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Trial registered on ANZCTR


Registration number
ACTRN12616001438448
Ethics application status
Approved
Date submitted
11/10/2016
Date registered
14/10/2016
Date last updated
29/11/2018
Date data sharing statement initially provided
29/11/2018
Date results information initially provided
29/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1, Safety and Pharmacokinetic Study of CSL312 in Healthy Subjects
Scientific title
A phase 1, single-centre, randomised, double-blind, placebo-controlled, single ascending dose study to investigate the safety, tolerability and pharmacokinetics of intravenous and subcutaneous CSL312 in healthy subjects.
Secondary ID [1] 290297 0
CSL312_1001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hereditary Angioedema 300542 0
Condition category
Condition code
Human Genetics and Inherited Disorders 300400 300400 0 0
Other human genetics and inherited disorders
Inflammatory and Immune System 300401 300401 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a single centre, randomised, double-blind phase 1 study to assess the safety, tolerability and pharmacokinetics (PK) of single ascending doses of intravenous (IV) or subcutaneous (SC) administrations of CSL312 in healthy subjects.

Subjects can participate in only 1 dose group and will be randomly assigned to receive a single dose of either CSL312 or placebo by IV infusion or SC injection (abdomen). Study drugs will be administered at the study site by study staff. CSL312 is a fully human recombinant anti-FXIIa antibody (Factor XIIa antagonist monoclonal antibody), solution for injection.

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 Pharmacodynamic (PD) data.
Eight groups of 6 subjects are planned; 5 groups for IV administration and 3 groups for SC administration. Dosing and initial dose escalation will begin with the IV groups, and upon reaching the third IV group, the study will progress to the SC groups. Dose escalation within the IV and SC groups will then progress in parallel with the SC groups staggered to start after initial dosing in their respective IV groups. For all IV groups and the first SC group, 2 sentinel subjects per group will be randomised to receive CSL312 or placebo in a 1:1 ratio, and the remaining 4 subjects per group will be randomised to receive CSL312 or placebo in a 3:1 ratio.
Intervention code [1] 296102 0
Treatment: Drugs
Comparator / control treatment
Placebo (formulation buffer without CSL312) will be administered as an IV infusion or SC injection at the same frequency, volume and duration as the CSL312 infusion(s) / injection(s).
Control group
Placebo

Outcomes
Primary outcome [1] 299841 0
The percentage of subjects with adverse events (AEs) overall, and by severity and relatedness.
AEs will be assessed through evaluation of physical examinations, vital signs, electrocardiograms, clinical laboratory parameters, and monitoring of AEs. AEs will be recorded during the study and summarised by relatedness and severity.
Timepoint [1] 299841 0
For the duration of the subject's participation in the study, up to 113 days per subject. Physical examinations, vital signs, electrocardiograms and clinical laboratory parameters will be assessed at screening, the day before dosing and approx. 12 weeks after dosing. Additional assessments will be conducted as follows: physical examinations after dosing at approx. 24, 48 and 96 hours, and weekly for 5 weeks and at week 8; vital signs immediately before dosing, and after dosing at approx. 0.25, 0.5, 0.75, 1, 6, 12, 24, 48 and 96 hours, and weekly for 5 weeks and at week 8; electrocardiograms immediately before dosing, and after dosing at approx. 1 hour (IV only), 48 hours (SC only), and at 96 hours; clinical laboratory parameters after dosing at approx. 1, 2, 7 and 28 days.
Secondary outcome [1] 328272 0
Maximum concentration (Cmax) of CSL312, derived from plasma CSL312 concentration-time profiles.
Timepoint [1] 328272 0
For both IV and SC dosing: before study drug administration, and at 1, 6, 12 and 24 hours and at approximately 2, 4, 7, 14, 21, 28, 35, 56 and 84 days after the start of dosing.
Additionally, at 30 minutes after the start of IV dosing, and at 32 hours after the start of SC dosing.
Secondary outcome [2] 328273 0
Area under the plasma concentration-time curve (AUC) of CSL312 from the time of dosing up to collection time t (AUC0-t)
Timepoint [2] 328273 0
For both IV and SC dosing: before study drug administration, and at 1, 6, 12 and 24 hours and at approximately 2, 4, 7, 14, 21, 28, 35, 56 and 84 days after the start of dosing.
Additionally, at 30 minutes after the start of IV dosing, and at 32 hours after the start of SC dosing.
Secondary outcome [3] 328274 0
Area under the plasma concentration-time curve (AUC) of CSL312 from the time of dosing extrapolated to time infinity (AUC0-inf)
Timepoint [3] 328274 0
For both IV and SC dosing: before study drug administration, and at 1, 6, 12 and 24 hours and at approximately 2, 4, 7, 14, 21, 28, 35, 56 and 84 days after the start of dosing.
Additionally, at 30 minutes after the start of IV dosing, and at 32 hours after the start of SC dosing.
Secondary outcome [4] 328275 0
Time of maximum concentration (tmax) of CSL312, derived from plasma CSL312 concentration-time profiles
Timepoint [4] 328275 0
For both IV and SC dosing: before study drug administration, and at 1, 6, 12 and 24 hours and at approximately 2, 4, 7, 14, 21, 28, 35, 56 and 84 days after the start of dosing.
Additionally, at 30 minutes after the start of IV dosing, and at 32 hours after the start of SC dosing.
Secondary outcome [5] 328276 0
Terminal elimination half-life (t1/2) of CSL312, derived from plasma CSL312 concentration-time profiles
Timepoint [5] 328276 0
For both IV and SC dosing: before study drug administration, and at 1, 6, 12 and 24 hours and at approximately 2, 4, 7, 14, 21, 28, 35, 56 and 84 days after the start of dosing.
Additionally, at 30 minutes after the start of IV dosing, and at 32 hours after the start of SC dosing.
Secondary outcome [6] 328277 0
Total systemic clearance (CLtot) of CSL312, derived from plasma CSL312 concentration-time profiles
Timepoint [6] 328277 0
For both IV and SC dosing: before study drug administration, and at 1, 6, 12 and 24 hours and at approximately 2, 4, 7, 14, 21, 28, 35, 56 and 84 days after the start of dosing.
Additionally, at 30 minutes after the start of IV dosing, and at 32 hours after the start of SC dosing.
Secondary outcome [7] 328278 0
Volume of distribution of CSL312 during the elimination phase (Vz), derived from plasma CSL312 concentration-time profiles
Timepoint [7] 328278 0
For both IV and SC dosing: before study drug administration, and at 1, 6, 12 and 24 hours and at approximately 2, 4, 7, 14, 21, 28, 35, 56 and 84 days after the start of dosing.
Additionally, at 30 minutes after the start of IV dosing, and at 32 hours after the start of SC dosing.
Secondary outcome [8] 328279 0
Percentage of subjects with anti-CSL312 antibodies by plasma assay
Timepoint [8] 328279 0
Before study drug administration and approximately 84 days after dosing.
Secondary outcome [9] 328280 0
Bioavailability of CSL312
The percentage of CSL312 available in plasma after SC dosing
Timepoint [9] 328280 0
Before study drug administration, and at approximately 1, 6, 12, 24 and 32 hours and at approximately 2, 4, 7, 14, 21, 28, 35, 56 and 84 days after the start of SC dosing.

Eligibility
Key inclusion criteria
- Capable of providing written informed consent and willing and able to adhere to all protocol requirements.
- Male aged 18 to 45 years of age at the time of providing written informed consent.
- Judged as healthy by an investigator after completing a comprehensive clinical assessment (detailed medical history and complete physical examination).
- Body mass index (BMI) of 18.0 to less than 30.0 kg/m^2.
Minimum age
18 Years
Maximum age
45 Years
Gender
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
- Evidence of a clinically significant medical condition, disorder or disease including any of the following: hepatic (hepatitis, cirrhosis); biliary; renal; cardiac; bronchopulmonary; vascular; haematologic; gastrointestinal; allergy; endocrine / metabolic (diabetes, thyroid disorders, adrenal disease); neurologic; psychiatric; immunodeficiency; cancer
- History of clinically significant arterial or venous thrombosis, bleeding disorder, or any abnormal coagulation test result at Screening (confirmed by repeat measurement)
- History of a severe allergic reaction with generalised urticaria; angioedema or anaphylaxis
- Abnormal clinical laboratory values and/or other study assessments, such as vital signs or ECG, deemed clinically significant by the investigator
- Positive serology test result for hepatitis B virus (HBV) surface antigen, human immunodeficiency virus (HIV) antibody, hepatitis A virus (HAV) antibody or hepatitis C virus (HCV) antibody at Screening

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled 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
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety
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)
SA

Funding & Sponsors
Funding source category [1] 294672 0
Commercial sector/Industry
Name [1] 294672 0
CSL Limited
Address [1] 294672 0
45 Poplar Road
Parkville VIC 3052
Country [1] 294672 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
CSL Limited
Address
45 Poplar Road
Parkville VIC 3052
Country
Australia
Secondary sponsor category [1] 293522 0
None
Name [1] 293522 0
Address [1] 293522 0
Country [1] 293522 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296102 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 296102 0
129 Glen Osmond Road
Eastwood SA 5063
Ethics committee country [1] 296102 0
Australia
Date submitted for ethics approval [1] 296102 0
14/09/2016
Approval date [1] 296102 0
17/10/2016
Ethics approval number [1] 296102 0

Summary
Brief summary
This is a single centre, randomised, double-blind phase 1 study to assess the safety, tolerability and pharmacokinetics (PK) of single ascending doses of intravenous (IV) or subcutaneous (SC) administrations of CSL312 in healthy subjects.
A maximum of 48 subjects will be randomised into this study. Eligible subjects will be enrolled and randomised to receive either CSL312 or placebo. Dosing and initial dose escalation will begin within the IV groups, and upon reaching the third IV cohort, the study will also progress to an SC group. Dose escalation within the IV and SC groups will then progress in parallel with the SC cohorts staggered to start after sentinel dosing in their respective IV cohorts.
Blood samples will be collected at various time points for safety, PK and pharmacodynamics (PD) evaluation, and immunogenicity (anti-CSL312 antibodies). Clinical evaluations will include electrocardiograms, vital signs, and physical examinations.
Safety follow-up will occur until approximately 84 days after dosing.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 69558 0
Prof Sepehr Shakib
Address 69558 0
CMAX, Level 5,
18a North Terrace,
Adelaide SA 5000
Country 69558 0
Australia
Phone 69558 0
+61 8 7088 7900
Fax 69558 0
Email 69558 0
cmax@cmax.com.au
Contact person for public queries
Name 69559 0
Ms Lucy Phillips
Address 69559 0
CMAX, Level 5,
18a North Terrace,
Adelaide SA 5000
Country 69559 0
Australia
Phone 69559 0
+61 8 7088 7900
Fax 69559 0
Email 69559 0
lucy.phillips@cmax.com.au
Contact person for scientific queries
Name 69560 0
Ms Lucy Phillips
Address 69560 0
CMAX, Level 5,
18a North Terrace,
Adelaide SA 5000
Country 69560 0
Australia
Phone 69560 0
+61 8 7088 7900
Fax 69560 0
Email 69560 0
lucy.phillips@cmax.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual Participant Data (IPD) will not be shared.
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary