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Trial registered on ANZCTR


Registration number
ACTRN12613000003774
Ethics application status
Approved
Date submitted
17/12/2012
Date registered
3/01/2013
Date last updated
14/01/2013
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
Nil
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

Intervention/exposure
Study type
Interventional
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
Active

Outcomes
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The proportions of patients who complete 8 weeks of primaquine; that is, patients who are not withdrawn from the study because of primaquine induced haematological toxicity.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
Baseline

Eligibility
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
Gender
Both males and females
Can healthy volunteers participate?
No
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
Treatment
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
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Safety
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
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 4759 0
Cambodia
State/province [1] 4759 0
Pailin

Funding & Sponsors
Funding source category [1] 286474 0
Other
Name [1] 286474 0
World Health Organisation
Address [1] 286474 0
Avenue Appia 20
1211 Geneva
Country [1] 286474 0
Switzerland
Primary sponsor type
Charities/Societies/Foundations
Name
National Center for Parasitology, Entomology & Malaria Control
Address
372 Monivong Boulevard
Phnom Penh
Country
Cambodia
Secondary sponsor category [1] 285266 0
None
Name [1] 285266 0
Address [1] 285266 0
Country [1] 285266 0

Ethics approval
Ethics application status
Approved
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
Cambodia
Date submitted for ethics approval [1] 288551 0
19/03/2012
Approval date [1] 288551 0
01/10/2012
Ethics approval number [1] 288551 0
39
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
Philippines
Date submitted for ethics approval [2] 288552 0
07/05/2012
Approval date [2] 288552 0
01/10/2012
Ethics approval number [2] 288552 0
2012.5.CAM.01.MVP

Summary
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

Contacts
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
Cambodia
Phone 36654 0
+85512307068
Fax 36654 0
Email 36654 0
khengsim@gmail.com
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
Cambodia
Phone 36655 0
+85512307068
Fax 36655 0
Email 36655 0
khengsim@gmail.com
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
Cambodia
Phone 36656 0
+85512307068
Fax 36656 0
Email 36656 0
khengsim@gmail.com

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