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Trial registered on ANZCTR


Registration number
ACTRN12611001203943
Ethics application status
Approved
Date submitted
21/11/2011
Date registered
23/11/2011
Date last updated
11/03/2014
Type of registration
Prospectively registered

Titles & IDs
Public title
Immune response in a human malaria challenge system.
Scientific title
An experimental study to characterize molecular signatures during early Plasmodium falciparum blood stage infection in healthy male volunteers.
Secondary ID [1] 273441 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 279228 0
Condition category
Condition code
Infection 279435 279435 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a single-centre, controlled study using a Blood Stage Plasmodium Falciparum Challenge (BSPC) inoculum challenge to characterize molecular signatures during early Plasmodium falciparum blood stage infection The study will be conducted in 2 or more cohorts (n equal to 8 and n equal 8). Cohort 2 will not commence until at least after day 13 of the previous cohort and review by Safety Review Team following day 10 exit of the previous cohort.
Each participant in the cohort will be inoculated on Day 0 with approximately 450 Plasmodium falciparum-infected human erythrocytes administered intravenously. On an outpatient basis, participants will be monitored daily (AM) or morning (AM) and evening (PM) (once PCR positive for presence of malaria parasites) from day 1 to day 9 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 antimalarial treatment. The threshold for commencement of treatment will be when PCR quantification is confirmed to be greater than or equal to 1,000 parasites/mL when the participants will be administered antimalarial treatment. If clinical or parasitological evidence of malaria (either the identification of two or more malaria parasites on a malaria thick film, platelet count less than 100 x109/L, 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 9 morning, allocated treatment will begin at this time.
Following treatment, participants will be followed up as inpatients for at least 36 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.
Adverse events will be monitored via telephone monitoring, within the clinical research unit and on outpatient review after malaria challenge inoculation and antimalarial study drug administration. Blood samples for safety evaluation, malaria monitoring and red blood cell antibodies will be drawn at baseline and at nominated times after malaria challenge.
Intervention code [1] 283772 0
Prevention
Comparator / control treatment
Cohort 2, which will not commence until at least after day 13 of the previous cohort and review by Safety Review Team following day 10 exit of the previous cohort.
Control group
Active

Outcomes
Primary outcome [1] 286005 0
Comparison of the gene expression profiles of whole blood and T cell subsets before and after experimental challenge with a low dose of Plasmodium falciparum blood stage parasites.
Timepoint [1] 286005 0
Using mass array analysis to compare gene expression profiles of whole blood and T cell subsets before and 28 days after experimental challenge with a low dose of Plasmodium falciparum blood stage parasites.
Secondary outcome [1] 294958 0
Identification of molecular signatures that predict disease outcome.
Timepoint [1] 294958 0
Compare signatures obtained in expression profile studies 28 days after challenge to those seen in natural malaria infection.
Secondary outcome [2] 294959 0
Investigation of gametocyte maturation during early blood stage infection.
Timepoint [2] 294959 0
Documenting transcription levels of gametocyte-specific genes between days 7 and 14.

Eligibility
Key inclusion criteria
1) Volunteers will be males, 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) Good peripheral venous access
Minimum age
18 Years
Maximum age
45 Years
Gender
Males
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., (15). 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 µg per day or fluticasone 750 µg)
19) Presence of acute infectious disease or fever (e.g., sub-lingual temperature ? 38.5°C) 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 must be =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 listed Appendix 2 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.

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
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Not applicable (nonrandomised 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
Single group
Other design features
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] 284235 0
Charities/Societies/Foundations
Name [1] 284235 0
Australian Centre for Vaccine Development, QIMR
Address [1] 284235 0
Queensland Institute of Medical Research
300 Herston Road, Herston, Brisbane, QLD, 4006
Country [1] 284235 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Queensland Institute of Medical Research
Address
300 Herston Rd, Herston, Queensland, 4006
Country
Australia
Secondary sponsor category [1] 269191 0
None
Name [1] 269191 0
Address [1] 269191 0
Country [1] 269191 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 286199 0
The Queensland Institute of Medical Research Human Research Ethics Committee
Ethics committee address [1] 286199 0
The Queensland Institute of Medical Research
300 Herston Road, Herston
Brisbane
Queensland
4006
Ethics committee country [1] 286199 0
Australia
Date submitted for ethics approval [1] 286199 0
04/10/2011
Approval date [1] 286199 0
21/11/2011
Ethics approval number [1] 286199 0
P1409

Summary
Brief summary
This is a Phase II clinical trial for the study of the efficacy of antimalarial drugs against Plasmodium falciparum by experimental challenge with a low dose of blood stage parasites in healthy male 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 compare the gene expression profiles of whole blood and T cell subsets before and after experimental challenge with a low dose of Plasmodium falciparum blood stage parasites;

To identify molecular signatures that predict disease outcome, as well as the safety and efficacy of future malaria vaccines and to investigate gametocyte maturation during early blood stage infection.
Trial website
http://www.qpharm.com.au/Volunteers/VolunteerRegistration.aspx
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 33417 0
Dr James McCarthy
Address 33417 0
Queensland Institute of Medical Research
300 Herston Rd
Herston, Brisbane
QLD 4006
Country 33417 0
Australia
Phone 33417 0
+61 7 33620222
Fax 33417 0
61 7 3845 3637
Email 33417 0
j.mccarthy@uq.edu.au
Contact person for public queries
Name 16664 0
Dr Suzanne Elliott
Address 16664 0
Q-Pharm Pty Ltd
QIMR
Clive Berghofer Cancer Research Centre
Level D
300 Herston Rd
Herston QLD 4006
Country 16664 0
Australia
Phone 16664 0
61 7 3845 3636
Fax 16664 0
61 7 3845 3637
Email 16664 0
s.elliott@qpharm.com.au
Contact person for scientific queries
Name 7592 0
Dr Suzanne Elliott
Address 7592 0
Q-Pharm Pty Ltd
QIMR
Clive Berghofer Cancer Research Centre
Level D
300 Herston Rd
Herston QLD 4006
Country 7592 0
Australia
Phone 7592 0
61 7 3845 3636
Fax 7592 0
61 7 3845 3637
Email 7592 0
s.elliott@qpharm.com.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary