Please note that IPD sharing statement and summary results sections will be added to the ANZCTR form in the coming months in order to comply with the updated WHO Trial Registration Data Set.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Trial ID
ACTRN12618000805279
Ethics application status
Approved
Date submitted
18/04/2018
Date registered
11/05/2018
Date last updated
4/06/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Assessing the pharmacokinetics, safety, and tolerability of CSL112 in healthy Japanese and Caucasian adults
Scientific title
A phase 1, randomized, double-blind, placebo-controlled study to evaluate the pharmacokinetics, safety, and tolerability of CSL112 in healthy Japanese and Caucasian subjects
Secondary ID [1] 294559 0
None
Universal Trial Number (UTN)
N/A
Trial acronym
N/A
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
Acute Coronary Syndrome 307335 0
Condition category
Condition code
Cardiovascular 306444 306444 0 0
Coronary heart disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
CSL112 / placebo will be administered to 3 dose cohorts (each cohort receiving a different dose from the other cohorts) of subjects as a single intravenous infusion into a peripheral or central vein over 2 hours by the Investigator and under their direct supervision. Subjects are dosed on Day 1 and are on site for observation until Day 7. Subjects are brought back to the site between day 30 and 37 for a follow-up observation.
Intervention code [1] 300852 0
Treatment: Drugs
Comparator / control treatment
Placebo (25% albumin solution diluted to 3.2% v/v) is to be administered as a single intravenous infusion into a peripheral or central vein over 2 hours at the same volume as the CSL112 infusion.
Control group
Placebo

Outcomes
Primary outcome [1] 305455 0
Area under the ApoA-1 plasma concentration-time curve (AUC) from time 0 to 72 hours (AUC0-72)
Timepoint [1] 305455 0
Assessed before CSL112 administration and at 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 144 hours after the start of CSL112 administration
Primary outcome [2] 305456 0
Maximum concentration of ApoA-1 in plasma (Cmax)
Timepoint [2] 305456 0
Assessed before CSL112 administration and at 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 144 hours after the start of CSL112 administration
Secondary outcome [1] 345287 0
The percentage of subjects with treatment-related adverse events (AEs) overall, by severity and by causality. 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 summarized by n (%) subjects overall, by severity, and by causality.
Timepoint [1] 345287 0
Assessed continually for the duration of the subject's participation in the study, up to 37 days per subject.
Secondary outcome [2] 345336 0
Clinically significant elevation in markers of liver function assessed through serum assay. Clinically significant elevations are defined as alanine aminotransferase > 3 x upper limit of normal, aspartate aminotransferase > 3 x upper limit of normal, or total bilirubin > 2 x upper limit of normal.
Timepoint [2] 345336 0
Assessed before CSL112 administration and at 24, 48 and 144 hours after the start of CSL112 administration
Secondary outcome [3] 345337 0
Serum creatinine > or = 1.5 x Baseline value
Timepoint [3] 345337 0
Assessed before CSL112 administration and at 24, 48 and 144 hours after the start of CSL112 administration
Secondary outcome [4] 345338 0
Clinically significant changes in individual clinical and / or other safety parameters:
• Clinical laboratory tests (biochemistry, hematology, urinalysis, and spot urine protein [total protein to creatinine ratio and albumin to creatinine ratio])
• ECGs
• Vital signs (supine blood pressure, pulse rate, tympanic temperature)
Timepoint [4] 345338 0
Biochemistry and hematology assessed before CSL112 administration and 24, 48 and 144 hours after the start of CSL112 administration. Urinalysis and ECGs assessed before CSL112 administration and at 144 hours after the start of CSL112 administration. Spot urine assessed before CSL112 administration and 24-36, 48 and 144 hours after the start of CSL112 administration. Vital Signs assessed before CSL112 administration and 2, 4, 6, 8, 12, 24, 48, 72, 96 and 144 hours after the start of CSL112 administration.
Secondary outcome [5] 345340 0
Clinically significant changes in individual clinical and / or other safety parameters:
• Immunogenicity (ie, presence of anti-CSL112 and / or anti-apoA-I antibodies)
• Serology (ie, presence of human immunodeficiency virus -1 and / or 2 antibodies, hepatitis A virus antibody, hepatitis B virus surface antigen, and / or hepatitis C virus antibody)
• Nucleic acid testing (ie, presence of parvovirus B19)
Timepoint [5] 345340 0
Assessed before CSL112 administration. Also assessed at 144 hours and during the last visit occurring between 30 and 37 days after the start of CSL112 administration.
Secondary outcome [6] 345426 0
Individual plasma PK parameters of ApoA-I including:
• AUC from time 0 to the last collection time (AUClast)
• AUC from time 0 extrapolated to time infinity (AUCinf)
• Partial AUC from time 0 to time point t (AUC0-t)
• Time to reach maximum concentration in plasma (Tmax)
• Terminal plasma half-life (t½)
• Clearance (CL)
• Volume of distribution (Vz)
Timepoint [6] 345426 0
Assessed before CSL112 administration and at 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 144 hours after the start of CSL112 administration
Secondary outcome [7] 345427 0
Individual Plasma PK parameters (apparent values where applicable) of phosphatidylcholine including:
• AUClast
• AUCinf
• AUC0-t
• Cmax
• Tmax
• t½
• CL
• Vz
Timepoint [7] 345427 0
Assessed before CSL112 administration and at 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 144 hours after the start of CSL112 administration
Secondary outcome [8] 345428 0
Individual Plasma PK parameters of sucrose including:
• AUClast
• AUCinf
• AUC0-t
• Cmax
• Tmax
• t½
• CL
• Vz
Timepoint [8] 345428 0
Assessed before CSL112 administration and at 1, 2, 4, 6, 8, 12, 24 and 48 hours after the start of CSL112 administration
Secondary outcome [9] 345429 0
Individual Plasma PK parameters of cholate including:
• AUClast
• AUCinf
• AUC0-t
• Cmax
• Tmax
• t½
• CL
• Vz
Timepoint [9] 345429 0
Assessed before CSL112 administration and at 1, 2, 4, 6, 8, 12 and 24 hours after the start of CSL112 administration
Secondary outcome [10] 345430 0
Individual Urinary excretion of apoA-I including measuring:
• Cumulative amount excreted into urine from time 0 up to time point t (Ae0-t)
• Percent fraction excreted into urine from time 0 up to time point t (%fe0-t)
• Renal clearance (CLR)
Timepoint [10] 345430 0
Assessed before CSL112 administration and assessed at ranges 0-4 hours, 4-8 hours, 8-12 hours, 12-24 hours, 24-36 hours and 36-48 hours after the start of CSL112 administration
Secondary outcome [11] 345431 0
Individual Urinary excretion of sucrose including measuring:
• Ae0-t
• %fe0-t
• CLR
Timepoint [11] 345431 0
Assessed before CSL112 administration and assessed at ranges 0-4 hours, 4-8 hours, 8-12 hours, 12-24 hours, 24-36 hours and 36-48 hours after the start of CSL112 administration
Secondary outcome [12] 345432 0
Individual Plasma PD parameters of cholesterol efflux capacity (total, ATP binding cassette transporter protein subfamily A member 1 [ABCA1]-independent, ABCA1-dependent [calculated]) including:
• Area under the effect curve (AUEC) from time 0 to the last collection time (AUEClast)
• AUEC from time 0 to time point t (AUEC0-t)
• Maximum response (Rmax)
• Tmax
Timepoint [12] 345432 0
Assessed before CSL112 administration and at 2, 4, 8, 24, 48, 72, 96 and 144 hours after the start of CSL112 administration

Eligibility
Key inclusion criteria
Healthy (determined by a comprehensive clinical assessment) male or female adult Japanese or Caucasian subjects with a body weight of >= 45 kg to <= 95 kg and a body mass index of >= 18.0 to <= 29.9 kg/m2. Japanese subjects must be of Japanese descent (ie, born in Japan with 2 Japanese biologic parents and 4 Japanese biologic grandparents) and have not lived outside of Japan for >= 10 successive years. Caucasian subjects must have origins in any of the original peoples of Europe, the Middle East, or North Africa.
Minimum age
20 Years
Maximum age
54 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Evidence of a clinically significant medical condition, disorder or disease.
2. Evidence of hepatobiliary disease.
3. Any clinically significant abnormalities in hematology, biochemistry, or urinalysis as judged by the Investigator and / or study Medical Monitor at Screening and / or Day -1.
4. Sustained and / or symptomatic hypotension (systolic blood pressure < 90 mmHg).
5. Any major illness requiring hospitalization within the 30 days before the Screening Visit or planned hospitalization at any time during the study.
6. Known history of soy bean or peanut allergies, hypersensitivity to the investigational product, or to any excipients of the investigational product or placebo (albumin), or IgA deficiency or antibodies to IgA.
7. A positive result for HAV antibody, HBV surface antigen, HCV antibody, or HIV -1 and / or 2 antibodies at Screening.
8. Evidence or history of substance or alcohol abuse or a positive drug test or alcohol breath test at Screening or Day -1.
9. Smokers, those who have smoked or used tobacco products within 6 months before Screening
10. Plans to participate in another investigational drug study while enrolled in this study or has participated in any investigational drug study within 30 days (or 5 half-lives, whichever is longer) or more than 3 investigational drug studies within the 12 months before Day 1.
11. Clinically significant abnormalities in vital signs or physical examination at Screening or Day -1 as judged by Investigator and / or Sponsor.
12. A mean QTcF > 450 ms for male subjects or > 470 ms for female subjects at Screening.
13. Subjects who have been a recipient of an organ transplant.

Study design
Purpose of the study
Treatment
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
The people analysing the results/data
Intervention assignment
Other
Other design features
Japanese subjects enrolled in the study will be assigned to Cohorts 1, 2, or 3 in a sequential manner. Caucasian subjects will be enrolled in the study and assigned to Cohort 3 only after subject matching by weight within 15% of the median weight of Japanese subjects in Cohort 3. All subjects will be randomized to treatment (CSL112 or placebo) within their cohort and within their race (Cohort 3 only). Milestones do not need to met for the next cohort to be enrolled.
Phase
Phase 1
Type of endpoint(s)
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
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)
NSW

Funding & Sponsors
Funding source category [1] 299180 0
Commercial sector/Industry
Name [1] 299180 0
CSL Limited
Address [1] 299180 0
45 Poplar Road
Parkville
VIC 3052
Australia
Country [1] 299180 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
CSL Limited
Address
45 Poplar Road
Parkville
VIC 3052
Australia
Country
Australia
Secondary sponsor category [1] 298439 0
None
Name [1] 298439 0
Address [1] 298439 0
Country [1] 298439 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300104 0
Bellberry Limited
Ethics committee address [1] 300104 0
129 Glen Osmond Road
Eastwood SA 5063
Australia
Ethics committee country [1] 300104 0
Australia
Date submitted for ethics approval [1] 300104 0
07/03/2018
Approval date [1] 300104 0
13/04/2018
Ethics approval number [1] 300104 0
2018-02-096

Summary
Brief summary
The purpose of this study is to assess the pharmacokinetics, safety, and tolerability of single doses of CSL112 after intravenous administration in healthy Japanese and Caucasian subjects. Japanese subjects enrolled in the study will be assigned to Cohorts 1, 2, or 3 in a sequential manner. Caucasian subjects will be enrolled in the study and assigned to Cohort 3 only after subject matching by weight within 15% of the median weight of Japanese subjects in Cohort 3. All subjects will be randomized to treatment (CSL112 or placebo) within their cohort and within their race (Cohort 3 only).
Trial website
Trial related presentations / publications
(none)
Public notes
N/A

Contacts
Principal investigator
Name 82578 0
Dr Charlotte Lemech
Address 82578 0
Scientia Clinical Research Ltd
Level 5, The Bright Alliance Building
Corner Avoca & High Street
Randwick NSW 2031
Australia
Country 82578 0
Australia
Phone 82578 0
+61-2-9382 5807
Fax 82578 0
N/A
Email 82578 0
charlotte.lemech@scientiaclinicalresearch.com.au
Contact person for public queries
Name 82579 0
Dr Charlotte Lemech
Address 82579 0
Scientia Clinical Research Ltd,
Level 5, The Bright Alliance Building
Corner Avoca & High Street
Randwick NSW 2031
Australia
Country 82579 0
Australia
Phone 82579 0
+1800 727 874
Fax 82579 0
N/A
Email 82579 0
recruitment@scientiaclinicalresearch.com.au
Contact person for scientific queries
Name 82580 0
Dr Charlotte Lemech
Address 82580 0
Scientia Clinical Research Ltd
Level 5, The Bright Alliance Building
Corner Avoca & High Street
Randwick NSW 2031
Australia
Country 82580 0
Australia
Phone 82580 0
+61-2-9382 5807
Fax 82580 0
N/A
Email 82580 0
charlotte.lemech@scientiaclinicalresearch.com.au