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Trial registered on ANZCTR


Registration number
ACTRN12624001111561
Ethics application status
Approved
Date submitted
14/08/2024
Date registered
16/09/2024
Date last updated
16/09/2024
Date data sharing statement initially provided
16/09/2024
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple- Ascending Dose Study to Evaluate the Safety and Tolerability of OLX75016 in Healthy Volunteers and Patients with Non-Alcoholic Fatty Liver Disease.
Scientific title
A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple- Ascending Dose Study to Evaluate the Safety and Tolerability of OLX75016 in Healthy Volunteers and Patients with Non-Alcoholic Fatty Liver Disease.
Secondary ID [1] 312551 0
OLX75016-01
Universal Trial Number (UTN)
Trial acronym
Linked study record
This study is related ACTRN12624000023550. ACTRN12624000023550 registered study is a Healthy volunteer part of the study and this application is for patient cohort part of the study.

Health condition
Health condition(s) or problem(s) studied:
(NAFLD) to Steatohepatitis (NASH) 334442 0
Fibrosis 334443 0
Cirrhosis 334444 0
Condition category
Condition code
Oral and Gastrointestinal 331066 331066 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
OLX75016 is a chemically synthesized double stranded siRNA targeting expression of the Mitochondrial Amidoxime Reducing Component 1 (MARC1) enzyme for the treatment of nonalcoholic fatty liver disease(NAFLD) with liver fibrosis. OLX75016, which is administered by subcutaneous (SC) injection,

OLX75016 and a matching placebo will be administered as SC injections in the abdominal region. This study will be conducted in two parts: Part A (SAD) and Part B (MAD).
Each study part will enrol patients with Non-Alcoholic Fatty Liver Disease (NAFLD).

- Part A (SAD) NAFLD Patients: Up to 12 patients over 3 dose escalation cohorts (4 patients per cohort)
- Part B (MAD) NAFLD Patients: Up to 8 patients over 2 dose escalation cohorts (up to 4 patients per cohort)

- Part A Single Ascending Dose (SAD) NAFLD Patients: NAFLD patients will be enrolled and randomized to 3 cohorts with each cohort having 4 participants to receive single ascending doses of OLX75016 or placebo (ratio 3:1 active: placebo). The starting dose will be 90 mg, with 3 dose levels planned (up to 450 mg). At the discretion of the study Sponsor, in consultation with the Safety Review committee (SRC), additional cohorts may be added to evaluate intermediate dose levels. Cohorts will be dosed in an escalating order. Patients with NAFLD will be screened between Day -28 to Day -2. Eligible participants will be admitted to the clinic on Day -1. Following confirmation of eligibility, participants will be randomized to receive OLX75016 or a placebo before dose administration on Day 1. Doses will be administered in the clinic, under the supervision of site staff . All participants will be confined to the clinic until the completion of all safety/tolerability and PK assessments on Day 3. Sentinels are not required for NAFLD patient cohorts.

Participants will be required to return to the clinic for additional outpatient safety/tolerability assessments on Day 4, 7, 14, 28 and 42. Participants will be discharged from each visit following completion of all safety and PK assessments, the end of study (EoS) visit will be on Day 56. Compliance will be monitored by site staff witnessing of dosing and will be documented in participant study files. If participants experience any clinically significant (CS) AEs during the confinement period, they may remain in the clinical facility for further observation at the discretion ofthe Principal Investigator (PI). After at least 6 out of 8 participants have completed the Day 28 visit, the SRC will review all available safety/tolerability data (including safety/tolerability data collected on Day 28),discuss the findings, and decide to:

• Enrol the next dose cohort in Part A at the protocol-defined dose level.
• Enrol the next dose cohort at an intermediate dose level not defined in the protocol; or
• Terminate enrolment in Part A of the study.

In conjunction with the above, following completion of SAD Cohort 3, the SRC may also determine a starting dose level for Part B (MAD) and determine whether sentinel dosing should be used for the first cohort in Part B (MAD). If the SRC determines sentinel dosing is required, the SRC will advise on the minimum length of time for participants to be followed prior to dosing the remaining participants in thecohort.

- Part B Multiple Ascending Dose (MAD) NAFLD Patients: Cohort 1-2 (Final dose levels will be confirmed prior to commencement of dosing in Part B). The planned starting dose on MAD cohort 1 is 90 mg and the maximum dose is up to 600 mg. NAFLD patients will be enrolled and randomized to 2 cohorts with 4 patients per cohort to receive multiple ascending doses of OLX75016 or placebo (ratio 3:1 active:placebo), with 2 dose levels planned. At the discretion of the study Sponsor, in consultation with the SRC, additional cohort(s) may be added to evaluate (an) additional dose level(s). Dosing in each patient cohort will commence only after the SRC confirms dosing in healthy participants for MAD Cohorts 2 and 3.

Sentinel dosing will not be required for MAD unless recommended by the SRC based on findings from PartA (SAD). Compliance will be monitored by site staff witnessing of dosing and will be documented in participant study files. If patients with NAFLD experience any clinically significant (CS) AEs during the confinement period, they may remain in the clinical facility for further observation at the discretion of the Principal Investigator (PI). After at least 8 out of 10 participants have completed the Day 56 visit, the SRCwill review all available safety/tolerability data (including safety/tolerability data collected on Day 56) andavailable PK data, discuss the findings, and decide to:

• Enrol the next dose cohort in Part B at the protocol-defined dose level.
• Enrol the next dose cohort at an intermediate dose level not defined in the protocol; or
• Terminate enrolment in Part B of the study.

In conjunction with the above, the SRC may also determine whether sentinel dosing should be employed in subsequent cohorts in Part B. If the SRC determines sentinel dosing is required, the SRC will advise on the minimum length of time for participants to be followed prior to dosing the remaining participants in the cohort.
Intervention code [1] 329072 0
Treatment: Drugs
Comparator / control treatment
The placebo will be the Normal saline (0.9% NaCl) identical in appearance to IP. Placebo will be administered as Subcutaneous injection.
Control group
Placebo

Outcomes
Primary outcome [1] 338844 0
Composite Outcome- To evaluate the safety and tolerability of multiple doses of OLX75016 in patients with NAFLD
Timepoint [1] 338844 0
• Local tolerability - site of subcutaneous injections- On Day 1 and Day 29 local tolerability assessments will be performed at 0.25, 0.5 and 1 hour post-dose. All other local tolerability assessments will be performed at any time on days 2, 3, 4, 7, 30, 31, 32, 35 and at 141 EOS/Early Termination.
• Clinical laboratory results - haematology, serum chemistry, urinalysis- Safety blood samples are collected at the time points -screening visit, Day -1, Days 1, 2, 3, 4, 7, 14, 28, 29, 30, 31, 32, 35, 42, 56, 84 and Day 141 (End of Study Visit(EoS). Urinalysis are collected at the time points - screening visit, Day -1, Days 1, 2, 28, 29, 30, 42, 56, 84 and Day 141 (End of Study Visit (EoS).
• Vital signs- Vital Signs are performed at Screening visit, Day -1, Days 1, 2,3, 4, 7, 14, 28, 29, 30, 31, 32, 35, 42, 56, 84 and Day 141 (EoS).
• Twelve-lead ECGs - All ECGs will be performed in triplicate. Twelve-lead ECGs are performed at Screening visit, Day -1, Days 1, 2, 3, 4, 7, 14, 28, 29, 30, 31, 32,35, 42, 56, 84 and 141 (EoS). Continuous 12-lead telemetry monitoring will be conducted from at least 1 hour pre-dose to at least 24 hours post-dose. Also, telemetry will be performed on Day 29.
• Evaluation of Inflammatory Markers - Blood samples are collected at Screening visit, Days 1, 2, 7, 29, 30, 35, 42, 56, 84 and 141 (EoS).
• Evaluation of Metabolic Panel - Blood samples are collected at Screening visit, Day -1, Days 1, 2,7, 29, 30, 35, 42, 56, 84 and 141 (EoS).
Primary outcome [2] 338846 0
composite primary outcome- To evaluate the safety and tolerability of a single dose of OLX75016 in patients with NAFLD.
Timepoint [2] 338846 0
• Local tolerability - site of subcutaneous injections- On Day 1, local tolerability assessments will beperformed at 0.25, 0.5 and 1 hour post-dose. All other local tolerability assessments will be performed atany time on the Days 2, 3, 4 and 7.
• Clinical laboratory results - haematology, serum chemistry, urinalysis-Safety blood samples and Urinalyses are collected at the time points - screening visit, Day -1, Days 1, 2, 3,4, 7, 14, 28, 42 and Day 56 (End of Study Visit (EoS).
• Vital signs- Vital Signs are performed at Screening visit,Day -1, Days 1, 2, 3, 4, 7, 14, 28, 42 and Day 56 (EoS).
• Twelve-lead ECGs - All ECGs will be performed intriplicate. Twelve-lead ECGs are performed at Screening visit, Day -1, Days 1, 2, 3, 4, 7, 14, 28, 42 and Day 56(EoS). Continuous 12-lead telemetry monitoring will be conducted from at least 1 hour pre-dose to at least24 hours post-dose.
• Evaluation of Infl ammatory Markers - Blood samples are collected at Screening visit,Days 1, 2, 7 and 56 (EoS).
• Evaluation of Metabolic Panel - Blood samples are collected at Screening visit,Day -1, Days 1, 2, 7, 28 and 56 (EoS).
Secondary outcome [1] 437657 0
To evaluate the pharmacokinetics (PK) of OLX75016 in plasma and urine following single dose administration in patients with NAFLD.
Timepoint [1] 437657 0
PK Timepoints include -
Day 1- pre-dose, 0.5 hr post-dose, 1 hour post-dose, 2 hour-post dose, 4 hour post-dose, 8 hour post-dose
Day 2- 24 hour post-dose
Day 3- 48 hour post-dose and in the instance of an early termination visit


Urine samples timepoints include: Day 1- Between 0-2 hour , 2-4 hour,4-8 hours, 8-24 hours post dose.
Secondary outcome [2] 437658 0
To evaluate the pharmacokinetics (PK) of OLX75016 in plasma and urine following multiple dose administration in patients with NAFLD.
Timepoint [2] 437658 0
PK timepoints include:
Day 1- pre-dose, 0.5 hr post-dose, 1 hour post-dose, 2 hour-post dose, 4 hour post-dose, 8 hour post-dose
Day 2- 24 hour post dose
Day 3- 48 hour post dose
Day 29- pre-dose, 0.5 hr post-dose, 1 hour post-dose, 2 hour-post dose, 4 hour post-dose, 8 hour post-dose
Day 30- 24 hour post dose
Day 31- 48 hour post dose.

Urine samples timepoints include: Day 1 and Day 29 - Between 0-2 hour , 2-4 hour, 4-8 hours, 8-24 hours post dose

Eligibility
Key inclusion criteria
1. Must have given written informed consent, before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse eff ects.
2. Willing, committed, and able to return for all clinic visits and complete all protocol specified procedures.
3. Male or female, aged between 18 and 65 years, inclusive at screening.
4. Body mass index (BMI) of greater than or equal to 22 kg/m2 and less than or equal to 40 kg/m2 at Screening.
5. Liver fat content greater than 10% and less than 33% as determined by MRI-PDFF.
6. Human immunodeficiency virus, viral hepatitis B and C serology, autoimmune hepatitis (Liver KidneyMicrosomal [LKM] Antibody), transferrin saturation less than 45%, at Screening.
7. On a stable diet for at least 4 weeks prior to Day -1, with no plans to significantly alter lifestyle for the duration of the study.
8. Patient has well controlled systolic blood pressure with or without stable medication in the range 90 to 140 and diastolic blood pressure in the range of 40 to 90 mmHg after 5 minutes in supine or semi-supine position.
9. Body temperature (tympanic), between 35.5°C and 37.5°C (inclusive).
10. Electrocardiogram (ECG) without clinically significant abnormal findings and average QT interval (QTc),QT interval corrected for Fredericia (QTcF) less than 450 msec for male participants and less than 470 msec for female participants. Note: The above assessments may be repeated, if abnormal values were recorded in the first instance, at the discretion of the Investigator (or delegate).
11. Patient is willing to refrain from consuming caffeine and/or xanthene products (e.g., coffee, tea, chocolate, and caffeine-containing sodas, colas), for:
a. At least 24 hours prior to Day -1 and while confined to the clinical facility and prior to each clinic visit from screening through to EoS (Part A, SAD).
b. At least 24 hours prior to each admission and while confined to the clinical facility and prior to each clinic visit from screening through to EoS (Part B, MAD).
12. Female patients must be of non-childbearing potential i.e., surgically sterilised (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before the screening visit) or post-menopausal(where post-menopausal is defined as no menses for 12 months without an alternative medical cause and a follicle-stimulating hormone (FSH) level consistent with post-menopausal status, per local laboratoryguidelines), or, if of child-bearing potential:
a. Must have a negative serum pregnancy test at the screening visit and a negative urine pregnancy test on Day -1.
b. Must agree not to donate ova or attempt to become pregnant from the time of signing consent until at least 30 days (or 5 half-lives of OLX75016, whichever is longer) after the last dose of study drug.
c. If not exclusively in a same-sex relationship, must agree to use adequate contraception (which is defi nedas use of a condom by the male partner combined with use of a highly eff ective method of contraception) from one month prior to screening until at least 30 days (or 5 half-lives of OLX75016, whichever is longer) after the last dose of study drug.
d. If in a same-sex relationship or being completely abstinent as a life-style choice, no form of contraception is required.
13. Male patients must:
a. Agree not to donate sperm from the time of signing consent until at least 90 days after the last dose of study drug.
b. If engaging in sexual intercourse with a female partner who could become pregnant, must agree to useadequate contraception (defined as use of a condom plus a highly effective method of contraception) from the time of signing consent until at least 90 days (or 5 half-lives of OLX75016, whichever is longer) after the last dose of study drug.
c. If engaging in sexual intercourse with a female partner who is not of childbearing potential or a same-sex partner, must agree to use a condom from the time of signing consent until at least 5 half-lives of OLX75016 after the last dose of study drug. If being completely abstinent as a life-style choice, no form of contraception is required.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Has any clinical safety laboratory result considered clinically significant by the Investigator (or designee)and that could compromise the interpretation of the study objectives.
2. Use of an investigational agent (including previous exposure to siRNAs) or device within 30 days or 5 half-lives of Day 1 drug administration in this trial, whichever is longer prior to dosing or current participation in an investigational study. History of having received long-duration RNA-based therapies.
3. In the opinion of the PI (or designee), has any uncontrolled or serious disease, medical or surgical condition that may interfere with participation or data interpretation.
4. Participant smokes greater than or equal to 5 cigarettes per week and/or is unwilling to refrain from smoking (and use of any tobacco products or nicotine-containing products) whilst confined to the clinical unit.
5. History of substance dependence (within the last 12 months) or positive urine drug screen at screening(Part A [SAD] and Part B [MAD]), Day -1 (Part A and Part B), Day 28 (Part B, only) or excessive alcohol consumption (defi ned as more than 14 standard drinks per week or regularly consuming more than 4 standard drinks on any one day; where one standard drink is 10g of pure alcohol and is equivalent to 285mL beer [4.9% Alc./Vol], 100 mL wine [12% Alc./Vol], 30 mL spirit [40% Alc./Vol]) during less than or equal to1 year prior to Screening.
6. Use of any vaccinations within 14 days prior to the first study drug administration (vaccination for COVID-19 is permitted with the most recent dose administered greater than 1 week prior to first study drug administration).
7. In the opinion of the PI (or designee), has an aversion to, or has history of site reactions to SC administrations that would make them unsuitable for inclusion in this trial.
8. Has contraindications to MRI (e.g., metal implants [excluding Titanium]; severe claustrophobia and inability to lie flat for 1 hour).
9. Has HbA1c greater than or equal to 8.5% (or serum fructosamine greater than or equal to 381 µmol if HbA1c measurement is not available). Patients are permitted to be on a stable dose of Metformin for 3months prior to Screening.
10. Has hemoglobin less than or equal to 110 g/L
11. Has International normalized ratio (INR) greater than or equal to 1.3
12. Use of anticoagulant medication within 6 months prior to first dose of study drug.
13. Has direct bilirubin greater than or equal to 0.3 mg/dL
14. Has total bilirubin greater than or equal to 1.3 x upper limit of normalization (ULN), unless due to analternate etiology such as Gilbert’s syndrome or hemolytic anemia
15. Has platelet count less than or equal to 150,000/µL
16. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of study intervention.
17. Participants with history or pre-existing renal disease, as defined below:
c. estimated glomerular filtration rate (eGFR) less than or equal to 60 mL/min (calculated using the Chronic Kidney Disease Epidemiology Collaboration formula); slight changes permitted as deemed appropriate by the PI/delegate or
d. urinary albumin-to-creatinine ratio greater than 3.5 mg/mmol (females) and greater than 2.5 mg/mmol (males).
18. Relevant history (in the opinion of the PI or designee) of cardiac arrythmias including long QT syndrome,sudden cardiac death, or Torsades de Pointes and/or syncope and/or clinically significant cardiovascular event within the last 6 months prior to the Screening Visit.
19. Participants with a positive SARS-CoV-2 infection (polymerase chain reaction [PCR] or rapid antigen test[RAT] as deemed appropriate by the site’s SOPs or PI discretion) at Screening or Day -1 Visit.
20. Participants with a signifi cant Coronavirus disease 2019 (COVID-19) illness within 6 months ofenrolment, defi ned by one of the following:
d. Participants with a diagnosis of COVID-19 pneumonia based on radiological assessment.
e. Participants with diagnosis of COVID-19 with signifi cant fi ndings from pulmonary imaging tests.
f. Participants with a diagnosis of COVID-19 requiring hospitalization and/or oxygen supplementationtherapy.
21. Weight loss of more than 10% within the last 3 months prior to screening.
22. Has donated blood or blood products within 3 months prior to fi rst dose administration.
23. Blood dyscrasias with increased risk of bleeding including idiopathic thrombocytopenic purpura andthrombotic thrombocytopenic purpura or symptoms of increased risk of bleeding (frequent bleeding gumsor nose bleeds).
24. History of major bleed or high-risk of bleeding diathesis.
25. Use of anabolic steroids and systemic treatment with glucocorticosteroids within 3 months prior to the Screening Visit.
26. Presence or evidence of recent sun burn, scar tissue, tattoo, open sore or branding that, in the opinion ofthe PI or medically qualified designee, would interfere with the interpretation of skin adverse reactions atthe injection site.
27. Any other condition or prior therapy that in the opinion of the PI (or designee) would make the participant unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of non compliance with any study requirements.

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)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
All study participants who sign an informed consent form at screening will receive a unique screening number. Participants who meet the study eligibility criteria will be assigned a randomization number prior to first dose administration on Day 1 by the unblinded pharmacy personnel as per site standard process,which corresponds to a study treatment (OLX75016 or placebo). The allocation to OLX75016 or placebo will be performed using a block randomization algorithm. and will be documented in the study randomization schedule.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
Detailed methodology for the summation and statistical analysis of the data collected will be documented in a Statistical Analysis Plan. Summaries will be presented separately for Part A (SAD) and PartB (MAD), by dose level within study part and overall within study part. For descriptive statistics, continuous data will be summarized by dose level and time point using the number of observations, arithmetic mean,standard deviation (SD), median, minimum and maximum. Discrete data will be summarized using counts and percentages. All available data will be included in data listings. Data tabulations will be performed forspecific analysis populations.

All Screened Analysis Set
The All Screened Analysis Set (ASS) will include all participants who sign an informed consent form at screening and receive a unique sequential number (i.e., screening number).

Safety Analysis Set
All participants who receive at least one dose of study drug will be included in the Safety Analysis Set and will be analysed as per the actual treatment received, if this differs from that to which the participant was randomized.

Pharmacokinetic Analysis Set
The PK Analysis Set will include all participants who receive at least one dose of study drug (OLX75016)and have sufficient post-dose data to be able to reliably determine at least one PK parameter. Participantswill be analysed according to treatment received.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
3/07/2024
Date of last participant enrolment
Anticipated
31/12/2024
Actual
Date of last data collection
Anticipated
30/04/2025
Actual
Sample size
Target
20
Accrual to date
2
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 26811 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment postcode(s) [1] 42862 0
4007 - Herston

Funding & Sponsors
Funding source category [1] 316978 0
Commercial sector/Industry
Name [1] 316978 0
OliX Pharmaceuticals
Country [1] 316978 0
Korea, Republic Of
Primary sponsor type
Commercial sector/Industry
Name
OliX AU Pty Ltd
Address
Country
Australia
Secondary sponsor category [1] 319225 0
Commercial sector/Industry
Name [1] 319225 0
Avance Clinical Pty Ltd
Address [1] 319225 0
Country [1] 319225 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315732 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 315732 0
Ethics committee country [1] 315732 0
Australia
Date submitted for ethics approval [1] 315732 0
23/05/2024
Approval date [1] 315732 0
29/05/2024
Ethics approval number [1] 315732 0

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

Contacts
Principal investigator
Name 135634 0
Mr Richard Friend
Address 135634 0
Nucleus Network Brisbane, Level 5 Clive Berghofer Cancer Research Centre, 300C Herston Road, Herston,Queensland, 4006
Country 135634 0
Australia
Phone 135634 0
+61 7 3707 2720
Fax 135634 0
Email 135634 0
[email protected]
Contact person for public queries
Name 135635 0
Gabrielle Robb
Address 135635 0
Nucleus Network Brisbane, Level 5, 300C Herston Road, Herston, Queensland 4006
Country 135635 0
Australia
Phone 135635 0
+61 737072784
Fax 135635 0
Email 135635 0
[email protected]
Contact person for scientific queries
Name 135636 0
June Hyun Park
Address 135636 0
OliX Pharmaceuticals, Ace Gwanggyo Tower 1, Suite 1008. 17 Daehak 4-ro, Yeongtong- gu, Suwon-si,Gyeonggi-do, 16226
Country 135636 0
Korea, Republic Of
Phone 135636 0
+82 10 3618 7891
Fax 135636 0
Email 135636 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Privacy and Intellectual property considerations


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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