Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623001161617
Ethics application status
Approved
Date submitted
14/09/2023
Date registered
9/11/2023
Date last updated
30/04/2024
Date data sharing statement initially provided
9/11/2023
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, Pharmacokinetics, Pharmacodynamics
and Effect of Food on the Bioavailability of SKY-0515 in Healthy Volunteers
Scientific title
A Phase I Randomised, Double Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics
and Effect of Food on the Bioavailability of SKY-0515 in Healthy Volunteers
Secondary ID [1] 310517 0
SKY-0515-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Huntington's Disease 331320 0
Condition category
Condition code
Neurological 328076 328076 0 0
Neurodegenerative diseases
Human Genetics and Inherited Disorders 328392 328392 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a randomised, double-blind, placebo-controlled, single ascending dose (SAD), multiple ascending dose (MAD) multi-cohort study. This study will be conducted in two distinct participant groups: a SAD and food effect part (Part A) in healthy participants and a MAD part (Part B) in healthy participants.

Part A (Single ascending oral dose) in up to 48 healthy male and female participants over 5 dose escalation cohorts (8 participants per cohort) plus 1 food effect cohort (8 participants). The starting dose for Cohort 1 will be 1 mg up to a maximum of 16 mg SKY-0515 or placebo.

Subsequent Cohorts 2 - 5, dose levels are to be confirmed by the Safety Review Committee (SRC) based on safety, tolerability and any available pharmacokinetic (PK) results from preceding cohorts. Cohorts 1 to 5 will receive a single oral dose administration of SKY-0515 or placebo on Day 1. For each participant enrolled in Cohorts 1 - 5, the confinement period will commence on Day -1, with dosing on Day 1 and discharge on Day 4. Participants will return to the clinic for their end of study (EoS) visit on Day 8 (±2 days).

Part A (Food Effect) in healthy male and female participants
Cohort 6 (food effect) a fed or fasted, 2-period, open label, crossover design, 8 healthy adult participants will be randomised to one of 2 treatment sequences (AB/BA), and will receive 2 oral dose administrations of SKY-0515, being a single dose each on Day 1 and 8. Dose level to be selected based on safety, tolerability and any available PK results from Cohorts 1 to 5.
In Period 1, participants in treatment sequence AB will receive SKY-0515 following a ten hour fasting period while participants in treatment sequence BA will receive SKY-0515 thirty minutes after commencing a standard high calorie breakfast. A standard high fat, high calorie meal includes:
Two eggs fried in butter, Two rashers of bacon, Two slices of toast with 16 g butter per slice, 125 g of hash browns, 240 mL of full cream milk. This high fat (50% of total caloric intake) high calorie (800-1000 calories) test meal derives approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively.
In Period 2, participants in treatment sequence AB will receive SKY-0515 under fed conditions while participants in treatment sequence BA will receive SKY-0515 under fasted conditions . Dose administration between periods will be separated by washout period of at least 7 days (and maximum of 10 days). For each participant enrolled in Cohort 6, the confinement period will commence on Day -1 with dosing on Days 1 and 8 with discharge on Day 15.

Part B (Multiple ascending oral dose) may commence following completion of at least 2 cohorts in Part A: Up to 32 healthy male and female participants over 4 dose escalation cohorts (8 participants per cohort)) with final dose levels to be determined by the SRC based on safety, tolerability and any available PK results from the preceding cohorts. A single oral dose will be administered of SKY-0515 or placebo once daily (QD) on Days 1 to 14 (inclusive), 14 doses total. On Day 2, the second dose will be administered the morning (approximately 24 hours [± 1 hour]) after the first dose, i.e., the morning of Day 2. All subsequent doses will be administered approximately every 24 hours (± 1 hour relative to first dose on Day 1), up to and including the morning of Day 14.
For each participant enrolled in Part B Cohort 7, the confinement period will commence on Day -1 and discharge on Day 17. Participants will return to the clinic for their EoS visit on Day 21 (±2 days). For each participant enrolled in Part B Cohorts 8, 9, and 10 the confinement period will commence on Day -1 to Day 21. The SRC will also review the safety and PK data after the first MAD cohort and Cerebrospinal Fluid samples will also be taken from participants enrolled in Cohorts 9 and 10.

Adherence to Intervention will be managed via recording in appropriate drug accountability records.
Intervention code [1] 326908 0
Treatment: Drugs
Comparator / control treatment
Placebo drug product is microcrystalline cellulose capsule, packaged and encapsulated to look identical in appearance to SKY-0515.
Control group
Placebo

Outcomes
Primary outcome [1] 335942 0
To investigate the safety and tolerability of a single oral dose administration of SKY-0515 in healthy adult participants

Safety endpoints include:
• Incidence, severity, and relationship of adverse events (AEs) and serious adverse events (SAEs) (including withdrawals due to AEs);
• Change from baseline in vital signs;
• Change from baseline in electrocardiogram (ECG) parameters;
• Change from baseline in clinical laboratory parameters (haematology, serum chemistry, coagulation and urinalysis).
• Mental health: Columbia-Suicide Severity Scale (C-SSRS)
Timepoint [1] 335942 0
Adverse events - will be graded using the most current version of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (Version 5) and assessed continuously as they are reported or observed and reviewed daily until Day 4 post-dose and then Day 8 post-dose (End of Study/Early Termination Visit).

Vital signs - Blood pressure and heart rate is measured using sphygmomanometer respiratory rate by manual breath count and temperature by thermometer. Measured at Screening, Day -1, pre-dose Day 1 post-dose, Day 2 post-dose, Day 3 post-dose, Day 4 post-dose and then Day 8 (End of Study/Early Termination Visit).

Electrocardiogram (ECG) - 12-lead ECG recordings will be obtained in triplicate at screening, single recordings will be obtained from Screening, Day -1, pre-dose Day 1 and post-dose Days 1, 2, 3 and 4 and then Day 8 (End of Study/Early Termination Visit).

Clinical laboratory evaluations (haematology, serum chemistry, coagulation and urinalysis) - blood and urine samples will be collected daily from screening up to Day 4 post-dose and then Day 8 post-dose (End of Study/Early Termination Visit).

Columbia-Suicide Severity Scale (C-SSRS) (baseline) Questionnaire will be completed during Screening. Columbia-Suicide Severity Scale (C-SSRS) (since last visit) Questionnaire will be completed on Day 4 post-dose.
Primary outcome [2] 335943 0
To investigate the safety and tolerability of multiple oral dose administrations of SKY-0515 in healthy adult participants.

Safety endpoints include:
• Incidence, severity, and relationship of adverse events (AEs) and serious adverse events (SAEs) (including withdrawals due to AEs);
• Change from baseline in vital signs;
• Change from baseline in electrocardiogram (ECG) parameters;
• Change from baseline in clinical laboratory parameters (haematology, serum chemistry, coagulation and urinalysis).
• Mental health: Columbia-Suicide Severity Scale (C-SSRS)
Timepoint [2] 335943 0
Adverse events - will be graded using the most current version of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (Version 5) and assessed continuously as they are reported or observed and reviewed daily until Day 16 post-first dose and then Day 21 post-first dose (End of Study/Early Termination Visit). Vital signs - Blood pressure and heart rate is measured using sphygmomanometer respiratory rate by manual breath count and temperature by thermometer. Measured at Screening, Day -1, pre-dose Day 1 post-dose, pre and post-dose on Days 2 - 14, Day 21 (End of Study/Early Termination Visit). Additionally, Cohorts 8, 9 & 10 will have Vitals measured on Day 17 (3 days post dose). Electrocardiogram (ECG) - 12-lead ECG recordings will be obtained in triplicate at Screening, Day -1, pre-dose Day 1 post-dose, pre-dose Day 7 post-dose, pre-dose Day 14 post-dose, Day 21 (End of Study/Early Termination Visit). Additionally, Cohorts 8, 9 & 10 will have ECG recordings obtained on Day 17 (3 days post dose). Clinical laboratory evaluations (haematology, serum chemistry, coagulation and urinalysis) - blood and urine samples will be collected daily from screening up to Day 14 post-first dose and then Day 21 post-first dose (End of Study/Early Termination Visit). Columbia-Suicide Severity Scale (C-SSRS) (baseline) Questionnaire will be completed during Screening. Columbia-Suicide Severity Scale (C-SSRS) (since last visit) Questionnaire will be completed on Day 7 and Day 17 post-first dose.
Secondary outcome [1] 426228 0
To measure the PK of SKY- 0515 in plasma following a single oral dose administration in healthy adult participants.

Pharmacokinetic endpoints include (but are not limited to):
plasma concentration-time curves, maximum observed plasma concentration, time to maximum plasma concentration, terminal half-life
Timepoint [1] 426228 0
Blood plasma samples will be collected at the following nominal timepoints: pre-dose Day 1 - 0.5, 1, 2, 4, 6, 8, 12 hrs post-dose, Day 2 24 and 36 hrs post-dose, Day 3 48 hrs post-dose, Day 4 72 hrs post-dose.
Secondary outcome [2] 426229 0
To measure the PK of SKY- 0515 in plasma following multiple oral dose administrations in healthy adult participants.

Pharmacokinetic endpoints include (but are not limited to):
plasma concentration-time curves, maximum observed plasma concentration, time to maximum plasma concentration, and terminal half-life.
Timepoint [2] 426229 0
Blood plasma samples will be collected at the following nominal timepoints: pre-dose Day 1 - 0.5, 1, 2, 4, 6, 8, 12 hrs post-dose, pre-dose and 4 hrs post-dose on Days 2 - 13 (Cohort 7 only), pre-dose Day 14 - 0.5, 1, 2, 4, 6, 8, 12 hrs post-dose, Day 15 24 and 36 hrs post-dose, Day 16 48 hrs post-dose, Day 17 72 hrs post-dose. Additional PK samples for Cohorts 8, 9 and 10 only on Day 18 at 96 hours. Day 19 at 120 hours. Day 20 at 144 hours. Day 21 at 168 hours.
Secondary outcome [3] 426230 0
To measure the PK of SKY-0515 in urine following a single dose administration in healthy adult participants.

Urine PK endpoints include (but are not limited to):
• Total amount of unchanged drug excreted (Ae) in urine.
• Total fraction of unchanged drug excreted (Fe) in urine.
• Renal clearance (CLr).
Timepoint [3] 426230 0
Urine samples will be collected pre-dose Day 1 post-dose then daily from Day 2 - Day 4 post-dose.
Secondary outcome [4] 426231 0
SKY-0515 levels in cerebrospinal fluid (Part B, select cohorts only)

Concentration of drug levels in the cerebrospinal fluid on Day 14
Timepoint [4] 426231 0
Cerebrospinal fluid will be collected on Day 14 post-dose.
Secondary outcome [5] 426232 0
To assess the metabolic profile of SKY-0515 (Part B, select cohorts only)

Metabolic profiling (measure the incidence of SKY-0515 metabolites in plasma on Day 14,
15, 16 and 17).
Timepoint [5] 426232 0
Blood plasma samples will be collected at the following nominal timepoints on: Day 14 0.5, 1, 2, 4, 6, 8, 12 hrs post-dose, Day 15 24 and 36 hrs post-dose, Day 16 48 hrs post-dose and Day 17 72 hrs post-dose. Additional PK samples for Cohorts 8, 9 and 10 only on Day 18 at 96 hours. Day 19 at 120 hours. Day 20 at 144 hours. Day 21 at 168 hours.
Secondary outcome [6] 427441 0
To assess the effects of food intake on absorption and PK of SKY-0515 in the Food Effect (FE) cohort.

PK endpoints include (but are not limited to):
• Maximum observed concentration (Cmax);
• Time to Cmax (tmax);
• Area under the concentration-time curve from 0 to time of last quantifiable concentration (AUClast);
• Area under the concentration-time curve from 0 to infinity (AUCinf);
• Apparent terminal elimination half-life (t1/2);
• Total apparent body clearance (CL/F);
• Apparent volume of distribution (Vz/F)
Timepoint [6] 427441 0
Blood plasma samples will be collected at the following nominal timepoints: pre-dose Day 1 - 0.5, 1, 2, 4, 6, 8, 12 hrs post-dose, Day 2 24 and 36 hrs post-dose, Day 3 48 hrs post-dose, Day 4 72 hrs post-dose, pre-second dose, Day 5 at 96 hours, Day 6 at 120 hours, Day 7 at 144 hours. Day 8 - 0.5, 1, 2, 4, 6, 8, 12 hrs post-second dose, Day 9 24 and 36 hrs post-second dose, Day 10 48 hrs post-second dose, Day 11 72 hrs post-second dose, Day 12 at 96 hours, Day 13 at 120 hours, Day 14 at 144 hours , Day 15 at 168 hours.

Eligibility
Key inclusion criteria
Volunteers 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 70 years, inclusive at screening.
3. Body mass index (BMI) of 18 to 35 kg/m2, inclusive, with body weight greater than or equal to 50.0 kg and < 130.0 kg.
4. Participant is medically healthy (in the opinion of the Investigator), as determined by pre-study medical history and without CS abnormalities
5. Female participants must be of non-child-bearing 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 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 after the last dose of study drug.
c. If not exclusively in a same-sex relationship or abstinent as a committed lifestyle, 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. Participants who choose true abstinence during study participation will be considered for study participation even if this is not in line with their typical lifestyle.
6. Male participants must:
a. Agree not to donate sperm from the time of signing consent until at least 180 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 use adequate contraception (defined as use of a condom plus a highly effective method of contraception for their partner from the time of signing consent until at least 180 days after the last dose of study drug).
7. Willing and able to comply with all scheduled visits, treatment plans, laboratory tests and
other study procedures.
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Volunteers will be excluded from Part A and B of the study if there is evidence of any of the
following:
1. Any 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. Active malignancy and/or any history of malignant disease in the last 5 years (excludes surgically resected skin squamous cell or basal cell carcinoma or low grade cervical intraepithelial neoplasia).
4. Evidence of clinically relevant immunosuppression, including (but not limited to), immunodeficiency conditions such as common variable hypogammaglobulinemia.
5. History of hypersensitivity reaction, anaphylaxis or other CS reactions or known allergy to the study drug or its ingredients.
6. Presence or history of cardiovascular disease (including unstable angina, myocardial infarction, chronic heart failure).
7. History of any CS disorder, including haematologic, pulmonary, hepatic, renal, GI, connective tissue disease, uncontrolled endocrine/metabolic, neurologic (including seizures, strokes, brain tumours), and psychiatric diseases, 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.
8. Presence or having sequelae of GI, liver, kidney, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs.
9. History of surgery or hospitalisation within 12 weeks prior to screening, or surgery planned during the study.
10. Lack of suitable veins for multiple venepunctures/cannulations as assessed by the Investigator or delegate at screening or Day -1.
11. Participant has significant (> 10%) weight gain or loss between screening and Day -1.
12. Participant has donated blood/blood products or experienced significant blood loss within 3 months prior to the first dose administration.
13. Any clinically relevant laboratory finding or medical condition that could place the subject at risk for participation in the study, in the opinion of the Investigator.
14. Regular consumption of >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]), and/or participant is unwilling to abstain from alcohol while confined to the study clinic.
15. Participant is unwilling to abstain from smoking for at least 48 hours prior to check-in (Day -1) and while confined to the study clinic.
16. Participant is breastfeeding/lactating or pregnant, or planning to breastfeed or become pregnant during the study.
17. 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.
18. 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)
Participants who meet the study eligibility criteria will be assigned a randomisation number
prior to first dose administration, which corresponds to a study treatment for SAD Cohorts 1-5 or MAD Cohorts 7-10 (SKY-0515 or placebo) or treatment sequence for SAD Cohort 6 only (SKY-0515 - AB, fasted/fed or SKY-0515 - BA, fed/fasted).
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.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The allocation to SKY- 0515 or placebo, or to treatment sequence (SKY-0515 AB or SKY-0515 BA for SAD Cohort 6 only), 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 SKY-0515. As such, no formal sample size calculations have been
performed.
The sample sizes of 40 participants (30 receiving SKY-0515 and 10 placebo) in Part A
(Cohorts 1 to 5), 8 participants (all receiving SKY-0515) in Part A (Cohort 6), 32 participants
(24 receiving SKY-0515 and 8 placebo) in Part B are considered adequate to meet the objectives of the study.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
16/11/2023
Actual
20/11/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
168
Accrual to date
46
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 25478 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 41290 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 314719 0
Commercial sector/Industry
Name [1] 314719 0
Skyhawk Therapeutics, Inc.
Country [1] 314719 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Skyhawk Therapeutics, Inc.
Address
77 4th Ave, Suite 340,Waltham, MA 02451, USA
Country
United States of America
Secondary sponsor category [1] 316690 0
Commercial sector/Industry
Name [1] 316690 0
Avance Clinical Pty Ltd
Address [1] 316690 0
213 Glynburn Road,Firle, SA 5070
Country [1] 316690 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313729 0
Bellberry Limited HREC
Ethics committee address [1] 313729 0
123 Glen Osmond Road,Eastwood, SA 5063
Ethics committee country [1] 313729 0
Australia
Date submitted for ethics approval [1] 313729 0
30/08/2023
Approval date [1] 313729 0
20/10/2023
Ethics approval number [1] 313729 0
2023-08-983

Summary
Brief summary
This is a randomised, double-blind, placebo-controlled, single ascending dose (SAD), multiple ascending dose (MAD) multi-cohort study to assess the safety and tolerability of SKY-0515 and how this drug acts in the body in healthy volunteers. SKY-0515 may be indicated for use in patients with Huntington’s Disease, but a trial of the drug in healthy volunteers is needed before trials in patients with Huntington's Disease can proceed.

Who is it for?
You may be eligible for this study if you are a healthy male or female volunteer aged 18 to 70 years of age who has met all inclusion criteria and do not meet any exclusion criteria will be eligible to be enrolled.

Study details
All healthy volunteer participants who choose to enroll in this study will be assigned by chance to receive either a single dose of SKY-0515 or placebo once daily for 14 days. All participants will have their vital signs checked (heart rate, blood pressure, temperature, etc), and will provide blood and urine samples for testing. If the drug appears safe, additional participants will be assigned by chance to receive a larger single dose of SKY-0515 or placebo once daily for 14 days, followed by blood and urine testing. This will continue until a maximum safe dose is determined.

It is hoped this research will determine the maximum dose of SKY-0515 that can be administered safely without causing severe reactions. Once the dose of SKY-0515 has been determined in healthy volunteers, a trial investigating the safety of SKY-0515 as a treatment for patients with Huntington's Disease may proceed.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 129166 0
Dr Michele de Sciscio
Address 129166 0
CMAX Clinical Research Pty Ltd, Ground Floor, 21-24 North Terrace, Adelaide, South Australia, 5000
Country 129166 0
Australia
Phone 129166 0
+61 422 447 902
Fax 129166 0
Email 129166 0
michele.desciscio@cmax.com.au
Contact person for public queries
Name 129167 0
Dr Michele de Sciscio
Address 129167 0
CMAX Clinical Research Pty Ltd, Ground Floor, 21-24 North Terrace, Adelaide, South Australia, 5000
Country 129167 0
Australia
Phone 129167 0
+61 422 447 902
Fax 129167 0
Email 129167 0
michele.desciscio@cmax.com.au
Contact person for scientific queries
Name 129168 0
Dr Michele de Sciscio
Address 129168 0
CMAX Clinical Research Pty Ltd, Ground Floor, 21-24 North Terrace, Adelaide, South Australia, 5000
Country 129168 0
Australia
Phone 129168 0
+61 422 447 902
Fax 129168 0
Email 129168 0
michele.desciscio@cmax.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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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