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Trial registered on ANZCTR


Trial ID
ACTRN12613000565741
Ethics application status
Approved
Date submitted
13/05/2013
Date registered
17/05/2013
Date last updated
13/02/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
Defining the effectiveness of Piperaquine in early Plasmodium falciparum malaria infection in healthy volunteers.
Scientific title
An experimental study to characterize the effectiveness of Piperaquine against early Plasmodium falciparum blood stage infection in healthy volunteers
Secondary ID [1] 282492 0
N/A
Universal Trial Number (UTN)
Nil
Trial acronym
Nil
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 289129 0
Condition category
Condition code
Infection 289470 289470 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a single-center, controlled, study using induced blood stage malaria (IBSM) challange inoculum to characterize the effectiveness of Piperaquine against early blood stage Plasmodium falciparum infection. 1800 viable Plasmodium falciparum infected human erythrocytes will be administered intravenously. A single dose of Piperaquine will be administered when the level of parasite in the blood rises above 800/mL. The study will be conducted in up to 3 cohorts (n= 8 in each) using different oral doses of Piperaquine. Subsequent cohorts will not commence until at least after day 15 of the previous cohort and review by Safety Review Team following day 14 of the previous cohort. The first dose of Piperaquine that will be investigated will be a single dose of 960 mg (as piperaquine phosphate). Subsequent doses in subsequent cohort(s) will be determined following a review of observed Piperaquine safety, and pharmacodynamic outcome as well as the activity of the drug as defined by parasite clearance kinetics. It is anticipated that subsequent doses will be between 320 and 640 mg (as piperaquine phosphate). The doses will be determined following review by the Safety Review Team, and will be selected based on patient safety and volunteers tolerability and by defining the desired broad concentration response profile. If no safe alternative dose can be determined the option exists to curtail the study to less than three cohorts.
Intervention code [1] 287145 0
Treatment: Drugs
Comparator / control treatment
There is no comparator/control treatment group. Data from each study cohort will be compared to data obtained in previous and subsequent studies. Data has been collected over the past 3 years. The source of the specific historical data that will be used as a comparator in this study is:
PLoS One. 2011;6(8):e21914. doi:10.1371/journal.pone.0021914.
Epub 2011 Aug 22.
A pilot randomised trial of induced blood-stage Plasmodium falciparum infections in healthy volunteers for testing efficacy of new antimalarial drugs.McCarthy JS, Sekuloski S, Griffin PM, Elliott S, Douglas N, Peatey C, Rockett R, O'Rourke P, Marquart L, Hermsen C, Duparc S, Möhrle J,Trenholme KR, Humberstone AJ.

Control group
Historical

Outcomes
Primary outcome [1] 289571 0
The pharmacokinetic-pharmacodynamic relationship between blood piperaquine levels on the clearance of Plasmodium falciparum parasites from the blood in healthy volunteers following infection with blood stage parasites. This outcome will be measured by monitoring blood levels of parasites by PCR and of drug levels by LCMS.
Timepoint [1] 289571 0
28 days
Secondary outcome [1] 302751 0
To characterize the pharmacokinetics of piperaquine in healthy volunteers following infection with blood stage Plasmodium falciparum. This outcome will be measured by monitoring drug levels in the blood
Timepoint [1] 302751 0
28 days
Secondary outcome [2] 302752 0
To assess the tolerability of piperaquine in the experimental malaria challenge system. This outcome will be assessed by reviewing the signs and symptoms of adverse effects of drug (eg gastrointestinal intolerance); changes in ECG; changes in haematology or biochemistry results.
Timepoint [2] 302752 0
28 days

Eligibility
Key inclusion criteria
1. Adults (males or non pregnant females), with no history of malaria, aged between 18 and 45 years who do not live alone (from Day 1 until at least the end of the antimalarial drug treatment).
2. A BMI within the range 18–30 kg/m2 and must weigh more than 50kg in adults in which the proposed dose has already been used.
3. Be contactable and available for the duration of the trial and be available up to 2 weeks following end of study visit. (maximum of 8 weeks).
4. Be non-smokers for at least three months prior to screening. Note: “Tobacco use” includes smoking and the use of snuff and chewing tobacco, and other nicotine or nicotine containing products and in good health, as assessed during pre-study medical examination and by review of screening results.
5. Female volunteers of childbearing potential, should be surgically sterile or using an insertable, injectable, transdermal, or combination oral contraceptive approved by the US FDA or TGA combined with a barrier contraceptive through completion of the study and have negative results on a serum or urine pregnancy test done before administration of study medication.
6. Good peripheral venous access.
Minimum age
18 Years
Maximum age
45 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. History of malaria or travelled to or lived (2 weeks or more ) in a malaria-endemic country during the past 12 months or planned travel to a malaria-endemic country during the course of the study.
2. Evidence of increased cardiovascular disease risk
3. History of splenectomy.
4. Pregnant or breast feeding
5. History of a severe allergic reaction, anaphylaxis or convulsions following any vaccination or infusion.
6. Presence of current or suspected serious chronic diseases such as cardiac or autoimmune disease, HIV or other immunodeficiencies, insulin dependent diabetes, progressive neurological disease, severe arthritis, asthma, epilepsy or obsessive compulsive disorder, skin carcinoma excluding non spreadable skin cancers such as basal cell and squamous cell carcinoma, significant psychiatric diagnosis.
7. Volunteers unwilling to defer blood donations to the ARCBS for 6 months.
8. Abnormal ECG findings
9. Recent or current therapy with an antibiotic or drug with potential antimalarial activity (tetracycline, azthromycin, clindamycin, hydroxychloroquine etc.).
10. Known hypersensitivity to Piperaquine, artemether or lumefantrine.
11. Concomitant use of any of the following drugs: those metabolised by the cytochrome enzyme CYP2D6 (e.g. flecainide, metoprolol, imipramine, amitriptyline, clomipramine); drugs that are known to prolong the QTc interval (e.g. antiarrhythmics of classes IA and III, neuroleptics, certain antidepressant agents, certain antibiotics, certain nonsedating antihistamines; corticosteroids, anti-inflammatory drugs, any immunomodulators or anticoagulants.
12. Presence of acute infectious disease or fever (e.g., sub-lingual temperature greater than 38.5 degree Celsius) within the five days prior to study product administration).
13. Evidence of acute illness within the four weeks before trial prior to screening.
14. Significant intercurrent disease of any type, in particular liver, renal, cardiac, pulmonary, neurologic, rheumatologic, or autoimmune disease by history, physical examination, and/or laboratory studies including urinalysis.
15. Participant has a clinically significant disease or any condition or disease that might affect drug absorption, distribution or excretion, e.g. gastrectomy, diarrhoea.
16. Alcohol consumption greater than community norms (i.e. more than 21 standard drinks per week for males and 14 standard drinks per week for females).
17. A history of drug habituation, or any prior intravenous usage of an illicit substance.
18. Medical requirement for intravenous immunoglobulin or blood transfusions.
19. Participation in any investigational product study within the 8 weeks preceding the study.
20. Participation in any research study involving significant blood sampling, or blood donation to Red Cross (or other) blood bank during the 8 weeks preceding the reference drug dose in the study.
21. Have ever received a blood transfusion.
22. Positive test for HIV, Hepatitis B, hepatitis C.
23. Any clinically significant biochemical or haematologic abnormality (Hb must be greater than or equal to 11.5g/dL for females; 13.5g/dL for males)
24. Ingestion of any poppy seeds within the 24 hours prior to the screening blood test (volunteers will be advised by phone not to consume any poppy seed in this time period).
25. Detection of any drug listed in this protocol in the urine drug screen unless there is an explanation acceptable to the medical investigator (e.g. the participant has stated in advance that they consumed a prescription or OTC product which contained the detected drug) and/or the participant has a negative urine drug screen on retest by the pathology laboratory.
26. Evidence of any condition that, in the opinion of the clinical investigator, might interfere with the evaluation of the study objectives or pose excessive risks to volunteers.
27. At the discretion of the Investigator the use of prescription or OTC medications, within 2 weeks of BSPC administration, or within 2 week of administration of the antimalarial drug. Excluded from this list is intermittent use of paracetamol at doses of less than or equal to 2 g/day.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Three groups of participants receive different doses of the same intervention at different times (i.e not concurrently)
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Parasite clearance will be determined by characterising the log-linear decay in the middle of the decay profile (slope of the log-linear relationship of parasitemia over time). The parasite reduction rate (PRR) will be calculated using the slope of the log-linear relationship of the parasitemia based on the optimal fit of the log-linear curve. The optimal fit will be derived after dealing with potential outliers, dealing with values below the limit of detection (LOD) and non-detectable values (ND), and obtaining an appropriate summary of replicate parasitemia values. The optimal fit of the log-linear parasitemia by time relationship is determined by using left and right censoring to systematically remove the potential lag phase and tail phase of the parasitemia decay.

Recruitment
Recruitment status
Completed
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)
QLD
Recruitment postcode(s) [1] 6882 0
4006 - Herston

Funding & Sponsors
Funding source category [1] 287276 0
Charities/Societies/Foundations
Name [1] 287276 0
Medicines for Malaria Venture (Not-for Profit)
Address [1] 287276 0
Medicines for Malaria Venture (MMV)
PO Box 1826
20, rte de Pre-Bois
1215 Geneva 15
Country [1] 287276 0
Switzerland
Primary sponsor type
Charities/Societies/Foundations
Name
Queensland Institute of Medical Research
Address
300 Herston Road, Herston, Brisbane, QLD, 4006
Country
Australia
Secondary sponsor category [1] 286029 0
None
Name [1] 286029 0
N/A
Address [1] 286029 0
N/A
Country [1] 286029 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289255 0
The Queensland Institute of Medical Research Human Research Ethics Committee
Ethics committee address [1] 289255 0
The Queensland Institute of Medical Research,
Post Office Royal Brisbane,QLD, 4029
Ethics committee country [1] 289255 0
Australia
Date submitted for ethics approval [1] 289255 0
Approval date [1] 289255 0
13/05/2013
Ethics approval number [1] 289255 0
P1530

Summary
Brief summary
This is a single-centre, controlled, study using induced blood stage malaria (IBSM) challange inoculum to characterize the effectiveness of Piperaquine against early blood stage Plasmodium falciparum infection. The study will be conducted in up to 3 cohorts (n= 8 in each) using different oral doses of Piperaquine.
Trial website
Trial related presentations / publications
James S. McCarthy, Silvana Sekuloski, Paul Griffin, Suzanne Elliott, Louise Marquart, Joerg Moehrle, Mark Baker;
A Phase IIa clinical trial to characterize the pharmacokinetic-pharmacodynamic relationship of piperaquine using the induced blood stage infection model, abstract 1490, poster session, The American Society of Tropical Medicine and Hygiene, New Orleans, November 2014
Public notes

Contacts
Principal investigator
Name 39998 0
Prof James McCarthy
Address 39998 0
Queensland Institute of Medical Research
300 Herston Road Herston QLD 4006
Country 39998 0
Australia
Phone 39998 0
+61 7 3845 3796
Fax 39998 0
+61 7 3362 0104
Email 39998 0
James.McCarthy@qimr.edu.au
Contact person for public queries
Name 39999 0
Dr Silvana Sekuloski
Address 39999 0
Queensland Institute of Medical Research
300 Herston Road Herston QLD 4006
Country 39999 0
Australia
Phone 39999 0
+61 7 38453856
Fax 39999 0
+61 7 38453507
Email 39999 0
Silvana.Sekuloski@qimr.edu.au
Contact person for scientific queries
Name 40000 0
Prof James McCarthy
Address 40000 0
Queensland Institute of Medical Research
300 Herston Road Herston QLD 4006
Country 40000 0
Australia
Phone 40000 0
+61 7 3845 3796
Fax 40000 0
+61 7 3362 0104
Email 40000 0
James.McCarthy@qimr.edu.au