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Trial registered on ANZCTR


Registration number
ACTRN12618001502224
Ethics application status
Approved
Date submitted
20/08/2018
Date registered
6/09/2018
Date last updated
6/09/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
The research project is investigating a new potential treatment for auto-immune diseases (where your own immune system attacks healthy organs and cells by mistake). The study drug being investigated is called HL161BKN.
Scientific title
A Phase 1, randomized, placebo-controlled, ascending dose study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of HL161BKN following single intravenous and subcutaneous doses in healthy subjects.
Secondary ID [1] 295856 0
Nil known
Universal Trial Number (UTN)
U1111-1219-2000
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Auto-Immune Diseases 309316 0
Condition category
Condition code
Inflammatory and Immune System 308183 308183 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Each participant will only receive One treatment Arm for the trial. Arms 8 and 9 will be decided by the Safety Monitoring Committee after review of all other cohorts, safety and PK/PD data.

Arm 1:
HL161BKN or Placebo
0.1mg/kg
Once
Intravenous Infusion administered over 60 minutes

Arm 2
HL161BKN or Placebo
0.5mg/kg
Once
Subcutaneous Injection

Arm 3
HL161BKN or Placebo
1.5mg/kg
Once
Subcutaneous Injection

Arm 4
HL161BKN or Placebo
3mg/kg
Once
Subcutaneous Injection

Arm 5
HL161BKN or Placebo
3mg/kg
Once
Intravenous Infusion administered over 60 minutes


Arm 6
HL161BKN or Placebo
7mg/kg
Once
Subcutaneous Injection

Arm 7
HL161BKN or Placebo
10mg/kg
Once
Subcutaneous Injection

Arm 8
HL161BKN or Placebo
Dose to be decided
Once
Subcutaneous Injection

Arm 9
HL161BKN or Placebo
Dose to be decided
Once
Subcutaneous Injection

At the conclusion of each dose group a safety monitoring committee will review all PK/PD and safety data to ensure increasing to the next dose level is safe to do so.
Intervention code [1] 312193 0
Treatment: Drugs
Comparator / control treatment
Placebo Controlled
Sterile normal saline for injection.
Control group
Placebo

Outcomes
Primary outcome [1] 307149 0
To evaluate the safety, tolerability of HL161BKN following single SC or IV doses in healthy subjects.
Timepoint [1] 307149 0
Safety and Tolerability Assessments Include:

Physical Examination at the following time points: Physical examinations will be performed by a physician and will include the examination of the following: general appearance, eyes, ears, nose, throat, chest/respiratory, heart/cardiovascular, gastrointestinal/liver, musculoskeletal/extremities, dermatological/skin, thyroid/neck, lymph nodes, neurological/psychiatric. The physical examinations will include specific surveillance for skin rashes and lymphadenopathy.
- Screening, Day -1 (prior to administration of drug), Day 1, Day 2, Day 3, Day 4, Day 5, Day 8, Day 11, Day, Day 15, Day 22, Day 29, Day 43, Day 57, and Day 85 (all post administration of drug)

Height and Body weight at the following time points: Screening and Day -1 prior to dosing

Vital Signs at the following time points: Blood pressure, pulse rate and oral temperature will be measured using an automated instrument after the subject has rested comfortably for 5 minutes in the supine position. Additional vital signs may be added for safety of the subjects at the discretion of the Investigator.
- At Screening, Day -1 pre-dose on Day 1 and 10, 60, 120 minutes and 4 hours after SC injection. At pre-dose on Day 1 and 10, 30 minutes and 2, 4, and 6 hours after start of IV infusions. On other non-dosing inpatient days, twice daily (except for Day 5, when 1 measurement is required). Day 5, Day 8, Day 11, Day 15, Day 22, Day 29, Day 43, Day 57 and Day 85.

Electrocardiograms at the following time points: 12-lead ECG will be obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, QTc and QTcF intervals.
- ECG at screening, Day 1 at pre-dose (performed in triplicate), and at 6, 24, 48 and 72 hours post start of infusion, at Day 8 and Day 85

Telemetry Assessment: To begin 30 to 60 minutes prior to dosing, continue until 6 hours post start of infusion.

Clinical Safety Laboratory Assessments: The Investigator must review the laboratory report, document this review, and record any clinically relevant changes occurring during the study as an Adverse Event
- Screening, Day -1 (prior to dose), Day 2, Day 4, Day 8, Day 15, Day 29, Day 43, Day 57 and Day 85

Local Injection Site/Infusion Site Reactions: Injection site/infusion site evaluations will be made by clinical staff following IV and SC administration of HL161BKN and placebo as described below; if an injection site/infusion site reaction is observed, a physician will characterize and document the reaction as an Adverse Event.

Adverse Events will be collected spontaneously from the time of Screening to the end of study participation (Day 85)
Primary outcome [2] 307150 0
To evaluate the PK results of HL161BKN following single SC or IV doses in healthy subjects using a validated plasma assay.

Serum Pharmacokinetic Parameters:
Cmax
tmax
AUC(0-inf)
F
Vss/F
Vss
T1/2
AUC(0-inf)/D
Cmax/D
A characterization of clearance using appropriate parameters to represent likely non-linear clearance will also be provided.
Timepoint [2] 307150 0
PK time points assessment includes:
Individual concentrations over time of HL161BKN will be listed and displayed graphically by dose cohort and route of administration in linear and semi-logarithmic scales (spaghetti plots).
- For IV infusion PK time points will be:
- Pre-dose, From start of infusion at 1, 1.5, 2, 4, 6, 8, 12, and 18 (if possible and if in clinic) hours and 24 and 48 hours after start of infusion, and on Days 4, 5, 8, 11, 15, 22, 29, 43, 57 and 85.
For SC injections, PK time points will be:
Pre-dose and at 0.5, 1, 2, 4, 8, 12, 18, 24, 36, and 48 hours after injection, and on Days 4, 5, 8, 11, 15, 22, 29, 43, 57, and 85.
Secondary outcome [1] 350917 0
To evaluate the PD (change in serum concentrations of immunoglobulin G [IgG] of HL161BKN following single IV and SC doses in healthy subjects.
Timepoint [1] 350917 0
Immunoglobulin G will be analyzed using a population PK/PD or a kinetic (K)-PD or another appropriate modelling approach characterizing the IgG responses to HL161BKN.
IgG samples will be collected at the following time points: Daily at Screening, Day -1 , Day1, Day2, Day3, Day4, Day 5, Day 8, Day 11, Day 15, Day 22, Day 29, Day 43, Day 47 and Day 85.
Secondary outcome [2] 351492 0
To measure anti-HL161BKN antibodies following SC and IV administration of HL161BKN.
Timepoint [2] 351492 0
Blood samples for analysis of antibodies to HL161BKN (ADA) will collected from all subjects according to the schedule below:
Day -1 (pre dose), Day 8, Day 15, Day 29, Day 57 and Day 85. Subjects with positive Day 85 samples for anti-HL161BKN antibody will be requested to return at approximately 6, 9 and 12 months post-dose for additional samples.

Eligibility
Key inclusion criteria
Subject has a body mass index (BMI) range of 18.5 to 32.0 kg/m2, inclusive, and weighs at least 50 kg and <100 kg at screening.

Healthy as determined by pre-study medical history, physical examination, vital signs and 12-lead ECG.

Review of immunization history to hepatitis B and diphtheria and tetanus (DT). Although desired, official immunization records are not required.

Normal clinical laboratory test results, or where outside the reference range judged as not clinically relevant by the Investigator.

Females must have a negative pregnancy test at screening and on admission to the unit, must not be lactating and must be of non-child-bearing potential, confirmed at screening by fulfilling one of the following criteria:
- Postmenopausal (defined as at least 1 year without any menses) prior to screening, or
- Documented permanent surgically sterile (hysterectomy, bilateral salpingectomy and bilateral oophorectomy).

Male subjects and their female spouse/partners who are of childbearing potential must be using 2 forms of birth control (one of which is an highly effective method and 1 must be a barrier method, or agree to abstinence, starting at screening and continue throughout the study period and for 60 days after the final study drug administration.

Male subject must not donate sperm starting at screening and throughout the study period and for 60 days after the final study drug administration.

Subject agrees not to participate in another interventional study while participating in the present study, defined as signing the Informed Consent Form (ICF) until completion of the last study visit.

Subjects who are non-smokers who have not used tobacco products or nicotine-containing products (including nicotine patches) for at least 3 months preceding screening.

Subject has adequate venous access.

Willing and able to comply with scheduled visits, treatment plan, clinical laboratory tests and other trial procedures including standardized meals.
Minimum age
18 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Female subjects of child bearing potential.

Subject has a known or suspected hypersensitivity to HL161BKN, or any components of the formulation used.

Subject has had previous exposure toHL161BKN.

Subject with liver chemistry tests (AST, ALT, ALP, and total bilirubin) equal to 1.25 × ULN at screening or above the ULN at Day -1.
A subject with marginally elevated fasting unconjugated serum bilirubin with documented Gilbert's syndrome may be enrolled.

Subject with an Estimated GFR of < 75mL/min for women and < 85mL/min for men (based on Cockcroft-Gault equation).

Subject has a total IgG level of <900 mg/dL at screening.

Subject has any clinically significant history of allergic conditions (including drug allergies, asthma, eczema, or anaphylactic reactions, but excluding untreated, asymptomatic, seasonal allergies or exercise-induced asthma prior to study drug administration).

Subject has any history or evidence of any clinically significant cardiovascular, gastrointestinal, endocrinology, hematology, hepatic, immunology, metabolism, urology, pulmonary, neurology, dermatology, psychiatry, renal, or other major disease or malignancy, as judged by the Investigator.

Subject has/had febrile illness or symptomatic, viral, bacterial (including upper respiratory infection), or fungal (noncutaneous) infection within 1 week prior to admission (Day -1).

Subject has had their spleen removed.

Subject has a past medical history of primary immunodeficiency, T-cell or humeral, including common variable immunodeficiency.

Subject has an active infection (eg, sepsis, pneumonia, and abscess) or has had a serious infection (resulting in hospitalization or requiring parenteral antibiotic treatment) within 6 weeks before the first dose of IMP.

Subject has any major episode of infection requiring hospitalization or treatment with IV anti-infective agents within 6 weeks prior to screening or oral anti-infective agents within 2 weeks prior to screening.

Subject has any clinically significant abnormality following the Investigator’s review of the physical examination, ECG and protocol defined clinical laboratory tests at screening or Day -1.

Subject has a mean pulse <40 or >100 bpm; mean systolic blood pressure >140 mmHg; mean diastolic blood pressure >90 mmHg at Day -1.

Subject has a mean QTcF interval of >430 ms (for males) and >450 ms (for females) at Day -1.

Subject has used any prescribed or nonprescribed drugs (including vitamins, hormone replacement therapy, natural, and herbal remedies, eg, St. John’s Wort) in 2 weeks prior to study drug administration, except for occasional use of paracetamol (up to 2 g per day).

Subject has a history of drinking more than 21 units of alcohol per week (1 unit is equal too 10 g pure alcohol, equal too 250 mL of beer [5%] or 35 mL of spirits [35%] or 100 mL of wine [12%]) (greater than 14 units of alcohol for female subjects) during the 3 months prior to admission to the study center or the subject tests positive for alcohol or drugs of abuse at screening or Day -1.

Subject has used any drugs of abuse within 3 months prior to admission to the study center.

Subject has used any inducer of metabolism (eg, barbiturates, rifampin) 1 month prior to admission to the study center or any strong inhibitor of drug or xenobiotic metabolism (such as CYP3A4 inhibitor itraconazole) within 2 weeks prior to admission to the study.

Subject has had significant blood loss, donated 1 unit (450 mL) or more of blood, or received a transfusion of any blood or blood products within 60 days or donated plasma within 7 days prior to Day -1.

Subject has a positive serology test for HBsAg, hepatitis B core antibody (anti-HBc), hepatitis C virus antibodies (anti-HCV), or antibodies to human immunodeficiency virus (HIV) type 1 and/or type 2 at screening.

Subject has a positive T-cell interferon-y release assay (TIGRA), ie, Quanti-FERON-TB Gold test, at screening. Subjects with an indeterminate result should have negative purified protein derivative (PPD) skin test and low risk of acquiring tuberculosis (TB) (eg, no close contact with TB-positive individual[s]), and/or chest x-ray performed within 6 months before the screening visit showing no evidence of latent/active TB.
Note: Subjects who have a negative Quanti-FERON-TB Gold test results from 28 days prior to screening, with no history of exposure to a person with TB or travel to endemic region in the same period, may be enrolled without the need to repeat QuantiFERON test post-signing of ICF.

Subject has participated in any clinical study or has been treated with any investigational drugs within 28 days or 5 half-lives whichever is longer, prior to screening.

Subject will require an immunization within 6 weeks following the last dose administered in this study.

Subject has any condition which, in the Investigator’s opinion, makes the subject unsuitable for study participation.

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)
On Day 1 subjects will be assigned a unique number (randomization number) in ascending numerical order. The randomization number encodes the subject’s assignment to 1 of the study treatments, according to the randomization schedule generated prior to the study by the Statistics Department at Quintiles. Each subject will be dispensed blinded study treatment, labeled with his/her unique randomization number.
There will be limited access to the randomization code. The investigational treatment and placebo solutions will be similar in physical appearance, the unblinded site staff will conceal the treatment for administration. This process is outlined in the Pharmacy Manual. The treatment each subject will receive will not be disclosed to the Investigator, study center staff (excluding the site pharmacist and 1 unblinded Investigator), subject, or the SMC voting members.
A sealed envelope that contains the study treatment assignment for each subject will be provided to the Investigator. The sealed envelope will be retained by the Investigator (or representative) in a secured area. In case of an emergency, the Investigator has the sole responsibility for determining if unblinding of a subject’s treatment assignment is warranted. Subject safety must always be the first consideration in making such a determination. If the Investigator decides that unblinding is warranted, the Investigator should make every effort to contact the Sponsor prior to unblinding a subject’s treatment assignment unless this could delay emergency treatment of the subject. If a subject’s treatment assignment is unblinded, the Sponsor must be notified within 24 hours after breaking the blind. Once the study is complete, all envelopes (sealed and opened) must be inventoried and returned to the Sponsor.
Subjects will be randomly assigned to receive HL161BKN or placebo, except in Cohorts 1 and 2, and the sentinel subjects where all subjects will receive HL161BKN. Investigators will remain blinded (except for Cohorts 1and 2, and the sentinel subjects) to each subject’s assigned study treatment throughout the course of the study. In order to maintain this blind, an otherwise uninvolved third party (pharmacist) will be responsible for the reconstitution and dispensation of all study treatment.
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded study treatment records at the study center(s) to verify that randomization/dispensing has been done accurately.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised 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
Single Ascending Dose
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
Inferential statistical analysis is not planned for this study. The study is designed to identify safe, tolerated doses of HL161BKN administered as a SC dose to healthy adult subjects. The data will be used to select doses for further investigation of the safety, tolerability and efficacy of HL161BKN administered to patients.
The sample size is not based on statistical considerations but is typical for studies of this nature, and is considered adequate to characterize the distribution of the planned endpoints. Any statistical testing will be considered exploratory and descriptive.

Recruitment
Recruitment status
Stopped early
Data analysis
Data analysis is complete
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
Sponsor decision to take study to another country.
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)
QLD
Recruitment hospital [1] 11782 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment postcode(s) [1] 23908 0
4007 - Herston

Funding & Sponsors
Funding source category [1] 300455 0
Commercial sector/Industry
Name [1] 300455 0
IQVIA
Address [1] 300455 0
Level 9, 67 Albert Avenue, Chatswood, NSW 2067, Australia.
Country [1] 300455 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
IQVIA
Address
Level 9, 67 Albert Avenue, Chatswood, NSW 2067, Australia.
Country
Australia
Secondary sponsor category [1] 299922 0
None
Name [1] 299922 0
Address [1] 299922 0
Country [1] 299922 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301258 0
Bellberry Human Research Ethics Committee H: EC00459
Ethics committee address [1] 301258 0
129 Glen Osmond Rd
Eastwood SA 5063
Ethics committee country [1] 301258 0
Australia
Date submitted for ethics approval [1] 301258 0
30/10/2017
Approval date [1] 301258 0
06/12/2017
Ethics approval number [1] 301258 0

Summary
Brief summary
HL161BKN is an experimental treatment. This means that it is not an approved treatment for auto-immune diseases in Australia by the Therapeutic Goods Administration (TGA).
Auto-immune diseases occur when a person’s own immune system mistakenly attacks their own body, and are particularly hard to treat because there is no cure currently available, only medications that can manage the symptoms. There are over 80 different types of auto-immune diseases that range in severity (from mild to disabling), depending on which system (nervous, vascular, respiratory, muscular etc.) is under attack and to what degree.
T lymphocytes (T cells) are immune cells that use special receptors on their surfaces to identify micro-organisms such as bacteria and viruses that may enter our bodies. Usually, the T cells are destroyed by the thymus, an organ of the immune system. Occasionally, they are not destroyed, and these rogue T cells may instruct another type of cell, B lymphocytes (B cells), to make antibodies against the body’s own tissues, organs or systems. Such antibodies are called 'autoantibodies'. HL161BKN acts as a “block” of special receptors in the tissues, organs or systems, so that autoantibodies cannot bind to them and cause an auto-immune reaction that causes damage.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 86390 0
Dr Paul Griffin
Address 86390 0
Q-Pharm Pty Ltd
Level 5, 300C Herston Road
Herston, QLD – 4006
Country 86390 0
Australia
Phone 86390 0
+61 7 3845 3636
Fax 86390 0
Email 86390 0
p.griffin@qpharm.com.au
Contact person for public queries
Name 86391 0
Ms Emma Fiddes
Address 86391 0
Quintiles Pty Limited
Level 9, 67 Albert Avenue
Chatswood, NSW 2067, Australia
Country 86391 0
Australia
Phone 86391 0
+61395196884
Fax 86391 0
Email 86391 0
emma.fiddes@iqvia.com
Contact person for scientific queries
Name 86392 0
Ms Emma Fiddes
Address 86392 0
Quintiles Pty Limited
Level 9, 67 Albert Avenue
Chatswood, NSW 2067, Australia
Country 86392 0
Australia
Phone 86392 0
+61395196884
Fax 86392 0
Email 86392 0
emma.fiddes@iqvia.com

No data has been provided for results reporting
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary