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Trial registered on ANZCTR

Registration number

ACTRN12624000849594

Ethics application status

Approved

Date submitted

3/06/2024

Date registered

9/07/2024

Date last updated

6/09/2024

Date data sharing statement initially provided

9/07/2024

Type of registration

Prospectively registered

Titles & IDs

Public title

A Phase 1 randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of single ascending doses and multiple ascending doses of SION-451 in healthy participants

Scientific title

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

Trial acronym

Linked study record

Part C is listed on registration ACTRN12624000848505. Parts A and B are being listed in this trial application

Health condition

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

Cystic Fibrosis

Condition category

Condition code

Human Genetics and Inherited Disorders

Cystic fibrosis

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

This is a Phase 1, randomised, double-blind, placebo-controlled study designed to evaluate the safety, tolerability, and Pharmacokinetics (PK) of single ascending doses (SAD) and multiple ascending doses (MAD) of SION 451 in healthy participants. Study drug (SION-451 and placebo) will be administered as an oral suspension.
This study is comprised of 2 Parts: Part A (SAD) and Part B (MAD). Each study part will include a Screening Period, a Treatment Period, and an End of Study (EoS) visit. Participants to be included in this study will be healthy male and female adults 18 to 55 years of age, inclusive, with no clinically significant concomitant medical conditions and who are not taking any concomitant medications.
All potential participants will be screened a maximum of 28 days (Day -28) prior to check-in (Day -1) to assess their eligibility to enter the study and dosing will be initiated on Day 1. Participants will generally be fasted prior to each dose of study drug. Participants in Parts A and B of the study, will be randomised 6:2 to active:placebo, and treatment assignments will be blinded.

SAD (Part A)
Participants in Part A of the study will be admitted to the Clinical Research Unit (CRU) on Day -1. On the following morning (Day 1), participants will receive a single dose of study drug (active or placebo depending on their randomised treatment assignment) in a fasted state (at least 10 hours pre-dose and 4 hours post-dose). Sentinel dosing will be employed for each Part A dose escalation cohort such that the first 2 participants will be enrolled and randomised to active drug or placebo; if no stopping rules are 1:1 met after 48 hours of monitoring, the remaining participants in the cohort will be randomised. Each cohort will enrol approximately 8 participants randomised 6:2 to active:placebo. Approximately 6 SAD cohorts are planned and dosing will begin at 75mg (Cohort 1) up to 750mg (Cohort 5). Dose escalation decisions will be made by the SRC composed of medically qualified representatives from Sionna, the CRO, and the investigative site (including the Principal Investigator) following review of all available safety data. The SRC will review key safety data (eg, AEs, safety laboratory results, physical examinations, vital signs, ECGs) after completion of each SAD cohort to approve proceeding to the next dose-escalation cohort; where available, PK results from prior cohorts may also be reviewed. No subsequent dose will exceed 2× the dose level of a preceding cohort that has been safe and well tolerated. The dose level for Cohort 6 will also be determined based on SRC review of safety and PK data from previous cohorts.
All participants will remain in the CRU until 72 hours following their final dose of study drug (Day 1) for safety monitoring and collection of blood samples for PK analysis. All participants will be contacted by phone for an EOS visit 7 (+/-1 day) after the last dose of study drug.

MAD (Part B)
Part B dosing will not begin until the SRC has reviewed the available safety data from at least the first 3 SAD cohorts and determines it is safe to proceed. A unique group of participants will be enrolled in Part B of the study and will be admitted to the CRU on Day -1. On Days 1 through 9, participants will receive a single dose level of study drug (active or placebo based on their randomised treatment assignment) administered twice daily. On Day 10, MAD cohort participants will only receive a morning dose.
Participants will fast for at least 10 hours pre-dose and 4 hours post-dose for the first dose on Day 1 and for the last dose given on the morning of Day 10; for all other doses, participants will fast for at least 2 hours pre-dose and 2 hours post-dose.
Each cohort will enrol approximately 8 participants randomised 6:2 to active:placebo.
The SRC may recommend lower or intermediate dose levels be explored, provided the selected dose or a higher dose has been declared safe and well tolerated in Part A. In addition, the SRC may recommend adjustment of the dose frequency from twice daily based on the available safety and PK data. Approximately 6 MAD cohorts are planned and dosing will begin at 75mg (Cohort 1) up to 750mg (Cohort 5). The dose level for Cohort 6 will be determined based on SRC review of safety and PK data from previous cohorts.
Participants will remain at the CRU for at least 72 hours following administration of their last dose (Day 13) for safety monitoring and collection of blood samples for PK analysis. All participants will return to the unit for an EoS visit 7 (±1) days after the last dose of study drug.

Clinical facility staff will administer the study drug only to participants included in the study following the procedures set out in the study protocol . Administration of study drugs will be recorded in the appropriate drug accountability records and the electronic case report form (eCRF). Administration of study drug will be verified by a second staff member. Each Participant will be given only the study drug preparation carrying his/her study number.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Placebo: SION-451 placebo oral suspension in OraBlend and purified water

Control group

Placebo

Outcomes

Primary outcome [1]

To assess the safety and tolerability of SION-451 when administered as single ascending oral doses in healthy participants

Timepoint [1]

Adverse Events: The severity of any AEs experienced during the study will be categorised by the Investigator as 'Mild', 'Moderate' or 'Severe' and classified in accordance with the Common Terminology Criteria for Adverse Events (CTCAE v5.0). AEs will be reviewed continuously monitored and assessed as soon as they are reported or observed and reviewed daily at Screening to Day -1 (check-in), Day 1, Day 2, Day 3, Day 4 (check-out), Early Termination (if applicable) and Day 8 (End of Study).

Vital Signs: Blood pressure measured using a sphygmomanometer, heart rate and oxygen saturation measured using a pulse oximeter, respiratory rate measured via manual breath count, and temperature measured by thermometer. Assessed at Screening, Day -1 (check-in), Day 1 pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 12 hours, Day 2 24 hours post Day 1 dose, Day 3 48 hours post Day 1 dose, Day 4 (check-out) 72 hours post Day 1 dose, Early Termination (if applicable) and Day 8 (End of Study).

Physical Examinations: complete physical examination will be performed at Screening and Day -1 (check-in). Subsequent symptom directed physical examinations will be performed as clinically indicated to assess AEs.

Clinical Laboratory Evaluations: chemistry (including liver function tests), haematology, coagulation study (Screening only) and urinalysis. Blood draws and urine samples will be collected at Screening, Day -1 (check-in), Days 1 through 4 (check-out), Day 8 (End of Study) and Early Termination (if applicable)

ECGs: 12-lead ECG recordings will be obtained in triplicated at the following timepoints, Screening, Day -1 (check-in), Day 1 pre-dose, and 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 12 hours, post-dose, Day 2 24 hours post Day 1 dose, Day 3 48 hours post Day 1 dose, Day 4 (check-out) 72 hours post Day 1 dose, Day 8 (End of Study) and Early Termination (if applicable).

Primary outcome [2]

To assess the safety and tolerability of SION-451 when administered as multiple ascending oral doses in healthy participants

Timepoint [2]

Adverse Events: The severity of any AEs experienced during the study will be categorised by the Investigator as 'Mild', 'Moderate' or 'Severe' and classified in accordance with the Common Terminology Criteria for Adverse Events (CTCAE v5.0). AEs will be reviewed continuously monitored and assessed as soon as they are reported or observed and reviewed daily at Screening to Day -1 (check-in), Days 1, through 13 (check-out), Early Termination (if applicable) and Day 17 (End of Study).

Vital Signs: Blood pressure measured using a sphygmomanometer, heart rate and oxygen saturation measured using a pulse oximeter, respiratory rate measured via manual breath count, and temperature measured by thermometer. Assessed at Screening, Day -1 (check-in), pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 12 (pre-second dose), and 14 hours post first dose, Day 2 through 9 pre-dose, 2.0, 12 (pre-second-dose) and 14 hours post first dose Day 10 pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, and 12, and 14 hours post dose, Day 11 24 hours post Day 10 dose, Day 12 48 hours post Day 10 dose, Day 13 (check-out) 72 hours post Day 10 dose, Early Termination (if applicable) and Day 17 (End of Study).

Physical Examinations: complete physical examination will be performed at Screening and Day -1 (check-in). Subsequent symptom directed physical examinations will be performed as clinically indicated to assess AEs.

Clinical Laboratory Evaluations: chemistry (including liver function tests), haematology, coagulation study (Screening only) and urinalysis. Blood draws will be collected at Screening, Day -1 (check-in), Days 1 through 13 (check-out), Day 17 (End of Study) and Early Termination (if applicable).

ECGs: 12-lead ECG recordings will be obtained in triplicate at the following timepoints, Screening, Day -1 (check-in), Day 1 pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 12 (pre-second dose), and 14 hours post first dose, Day 2 through 9 pre-morning dose only, Day 10 pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, and 12 hours post dose, Day 11 24 hours post Day 10 dose, Day 12 48 hours post Day 10 dose, Day 13 (check-out) 72 hours post Day 10 dose, Day 17 (End of Study) and Early Termination (if applicable).

Secondary outcome [1]

To assess the single dose PK of SION-451 in healthy participants

Timepoint [1]

Plasma samples for single dose PK will be collected as follows:
Day 1 pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0,1 2 and 16 hours post-dose, Days 2 to 3 24, 36 and 48 hours post-dose and Early Termination (if applicable)

Secondary outcome [2]

To assess the multiple dose PK of SION-451 in healthy participants

Timepoint [2]

Plasma samples for multiple dose PK will be collected as follows:
Day 1 pre-dose, 0.25, 0.5,0, 75, 1.0, 2.0, 2.5, 4.0, 6.0, 8.0 and 12 hours post-dose and pre-dose on Days 2, 4, 6 and 8, Day 10 pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 16 hours post-dose, Days 11-12 at 24, 36 and 48 hours post-dose and Early Termination (if applicable)

Secondary outcome [3]

Exploratory Outcome: To evaluate metabolites of single dose SION-451 in plasma samples

Timepoint [3]

Plasma samples for potential metabolites will be collected as follows:
Day 1 pre-dose, 2.0, 4.0 and 8.0 hours post-dose, Days 2 to 3 at 24, 36 and 48 hours post-dose and Early Termination (if applicable).

Secondary outcome [4]

Exploratory Outcome: To evaluate multiple dose metabolites of SION-451 in plasma samples

Timepoint [4]

Plasma samples for potential metabolites of multiple dose SION-451 will be collected as follows:
Day 1 pre-dose, 1.0, 2.0, 4.0 and 8 hours post-dose, Day 2 pre-dose, Day 4 pre-dose, Day 6 pre-dose, Day 8 pre-dose, Day 10 pre-dose, 1.0, 2.0, 4.0, 8.0 hours post-dose, Day 11 to 12 at 24, 36 and 48 hours and Early Termination (if applicable)

Eligibility

Key inclusion criteria

Participants must meet all of the following criteria to be included in the study:
1. Healthy male or female adult participants aged 18 to 55 years, inclusive, at the time of consent.
2. Weight of at least 45 kg and body mass index between 18.0 and 32.0 kg/m2, inclusive, at Screening.
3. Participant is willing to abstain from alcohol, caffeine, smoking and nicotine-containing products for 72 hours prior to Day -1 through the duration of the study. Participant is willing to abstain from eating cruciferous vegetables, charcoal-grilled meats, and poppy seeds for 48 hours prior to dosing throughout the duration of the study.
4. Participant has read, understood, and voluntarily provided written informed consent
5. Participant has an understanding, ability, and willingness to fully comply with study procedures and restrictions.
6. Female participants (sex assigned at birth) must be of non-childbearing potential or willing to comply with acceptable highly effective contraceptive requirements (including negative pregnancy tests). Male participants (sex assigned at birth) must be infertile or willing to comply with acceptable highly effective contraceptive requirements.

Minimum age

18 Years

Maximum age

55 Years

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

Participants who meet any of the following criteria must be excluded from the study:
1. Participant has clinically significant, in the opinion of the investigator, current or recurrent illness, such as cardiovascular (including but not limited to known structural cardiac abnormalities, family history of long QT syndrome, or cardiac syncope or recurrent, idiopathic syncope), neurologic, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, endocrine, or psychiatric disease or disorder, or other abnormality which may affect safety or clinical laboratory evaluations.
2. Participant has a history of malignancy, except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of recurrence for at least 1 year.
3. Participant has clinically significant abnormalities, in the opinion of the investigator, on ECG, physical examination, or vital sign assessment at Screening or Day -1.
4. Participant has any single reading of QTcF >470 ms (females) or >450 ms (males) at Screening or Day -1.
5. Chronic or habitual alcohol (>10 standard drinks per week) or tobacco (>10 cigarettes per week) use or use of recreational drugs (>1 use per month). The Investigator may exclude a participant with lower levels of alcohol, tobacco, or recreational drug use based on discretion and the pattern or history of use.
6. Participant is positive for drug screen at Screening or Day -1. Of note, the drug screen does not include cannabis, cotinine or alcohol testing at Screening but does include this testing at study Check-in (Day -1).
7. Participant has taken any prescription or over the counter medications within 14 days (or 5 half-lives of the medication, whichever is longer) prior to dosing or requires the use of these medications during the study, including herbal or homeopathic preparations excluding prophylactic doses of vitamin/mineral supplements and occasional paracetamol or ibuprofen, which are allowed.
8. Participant has clinically significant abnormalities, in the opinion of the Investigator, at Screening or Day -1 on safety laboratory tests including serum chemistry, haematology, coagulation tests, and urinalysis.
a. Participant must have an estimated glomerular filtration rate >90 mL/min/1.73 m2 using the CKD-EPI 2021 formula and based on individual body surface area at Screening and Day -1.
b. Participant must have ALT, AST, alkaline phosphatase, and direct bilirubin less than or equal to the ULN at Screening and Day -1.
9. Participant has a positive test for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at Screening. Healthy volunteers who have no evidence of cirrhosis and have completed a curative intent regimen for HCV, with a negative HCV polymerase chain reaction (PCR) test, will not be excluded.
10. Please refer to private notes for additional exclusion criteria.
11. Participant has used any medication listed on the Flockhart table that is a substrate, inhibitor, or inducer of CYP3A4, or a substrate of CYP1A2 (with the exception of caffeine), CYP2B6, CYP2C8, CYP2C19 or CYP2D6 within 28 days or 10 half-lives (whichever is longer) prior to the planned first study drug administration. Additionally, participants must not have consumed other substances known to be potent inhibitors or inducers of CYP450 such as Seville orange, grapefruit or cranberry juice-containing products and herbal supplements such as St. John’s Wort within 14 days before the planned first study drug administration.
12. Participant has used any other prescription or over-the-counter medication that the Investigator judges is likely to interfere with the study or pose an additional risk in participating, within 14 days or 5 half-lives (whichever is longer) or has received any vaccinations within 14 days prior to the planned first study drug administration.
13. Participant has received an investigational product within 30 days or 5 half-lives (whichever is longer) of the first study drug administration or will start any other investigational product before the planned End of Study Telephone Contact visit.
14. Participant has been treated with an investigational device within 30 days prior to first study drug administration or will start an investigational device study before the planned End of Study Telephone Contact visit.
15. Participant has donated or lost greater than 400 mL blood (or plasma) within the last 6 weeks preceding the first study drug administration.
16. Participant has known or suspected intolerance or hypersensitivity to the investigational product, or any of the stated ingredients (including OraBlend and hypromellose polymer).
17. Females who are breastfeeding or planning to breastfeed within 90 days of the End of Study Visit.
18. Participant has an inability to follow a standardised meal schedule and diet or inability to fast, as required during the study.

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)

Central randomisation by computer

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

Masking / blinding

Who is / are masked / blinded?

Intervention assignment

Other design features

Phase

Phase 1

Type of endpoint/s

Statistical methods / analysis

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

9/07/2024

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)

VIC

Recruitment hospital [1]

Nucleus Network - Melbourne

Recruitment postcode(s) [1]

3004 - Melbourne

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Sionna Therapeutics, Inc

Address [1]

Country [1]

United States of America

Primary sponsor type

Commercial sector/Industry

Name

Sionna Therapeutics, Inc

Address

Country

United States of America

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]

Alfred Hospital Ethics Committee

Ethics committee address [1]

https://www.alfredhealth.org.au/research/ethics-research-governance

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

05/06/2024

Approval date [1]

01/07/2024

Ethics approval number [1]

Summary

Brief summary

This is a Phase 1, first-in-human (FIH), randomised, double-blind, placebo controlled study to evaluate the safety, tolerability, and pharmacokinetics (PK) of single ascending doses (SAD) and multiple ascending doses (MAD) of SION-451 administered as an oral suspension in healthy participants.

Trial website

Trial related presentations / publications

Public notes

Exclusion Criteria 10. Participant has a positive test for Coronavirus Disease 2019 (COVID-19) at Day -1.

Contacts

Principal investigator

Name

Dr Philip Ryan

Address

Nucleus Network Melbourne, 235 Ryrie Street, Geelong, 3220, Victoria

Country

Australia

Phone

+61 3 85939801

Fax

[email protected]

Contact person for public queries

Name

Nucleus Network Melbourne

Address

Level 5, Burnet Tower, 89 Commercial Rd, Melbourne, Victoria, 3004

Country

Australia

Phone

+61 1800243733

Fax

[email protected]

Contact person for scientific queries

Name

Nucleus Network Melbourne

Address

Level 5, Burnet Tower, 89 Commercial Rd, Melbourne, Victoria, 3004

Country

Australia

Phone

+61 1800243733

Fax

[email protected]

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

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No documents have been uploaded by study researchers.

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No additional documents have been identified.

Trial Review

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