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Trial registered on ANZCTR

Registration number
Ethics application status
Date submitted
Date registered
Date last updated
Type of registration
Prospectively registered

Titles & IDs
Public title
Looking at the safety of primaquine when given by mouth once a week for 8 weeks to Cambodian patients with vivax malaria.
Scientific title
Assessing the safety of weekly administered primaquine in vivax malaria infected Cambodians.
Secondary ID [1] 281685 0
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Vivax malaria 287973 0
Condition category
Condition code
Infection 288354 288354 0 0
Studies of infection and infectious agents

Study type
Description of intervention(s) / exposure
Oral primaquine at a dose of 0.75 mg/kg given once per week for 8 weeks AND

Oral dihydroartemisinin piperaquine given once per day for 3 days according to the maufacturer's dosing instructions.

This regimen will be given to patients with vivax malaria and G6PD deficiency.
Intervention code [1] 286221 0
Treatment: Drugs
Comparator / control treatment
Oral primaquine at a dose of 0.75 mg/kg given once per week for 8 weeks AND

Oral dihydroartemisinin piperaquine given once per day for 3 days according to the maufacturer's dosing instructions.

This regimen will be given to patients with vivax malaria but without G6PD deficiency. This is the control group.
Control group

Primary outcome [1] 288522 0
The proportions of patients who complete 8 weeks of primaquine; that is, patients who are not withdrawn from the study because of primaquine induced haematological toxicity. This is defined as:

1. Fall in baseline Hb >25% by D7

2. Development of severe anaemia by D7, defined as a Hb < 7 g/dL for all ages

3. Haemoglobinuria for 2 days, defined as a urine colour >=8 based on a urine colour chart (Hillmen, Hall et al. 2004)

4. Development of metHaemoglobinaemia > 20%

5. Increase in baseline creatinine > 50% with evidence of acute haemolytic anaemia
Timepoint [1] 288522 0
Day 56
Secondary outcome [1] 300386 0
Determine risk factors (e.g. age, sex, G6PD activity, level of parasitaemia) for primaquine related toxicity by logistic regression

Timepoint [1] 300386 0
Day 56
Secondary outcome [2] 300420 0
Hb dynamics over 8 weeks by measuring the Hb concentration at each time point and seing how these concnetrations change over time
Timepoint [2] 300420 0
Day 56
Secondary outcome [3] 300421 0
Incidence of protocol defined adverse events e.g. abdominal pain, vomiting, any skin rashes.
Timepoint [3] 300421 0
Day 56
Secondary outcome [4] 300423 0
Sensitivity, specificity, positive & negative predictive values of the G6PD rapid test vs. quantitative G6PD assay + G6PD PCR
Timepoint [4] 300423 0

Key inclusion criteria
Male or non pregnant females aged > 1 year

Weight >= 10 kg

Presentation with: (i) acute (within 10 days), symptomatic (i.e. history of fever), uncomplicated, Plasmodium vivax mono- or mixed infection, AND (ii) vivax asexual parasitaemia = 200 & < 200,000 parasites/microL

Written informed consent provided by the volunteer. Witnessed consent is permitted, if the individual cannot write.

Able and willing to participate based on information given to the volunteer

Not currently taking any prescribed, over the counter or herbal drugs that could cause haemolysis in G6PD deficiency
Minimum age
1 Years
Maximum age
No limit
Both males and females
Can healthy volunteers participate?
Key exclusion criteria
Hb < 8 g/dL for a patients of all ages

Have any malaria danger signs: unable to swallow because of vomiting, >=2 convulsions within previous 24 hours, reduced level of consciousness, unable to sit or walk unaided.

Any clinically significant disease requiring treatment or further investigation

Pregnant, planning to become pregnant

Breast feeding

For a G6PD deficient child under 5 – living more than 25 km from the research site

Allergic to primaquine or DHA-PP known to have had a clinically significant, contraindicating adverse reaction to either drug

Having taken part in research involving an investigational drug within the past 8 weeks.

Study design
Purpose of the study
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Patients with fever who attend the local clinic will be managed according to local practice. This usually involves either the preparation of a blood film or use of a rapid test or both tests to determine if the patient has malaria. Prestudy training will be given on slide preparation.

If a subject has vivax malaria, he or she will be asked if they would like to be part of a research study. If the answer is yes, a copy of the consent form in Khmer will be given to them to read or the consent form will be read to them. A trained study nurse may assist the research physicians in the consent process. Any questions that may arise will be answered by one of the study doctors.
If the potential study subjects / guardians are happy to join the study, they will be asked to sign the consent form. A screening number will be assigned to them starting at SC001 and will also have a code for the study site.

After the consent form has been signed, all mandated study investigations to determine eligibility to the study will be performed. Patients found to be eligible will then be allocated a study number.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?

Intervention assignment
Other design features
Phase 4
Type of endpoint(s)
Statistical methods / analysis
Risk/proportional data - These data will be compared by chi squared or Fisher’s exact test, as appropriate. The primary endpoint will also be analysed using simple proportions and Kaplan Meier survival method; the survival curves compared using the log rank test. The risk difference and attributable risk in unacceptable haematological toxicity will be calculated.

Continuous data - These data will be summarised by medians (ranges) and means (standard deviations), as appropriate, and will include the haematological and biochemical parameters. Between group means/mean changes analyses will be unpaired ‘t’ test, or the non parametric tests, as appropriate. Changes relative to baseline will be by paired test or ranksum test, as appropriate.

Exploratory, simple regression analyses will be done to determine relationships e.g. between G6PD enzyme activity and free Hb concentrations, metHb concentrations & degree of haemolysis.

Risk factors for haemolysis - These will be assessed in a logistic regression model.

Time to event - The time for the Hb to return to baseline will be determined by KM survival analysis; time curves will be compared by the log rank test.

Test characteristics - The sensitivity, specificity, positive & negative predictive values of the G6PD rapid test vs. quantitative G6PD assay + G6PD PCR will be calculated.

The positive predictive values for clinically significant haemolysis of the rapid test and qualitative G6PD test will also be determined.

Recruitment status
Not yet recruiting
Date of first participant enrolment
Date of last participant enrolment
Date of last data collection
Sample size
Accrual to date
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 4759 0
State/province [1] 4759 0

Funding & Sponsors
Funding source category [1] 286474 0
Name [1] 286474 0
World Health Organisation
Address [1] 286474 0
Avenue Appia 20
1211 Geneva
Country [1] 286474 0
Primary sponsor type
National Center for Parasitology, Entomology & Malaria Control
372 Monivong Boulevard
Phnom Penh
Secondary sponsor category [1] 285266 0
Name [1] 285266 0
Address [1] 285266 0
Country [1] 285266 0

Ethics approval
Ethics application status
Ethics committee name [1] 288551 0
National Ethics Committee for Health Research
Ethics committee address [1] 288551 0
Ministry of Health,
2 Boulevard Km Yl Sung
Phnom Penh
Ethics committee country [1] 288551 0
Date submitted for ethics approval [1] 288551 0
Approval date [1] 288551 0
Ethics approval number [1] 288551 0
Ethics committee name [2] 288552 0
WHO WPRO Ethics Review Committee
Ethics committee address [2] 288552 0
P.O. Box 2932,
1000 Manila
Ethics committee country [2] 288552 0
Date submitted for ethics approval [2] 288552 0
Approval date [2] 288552 0
Ethics approval number [2] 288552 0

Brief summary
Primaquine is a drug that is used to kill malaria parasites that sleep in the liver. Plasmodium vivax and plasmodium ovale are the scientific names of the malaria species that can sleep in the liver. The species These sleeping forms of malaria can wake up and enter the blood where they will cause another bout of malaria.

Primaquine is not widely used because it can cause red cells on the blood to break open if they are short of an enzyme called glucose 6 phosphate dehydrogenase, G6PD for short.

With little or no G6PD, the red cell cannot produce certain substances to protect itself when it is under stress from certain drugs like primaquine and also fava beans.

G6PD deficiency is common in many parts of the world, especially where there is malaria. There are tests that can be used to see if someone is G6PD deficient but many countries do not use them because of cost and the logistical challenges involved. As a result primaquine is not used because of the risk of causing harm to patinets due to the red cells breaking apart is too high.

Our research project will look closely at the risk of effects of red cells breaking apart by giving G6PD deficient patients and seeing what happens. We will monitor the patients very closely and have developed a good safety net to detect any health problems quickly.

The results of this research will provide useful information for the Ministries of Health that are trying to control malaria.

Trial website
Trial related presentations / publications
Public notes

Principal investigator
Name 36654 0
Dr Kheng Sim
Address 36654 0
National Center for Parasitology,
Entomology and Malaria Control,
372 Monivog Boulevard,
Phnom Penh.
Country 36654 0
Phone 36654 0
Fax 36654 0
Email 36654 0
Contact person for public queries
Name 36655 0
Dr Kheng Sim
Address 36655 0
National Center for Parasitology,
Entomology and Malaria Control,
372 Monivog Boulevard,
Phnom Penh.
Country 36655 0
Phone 36655 0
Fax 36655 0
Email 36655 0
Contact person for scientific queries
Name 36656 0
Dr Kheng Sim
Address 36656 0
National Center for Parasitology,
Entomology and Malaria Control,
372 Monivog Boulevard,
Phnom Penh.
Country 36656 0
Phone 36656 0
Fax 36656 0
Email 36656 0

No information has been provided regarding IPD availability
Summary results
No Results