ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12624000374561

Ethics application status

Approved

Date submitted

15/02/2024

Date registered

2/04/2024

Date last updated

2/04/2024

Date data sharing statement initially provided

2/04/2024

Type of registration

Prospectively registered

Titles & IDs

Public title

A Phase I, Randomised, Double Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of OXT-328 in Healthy Adult Volunteers

Scientific title

A Phase I, Randomised, Double Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of OXT-328 in Healthy Adult Volunteers

Secondary ID [1]

OXT328-NEU-01

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Chemotherapy-Induced Peripheral Neuropathy (CIPN)

Condition category

Condition code

Neurological

Other neurological disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

This is a Phase Ia/b, randomised double blind, placebo-controlled, single ascending dose (SAD), multiple ascending dose (MAD) multi-cohort study.

Part A: Single Ascending Dose (SAD)
Thirty two healthy participants will be enrolled into 4 cohorts and randomised to receive single ascending doses of OXT-328 or placebo which will be administered as a topical gel.
Four dose levels are planned with a single topical dose to be administered on Day 1:

• Cohort 1: 15 mg (1 mL of 1.5% w/w strength study drug on hand)
• Cohort 2: 30 mg (1 mL of 3.0% w/w strength study drug on hand)
• Cohort 3: 50 mg (1 mL of 5.0% w/w strength study drug on hand)
• Cohort 4: 100 mg (2 mL of 5.0% w/w strength study drug on foot)

Cohorts will be dosed in a sequential, dose-escalating order.

Part B: Multiple Ascending Dose (MAD)
Part B may commence following completion of SRC review of at least 3 cohorts in Part A. Twenty four healthy adult participants will be enrolled to 1 of 3 cohorts and randomised to receive multiple ascending doses of OXT-328 or placebo administered as a topical gel. Doses will be administered on Days 1 to 7 (inclusive), with the dosing schedule once daily (QD), twice daily (BID) or three times daily (TID) to be determined based on results from Part A, prior to commencement of dosing in Part B. The starting dose will be 30 mg, with up to 3 dose levels planned (up to 100 mg).

Cohorts will be dosed in a sequential, dose- escalating order.

Dose administration will be performed by site staff and adherence to Intervention will be managed via recording in appropriate drug accountability records

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

The placebo gel contains no active ingredient and is formulated to match the appearance of OXT-328 gel formulation in colour and consistency, and to match the appearance of OXT-328 upon contact with skin. The placebo gel is also odourless and will also be supplied in an identical 50 gram tube as the OXT-328 gel.

Control group

Placebo

Outcomes

Primary outcome [1]

To evaluate the safety and tolerability of OXT-328 following single doses of OXT-328 topical gel compared with placebo in healthy adult volunteers

Timepoint [1]

Adverse events - will be graded using a five-point severity scale (mild, moderate, severe, life-threatening, death) and assessed continuously as they are reported or observed and reviewed daily from Screening until Day 8 post-dose (End of Study/Early Termination [EOS/ET]).

Vital signs - Blood pressure and heart rate is measured using sphygmomanometer respiratory rate by manual breath count, temperature by thermometer. Measured from Screening, Day -1, pre-dose Day 1 0.25 hr, 4 hrs post-dose and Day 8 post-dose (EOS/ET).

Clinical Laboratory Assessments (haematology, serum chemistry and urinalysis) blood and urine will be collected at Screening, Day -1, Day 2 post-dose and Day 8 post-dose (EOS/ET).

Full physical assessment will include at a minimum, assessment of the following: general appearance, head, ears, eyes, nose, and throat examination, neck (including thyroid and nodes), cardiovascular, respiratory, GI, renal, neurological, musculoskeletal, skin and occur at Screening and Day 8 post-dose (EOS/ET) with symptom directed assessments to occur on Day -1 then at any time pre and post dose Day 1 and Day 2.

Electrocardiogram (ECG) 12-lead ECG recordings will be obtained in triplicate at Screening, Day -1, pre-dose Day 1 1 hr post-dose and ET visit.

Local tolerability will be graded using a Local Skin Tolerability Questionnaire and assessed at Day -1, Day 1 8 hrs post-dose, Day 2 24 hrs post-dose and Day 8 post-dose (EOS/ET).

Primary outcome [2]

To evaluate the safety and tolerability of OXT-328 following multiple doses of OXT-328 topical gel compared with placebo in healthy adult volunteers

Timepoint [2]

Adverse events - will be graded using a five-point severity scale (mild, moderate, severe, life-threatening, death) and assessed continuously as they are reported or observed and reviewed daily from Screening until Day 14 post-dose (End of Study/Early Termination [EOS/ET]).

Vital signs - Blood pressure and heart rate is measured using sphygmomanometer respiratory rate by manual breath count, temperature by thermometer. Measured from Screening, Day -1, pre-dose Day 1 0.25 hr, 4 hrs post-dose, pre-second dose Day 2 - 0.25 hr, 1 hr and 4 hrs post-second dose, pre-third dose Day 3 1 hr post-third dose, pre-fourth dose Day 4 1 hr post-fourth dose, pre-fifth dose Day 5 1 hr post-fifth dose, pre-seventh dose Day 7 1 hr post-seventh dose and Day 14 post-dose (EOS/ET).

Clinical Laboratory Assessments (haematology, serum chemistry and urinalysis) blood and urine will be collected at Screening, Day -1, Day 1 1-2 hrs post-dose, pre-second dose Day 2, pre-third dose Day 3, pre-seventh dose Day 7 and Day 14 post-dose (EOS/ET).

Full physical assessment will include at a minimum, assessment of the following: general appearance, head, ears, eyes, nose, and throat examination, neck (including thyroid and nodes), cardiovascular, respiratory, GI, renal, neurological, musculoskeletal, skin and occur at Screening and Day 14 post-dose (EOS/ET) with symptom directed assessments to occur on Day -1 then at any time pre and post-dose Day 1, Day 2. Day 3, Day 4, Day 5, Day 6 and Day 7.

Electrocardiogram (ECG) 12-lead ECG recordings will be obtained in triplicate at Screening, Day -1, pre-dose Day 1 1 hr post-dose, pre-second dose Day 2 1 hr post-second dose, pre-fourth dose Day 4 1 hr post-fourth dose, pre-seventh dose Day 7 1 hr post-seventh dose and ET visit.

Local tolerability will be graded using a Local Skin Tolerability Questionnaire and assessed pre-dose Day 1 - 2, 4, 6 and 8 hrs post-dose, Day 2 post-second dose, Day 4 - 2, 4, 6 and 8 hrs post-fourth dose, Day 6 - 2, 4, 6 and 8 hrs post-sixth dose and Day 14 post-dose (EOS/ET).

Secondary outcome [1]

To evaluate the PK plasma profile of OXT-328 following single topical doses in healthy adult volunteers

Timepoint [1]

Blood plasma samples to be collected pre-dose Day 1 - 1, 2, 4, 6, 8, and 12 hrs post-dose, Day 2 24 hrs post-dose and Day 8 post-dose (EOS/ET).

Secondary outcome [2]

To evaluate the PK plasma profile of OXT-328 following multiple topical doses in healthy adult volunteers

Timepoint [2]

Blood plasma samples to be collected pre-dose Day 1 - 1, 2, 4, 6 and 8 hrs post-dose, pre-fourth dose Day 4, pre-seventh dose Day 7 - 1, 2, 4, 6 and 8 hrs post-seventh dose and Day 14 post-dose (EOS/ET).

Secondary outcome [3]

To measure the three metabolites of OXT-328: sulindac in plasma (Part A)

Timepoint [3]

Blood plasma samples to be collected pre-dose Day 1 - 1, 2, 4, 6, 8, and 12 hrs post-dose, Day 2 24 hrs post-dose and Day 8 post-dose (EOS/ET).

Secondary outcome [4]

To measure the three metabolites of OXT-328: sulindac in plasma (Part B)

Timepoint [4]

Secondary outcome [5]

To measure the metabolites of OXT-328: sulindac sulfone in plasma (Part A)

Timepoint [5]

Blood plasma samples to be collected pre-dose Day 1 - 1, 2, 4, 6, 8, and 12 hrs post-dose, Day 2 24 hrs post-dose and Day 8 post-dose (EOS/ET).

Secondary outcome [6]

To measure the metabolites of OXT-328: sulindac sulfide in plasma (Part A)

Timepoint [6]

Blood plasma samples to be collected pre-dose Day 1 - 1, 2, 4, 6, 8, and 12 hrs post-dose, Day 2 24 hrs post-dose and Day 8 post-dose (EOS/ET).

Secondary outcome [7]

To measure the three metabolites of OXT-328: sulindac sulfone in plasma (Part B)

Timepoint [7]

Secondary outcome [8]

To measure the metabolites of OXT-328: sulindac sulfide in plasma (Part B)

Timepoint [8]

Eligibility

Key inclusion criteria

Participants will be included in Part A and B of the study only if they satisfy all the following 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 effects.
2. Healthy male or female, aged between 18 and 65 years, inclusive at screening.
3. Body mass index (BMI) of 18 to 35 kg/m2, inclusive at screening, with body weight greater than or equal to 50.0 kg (males) or greater than or equal to 45.0 kg (females), at screening.
4. Participant is medically healthy (in the opinion of the Investigator [or delegate]), as determined by pre-study medical history and without clinically significant abnormalities including:
a. Physical examination without any additional clinically relevant findings
b. Systolic blood pressure (BP) in the range of 90 to 160 mmHg and diastolic BP in the range of 50 to 95 mmHg after 5 minutes in supine or semi-supine position.
c. Pulse rate in the range of 40 to 100 beats/minute after 5 minutes rest in supine or semi-supine position.
d. Body temperature between 35.5°C and 37.7°C.
e. Electrocardiogram without clinically significant abnormalities including QT interval corrected for Fredericia (QTcF) < 450 msec for male subjects and < 470 msec for female subjects.
f. No clinically significant findings in serum chemistry, haematology or urinalysis (in the opinion of the Investigator).
Note: The above assessments may be repeated, if abnormal values were recorded in the first instance, at the discretion of the Investigator (or delegate).
5. Participant is willing to refrain from consuming food or beverages containing caffeine and/or xanthene products, within 24 hours prior to check-in on Day -1 and while confined to the study clinic.
6. Female participants must be of non-childbearing potential i.e., surgically sterilised (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before the screening visit) or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause and a follicle-stimulating hormone [FSH] level consistent with postmenopausal status, per local laboratory guidelines), or, if of childbearing potential:
a. Must have a negative serum pregnancy test at the screening visit and a negative urine pregnancy test on Day -1, prior to dose administration.
b. Must agree not to donate ova or attempt to become pregnant from the time of signing consent until at least 30 days after the last dose of study drug.
c. If not exclusively in a same-sex relationship, must agree to use adequate contraception (which is defined as use of a condom by the male partner combined with use of a highly effective method of contraception) from one month prior to screening until at least 30 days after the last dose of study drug.
7. Male participants 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, agree to use adequate 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 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, agree to use a condom from the time of signing consent until at least 90 days after the last dose of study drug.
8. Negative alcohol breath test at Screening or upon admission go the clinic on Day -1.
9. Negative urine drugs of abuse test at Screening or upon admission go the clinic on Day -1.
10. Negative carbon monoxide breath test at Screening or upon admission to the clinic on Day -1.
11. Willing and able to comply with all scheduled visits, treatment plans, laboratory tests and other study procedures.

Minimum age

18 Years

Maximum age

65 Years

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

Participants will be excluded from Part A and B of the study if there is evidence of any of the following:
1. Current, active infection that requires systemically absorbed antibiotic, antifungal, antiparasitic or antiviral medications.
2. Suffers from frequent or recurrent infections (defined as greater than or equal to 3 recurrent or separate occurrences in the 12 months preceding first study drug administration or 2 recurrent or separate occurrences in the 6 months preceding first study drug administration).
3. Use of antioxidant-containing medications, supplements or products within 30 days prior to the first study drug administration.
4. Use of systemic corticosteroid, sulindac, or any other NSAID within 7 days or 5 half-lives of the medication (whichever is longer) prior to the first study drug administration.
5. Use of tricyclics, serotonin and norepinephrine reuptake inhibitors (SNRIs) (e.g., duloxetine, venlafaxine), sodium channel blockers, and gabapentinoids within 30 days or 5 half-lives of the medication (whichever is longer) prior to first study drug administration.
6. Use of selective serotonin reuptake inhibitors (SSRIs) (citalopram, escitalopram, sertraline, etc.) within 30 days prior to the first study drug administration.
Note: Participant on stable doses of SSRIs is permitted.
7. Experienced myocardial infarction or undergone coronary artery bypass grafting within 6 months of Screening.
8. Diagnosis with congestive heart failure, defined as New York Heart Association (NYHA) Class II-IV.
9. History of hypersensitivity reaction, anaphylaxis or other clinically significant reactions or known allergy to any of the study drug ingredients (including any of its metabolic derivatives – sulindac, sulindac sulfone and sulindac sulfide), or any other NSAIDs.
10. History of or currently existing aspirin-induced asthma, gastric ulcers, non-iatrogenic intestinal perforation, or GI bleeding from NSAID usage for which intervention was required.
11. History of any clinically significant disorder (which, in the opinion of the Investigator [or delegate] would make implementation of the protocol or interpretation of study results difficult, or that would put the subject at risk by participating in the study), including cardiovascular, haematologic, pulmonary, hepatic, renal, GI, connective tissue, uncontrolled endocrine/metabolic (including but not limited to diabetes), oncologic (within the last 5 years), neurologic, and psychiatric (including substance abuse disorder), or any disorder that may prevent the successful completion of the study or influence the absorption, distribution, metabolism, excretion, or action of the study drug (including any of its metabolic derivatives – sulindac, sulindac sulfone and sulindac sulfide).
Note: Participants with history of resolved childhood asthma, history of migraine (if less than or equal to 1 monthly episode and not on preventative medication), or history of non-hospitalised depression (if not on any anti-depressant) will be allowed to participate in the study.
12. History of surgery or hospitalisation within 12 weeks prior to screening, or surgery planned during the study.
13. Lack of suitable veins for multiple venepunctures/cannulations as assessed by the Investigator or delegate at screening.
14. Presence of any tattoos, scarring or active skin infection or other condition (including open sores, pressure ulcers, stasis ulcers, or other dermatitides), which (in the opinion of the Investigator [or delegate]) would interfere with skin local tolerability assessments at the study drug application site.
15. Laboratory results at screening that indicate inadequate renal function (estimated creatinine clearance of < 60 mL/min calculated by the Cockcroft and Gault formula).
16. Liver function test results elevated more than 1.5-fold above the ULN for gamma glutamyl transferase, ALP, AST or ALT. Participants with ALP and/or ALT/AST above the limits specified may be included, at the discretion of the Investigator, if the levels are unaccompanied by clinical signs and are determined to be normal variants.
17. Liver function tests outside the normal range for bilirubin (more than 1.5-fold above the ULN for total bilirubin).
18. Any clinically relevant laboratory finding or medical condition that could place the subject at risk for participation in the study.
19. Use of opioid analgesics within 5 half-lives of the medication prior to first dose of study drug.
20. Currently using any prescription medication or over-the-counter medication/vitamins/supplements/herbal remedies which (in the opinion of the Investigator [or delegate], in consultation with the study medical monitor) may interfere with a participant’s ability to participate in the study or affect trial outcomes.
Note: Use of standard doses (2 g per day) of paracetamol is permitted.
21. Concurrent enrolment in another clinical study, or participation in another clinical study within 30 days or 5 half-lives of the study drug (whichever is longer) prior to first dose of study drug.
22. Currently consume > 10 standard alcoholic drinks/week where 1 standard drink is 10 g of pure alcohol and is equivalent to 285 mL beer [4.9% Alc/Vol], 100 mL wine [12% Alc/Vol], 30 mL spirit [40% Alc/Vol]).
23. Participant is unwilling to abstain from smoking while confined to the clinic.
24. History of substance abuse or dependency within 12 months prior to Screening, or recreational intravenous drug use within 5 years prior to Screening (by self-declaration).
25. Participant is breastfeeding or pregnant, or planning to breastfeed or become pregnant during the study.
26. Known substance abuse or medical, psychological, or social conditions that, in the opinion of the PI (or delegate), may interfere with the participants inclusion in the clinical study or evaluation of the clinical study results.
27. Positive Hepatitis B surface antigen (HBsAg), Hepatitis C (HepC) virus antibody, or human immunodeficiency virus (HIV) antibody tests at Screening.
28. Participant has donated blood/blood products, experienced significant (> 400 mL) blood loss within 3 months prior to the first dose administration or receipt of a blood transfusion within 1 year prior to the first dose administration.
29. Any other condition or prior therapy that in the opinion of the Investigator (or delegate) would make the participant unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance 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)

All study participants will receive a unique sequential number and will be assigned a randomisation number prior to first dose administration, which corresponds to a study treatment (OXT-328 or placebo). The randomisation schedule will be prepared by an unblinded statistician and maintained under controlled access. A copy of the randomisation schedule will be provided to unblinded personnel responsible for dispensing the study drugs. The unblinded personnel will store the randomisation schedule in a secure, restricted access area. Code break envelopes will be provided to clinic site prior to first dose administration in the study.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

The allocation to OXT-328 or placebo will be performed using a block randomisation algorithm and will be documented in the study randomisation 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

This is a FIH study for OXT-328. As such, no formal sample size calculations have been performed, and the sample size is empirical.
The sample size of 32 healthy participants in Part A, 24 healthy participants in Part B are considered adequate to meet the objectives of the study.

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

8/04/2024

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

Recruitment hospital [1]

Scientia Clinical Research - Randwick

Recruitment postcode(s) [1]

2031 - Randwick

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Cleothena Enterprises Pty Ltd

Address [1]

C/o Prime Accounting & Business Advisory Level 17, HWT Tower 40 City Road Southbank VIC

Country [1]

Australia

Primary sponsor type

Commercial sector/Industry

Name

Cleothena Enterprises Pty Ltd

Address

C/o Prime Accounting & Business Advisory Level 17, HWT Tower 40 City Road Southbank VIC

Country

Australia

Secondary sponsor category [1]

Commercial sector/Industry

Name [1]

Avance Clinical Pty Ltd

Address [1]

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Bellberry Human Research Ethics Committee E

Ethics committee address [1]

https://bellberry.com.au/

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

20/12/2023

Approval date [1]

23/02/2024

Ethics approval number [1]

Summary

Brief summary

This is a first-in-human, single-centre, randomised, double blind, three-part single and multiple ascending dose study to assess the safety and tolerability of OXT-328 and how this drug acts in the body in healthy volunteers.

Who is it for?
You may be eligible for this study if you are aged 18 to 65 years and are in good general health without a clinically significant medical history.

Study details:
All healthy volunteer participants who choose to enrol in this study will be assigned by chance to receive either a single or multiple doses of OXT-328 or placebo. All participants will have their vital signs checked (heart rate, blood pressure, temperature, etc), and will provide blood and urine samples for testing.

The data generated in this study will inform the design of future clinical studies and to select the dose(s) for future studies in patients with CIPN.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Christopher Argent

Address

Scientia Clinical Research, Bright Building, Level 5, Corner High and Avoca Street, Randwick, NSW 2031

Country

Australia

Phone

+61 0458 639 115

Fax

christopher.argent@scientiaclinicalresearch.com.au

Contact person for public queries

Name

Dr Christopher Argent

Address

Scientia Clinical Research, Bright Building, Level 5, Corner High and Avoca Street, Randwick, NSW 2031

Country

Australia

Phone

+61 0458 639 115

Fax

christopher.argent@scientiaclinicalresearch.com.au

Contact person for scientific queries

Name

Dr Christopher Argent

Address

Scientia Clinical Research, Bright Building, Level 5, Corner High and Avoca Street, Randwick, NSW 2031

Country

Australia

Phone

+61 0458 639 115

Fax

christopher.argent@scientiaclinicalresearch.com.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

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.

Trial Review

Documents added manually

Documents added automatically