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Trial registered on ANZCTR


Registration number
ACTRN12618002060224
Ethics application status
Approved
Date submitted
20/12/2018
Date registered
21/12/2018
Date last updated
21/12/2018
Date data sharing statement initially provided
21/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1, Randomised, Double-Blind, placebo controlled, single and multiple ascending dose study to evaluate the safety, tolerability and pharmacokinetics of KZR-616 in healthy female subjects.
Scientific title
A Phase 1, Randomised, Double-Blind, placebo controlled, single and multiple ascending dose study to evaluate the safety, tolerability and pharmacokinetics of KZR-616 in healthy female subjects.
Secondary ID [1] 296345 0
Protocol Number: KZR-616-004
Universal Trial Number (UTN)
U1111-1222-3885
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic inflammatory conditions for example rheumatoid arthritis 310060 0
Autoimmune disorders for example systemic lupus erythematosus 310883 0
Condition category
Condition code
Inflammatory and Immune System 308817 308817 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
KZR-616 is a selective inhibitor of the immunoproteasome. This Phase I study is designed to investigate a lyophilized formulation of KZR-616 administered either as multiple (weekly) subcutaneous doses into the abdomen (Part 1) over 2 (Cohorts 1b and 1c) or 4 weeks (Cohort 1a only) or as a single 30-minute intravenous infusion (Part 2).



Part 1: Multiple Ascending Subcutaneous Dose
Each cohort will participate in intrasubject dose escalation in which the initial SC dose (Dose 1) will be 30 mg and the second SC dose (Dose 2) will involve a higher dose. Subjects will be enrolled into sequential cohorts as described below.
Cohort
1a Dose 1- 30mg, Dose 2- 45mg Dose 3 - 60mg, Dose 4 - 75mg
1b Dose 1 - 30mg, Dose 2 - 60mg, Dose 3 - N/A, Dose 4- N/A
1c Dose 1 - 30mg, Dose 2 - 75mg, Dose 3 - N/A, Dose 4- N/A

In Cohort 1a, two sentinel subjects will receive the first 2 doses of study drug and one sentinel subject will receive the first 2 doses of placebo (under double-blinded conditions).
In Cohort 1b and 1c, two sentinel subjects will receive the first dose of study drug and one sentinel subject will receive the first dose of placebo (under double blinded conditions)
If dosing of the sentinels proceeds without clinically significant safety signals over 48 hours after dosing, the remaining subjects for each cohort will be dosed according to the randomisation schedule.

Part 2: Single Ascending IV Dose

KZR-616 will be administered as a 30 minute IV infusion in sequential cohorts as described below:

Cohort Dose (mg)
2a 15
2b 30
2c 45
2d 60

In all cohorts, one sentinel subject will receive study drug and one sentinel subject will receive placebo (under double-blinded conditions) on Day 1. If dosing of the sentinels proceeds without clinically significant safety signals over 48 hours after dosing, the remaining subjects in the cohort will be dosed according to the randomisation schedule.
Intervention code [1] 312670 0
Treatment: Drugs
Comparator / control treatment
Placebo will be 5% dextrose in water
Control group
Placebo

Outcomes
Primary outcome [1] 307792 0
Safety and tolerability of KZR-616 as assessed by the incidence, nature and severity of AEs and serious adverse events (SAEs).
Known possible adverse events include:
- Injection site reactions.
-Nausea
-myalgia (muscle aches)
-headache
-rash
-dizziness
-fatigue
-upper respiratory tract infection
-influenza like (flu like) illness
These will be assessed by clinical examination.
Timepoint [1] 307792 0
After any subject has been enrolled to 30 days following final dose, whether or not they are related to the study
Secondary outcome [1] 352930 0
To characterize the pharmacokinetics (PK) of KZR-616 in healthy female subjects. Pharmacokinetic measurements include: Tmax, Cmax, AUC from time zero to the time of the last measurable concentration , T1/2
Timepoint [1] 352930 0
PK Samples to be collected pre-dose and at 5, 15 and 30 minutes and 1, 2, 4 , 8 and 24 hours post-dose on dosing days.
Secondary outcome [2] 352931 0
To assess the pharmacodynamic (PD) effect of KZR-616 through measurement of the inhibition of chymotrypsin-like (CT-L) activity in whole blood using an enzymatic cleavage assay, Succinyl-Leucine-Leucine-Valine-Tyrosine-7-Amino-4-Methylcoumarin (LLVY).
Timepoint [2] 352931 0
PD samples will be obtained pre-dose and at 4 and 24 hours after dosing for all dosing visits.
Secondary outcome [3] 365195 0
To assess the pharmacodynamic (PD) effect of KZR-616 through measurement of the inhibition of chymotrypsin-like (CT-L) activity in peripheral blood mononuclear cells (PBMCs) using an enzymatic cleavage assay, Succinyl-Leucine-Leucine-Valine-Tyrosine-7-Amino-4-Methylcoumarin (LLVY).
Timepoint [3] 365195 0
PD samples will be obtained pre-dose and at 4 and 24 hours after dosing for all dosing visits.

Eligibility
Key inclusion criteria
1. Female, normal healthy volunteer (NHV), age at screening 18 to 55 years, inclusive.
2. In good general health, with no significant medical history and with no clinically significant
abnormalities on physical examination at Screening or before administration of the initial
dose of study drug.
3. Body mass index (BMI) between 18 and 32 kg/m2 inclusive.
4. Suitable injection sites on abdomen without confounding scars or lesions (for Part 1 subjects)
or accessible venous access (for Part 2 subjects).
5. Agrees to abstain from alcohol intake 48 hours before administration of study agent, during
the inpatient period of the study and during the 24 hours prior to a study visit.
6. Have the ability and willingness to attend the necessary visits to the study centre.
7. Have provided written informed consent prior to entry into the study.
8. If of childbearing potential, subject has a negative serum pregnancy test at Screening and a
negative urine pregnancy test at Day -1 and agrees to employ adequate birth control measures
for the duration of the study from Screening and for 90 days following the last dose of
KZR-616 Lyophile.
a. For the purposes of this trial, women of childbearing potential (WOCBP) are defined as
all female subjects after puberty unless they are postmenopausal (defined by amenorrhea
for at least 1 year with confirmatory follicle stimulating hormone [FSH] level in the
postmenopausal range if subject is not on supplementary hormonal therapy; or if onhormonal replacement therapy, age over 55 and 2 years of amenorrhea) or are surgically
sterile (i.e. tubal ligation, hysterectomy, bilateral salpingoophorectomy) with procedure
performed at least 12 months prior to Screening with no evidence of pregnancy since the
procedure.
b. Adequate birth control is defined as the use of double-barrier contraception which is
defined as use of a condom by the male partner and one other form of the following:
- i. Hormonal contraceptives: oral, implant, ring, patch, or depot/injectable method
which has been used for at least 4 weeks before Screening in a stable manner
- ii. Intrauterine device (IUD)
- iii. Male partner with vasectomy with documented aspermia post procedure or
documented congenital sterility
c. Rhythm, withdrawal and periodic abstinence (e.g., calendar, ovulation) methods will not
be considered adequate birth control for this study. Subject abstinence for the duration of
the study and 90 days after the last dose of KZR-616 Lyophile is acceptable. Subjects
with same sex partners are not required to be using contraception.
Minimum age
18 Years
Maximum age
55 Years
Sex
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Subjects must NOT meet any of the following exclusion criteria to be enrolled:
1. Positive test for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg),
hepatitis B core antibody (HBcAb) or hepatitis C antibodies (HCV) at Screening.
2. Positive QuantiFERON-TB (QFT) assay (or indeterminate result from repeat assessment) at
Screening.
3. Active infection (diagnosed or suspected) or a history of recurrent infections (defined as 3 or
more infections requiring antimicrobial intervention in the last 12 months prior to Day 1).
4. Serious local infection or systemic infection within 3 months of Day 1 requiring injectable
antimicrobial treatment.
5. Any clinically significant acute illness within 30 days prior to Day 1.
6. Any underlying physical or psychological medical condition that, in the opinion of the PI,
would make it unlikely that the subject will complete the study.
7. Surgery within the past 3 months prior to the first study drug administration determined by
the PI to be clinically relevant.
8. Evidence of any ongoing chronic medical condition (e.g., hypertension, asthma or diabetes).
9. Use of any prescription or over-the counter (OTC) medication (with the exception of
multivitamin, paracetamol and hormonal contraceptives) within 7 days of randomization
unless PI and Sponsor agree that the specific use of a prior medication is unlikely to impact
the state objectives of this trial.
10. Receipt of any live vaccine within 1 month of randomization.
11. Any clinically significant laboratory abnormality.
12. Absolute neutrophil count <1500/µL or haemoglobin <11 g/dL.
13. Any other clinical laboratory values >1.2 x upper limit of normal (ULN) as specified by the
testing laboratory, unless deemed not clinically significant (NCS) by the PI.
14. History or presence of alcoholism or drug abuse within the 2 years prior to the first study
drug administration.
15. Positive urine drug screen or alcohol breath test at Screening or Day -1.
16. Donated or received blood products or experienced significant blood loss within 60 days prior
to the first study drug administration.
17. Donated or received plasma within 7 days prior to the first study drug administration.
18. Received investigational product (IP) in another trial within 30 days prior to the first study
drug administration.
19. Previously received KZR-616.
20. Pregnant or lactating.
21. Failure to satisfy the PI of fitness to participate in the study for any other reason.
22. Known or suspected hypersensitivity to a, a-trehalose dihydrate (trehalose).

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)
Yes. The unblinded Pharmacy Team will hold the Randomisation List.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation list created by 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
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
Continuous safety data will be summarised with descriptive statistics (arithmetic mean, SD, median, minimum and maximum) by dose level. Categorical safety data will be summarised with frequency counts and percentages by dose level.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
21/01/2019
Actual
Date of last participant enrolment
Anticipated
18/04/2019
Actual
Date of last data collection
Anticipated
20/05/2019
Actual
Sample size
Target
72
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 12188 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 24357 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 300947 0
Commercial sector/Industry
Name [1] 300947 0
Kezar Life Sciences
Country [1] 300947 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Clinical Netwprk Services
Address
Level 4, 88 Jephson St, TOOWONG QLD 4066,
Country
Australia
Secondary sponsor category [1] 300521 0
None
Name [1] 300521 0
Address [1] 300521 0
Country [1] 300521 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301713 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 301713 0
Ethics committee country [1] 301713 0
Australia
Date submitted for ethics approval [1] 301713 0
31/10/2018
Approval date [1] 301713 0
18/12/2018
Ethics approval number [1] 301713 0
599/18

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

Contacts
Principal investigator
Name 87858 0
Dr Ben Snyder
Address 87858 0
Centre for Clinical Studies
55 Commercial Rd, Melbourne VIC 3004
Country 87858 0
Australia
Phone 87858 0
+61 03 8593 9800
Fax 87858 0
Email 87858 0
b.snyder@nucleusnetwork.com.au
Contact person for public queries
Name 87859 0
Darrin Bomba
Address 87859 0
4000 Shoreline Court, Suite 300, South San Francisco, CA 94080
Country 87859 0
United States of America
Phone 87859 0
+1 (650) 822-5600
Fax 87859 0
Email 87859 0
dbomba@kezarbiio.com
Contact person for scientific queries
Name 87860 0
Darrin Bomba
Address 87860 0
4000 Shoreline Court, Suite 300, South San Francisco, CA 94080
Country 87860 0
United States of America
Phone 87860 0
+1 (650) 822-5600
Fax 87860 0
Email 87860 0
dbomba@kezarbiio.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Data will be contained in the Trial Master File.


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
No additional documents have been identified.