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Trial registered on ANZCTR


Trial ID
ACTRN12612000323820
Ethics application status
Approved
Date submitted
20/03/2012
Date registered
21/03/2012
Date last updated
17/01/2013
Type of registration
Prospectively registered

Titles & IDs
Public title
An experimental study to characterize the effectiveness of Lariam (Registered Trademark) (Mefloquine) against early malaria blood stage infection in healthy volunteers.
Scientific title
An experimental study to characterize the effectiveness of Lariam(Registered Trademark) (Mefloquine) against early Plasmodium falciparum blood stage infection in healthy volunteers.
Secondary ID [1] 280174 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 286085 0
Condition category
Condition code
Infection 286280 286280 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a single-center, controlled, study using a blood stage Plasmodium Falciparum challenge (BSPC) inoculum to characterize the effectiveness of mefloquine against early Plasmodium falciparum blood stage infection. The study will be conducted in up to 3 cohorts (n= 8 in each) using different doses of mefloquine.A single dose of oral tablet mefloquine will be administered when PCR quantification is confirmed to be greater than or equal to 1,000 parasites/mL. The first dose of mefloquine investigated will be 5 mg/kg. Subsequent doses will be determined following a review of observed mefloquine safety, and pharmacodynamic outcome. It is anticipated that subsequent doses will be 10 and 15 mg/kg. However the doses will be determined following review by the Safety Review Team, and will be selected based on patient safety and 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.
Each participant in the cohort will be inoculated on Day 0 with ~1,800 viable Plasmodium falciparum-infected human erythrocytes administered intravenously. On an outpatient basis, participants will be monitored daily (AM) or morning (AM) and evening (PM) (from day 3 until PCR positive for presence of malaria parasites) for adverse events and the unexpected early onset of symptoms, signs or parasitological evidence of malaria. On the day designated for commencement of treatment, as determined by qPCR results, participants will be admitted to the study unit and confined for safety monitoring and mefloquine administration with parasite load and drug levels being monitored. The threshold for commencement of treatment will be when PCR quantification is confirmed to be greater than or equal to 1,000 parasites/mL. If clinical or parasitological evidence of malaria (either the identification of two or more malaria parasites on a malaria thick film, or the onset of clinical features of malaria) occurs, or PCR quantification of greater than or equal to 1,000 parasites/mL is detected before day 7 morning, allocated treatment will begin at this time. Following treatment with mefloquine, participants will be followed up as inpatients for at least 48 hours, to ensure tolerance of the therapy and clinical response, then if clinically well on an outpatient basis for safety and continued presence of malaria parasites via PCR and thick blood film review.
Intervention code [1] 284487 0
Treatment: Drugs
Comparator / control treatment
There is no comparison treatment as this trial is not randomised within cohort i.e.all subjects in each cohort get the same treatment.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 286746 0
To characterize the pharmacokinetic-pharmacodynamic relationship of mefloquine on clearance of Plasmodium falciparum parasites from the blood in healthy volunteers following infection with blood stage parasites.
This outcome will be assessed by PCR quantitation of parasite clearance kinetics in conjunction with drug levels.
Timepoint [1] 286746 0
Day 90
Secondary outcome [1] 296581 0
To characterize the pharmacokinetics of mefloquine in healthy volunteers following infection with blood stage Plasmodium falciparum.
This outcome will be assessed by an assay of plasma drug levels
Timepoint [1] 296581 0
Day 28
Secondary outcome [2] 296582 0
To characterize the relationship between mefloquine pharmacokinetics and parasite kinetics in healthy volunteers following infection with blood stage Plasmodium falciparum.
This outcome will be assessed by PCR quantitation of parasite clearance kinetics in conjunction with drug levels.
Timepoint [2] 296582 0
Day 90
Secondary outcome [3] 296583 0
To assess the tolerability of mefloquine in the experimental malaria challenge system.
This outcome will be assessed by using a directed questionnaire to elicit mood, nausea and sleeping disturbance
Timepoint [3] 296583 0
Day 14

Eligibility
Key inclusion criteria
1. Volunteers will be adults (males or non pregnant females), 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. Volunteers must have a BMI within the range 18–30.
3. Volunteers must understand the procedures involved and agree to participate in the study by giving fully informed, written consent.
4. Be contactable and available for the duration of the trial (maximum of 4 weeks).
5. Volunteers must be non-smokers and in good health, as assessed during pre-study medical examination and by review of screening results.
6. Female participants 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.
7. 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
2) Travelled to or lived (>2 weeks) in a malaria-endemic country during the past 12 months or planned travel to a malaria-endemic country during the course of the study
3) Has evidence of increased cardiovascular disease risk (defined as >10%, 5 year risk) as determined by the method of Gaziano et al. Risk factors include sex, age, systolic blood pressure (mm Hg), smoking status, body mass index (BMI, kg/mm2), reported diabetes status and blood pressure
4) History of splenectomy
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 malnutrition, acute or progressive hepatic disease, acute or progressive renal disease, psoriasis, rheumatoid arthritis, asthma, epilepsy or obsessive compulsive disorder, skin carcinoma excluding non spreadable skin cancers such as basal cell and squamous cell carcinoma
7) Known inherited genetic anomaly (known as cytogenetic disorders) e.g., Down’s syndrome
8) Volunteers wishing to be able to donate blood to the ARCBS in the future
9) Presence of retinal or visual field changes either attributable to 4-aminoquinoline compounds or to any other etiology
10) The volunteer has a diagnosis of schizophrenia, bi-polar disease, or other severe (disabling) chronic psychiatric diagnosis
11) The volunteer has been hospitalized within the past 5 years prior to enrollment for psychiatric illness, history of suicide attempt or confinement for danger to self or others
12) The volunteer is receiving psychiatric drugs. Participants who are receiving a single antidepressant drug and are stable for at least 3 months prior to enrollment without decompensating may be allowed to enroll in the study at the investigator’s discretion.
13) Known pre-existing prolongation of the QTc interval
14) Family history of congenital prolongation of the QTc interval on electrocardiograms or of sudden death or any other clinical condition known to prolong the QTc interval, e.g. volunteers with a history of symptomatic cardiac arrhythmias, with clinically relevant bradycardia or with severe cardiac disease
15) Recent or current therapy with an antibiotic or drug with potential antimalarial activity (tetracycline, azthromycin, clindamycin, hydroxychloroquine etc.)
16) Known hypersensitivity to sulfa drugs
17) Concomitant use of any drug which is metabolised by the cytochrome enzyme CYP2D6 (e.g. flecainide, metoprolol, imipramine, amitriptyline, clomipramine) OR drugs that are known to prolong the QTc interval, e.g. antiarrhythmics of classes IA and III, neuroleptics, antidepressant agents, certain antibiotics (including some agents of the following classes: macrolides, fluoroquinolones, imidazole and triazole antifungal agents), certain nonsedating antihistamines (terfenadine, astemizole), cisapride.
18) Use of corticosteroids, anti-inflammatory drugs, any immunomodulators or anticoagulants. Currently receiving or have previously received immunosuppressive therapy, including systemic steroids including ACTH or inhaled steroids in dosages which are associated with hypothalamic-pituitary-adrenal axis suppression such as 1mg/kg/day of prednisone or its equivalent or chronic use of inhaled high potency corticosteroids (budesonide 800 micrograms per day or fluticasone 750 micrograms)
19) Presence of acute infectious disease or fever (e.g., sub-lingual temperature 38.5 degrees celsius) within the five days prior to study product administration)
20) Evidence of acute illness within the four weeks before trial prior to screening
21) 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
22) Alcohol consumption greater than community norms (i.e. more than 21 standard drinks per week for males)
23) A history of drug habituation, or any prior intravenous usage of an illicit substance
24) Medical requirement for intravenous immunoglobulin or blood transfusions
25) Participation in any investigational product study within the 8 weeks preceding the study 26) 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
27) Have ever received a blood transfusion
28) Positive test for HIV, Hepatitis B, hepatitis C, Human T-cell Lymphotropic Virus I & II (HTLVI & HTLVII), and syphilis
29) Any clinically significant biochemical or haematologic abnormality (Hb greater than or equal to 13.5g/dL)
30) 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)
31) Detection of any drug in the urine drug screen unless there is an explanation acceptable to the medical investigator (e.g. the subject has stated in advance that they consumed a prescription or OTC product which contained the detected drug) and/or the subject has a negative urine drug screen on retest by the pathology laboratory
32.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 participants.

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)
Not applicable (non-randomised trial)
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
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

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)

Funding & Sponsors
Funding source category [1] 284910 0
Charities/Societies/Foundations
Name [1] 284910 0
Medicines of Malaria Venture
Address [1] 284910 0
Australian centre for vaccine development
300 Herston Road, Herston, Brisbane, QLD
Australia
4006
Country [1] 284910 0
Australia
Funding source category [2] 284927 0
Charities/Societies/Foundations
Name [2] 284927 0
Queensland Institute of Medical Research
Address [2] 284927 0
300 Herston Road, Herston, Brisbane, QLD
Australia
4006
Country [2] 284927 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
The Queensland Institute of Medical Research
Address
300 Herston Rd, Herston,Brisbane, Queensland, 4006
Country
Australia
Secondary sponsor category [1] 283786 0
None
Name [1] 283786 0
Address [1] 283786 0
Country [1] 283786 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 286908 0
The Queensland Institute of Medical Research Human Research Ethics Committee
Ethics committee address [1] 286908 0
The Queensland Institute of Medical Research, Post Office Royal Brisbane,QLD, 4029
Ethics committee country [1] 286908 0
Australia
Date submitted for ethics approval [1] 286908 0
29/02/2012
Approval date [1] 286908 0
09/03/2012
Ethics approval number [1] 286908 0
P1444

Summary
Brief summary
This is a Phase II clinical trial for the study of the efficacy of Lariam (Mefloquine) antimalarial drugs against Plasmodium falciparum by experimental challenge with a low dose of blood stage parasites in healthy adult volunteers. This trial is to be conducted under the Australian Therapeutic Goods Administration (TGA) Clinical Trial Notification Scheme(CTN). The purpose of the study is to characterize the pharmacokinetic-pharmacodynamic relationship of mefloquine on clearance of Plasmodium falciparum parasites from the blood in healthy volunteers following infection with blood stage parasites, to characterize the pharmacokinetics and the relationship between mefloquine pharmacokinetics and parasite kinetics in healthy volunteers following infection with blood stage Plasmodium falciparum.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 33935 0
Dr James McCarthy
Address 33935 0
Queensland Institute of Medical Research 300 Herston Rd Herston QLD 4029
Country 33935 0
Australia
Phone 33935 0
+61 7 3845 3796
Fax 33935 0
61 7 3362 0104
Email 33935 0
James.McCarthy@qimr.edu.au
Contact person for public queries
Name 17182 0
Dr Suzanne Elliott
Address 17182 0
Q-Pharm Pty Ltd
QIMR
Clive Berghofer Cancer Research Centre
Level D
300 Herston Rd
Herston QLD 4006
Country 17182 0
Australia
Phone 17182 0
61 7 3845 3636
Fax 17182 0
61 7 3845 3637
Email 17182 0
s.elliott@qpharm.com.au
Contact person for scientific queries
Name 8110 0
Dr Suzanne Elliott
Address 8110 0
Q-Pharm Pty Ltd
QIMR
Clive Berghofer Cancer Research Centre
Level D
300 Herston Rd
Herston QLD 4006
Country 8110 0
Australia
Phone 8110 0
61 7 3845 3636
Fax 8110 0
61 7 3845 3637
Email 8110 0
s.elliott@qpharm.com.au