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Trial registered on ANZCTR


Trial ID
ACTRN12613001040752
Ethics application status
Approved
Date submitted
13/09/2013
Date registered
18/09/2013
Date last updated
15/07/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
An experimental study to characterize the effectiveness of ferroquine against early Plasmodium falciparum malaria in healthy volunteers
Scientific title
An experimental study to characterize the effectiveness of ferroquine against early Plasmodium falciparum blood stage infection in healthy volunteers
Secondary ID [1] 283214 0
Nil
Universal Trial Number (UTN)
Nil
Trial acronym
Nil
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria Infection 290077 0
Condition category
Condition code
Infection 290459 290459 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a single-centre, controlled, study using induced blood stage malaria (IBSM) infection to characterize the effectiveness of ferroquine against early Plasmodium falciparum blood stage infection. The study will be conducted in 2 cohorts (n= 8 in each). Each participant in the cohort will be inoculated on Day 0 with ~1,800 viable Plasmodium falciparum-infected human erythrocytes (BSPC) administered intravenously. On the day designated for commencement of treatment, as determined by qPCR results, participants will begin treatment with ferroquine. The threshold for commencement of treatment will be when PCR quantification of all subjects is greater than or equal to 1,000 parasites/mL. If the PCR quantification of a subject is greater than or equal to 5,000 parasites/mL or if clinical or parasitological evidence of malaria occurs in a subject, before all subjects have reached the treatment threshold, of =1,000 parasites/mL then allocated treatment of that subject will begin at this time . It is expected that treatment will commence 7-8 days following inoculation.
The first cohort will be dosed with a single oral dose of 800mg ferroquine. The subsequent dose in the second cohort will be determined following a review of observed ferroquine safety, and pharmacodynamic outcome (activity of the drug as defined by parasite clearance kinetics). It is anticipated that the subsequent dose will be between 300mg and 1200mg. Cohort 1 data will be reviewed by the by Safety Review Team, to determine cohort 2 start date and dose. All participants will be administered Riamet which is a standard treatment for Malaria at the end of study to ensure clearance of parasites.
Intervention code [1] 287940 0
Treatment: Drugs
Comparator / control treatment
The study involves 2 cohorts. The first cohort will receive an oral dose 800mg ferroquine. The second cohort will receive an oral dose of ferroquine at a dose to be determined following a review of observed ferroquine safety, and pharmacodynamic outcome (as defined by parasite clearance kinetics). It is anticipated that the subsequent dose will be between 300mg and 1200mg
Control group
Dose comparison

Outcomes
Primary outcome [1] 290485 0
To characterize the pharmacokinetic-pharmacodynamic relationship of ferroquine on 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 PK sampling.
Timepoint [1] 290485 0
Blood testing Day 0 pre inoculums then 2, 4, 8, 12, 16, 20, 24, 30, 36, 48, 72 hours then AM/PM or AM sampling until 2 consecutive negative PCR results.
Blood sampling for PK: Pre ferroquine dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144 hours, 8, 11, 14 Days post ferroquine dose, then end of study day 28
Secondary outcome [1] 304605 0
To characterize the pharmacokinetics of ferroquine in the challenge model. This outcome will be measured by monitoring drug levels in the blood by PK sampling
Timepoint [1] 304605 0
Pre ferroquine dose, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144 hours, 8, 11, 14 Days post ferroquine dose, then end of study day 28
Secondary outcome [2] 304606 0
To assess the tolerability of ferroquine in the challenge model.
This outcome will be measured by Physical examination, vital signs, clinical laboratory blood testing, ECG, Urine screening, Assessment of Adverse events such as fever, nausea, muscle and joint pain, fatigue
Timepoint [2] 304606 0
Physical examination, vital signs: Screening, Day 0 4-28
Clinical laboratory blood testing: Screening, Day 0 4-28
ECG: screening, Day 0 on admission prior to ferroquine administration final study day 28
Urine screening: screening, Day 0, on confinement, on commencement of rescue medication.
Assessment of Adverse events: Day 0-28

Eligibility
Key inclusion criteria
Demography:
*Male and non-pregnant female volunteers, between 18 and 50 years of age, inclusive; Body weight, minimum 50.0 kg, body mass index between 18.0 and 32.0 kg/m2, inclusive.

Health status:
*Certified as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination), including normal vital signs
*Normal standard 12-lead electrocardiogram (ECG)
*Laboratory parameters within the normal range, unless the Investigator considers an abnormality to be clinically irrelevant for healthy subjects.
*Female volunteers not to have childbearing potential through completion of the study and have negative results on a serum pregnancy test done before administration of study medication.
*Male volunteers must agree to use appropriate protection to prevent pregnancy in female partner for at least 14 days prior to the time of the first dose of study drug through 90 days after the last dose of study drug
Regulations:
*Having given written informed consent prior to undertaking any study-related procedure.
Minimum age
18 Years
Maximum age
50 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Medical history and clinical status:
*Any history of malaria or having travelled to or lived in a malaria-endemic country during the past 12 months.
*Increased cardiovascular disease risk
*History of splenectomy.
*Pregnant or breast feeding
*Presence or history of drug hypersensitivity, or allergic disease
*Presence of current or suspected serious chronic diseases including psychiatric illness
*Evidence of acute illness within the four weeks before trial prior to screening.
*Condition or disease that might affect drug absorption, distribution or excretion
*Participation in any investigational product study within the 8 weeks preceding the study.
*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.
*Volunteer unwilling to defer blood donations to the ARCBS for 6 months.
*Volunteer who have ever received a blood transfusion.
*History or presence of alcohol or drug abuse
*Smoking more than 5 cigarettes or equivalent per day
Interfering substance:
*Any medication (including St John’s Wort or therapy with an antibiotic or drug with potential antimalarial activity (tetracycline, azithromycin, clindamycin, hydroxychloroquine etc.) within 14 days before inclusion or within 5 times the elimination half-life or pharmacodynamic half-life of the medication, any vaccination within the last 28 days.

General conditions:
*Any subject who, in the judgment of the Investigator, is likely to be noncompliant during the study, or unable to cooperate because of a language problem or poor mental development.
*Any subject who do live alone (from Day 0 until at least the end of the antimalarial drug treatment and who cannot be contacted in case of emergency for the duration of the trial and up to 2 weeks following end of study visit.
*Any subject without a good peripheral venous access.

Biological status:
*Positive result on any of the following tests: hepatitis B surface (HBs Ag) antigen, antihepatitis B core antibodies (anti-HBc Ab), anti-hepatitis C virus (anti-HCV) antibodies, anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti HIV2 Ab),
*Any illicit drugs in the urine drug screen unless there is an explanation acceptable to the medical investigator or Positive alcohol test.

*Known hypersensitivity to ferroquine or other 4-aminoquinolines, artemether or other artemisinin derivatives, lumefantrine or other arylaminoalcohols.
*Unwillingness to abstain from consumption of citrus (grapefruit, Seville orange, etc) or their juices, as well as all fruit juices, from admission to the clinical unit until Day 28 (End of Study) visit.
*Any history or presence of lactose intolerance.

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
Data obtained from the first cohort of the study (n=8) will be reviewed by the by Safety Review Team before cohort 2 (n=8) can begin, and the dose for cohort 2 is selected.
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
This is a study designed to determine the relationship between different drug exposures and their effects on parasite growth kinetics. Historically 8 volunteers in a dose cohort have proven sufficient to characterize the effects of a drug on malaria parasite kinetics following induction in healthy volunteers using inoculation with blood stage Plasmodium falciparum. Descriptive statistical analysis will be used. Growth and clearance of parasitemia will be compared to data on hand.

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

Funding & Sponsors
Funding source category [1] 287959 0
Charities/Societies/Foundations
Name [1] 287959 0
Medicines for Malaria Venture
Address [1] 287959 0
Medicines for Malaria Venture (MMV)
Route de Pre-Bois 20
1215 Geneva, Switzerland
Country [1] 287959 0
Switzerland
Primary sponsor type
Charities/Societies/Foundations
Name
QIMR Berghofer Medical Research Institute
Address
300 Herston Road, Herston, Brisbane, QLD, 4006
Country
Australia
Secondary sponsor category [1] 286680 0
None
Name [1] 286680 0
Address [1] 286680 0
Country [1] 286680 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289884 0
The Queensland Institute of Medical Research Human Research Ethics Committee
Ethics committee address [1] 289884 0
The Queensland Institute of Medical Research HREC
QIMR Berghofer Medical Research Institute.
300 Herston Rd
Herston QLD 4006
Australia
Ethics committee country [1] 289884 0
Australia
Date submitted for ethics approval [1] 289884 0
04/10/2013
Approval date [1] 289884 0
15/10/2013
Ethics approval number [1] 289884 0
P2012

Summary
Brief summary
This is a single-centre, controlled, study using induced blood stage malaria (IBSM) infection to characterize the effectiveness of ferroquine as a potential treatment of early Plasmodium falciparum blood stage infection in healthy volunteers. The study will be conducted in 2 cohorts (n= 8 in each) using different oral doses of ferroquine.
Trial website
Nil
Trial related presentations / publications
nil to date
Public notes

Contacts
Principal investigator
Name 42946 0
Dr James McCarthy
Address 42946 0
QIMR Berghofer Medical Research Institute
300 Herston Rd
Herston QLD 4006
Country 42946 0
Australia
Phone 42946 0
+61 7 33620222
Fax 42946 0
+61 7 3845 3637
Email 42946 0
j.mccarthy@uq.edu.au
Contact person for public queries
Name 42947 0
Ms Silvana Sekuloski
Address 42947 0
QIMR Berghofer Medical Research Institute
300 Herston Rd
Herston QLD 4006
Country 42947 0
Australia
Phone 42947 0
+61 7 38453856
Fax 42947 0
+61 7 38453507
Email 42947 0
Silvana.Sekuloski@qimr.edu.au
Contact person for scientific queries
Name 42948 0
Dr James McCarthy
Address 42948 0
QIMR Berghofer Medical Research Institute
300 Herston Rd
Herston QLD 4006
Country 42948 0
Australia
Phone 42948 0
+61 7 33620222
Fax 42948 0
+61 7 3845 3637
Email 42948 0
j.mccarthy@uq.edu.au