Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616001040459
Ethics application status
Approved
Date submitted
2/08/2016
Date registered
4/08/2016
Date last updated
30/08/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1, Randomized, Double Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of KZR-616 in Healthy Subjects
Scientific title
A Phase 1, Randomized, Double Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of KZR-616 in Healthy Subjects
Secondary ID [1] 289793 0
Kezar Life Sciences, KZR-616-001
Universal Trial Number (UTN)
U1111-1185-8847
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Autoimmune diseases; 299781 0
Condition category
Condition code
Inflammatory and Immune System 299631 299631 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a first time in human, randomised, double blind, placebo controlled, single (SAD) and multiple ascending dose (MAD) study to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of KZR-616 in healthy subjects. It will be conducted at a single centre in Australia, Up to approximately 128 subjects will be enrolled; the study will be conducted in four parts: SAD subcutaneous (SC) (Part 1), MAD SC (Part 2); SAD intravenous (IV) (Part 3) and MAD IV (Part 4). Each cohort will comprise 8 subjects randomized 6:2 to receive KZR-616 or placebo. No subject will be a member of more than one cohort.
Subjects will receive a single dose of KZR-616 by SC injection (Part 1) or IV infusion (Part 3) or 4 weekly doses by SC injection(Part 2) or IV infusion (Part 4), Dose levels to be investigated are 7.5 mg, 15 mg, 30 mg, 60 mg, 90 mg, 120 mg, 150 mg and 180 mg.
Safety will be assessed throughout the study; serial blood and urine samples will be collected for these assessments. Blood samples will also be collected for pharmacokinetic (PK), pharmacodynamic (PD), and immunomodulatory assessments of KZR-616. The safety, PK, PD and immunomodulatory profiles of KZR-616 will be compared to placebo.
KZR-616 for SC Injection will be supplied as a 180 mg/mL solution of KZR-616 maleate (equivalent to 150 mg/mL free base) in aqueous 10% (w/w) polysorbate 80 at pH 4.2. KZR-616 for IV Infusion will be supplied as a 18.0 mg/mL solution of KZR-616 maleate (equivalent to 15.0 mg/mL free base) in water for injection at pH 4.2.
Each IV dose will be administered as a 30-minute infusion in an infusion bag containing 50 mL IP with 5% glucose in water.
Dose-escalation to the next dose level (i.e. next cohort) and initiation of Parts 2, 3 and 4 will not take place until a Safety Monitoring Committee (SMC) comprised of the Principal Investigator (PI), the Medical Monitor, and the Sponsor have determined that adequate safety and tolerability from the previous cohort/part has been demonstrated to permit proceeding to the next cohort/initiating the next part. PK and PD data will also be reviewed by the SMC.
Intervention code [1] 295460 0
Treatment: Drugs
Comparator / control treatment
The placebo solution for SC injection will be supplied as an aqueous 10% polysorbate 80 (w/w) solution.
Placebo for IV infusion will consist of 50 mL 5% glucose in water for injection.
Control group
Placebo

Outcomes
Primary outcome [1] 299106 0
Incidence of adverse events (AEs) and serious adverse events (SAEs).
This will be assessed through evaluation of physical examinations, vital signs, electrocardiograms (ECGs), clinical laboratory parameters, and monitoring of AEs.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA, Registered trademark). The number of subjects experiencing AEs and number of AEs will be summarized by treatment group, system organ class and preferred term using frequency counts. Adverse events will also be summarised by treatment group and relationship to study drug
Timepoint [1] 299106 0
This will be assessed continuously from dosing to 24 hours post-dose whilst subjects are in-house for Parts 1 and 3 and for the first and third dosing for Parts 2 and 4. For Parts 1 and 3, safety will also be assessed at the follow-up visits on Days 4 and 7 and for Parts 2 and 4, at visits on Days 7, 8, 14, 15, 21, 22 and 28 or at the early withdrawal visit.
Primary outcome [2] 299107 0
Nature of adverse events (AEs) and serious adverse events (SAEs).
This will be assessed through evaluation of physical examinations, vital signs, electrocardiograms (ECGs), clinical laboratory parameters, and monitoring of AEs.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA, Registered trademark). Adverse events will be summarised by treatment group and relationship to study drug
Timepoint [2] 299107 0
This will be assessed continuously from dosing to 24 hours post-dose whilst subjects are in-house for Parts 1 and 3 and for the first and third dosing for Parts 2 and 4. For Parts 1 and 3, safety will also be assessed at the follow-up visits on Days 4 and 7 and for Parts 2 and 4, at visits on Days 7, 8, 14, 15, 21, 22 and 28 or at the early withdrawal visit.
Primary outcome [3] 299108 0
Severity of adverse events (AEs) and serious adverse events (SAEs).
This will be assessed through evaluation of physical examinations, vital signs, electrocardiograms (ECGs), clinical laboratory parameters, and monitoring of AEs.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA, Registered Trademark). Adverse events will be summarised by treatment group and severity, as well as treatment group and relationship to study drug
Timepoint [3] 299108 0
This will be assessed continuously from dosing to 24 hours post-dose whilst subjects are in-house for Parts 1 and 3 and for the first and third dosing for Parts 2 and 4. For Parts 1 and 3, safety will also be assessed at the follow-up visits on Days 4 and 7 and for Parts 2 and 4, at visits on Days 7, 8, 14, 15, 21, 22 and 28 or at the early withdrawal visit.
Secondary outcome [1] 326208 0
All pharmacokinetic parameters will be assessed from plasma samples and calculated for KZR-616 at various time-points.
Parameters to be assessed:
Parts 1 and 3 (SAD):
Cmax Maximum observed drug concentration.
Tmax Time to maximum observed drug concentration. AUC0-t Area under the drug concentration-time curve, .
Kel Apparent terminal elimination rate constant,
AUC0-inf Area under the drug concentration-time curve from time zero to infinity,
t1/2 [Apparent; for SC] Elimination half-life, calculated as ln(2)/kel.
CL/F for SC
CL for IV [Apparent; for SC] Clearance calculated as Dose/AUC0-inf.
Vz/F for SC
Vz for IV [Apparent; for SC] Volume of distribution at the terminal phase, calculated as Dose/(kel * AUC0-inf).

Part 2 and 4 (MAD); Day 1 dose:
Cmax, Tmax and AUCtau Area under the drug concentration-time curve over the dosing interval

Part 2 and 4 (MAD); Day 22 dose:
Cmax, Tmax, AUC0-t, AUCtau, Kel,, AUC0-inf, t1/2
CL/Fss for SC
CLss for IV [Apparent; for SC] Clearance at steady-state calculated as Dose/AUCtau.
Vz/F for SC
Vz for IV [Apparent; for SC] Volume of distribution at the terminal phase, calculated as Dose/(kel * AUC0-inf).
Cssave Average drug concentration at steady state calculated as AUCtau /dosing interval.
AI Accumulation index calculated as 1 / (1- exp(-kel x tau)). If kel cannot be estimated for the majority of subjects accumulation index may be calculated by comparison of AUCtau after first dose and after day 22 dose.
Timepoint [1] 326208 0
SAD SC: pre-dose and post-dose at 5,15, 30 min and 1,2,4,8, and 24 hr
SAD IV: pre-dose, 15 min post-infusion start, just prior to end infusion, 2 , 5,10,15 and 30 min post-infusion and 1,2,4,and 24 hr post-infusion
MAD SC, Days 1 and 22: Pre dose, then 5min, 15min, 30min, 1hr, 2hr, 4hr, 8hr & 24hr post dose
MAD IV, Days 1 and 22: pre-dose, 15 min post start of infusion, just prior to the end of infusion, 2min post-infusion, 24 hrs
Secondary outcome [2] 326209 0
Pharmacodynamic effect of KZR-616 will be assessed through measurement of the inhibition of chymotrypsin-like (CT-L) activity in whole blood and peripheral blood mononuclear cells (PBMCs) using an enzymatic cleavage assay, Succinyl-Leucine-Leucine-Valine-Tyrosine-7-Amino-4-Methylcoumarin (LLVY). The Inhibition of proteasome activity in whole blood and PBMCs will be expressed relative to matched pre-dose levels.
Timepoint [2] 326209 0
SAD SC cohorts dosed at less than 30mg: pre-dose, 4 and 24 hr post-dose
SAD SC cohorts dosed at 30mg or more: pre-dose, 4 and 24 hr post-dose and Day 7
MAD SC and IV: Days 1 and 22: pre-dose, 4 and 24 hr

Eligibility
Key inclusion criteria
1. Normal healthy volunteers, age at screening 18 to 65 years, inclusive.
2. Subjects must be in good general health, with no significant medical history, have no clinically significant abnormalities on physical examination at screening, and/or before administration of the initial dose of study drug.
3. Subjects must weigh more than or equal to 50 kg and have a Body Mass Index between 20 and 29 kg/m2 Inclusive.
4. Subjects must have clinical laboratory values less than 1.5 x upper limit of normal (ULN) as specified by the testing laboratory, unless deemed not clinically significant by the Investigator.
5. Must agree to abstain from alcohol intake 48 hours before administration of study agent and during the inpatient period of the study.
6. Negative urine drug screen /alcohol breath test at screening and Day -1.
7. Subjects must have the ability and willingness to attend the necessary visits to the study centre.
8. Written informed consent signed prior to entry into the study.
9. Subjects using highly effective, double barrier contraception (both male and female partners) during the study and for 90 days following the last dose of KZR-616
Double barrier contraception is defined as a condom AND one other form of the following:
-Birth control pills (The Pill)
-Depot or injectable birth control
-IUD (Intrauterine Device)
-Birth Control Patch (e.g., Othro Evra)
-NuvaRing, Registered Trademark
-Documented evidence of surgical sterilization at least 6 months prior to screening visit. i.e., tubal ligation or hysterectomy for women or vasectomy for men.

Males must not donate sperm for at least 90 days post-dose of the last study treatment. Male partners of female subjects and female partners of male subjects must also use contraception, if they are of childbearing potential.
Females of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Day -1.
Females not of childbearing potential must be post-menopausal (defined as cessation of regular menstrual periods for at least 12 months), confirmed by follicle stimulating hormone (FSH) level greater than 40 mIU/mL.
Rhythm methods will not be considered as highly effective methods of birth control. Subject abstinence for the duration of the study and 90 days after the dose of KZR-616 is acceptable.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Positive testing for human immunodeficiency virus (HIV),hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HCV).
2. Have any underlying physical or psychological medical condition that, in the opinion of the investigator, would make it unlikely that the subject will complete the study
3. Have evidence of any chronic medical condition (e.g., hypertension, elevated cholesterol/triglycerides, asthma, or diabetes).
4. Use of any prescription or over-the counter medication (with the exception of paracetamol and oral contraceptives) within 7 days of randomization.
5. Any clinically significant laboratory abnormality.
6. Absolute neutrophil count less than 1500/microliter.
7. Aspartate aminotransferase (AST) or alanine transaminase (ALT) greater than 1.5 x ULN unless not clinically significant (NCS) by investigator discretion.
8. History or presence of alcoholism or drug abuse within the 2 years prior to the first study drug administration.
9. Blood donation or significant blood loss within 60 days prior to the first study drug administration.
10. Plasma donation within 7 days prior to the first study drug administration.
11. Administration of investigational product (IP) in another trial within 30 days prior to the first study drug administration.
12. Females who are pregnant or lactating.
13. Surgery within the past three months prior to the first study drug administration determined by the PI to be clinically relevant.
14. Failure to satisfy the PI of fitness to participate for any other reason.
15. Active infection (diagnosed or suspected) or history of recurrent infections.
16. Serious local infection or systemic infection within 3 months requiring antibiotic treatment.
17. Any acute illness within 30 days prior to Day 1.
18. Known or suspected hypersensitivity to polysorbate 80 (PS-80, also known as (aka) Tween 80)

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)
This study is a randomized, double-blind study. Study subjects, site staff including the principal investigator, sub-investigators and study co-ordinators, monitoring staff and sponsor staff will all be blinded to treatment allocation. Unblinded personnel will include the site pharmacists who will prepare the subcutaneous injections and the intravenous infusions and one biostatistician.
Subjects will be centrally randomized to either KZR-616 or placebo in a 6:2 ratio.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Central randomization will be undertaken with randomization numbers assigned sequentially to each subject in a cohort as they are confirmed eligible for dosing and enrolled in the study.
The study plans to enrol up to approximately 128 subjects in up to 16 cohorts. All subjects within a cohort will be dosed on the same day except for cohorts where sentinel subjects will be included. Sentinel subjects will be dosed on Day 1 and if dosing of the sentinels proceeds without clinically-significant adverse events over 24 hours, the remaining 6 subjects in the cohort will then be dosed according to the randomisation schedule in order to maintain a 6:2 allocation of KZR-616 to placebo. Thus no blocking or stratification will be performed.
Upon enrolment, a randomisation number will be assigned to each subject by the unblinded site pharmacist in accordance with a computerized randomization list generated by the unblinded statistician.
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
Parallel
Other design features
Not applicable
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
The sample size chosen for this study was selected without statistical considerations. It has been determined to be adequate to meet the study objectives. The number of subjects was selected to allow sufficient evaluation of safety, tolerability, PK and PD of the various single- and multiple dose levels to be administered in this study and is consistent with standards of practice for Phase 1 studies.
1. Safety Analysis
No formal inferential statistics will be performed on safety assessments. Listings and summaries for all safety data will be presented using the Safety Population-all subjects who are dosed will be included. Descriptive statistics (mean, SD, median, minimum and maximum) will be calculated for summaries of continuous safety data and frequency counts and percentages (where appropriate) will be calculated for summaries of discrete/categorical safety data.
2. Pharmacokinetic Analysis
Concentration-time Data
Individual plasma KZR-616 concentration data will be listed for each individual and summarised by nominal sampling time point and treatment group with descriptive statistics (sample size [N], arithmetic mean, standard deviation [SD], median, minimum, maximum and geometric mean). Individual and mean KZR-616 concentration-time profiles for each treatment group will also be presented graphically.
Pharmacokinetic Parameters
Pharmacokinetic parameters will be computed from the individual plasma and urine KZR-616 concentrations using a non-compartmental approach. Appropriate validated PK software (e.g., Phoenix WinNonlin v6.3) will be used.
Statistical Methods for Pharmacokinetic Analyses
PK parameters will be summarized by cohort using descriptive statistics (arithmetic means, SD, coefficients of variation [CV], sample size [N] minimum, maximum, median and geometric mean).
No value for kel, t1/2, AUC0-inf, CL/F (of CL for IV), Vz/F (or Vz for IV), as appropriate, will be reported for cases that do not exhibit a terminal log-linear phase in the concentration versus time profile or do not contain sufficient data during this phase for parameter estimation.
Additional analyses will be performed as deemed necessary upon review of the data.
Dose Proportionality Analysis
Dose proportionality will be evaluated for KZR-616 Cmax, AUC0-t and AUC0-inf after single dose administration (Part 1).
Dose proportionality will be assessed using the power model with log-transformed PK parameter values and log-transformed dose. The power model will be used to estimate the slope parameter and the 90% confidence intervals for the slope. Dose proportionality is generally concluded if the 90% confidence intervals around the slope estimate include the value of 1..
3. Pharmacodynamic Analysis
Individual proteasome activity and Peripheral blood mononuclear cell data will be listed for each individual and summarised by nominal sampling time point and treatment group with descriptive statistics (sample size [N], arithmetic mean, SD, median, minimum and maximum).
A summary of change from baseline at each protocol specified time-point by treatment group will also be presented. Individual and summary (by treatment group) parameter values over time will also be presented graphically.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
9/08/2016
Actual
9/08/2016
Date of last participant enrolment
Anticipated
30/06/2017
Actual
19/04/2017
Date of last data collection
Anticipated
7/07/2017
Actual
16/05/2017
Sample size
Target
128
Accrual to date
Final
82
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 6319 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 13854 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 294183 0
Commercial sector/Industry
Name [1] 294183 0
Kezar Life Sciences
Country [1] 294183 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Clinical Network Services
Address
Level 4, 88 Jephson St Toowong
Queensland 4066
Country
Australia
Secondary sponsor category [1] 293009 0
None
Name [1] 293009 0
Address [1] 293009 0
Country [1] 293009 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295584 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 295584 0
Ethics committee country [1] 295584 0
Australia
Date submitted for ethics approval [1] 295584 0
01/06/2016
Approval date [1] 295584 0
29/07/2016
Ethics approval number [1] 295584 0
249/16

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 67838 0
Dr Jason Lickliter
Address 67838 0
Nucleus Network Limited
Level 5 Burnet Institute, AMREP Precinct,
89 Commercial Road, Melbourne
VIC 3004
Country 67838 0
Australia
Phone 67838 0
+61 3 9076 8906
Fax 67838 0
+61 3 9076 8911
Email 67838 0
[email protected]
Contact person for public queries
Name 67839 0
Darrin Bomba
Address 67839 0
Kezar Life Sciences Australia Pty Ltd, L15 300 Queen Street, Griffith Hack Brisbane City QLD 4000
Country 67839 0
Australia
Phone 67839 0
+1 650 822 5617
Fax 67839 0
NA
Email 67839 0
[email protected]
Contact person for scientific queries
Name 67840 0
Darrin Bomba
Address 67840 0
Kezar Life Sciences Australia Pty Ltd, L15 300 Queen Street, Griffith Hack Brisbane City QLD 4000
Country 67840 0
Australia
Phone 67840 0
+1 650 822 5617
Fax 67840 0
NA
Email 67840 0
[email protected]

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