Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000602527
Ethics application status
Approved
Date submitted
16/04/2024
Date registered
9/05/2024
Date last updated
9/05/2024
Date data sharing statement initially provided
9/05/2024
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, Pharmacokinetics, Pharmacodynamics and Effect of Food on the Bioavailability of SKY-0515 in Healthy Volunteers and Patients with Huntington’s Disease
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 and Patients with Huntington’s Disease
Secondary ID [1] 311893 0
SKY-0515-001
Universal Trial Number (UTN)
Trial acronym
Linked study record
This study is a sub-study of ACTRN12623001161617.

Health condition
Health condition(s) or problem(s) studied:
Huntington’s Disease 333478 0
Condition category
Condition code
Human Genetics and Inherited Disorders 330153 330153 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study will be conducted in three parts:
- Part A: Single Ascending Dose (SAD) and food effect part in healthy participants
- Part B: Multiple Ascending Dose (MAD) in healthy participants
- Part C: has 2 parts - Part C (i) a non-interventional observational part and Part C (ii) multiple dose part in Huntington's Disease (HD) patients.

Parts A & B are listed on previously registered trial ACTRN12623001161617.
Part C is being listed in this trial application.

Part C (i): Participants will be required to attend 2 clinic visits over a period of 28 days. Health information and blood samples will be collected at these 2 visits. No treatment is given in this part of the study. Upto 50 participants will be enrolled.
Following completion of Part C [i], participants will be invited to participate in the treatment portion of the study - Part C [ii], based on eligibility.

Part C (ii): Two dose levels (high and low-dose level) of study drug SKY-0515-001 in the range of 1 mg to 16 mg will be evaluated. Final dose levels will be determined from results of Part A & B. A single dose of SKY-0515 or placebo will be administered orally once daily on Days 1 to 28 (inclusive); 28 doses total. Participants will maintain a diary to record exact date and time of dose administration.
Enrolled HD patients will be randomised to 3 parallel treatment arms at 2:3:3 ratio:
- Arm 1: Placebo (n=6)
- Arm 2: Low dose SKY-0515 (n=9)
- Arm 3: High dose SKY-0515 (n=9)
Intervention code [1] 328366 0
Treatment: Drugs
Comparator / control treatment
Capsules of matching appearance and formulation to the investigational product, however without the SKY-0515 active ingredient will be administered as placebo in this study.
Control group
Placebo

Outcomes
Primary outcome [1] 337905 0
Part C (i) only: To explore the natural variability of Huntington's Disease (HD) markers, Huntington (HTT) mRNA (messenger Ribonucleic Acid) and protein levels in HD patients.
This is a composite outcome.
Timepoint [1] 337905 0
Blood samples will be collected at Day 1 and Day 28 at any time during the visit to site. Part C (i) is non-interventional.
Primary outcome [2] 337907 0
Part C (ii) only: To investigate the safety and tolerability of SKY-0515 in Huntington's Disease (HD) patients
Timepoint [2] 337907 0
- Adverse events will be assessed continuously as they are reported or observed and reviewed at Clinic visits on Screening, and post commencement of treatment on Day 1, Day 8, Day 15, Day 22, Day 28, Followup visit on Day 29 and End of study visit on Day 56

-Vital signs: Blood pressure, heart rate and temperature will be measured at Screening, and post commencement of treatment on Day 1, Day 8, Day 15, Day 22, Day 28, Followup visit on Day 29 and End of study visit on Day 56

-ECG - recordings will be obtained at Screening, and post commencement of treatment on Day 1, Day 15, Day 28, and End of study visit on Day 56

-Clinical lab parameters (haematology, serum chemistry, coagulation and urinalysis) will be assessed at Screening, and post commencement of treatment on Day 1, Day 15, Day 28, and End of study visit on Day 56

- Columbia-Suicide Severity Scale (C-SSRS) questionnaire will be completed at Screening, and post commencement of treatment on Day 15 and End of study visit at Day 56
Secondary outcome [1] 433667 0
Part C (ii) only: To measure the pharmacokinetics of SKY-0515 in plasma in HD patients
Timepoint [1] 433667 0
Blood plasma samples will be collected Pre dose on Day 1, 8, 15, 22 and 28; Post dose on Day 1 at 0.5hrs, 1hr, 2hrs, 4hrs, 6hrs; Day 28 at 0.5hrs, 1hr, 2hrs, 4hrs, 6hrs, 8hrs and 24hrs; anytime at end of study visit on Day 56.

Eligibility
Key inclusion criteria
Part C (i):
1. Must have given written informed consent
2. Males and females, aged between 25 and 65 years.
3. Confirmed diagnosis of HD as defined by:
a. Genetically confirmed HD diagnosis by direct DNA testing. CAG repeat length greater than or equal to 40, and
b. Huntington’s Disease Integrated Staging System (HD-ISS) Stage 1: CAG greater than or equal to 40 & biomarker of pathogenesis. Atrophy identified in caudate volumetric magnetic resonance imaging (vMRI) and putamen vMRI, or
c. HD-ISS Stage 2: CAG greater than or equal to 40 & biomarker of pathogenesis & sign/symptom. Total Motor Score (TMS) greater than 6; Independence Score (IS) equal to 100 and Total Functional Capacity (TFC) equal to 13, or
d. HD-ISS Stage 3 (Mild): CAG greater than or equal to 40 & biomarker of pathogenesis & sign/symptom & functional change. TMS greater than 6, IS greater than or equal to 70, and TFC greater than or equal to 8.

Part C (ii):
1. Must have given written informed consent
2. Males and females, aged between 25 and 65 years.
3. Must have completed Part C (i) of the study.
4. Confirmed diagnosis of HD as defined by:
a. Genetically confirmed HD diagnosis by direct DNA testing. CAG repeat length greater than or equal to 40, and
b. Huntington’s Disease Integrated Staging System (HD-ISS) Stage 1: CAG greater than or equal to 40 & biomarker of pathogenesis. Atrophy identified in caudate volumetric magnetic resonance imaging (vMRI) and putamen vMRI, or
c. HD-ISS Stage 2: CAG greater than or equal to 40 & biomarker of pathogenesis & sign/symptom. Total Motor Score (TMS) greater than 6; Independence Score (IS) equal to 100 and Total Functional Capacity (TFC) equal to 13, or
d. HD-ISS Stage 3 (Mild): CAG greater than or equal to 40 & biomarker of pathogenesis & sign/symptom & functional change. TMS greater than 6, IS greater than or equal to 70, and TFC greater than or equal to 8.
5. Participant is otherwise medically healthy (in the opinion of the Investigator), as
determined by pre-study medical history and without clinically significant (CS) abnormalities including:
a. Physical examination without any clinically relevant findings
b. Systolic blood pressure in the range of 90 to 160 mmHg (inclusive) and diastolic blood pressure in the range of 50 to 95 mmHg (inclusive) after 5 minutes in supine or semi-supine position.
c. Heart rate in the range of 45 to 100 beats/minute (inclusive) after 5 minutes rest in supine or semi-supine position.
d. Body temperature (tympanic), between 35.5°C and 37.7°C (inclusive).
e. ECG without CS abnormal including QTcF lesser than 450 msec for male subjects and lesser than 470 msec for female subjects.
f. No CS findings in serum chemistry, haematology, coagulation or urinalysis (in the opinion of the Investigator).
g. Neutrophil count greater than or equal to 2x10^9/L, platelets count greater than or equal to 150x10^9/L and reticulocyte count greater than or equal to 0.2% of total red blood cells count.
6. Female participants must be of non-child-bearing potential i.e., surgically sterilised (hysterectomy, bilateral salpingectomy or 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 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, 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 or abstinent as a committed lifestyle or abstinent from 30 days prior to screening and unwilling to remain abstinent to until at least 30 days after last dose of study drug, 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 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.
8. Must be able and willing to meet all study requirements in the opinion of the Investigator including:
a. Adequately supportive psychosocial circumstances; able to read, write, and communicate.
b. Patients must be able to tolerate blood draws
9. Willing and able to comply with all scheduled visits, treatment plans, laboratory tests and other study procedures.
Minimum age
25 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
No exclusion criteria for Part C (i).

Part C (ii):
Huntington’s Disease patients will be excluded from Part C (ii) 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 clinically significant (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, oncologic (within the last 5 years), 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.
Note: Participants with history of resolved childhood asthma, history of migraine (if lesser 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.
8. Presence or having sequelae of GI, liver, kidney, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs (prior gall bladder and/or appendix removal is not exclusionary if the procedure was undertaken greater than or equal to 3 months prior to study drug administration; if less than 3 months, history of such procedures may still be considered not exclusionary if it is deemed appropriate by the Investigator).
9. History of surgery or hospitalisation within 12 weeks prior to screening, or surgery planned during the study.
10. Are a suicide risk, as determined by meeting any of the following criteria:
a. Suicide attempt within one year prior to screening
b. Suicidal ideation as defined by a positive response to Question 5 on the C-SSRS (Baseline Visit Form) at screening
c. Presence or previous history of uncontrolled major depression
d. Significant suicide risk, per Investigator discretion.
11. Have marked cognitive impairment with a Montreal Cognitive Assessment (MoCA) score lesser than or equal to 22.
12. Presence of CS psychosis and/or confusional states, in the opinion of the Investigator.
13. Lack of suitable veins for multiple venepunctures/cannulations as assessed by the Investigator or delegate at screening and Day 1 (pre-dose)
14. Participant has donated blood/blood products or experienced significant blood loss within 3 months prior to the first dose administration.
15. Laboratory results at screening that indicate inadequate renal function (estimated creatinine clearance of lesser than 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 GGT, ALP, AST or ALT. Volunteers 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 or patient at risk for participation in the study, in the opinion of the Investigator.
19. Use of any vaccinations within 14 days (within 4 weeks for live virus vaccines) prior to the first study drug administration.
20. Recently initiated use of any non-HD prescription medication or over-the-counter medication/ supplements/herbal medications less than 12 weeks prior to first dose of study drug. Exceptions include:
a. Contraception;
b. Antihistamines;
c. Occasional use of paracetamol (doses of 500 mg up to every 6 hours or 2 g per day maximum for no more than 3 consecutive days) or ibuprofen (doses of 400 mg up to every 6 hours or 1.2 g per day maximum for no more than 3 consecutive days);
d. Standard doses of multivitamins;
e. Medications used for management for HD may be permitted (at the discretion of the Investigator), if patient commenced medication at least 12 weeks prior to first drug administration and are on a dose regimen that is not anticipated to change during the study;
f. St. John’s Wort (hypericin) may not be taken within 30 days prior to first dose of study drug.
21. Recently initiated therapy with or used antipsychotics, anti-depressant, or tetrabenazine less than 12 weeks prior to Day 1.
Note: participants who have been on a stable dose of the aforementioned therapies for at least 12 weeks prior to screening and who are on a dose regimen that is not anticipated to change during the study may be included (at the discretion of the Investigator).
22. Concurrent enrolment in another clinical study, or participation in another clinical study within 45 days prior to screening.
23. Concurrent enrolment or previous participation at any time in any Huntingtin lowering antisense oligonucleotide, small molecule, gene therapy study.
24. Regular consumption of greater than 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]).
25. Positive alcohol breath test at screening and pre-dose on Day 1.
26. Positive urine drugs of abuse test at screening and pre-dose on Day 1.
27. Participant is unwilling to smoke less than 5 cigarettes or equivalent per week during study participation (screening to End of study).
28. Participant is breastfeeding/lactating or pregnant, or planning to breastfeed or become pregnant during the study.
29. 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.
30. Positive HBsAg, HepC virus antibody, or HIV antibody tests.
31. Any other CS medical condition (other than HD) 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 will be randomized in Part C (ii) to receive SKY-0515 or Placebo according to the randomisation schedule and plan prepared prior to study start. Code-break tamper-evident envelopes containing treatment allocation per participant will be provided to the study site for emergency unblinding if required.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants who meet the study eligibility criteria in Part C (ii) will be assigned a randomisation number pre-dose on Day 1, which corresponds to a study treatment (SKY-0515 or placebo). The allocation to SKY-0515 or placebo will be performed using a block randomisation algorithm and will be documented in the study randomisation schedule.
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
Not yet recruiting
Date of first participant enrolment
Anticipated
3/06/2024
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
74
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC

Funding & Sponsors
Funding source category [1] 316242 0
Commercial sector/Industry
Name [1] 316242 0
Skyhawk Therapeutics, Inc
Country [1] 316242 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Skyhawk Therapeutics, Inc
Address
Country
United States of America
Secondary sponsor category [1] 318428 0
Commercial sector/Industry
Name [1] 318428 0
Avance Clinical Pty Ltd
Address [1] 318428 0
Country [1] 318428 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315063 0
Bellberry Human Research Ethics Committee F
Ethics committee address [1] 315063 0
https://bellberry.com.au/
Ethics committee country [1] 315063 0
Australia
Date submitted for ethics approval [1] 315063 0
22/03/2024
Approval date [1] 315063 0
15/04/2024
Ethics approval number [1] 315063 0

Summary
Brief summary
This study is a first-in-human multi-center, Phase 1, randomised, double blind, placebo controlled study to evaluate the safety and tolerability of SKY-0515 in patients with Huntington’s Disease. The study has 2 parts: Part C (i) a non-interventional observational arm and Part C (ii) where two dose levels (high and low-dose level) in the range of 1 mg to 16 mg will to be evaluated in HD patients.

Part C (i): Participants will be required to attend 2 clinic visits over a period of 28 days. Health information and blood samples will be collected at these 2 visits. No treatment is given in this part of the study. Upto 50 participants will be enrolled.
Following completion of Part C [i], participants will be invited to participate in the treatment portion of the study - Part C [ii], based on eligibility.
Part C (ii): Enrolled HD patients will be randomised to 3 parallel treatment arms to receive low dose study drug , high dose study drug or placebo for a period of 28days. Final dose levels will be determined from results of Part A & B.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 133554 0
Dr Michele de Sciscio
Address 133554 0
CMAX Clinical Research Pty Ltd, 21-24 North Terrace, Adelaide, South Australia 5000
Country 133554 0
Australia
Phone 133554 0
+61 422447902
Fax 133554 0
Email 133554 0
michele.desciscio@cmax.com.au
Contact person for public queries
Name 133555 0
Michele de Sciscio
Address 133555 0
CMAX Clinical Research Pty Ltd, 21-24 North Terrace, Adelaide, South Australia 5000
Country 133555 0
Australia
Phone 133555 0
+61 422447902
Fax 133555 0
Email 133555 0
michele.desciscio@cmax.com.au
Contact person for scientific queries
Name 133556 0
Michele de Sciscio
Address 133556 0
CMAX Clinical Research Pty Ltd, 21-24 North Terrace, Adelaide, South Australia 5000
Country 133556 0
Australia
Phone 133556 0
+61 422447902
Fax 133556 0
Email 133556 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

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.