are measured using malaria slide results at days one, two and three
12. Therapeutic efficacy of AL and DHAPP is measured using the WHO criteria at day 42
13. Gametocytaemia over time is measured using thick blood films at baseline and days one, two, three, seven, 14, 21, 28, 35 and 42
14. Proportion of patients with gametocytes over time is measured using those with a positive thick blood film at baseline and on days one, two, three, seven, 14, 21, 28, 35 and 42
Overall study start date
01/02/2017
Overall study end date
02/11/2020
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Aged six months to 11 years old
2. Clinically uncomplicated disease
3. Fever (≥ 37.5⁰C aural) or history of fever within the previous 72 hours
4. Positive malaria RDT (Uganda only)
5. Positive malaria slide for P. falciparum (mono or mixed infection) of any parasitaemia (Kinshasa only)
6. Informed consent provided by patient or relative/legal guardian
Participant type(s)
Patient
Age group
Child
Lower age limit
6 Months
Upper age limit
11 Years
Sex
Both
Target number of participants
1,600
Total final enrolment
1137
Participant exclusion criteria
1. Malaria danger signs, sign(s) of severe malaria, or decompensated anaemia, including: an inability to take or retain fluids or oral medications, confusion, prostration, convulsions, respiratory distress, passing of red or cola-coloured urine (putative “blackwater fever”)
2. Severe anaemia (Hb <6 g/dL)
3. Comorbid illness that requires treatment in hospital (physician’s judgement)
4. Patients on drugs known to cause haemolysis in G6PDd e.g. dapsone, nalidixic acid
5. Known to be allergic to PQ, AL, or DHAPP
6. Previous enrolment in the current trial or current enrolment in another trial
Recruitment start date
17/07/2017
Recruitment end date
07/10/2019
Locations
Countries of recruitment
Congo, Democratic Republic, Uganda
Study participating centre
Kinshasa Mahidol Oxford Tropical Medicine Research Unit
The Kinshasa School of Public Health
University of Kinshasa
Avenue Tombalbaye 68-78
Kinshasa
1015
Congo, Democratic Republic
Study participating centre
The Mbale Regional Referral Hospital
Mbale Clinical Research Institute
Mbale Regional Referral & Teaching Hospital
Mbale
209
Uganda
Sponsor information
Organisation
The University of Oxford
Sponsor details
Research Services
University Offices
Wellington Square
Oxford
OX1 2 JD
United Kingdom
Sponsor type
University/education
Website
ROR
Funders
Funder type
Other
Funder name
DFID/MRC/Wellcome Trust
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Current publication and dissemination plan as of 06/08/2020:
Planned publication in a high-impact peer-reviewed journal
Intention to publish date
01/10/2022
Individual participant data (IPD) sharing plan
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request
Previous publication and dissemination plan:
Planned publication in a high-impact peer reviewed open access journal.
IPD sharing plan:
The current data sharing plans for the current study are unknown and will be made available at a later date
IPD sharing plan summary
Available on request
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | version V2 | 14/02/2017 | 01/06/2017 | No | Yes |
| Participant information sheet | version V2 | 14/02/2017 | 01/06/2017 | No | Yes |
| Other publications | Age-based dosing regimen development | 18/01/2018 | 21/10/2021 | Yes | No |
| Protocol file | version 2 | 01/09/2018 | 22/08/2022 | No | No |
| Results article | 30/11/2022 | 05/12/2022 | Yes | No | |
| Results article | 20/10/2023 | 20/10/2023 | Yes | No |
Additional files
- ISRCTN11594437_PIS_14Feb17_V2_Uganda.pdf Uploaded 01/06/2017
- ISRCTN11594437_PIS_14Feb17_V2.pdf Uploaded 01/06/2017
- ISRCTN11594437_PROTOCOL_V2_01Sep18.pdf