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Trial Review
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Trial registered on ANZCTR
Registration number
ACTRN12616000846426
Ethics application status
Approved
Date submitted
20/06/2016
Date registered
29/06/2016
Date last updated
29/11/2018
Date data sharing statement initially provided
29/11/2018
Type of registration
Prospectively registered
Titles & IDs
Public title
Dose escalation, placebo-controlled phase 1 study to assess the safety and tolerability of CSL324 in healthy adults
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Scientific title
A single dose ascending and repeated dose, randomised, double-blind, placebo-controlled study to assess the safety, pharmacokinetics and pharmacodynamics of CSL324 in healthy, adult male and female subjects.
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Secondary ID [1]
289161
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CSL324_1001
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Inflammatory and immune system disorders
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Condition category
Condition code
Inflammatory and Immune System
298747
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0
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Other inflammatory or immune system disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
The study will consist of 3 parts (Parts A, B and C). Subjects can participate in only 1 part and in only 1 dose group; in each part, subjects will be randomly assigned to either CSL324 or placebo. In Parts A and B a single infusion of either CSL324 or placebo will be administered; dose escalation may occur in these parts. There may be up to 6 subjects per dose in Parts A and B. In Part C, 10 subjects will receive 3 infusions at 21 day intervals of either CSL324 or placebo (according to their randomisation and at the same dose per infusion).
Intervention 1: Single (Parts A and B) or repeat (Part C) dose(s) of anti-human granulocyte-colony stimulating factor (G-CSF) receptor monoclonal antibody (CSL324) will be administered intravenously. The dose and infusion volume will be based upon the subject's body weight and the allowable drug concentration. Dose escalation requires Safety Review Committee review (of available blinded safety, tolerability, PK and selected PD data) and approval.
In addition to CSL324 or placebo, subjects may also receive other interventions (G-CSF and/or Cantharidin) as described below.
Intervention 2: Filgrastim (Registered Trademark: Neupogen), a recombinant form of human G-CSF, will be administered subcutaneously once a day, at approximately the same time each day on up to 6 consecutive days (from 3 days before and/or up to 3 days after CSL324 or placebo infusion depending upon the CSL324 or placebo dose amount) at a dose based upon the subject's body weight (5 microgram/kg; all Part B subjects only)
Intervention 3: Cantharidin (Registered Trademark: Cantharone), will be applied topically to the skin (on the arm), to induce a blister (all Parts A and B subjects only). Cantharidin (25 microlitres at 0.1 % weight/volume) will be administered once a day, on 2 separate days, 2 or 3 days apart (from 1 day before and up to 2 days after CSL324 or placebo infusion depending upon the CSL324 or placebo dose amount).
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Intervention code [1]
294687
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Treatment: Drugs
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Comparator / control treatment
Placebo (saline) will be administered as an IV infusion at the same frequency, volume and duration as the CSL324 infusion(s) in Parts A, B and C.
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Control group
Placebo
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Outcomes
Primary outcome [1]
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Percentage of subjects with adverse events (AEs) overall and by relatedness and severity.
AEs will be assessed through evaluation of physical and neurological examinations, vital signs, electrocardiograms, clinical laboratory parameters, and monitoring of AEs. AEs will be recorded during the study and summarised by relatedness and severity using descriptive statistics.
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Assessment method [1]
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Timepoint [1]
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For the duration of the subject's participation in the study, up to 5 months per subject
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Secondary outcome [1]
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Area under the plasma concentration versus time curve (AUC) of CSL324 from the time of dosing extrapolated to time infinity (AUC0-inf) (Parts A and B)
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Assessment method [1]
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Timepoint [1]
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Before study drug infusion, at the end of infusion, and at approximately 6, 12, 24, 36, 48, 72 and 96 hours after the end of infusion, and at approximately 8, 11, 15, 23, 29, 41, 51 and 85 days after infusion
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Secondary outcome [2]
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Area under the plasma concentration versus time curve of CSL324 from the time of dosing up to collection time t (AUC0-t)
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Assessment method [2]
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Timepoint [2]
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Parts A and B: Before study drug infusion, at the end of infusion, and at approximately 6, 12, 24, 36, 48, 72 and 96 hours after the end of infusion, and at approximately 8, 11, 15, 23, 29, 41, 51 and 85 days after infusion
Part C: Before each study drug infusion, at the end of infusion for the 1st and 3rd infusions, at 1, 2, 4 and approximately 7 days after the 1st infusion, at 1 and approximately 7 days after the 2nd infusion, and at approximately 6 hours and at approximately 1, 2, 6, 13, 20, 27 and 83 days after the 3rd infusion.
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Secondary outcome [3]
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Area under the plasma concentration versus time curve of CSL324 during dosing interval at steady state (AUC0-tau; Part C).
AUC0-tau will be derived from serum CSL324 concentration-time profiles.
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Assessment method [3]
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Timepoint [3]
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Part C: Before each study drug infusion, at the end of infusion for the 1st and 3rd infusions, at 1, 2, 4 and approximately 7 days after the 1st infusion, at 1 and approximately 7 days after the 2nd infusion, and at approximately 6 hours and at approximately 1, 2, 6, 13, 20, 27 and 83 days after the 3rd infusion.
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Secondary outcome [4]
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Maximum serum CSL324 concentration (Cmax; Parts A and B), and Cmax at steady state (Cmax,ss; Part C)
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Assessment method [4]
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Timepoint [4]
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Parts A and B: Before study drug infusion, at the end of infusion, and at approximately 6, 12, 24, 36, 48, 72 and 96 hours after the end of infusion, and at approximately 8, 11, 15, 23, 29, 41, 51 and 85 days after infusion.
Part C: Before each study drug infusion, at the end of infusion for the 1st and 3rd infusions, at 1, 2, 4 and approximately 7 days after the 1st infusion, at 1 and approximately 7 days after the 2nd infusion, and at approximately 6 hours and at approximately 1, 2, 6, 13, 20, 27 and 83 days after the 3rd infusion.
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Secondary outcome [5]
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Clearance of CSL324 (CLtot; Parts A and B), and Clearance at steady state (Cltot,ss; Part C).
Clearance will be derived from the serum CSL324 concentration-time profiles.
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Assessment method [5]
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Timepoint [5]
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Parts A and B: Before study drug infusion, at the end of infusion, and at approximately 6, 12, 24, 36, 48, 72 and 96 hours after the end of infusion, and at approximately 8, 11, 15, 23, 29, 41, 51 and 85 days after infusion.
Part C: Before each study drug infusion, at the end of infusion for the 1st and 3rd infusions, at 1, 2, 4 and approximately 7 days after the 1st infusion, at 1 and approximately 7 days after the 2nd infusion, and at approximately 6 hours and at approximately 1, 2, 6, 13, 20, 27 and 83 days after the 3rd infusion.
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Secondary outcome [6]
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Time to maximum serum CSL324 concentration (Tmax; Parts A and B), and Tmax at steady state (Tmax,ss; Part C)
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Assessment method [6]
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Timepoint [6]
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Parts A and B: Before study drug infusion, at the end of infusion, and at approximately 6, 12, 24, 36, 48, 72 and 96 hours after the end of infusion, and at approximately 8, 11, 15, 23, 29, 41, 51 and 85 days after infusion.
Part C: Before each study drug infusion, at the end of infusion for the 1st and 3rd infusions, at 1, 2, 4 and approximately 7 days after the 1st infusion, at 1 and approximately 7 days after the 2nd infusion, and at approximately 6 hours and at approximately 1, 2, 6, 13, 20, 27 and 83 days after the 3rd infusion.
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Secondary outcome [7]
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Terminal elimination half-life of CSL324 (t1/2; Parts A and B), and t1/2 at steady state (T1/2,ss; Part C).
t1/2 will be derived from serum CSL324 concentration-time profiles.
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Assessment method [7]
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Timepoint [7]
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Parts A and B: Before study drug infusion, at the end of infusion, and at approximately 6, 12, 24, 36, 48, 72 and 96 hours after the end of infusion, and at approximately 8, 11, 15, 23, 29, 41, 51 and 85 days after infusion.
Part C: Before each study drug infusion, at the end of infusion for the 1st and 3rd infusions, at 1, 2, 4 and approximately 7 days after the 1st infusion, at 1 and approximately 7 days after the 2nd infusion, and at approximately 6 hours and at approximately 1, 2, 6, 13, 20, 27 and 83 days after the 3rd infusion.
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Secondary outcome [8]
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Volume of distribution (Vz; Parts A and B), and Vz at steady state during the terminal phase (Vz,ss; Part C).
Vz will be derived from serum CSL324 concentration-time profiles.
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Assessment method [8]
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Timepoint [8]
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Parts A and B: Before study drug infusion, at the end of infusion, and at approximately 6, 12, 24, 36, 48, 72 and 96 hours after the end of infusion, and at approximately 8, 11, 15, 23, 29, 41, 51 and 85 days after infusion.
Part C: Before each study drug infusion, at the end of infusion for the 1st and 3rd infusions, at 1, 2, 4 and approximately 7 days after the 1st infusion, at 1 and approximately 7 days after the 2nd infusion, and at approximately 6 hours and at approximately 1, 2, 6, 13, 20, 27 and 83 days after the 3rd infusion.
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Secondary outcome [9]
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Concentrations of CSL324 and G-CSF in cerebrospinal fluid (Part A only)
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Assessment method [9]
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Timepoint [9]
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At approximately 3 days after the end of infusion of the last dose of study drug
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Secondary outcome [10]
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Number of subjects with anti-CSL324 antibodies in serum
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Assessment method [10]
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Timepoint [10]
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Parts A and B: Before study drug infusion and at approximately 29, 51 and 85 days after infusion.
Part C: Before each study drug infusion and at approximately 20, 27 and 83 days after the last infusion.
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Secondary outcome [11]
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Maximum neutrophil concentration after filgrastim dosing (Emax,ANC; Part B).
Maximum effect of blood absolute neutrophil count after filgrastim dosing will be assessed using non-compartmental method
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Assessment method [11]
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Timepoint [11]
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Before each filgrastim infusion, and at approximately 8 hours after filgrastim infusions 1 to 5, and at approximately 8, 12 and 24 hours after the last filgrastim infusion.
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Secondary outcome [12]
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Area under the effect curve for absolute neutrophil count after filgrastim dosing (AUEC0-24,ANC; Part B).
AUEC0-24, ANC for blood absolute neutrophil count after filgrastim dosing will be assessed using non-compartmental method.
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Assessment method [12]
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Timepoint [12]
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Before each filgrastim infusion, and at approximately 8 hours after filgrastim infusions 1 to 5, and at approximately 8, 12 and 24 hours after the last filgrastim infusion.
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Secondary outcome [13]
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Minimum (trough) serum CSL324 concentration at steady state (Cmin,ss; Part C)
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Assessment method [13]
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Timepoint [13]
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Part C: Before each study drug infusion, at the end of infusion for the 1st and 3rd infusions, at 1, 2, 4 and approximately 7 days after the 1st infusion, at 1 and approximately 7 days after the 2nd infusion, and at approximately 6 hours and at approximately 1, 2, 6, 13, 20, 27 and 83 days after the 3rd infusion.
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Eligibility
Key inclusion criteria
- Healthy, male or female, 18 to 55 years of age
- Body mass index range of 18.5 to 32.0 kg/m^2, inclusive, and weight at least 50 kg and less than 100 kg
- Females must be of non-childbearing potential
- Male subject and their female spouse/partners who are of childbearing potential must be using 2 forms of highly effective birth control
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Minimum age
18
Years
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Maximum age
55
Years
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Sex
Both males and females
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Can healthy volunteers participate?
Yes
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Key exclusion criteria
- History or evidence of any clinically significant cardiovascular, gastrointestinal, endocrine, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal and/or other major disease or malignancy
- History of venous thrombosis, polycythaemia or thrombophilia
- History of autoimmune disease with the exception of seasonal allergic rhinitis managed without systemic glucocorticoid treatment
- Any history of cyclic neutropenia or a Screening absolute neutrophil count < 2.0 × 10^9/L
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people assessing the outcomes
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Intervention assignment
Other
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Other design features
Sequential single ascending dose groups (Parts A and B); repeat dose group (Part C).
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Phase
Phase 1
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Type of endpoint/s
Safety
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Date of first participant enrolment
Anticipated
30/06/2016
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Actual
30/06/2016
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Date of last participant enrolment
Anticipated
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Actual
17/08/2017
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Date of last data collection
Anticipated
4/01/2018
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Actual
2/01/2018
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Sample size
Target
58
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Accrual to date
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Final
56
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Recruitment in Australia
Recruitment state(s)
VIC
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Funding & Sponsors
Funding source category [1]
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Commercial sector/Industry
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Name [1]
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CSL Limited
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Address [1]
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45 Poplar Rd,
Parkville, VIC 3052
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Country [1]
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Australia
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Primary sponsor type
Commercial sector/Industry
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Name
CSL Limited
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Address
45 Poplar Rd,
Parkville, VIC 3052
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Country
Australia
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Secondary sponsor category [1]
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None
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Name [1]
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Address [1]
292365
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Country [1]
292365
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
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Alfred Hospital Ethics Committee
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Ethics committee address [1]
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Office of Ethics & Research Governance 55 Commercial Road Melbourne, VIC, 3004
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Ethics committee country [1]
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Australia
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Date submitted for ethics approval [1]
294990
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Approval date [1]
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12/05/2016
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Ethics approval number [1]
294990
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Summary
Brief summary
This is a first-in-human, randomised, double-blind, placebo-controlled study. The study is designed to assess the safety, tolerability and pharmacokinetics of single ascending dose (Parts A and B) and repeated (Part C) intravenous infusions of CSL324 or placebo (saline) in healthy subjects. Subjects will have blood collected at various time points for safety laboratory evaluations, absolute neutrophil count (ANC) and pharmacokinetic (PK) and pharmacodynamic (PD) sampling, and will be assessed for 3 months after infusion to assess immunogenicity and longer term safety. Skin test(s) will be used to assess the anti-inflammatory effect of CSL324 in response to an inflammatory stimulus (Parts A and B). Cerebrospinal fluid will be collected by lumbar puncture from subjects in the highest dose group in Part A after the last infusion of CSL324 or placebo, to determine whether CSL324 distributes into the cerebrospinal fluid. Subjects in Part B will also receive multiple subcutaneous doses of filgrastim to stimulate an increase in circulating neutrophils and provide additional PD data.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Dr Jason Lickliter
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Address
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Nucleus Network
89 Commercial Road
Melbourne, VIC 3004
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Country
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Australia
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Phone
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+61 3 9076 8960
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Fax
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Email
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j.lickliter@nucleusnetwork.com.au
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Contact person for public queries
Name
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Biljana Georgievska
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Address
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Nucleus Network
89 Commercial Road,
Melbourne VIC 3004
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Country
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Australia
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Phone
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1800 243 733
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Fax
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Email
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b.georgievska@nucleusnetwork.com.au
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Contact person for scientific queries
Name
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Biljana Georgievska
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Address
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Nucleus Network
89 Commercial Road,
Melbourne VIC 3004
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Country
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Australia
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Phone
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1800 243 733
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Fax
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Email
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b.georgievska@nucleusnetwork.com.au
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
Individual Participant Data (IPD) will not be shared.
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What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
Documents added manually
No documents have been uploaded by study researchers.
Documents added automatically
Source
Title
Year of Publication
DOI
Embase
CSL324, a granulocyte colony-stimulating factor receptor antagonist, blocks neutrophil migration markers that are upregulated in hidradenitis suppurativa.
2023
https://dx.doi.org/10.1093/bjd/ljad013
N.B. These documents automatically identified may not have been verified by the study sponsor.
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