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Trial registered on ANZCTR


Registration number
ACTRN12624001026516
Ethics application status
Approved
Date submitted
1/08/2024
Date registered
23/08/2024
Date last updated
23/08/2024
Date data sharing statement initially provided
23/08/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
A Study Assessing the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of K-3505 in Healthy Volunteers (PART II)
Scientific title
A Study Assessing the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of K-3505 in Healthy Volunteers (PART II)
Secondary ID [1] 312621 0
K-3505 P001
Universal Trial Number (UTN)
Trial acronym
Linked study record
Part I of this study has now been registered- ACTRN12624000990527. PART II is dependent on results from PART I and will only be conducted if K-3505 is shown to induce miosis at well-tolerated doses in Part I.

Health condition
Health condition(s) or problem(s) studied:
Migraine 334562 0
Condition category
Condition code
Neurological 331166 331166 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
K-3505 P001 (Part II) is an open-label, 2-day dosing study comprised of 2 sequential Panels (C and D) of 6 subjects each.Subjects will participate in either Panel C or Panel D. Panel D will only be conducted if the goals of Part II are not fully achieved in Panel C. The K-3505 dose levels administered in Part II of this study will be based on the results of Part I (ACTRN12624000990527). The dose the participant will receive will be within a range that was safe and caused pupil narrowing in Part I. The participant will be told the exact dose when they check into the clinical unit.

Each panel will have Screening (up to 28 days prior to first dose of study drug), Treatment, and Follow-Up (approximately 14 days after their last dose of study medication) periods. Dosing is open-label meaning that both the unit staff and study participants will know which treatments they are receiving.

For both panels, the Treatment period will involve 2 consecutive days of dosing. On Day 1, all subjects will receive a single dose of K-3505. On Day 2, all subjects will receive a single dose of another drug, fezolinetant, followed by the same dose of K-3505 they received on Day 1.

The doses of K-3505 used in Panel C and Panel D will be within the dose range that was tested and shown to cause pupil narrowing in PART I. Therefore, the doses of K-3505 tested in the study will fall within the planned dose range for K-3505 P001 (PART I) (3ug- 2000ug). The dose of K-3505 used in Panel D will also be informed by the results of Panel C and may be same as or different (higher or lower) than the dose used in Panel C. All doses of K-3505 will be administered by nursing staff as an intravenous (i.v) infusion over approximately 2 minutes.

Fezolinetant will be administered orally as 45mg tablets. For Panel C, the dose of fezolinetant will be 45mg (1 tablet). For Panel D, the dose of fezolinetant will be 45 or 90mg (1 or 2 tablets). The dose of fezolinetant in Panel D will be determined based on the results of Panel C. The higher (90mg) dose of fezolinetant may be selected if the lower (45mg) dose had limited or no effect on the pupillary response to K-3505 in Panel C.

Participants will be admitted into the study unit on the day prior to the first K-3505 administration (Day -1). They will fast a minimum of 10 hours (overnight fast) prior to K-3505 administration on Days 1 and 2. Participants will remain domiciled for at least 24 hours after K-3505 administration on Day 2 for safety monitoring and to assess pupillary responses by nursing staff and PI. Compliance will be monitored by site staff witnessing of dosing and will be documented in participant study files.
Intervention code [1] 329137 0
Treatment: Drugs
Comparator / control treatment
Responses to K-3505 after fezolinetant (on Day 2) will be compared to K-3505 alone (on Day 1).
Control group
Active

Outcomes
Primary outcome [1] 338961 0
To assess the safety and tolerability of i.v. doses of K-3505 when administered alone and after prior oral administration of fezolinetant.
Timepoint [1] 338961 0
TEAEs are AEs that start or worsen during or after the first dose of study medication.

For both Panels (C and D), TEAEs will be assessed on Day 1 (after start of dosing), Day 2, and Day 3, and at the post-study visit 14 days after the final dose.

For any subjects from Panel C or D who discontinue study medication early, TEAEs will also be assessed at the early termination (ET) visit.

Discontinuation of study medication for a TEAE may occur between start of dosing on Day 1 and completion of dosing on Day 2.
Secondary outcome [1] 438034 0
To assess the impact of pre-administration of oral fezolinetant on change sin pupil diameter afetr i.v doses of K-3505.
Timepoint [1] 438034 0
Day 1 and Day 2: -3 hrs, -2.5 hrs, -70, -40, -10 minutes prior to K-3505 dosing; 5, 10, 20, 30, 40, 60, 80, 100,120, 150, 180 minutes (3 hours), 4, 6, 12 hours after K-3505 dosing; Day 2 only: 24 hours after K-3505 dosing.

Eligibility
Key inclusion criteria
1.Must have given written informed consent
2. Be willing and able to comply with the study schedule of visits, all trial procedures and restrictions,including following study diet requirements.
3. Be between 18 to 45 years of age, inclusive, at the time of signing informed consent.
4. Have a body mass index (BMI) of 18.5 to 30.0. kg/m2, inclusive.
5. Be a nonsmoker/non-user of tobacco or other nicotine products, who has not used tobacco- or nicotine-containing products (eg, nicotine patch) for at least 1 month before administration of the initial dose of trialdrug, has used no more than 5 tobacco or nicotine forms (eg less than or equal to 5 cigarettes) per weekwithin 3 months of screening, and agrees to abstain from smoking tobacco or the use of nicotine-containing products throughout study participation (through completion of the Poststudy visit).
6. Be judged to be in good health by the Investigator, based on clinical evaluations including laboratorysafety tests, medical history, physical examination, 12-lead ECG, and vital sign measurements performed atthe Screening Visit and before administration of the initial dose of trial drug.
7. Dark-adapted pupil diameter (measured with pupillometer after greater than or equal to 5 minutes at approximately 5lux) is between 5.0 mm and 8.5 mm in both eyes, and the diff erence in pupil diameter between the rightand left eyes is less than 0.4 mm. Pupil diameter will be measured in triplicate. The middle (median) value for each eye will be used to assess eligibility.
8. Screening ophthalmic exam performed by an ophthalmologist or similarly licensed professional(including assessment of visual acuity, visual fi elds, intra-ocular pressure, and fundoscopy) identifi es noclinically signifi cant abnormalities. Note: Routine refractive errors are not exclusionary, with the exceptionof myopia with refractive error greater than or equal to 3D
9. Meet the following requirements:
a. Is a male who agrees to all of the following:
• To use an appropriate method of contraception, including a condom, from the fi rst dose of study drug until greater than or equal to 90 days after the last dose of study drug. A male participant who had a vasectomy procedure mustfollow the same restrictions as a non-vasectomized male. This requirement is waived for male participantswith male partners.
• To not donate sperm from the fi rst dose of study drug until greater than or equal to 90 days after the last dose of study drug.
OR
b. Is a pre-menopausal female (confi rmed via screening follicle stimulating hormone [FSH] test) who is ofreproductive potential or surgically sterile due to hysterectomy or bilateral salpingectomy and:
• agrees to not donate eggs from the first dose of study drug for greater than or equal to 30 days after the last dose of study drug AND
• agrees to remain abstinent from heterosexual activitya from Screening through greater than or equal to 30 days after the last dose of study drug OR
• agrees to use (or have their partner use) a birth control method that is highly eff ective and has low userdependency from Screening through greater than or equal to 30 days after the last dose of study drug.Acceptable methods of birth control are:
- Progestogen-only implant (e.g. etonogestrel implant)
- Intrauterine device (IUD)
- Intrauterine hormone-releasing system (IUS)
- Bilateral tubal occlusion
- Vasectomized partner
a Abstinence can be used as the sole method of contraception if it is in line with the subject’s preferredand usual lifestyle and if considered acceptable by local regulatory agencies and ethics committees.Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) andwithdrawal are not acceptable methods of contraception.
Minimum age
18 Years
Maximum age
45 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Has participated in another investigational study within the following time period: 30 days, 5 half-lives ortwice the duration of the biological eff ect of the investigational product (whichever is longer or based onlocal regulations) prior to the Screening Visit. The window will be derived from the date of the last studyprocedure and/or AE related to the study procedure in the previous study to the Screening Visit of thecurrent study.
2. Is an employee of the Sponsor or study site or immediate family member (eg, spouse, parent, child,sibling) of the Sponsor or study site.
3. Has a history of multiple signifi cant and or any severe allergies (eg, food, drug, latex allergy) or has hadan anaphylactic reaction or signifi cant intolerance to prescription or nonprescription drugs or food.
4. Has a known hypersensitivity or contraindication to any component of K-3505, fezolinetant (Part II only),their excipients, or related compounds.
5. Has a positive alcohol or drug screen at Screening and admission.
6. Has a positive pregnancy test at Screening and Period 1 Day -1.
7. Is a lactating/nursing female.
8. Has a positive test result for hepatitis B surface antigen, hepatitis C virus antibody, or humanimmunodefi ciency antibody, at the Screening Visit. Note: Subjects with positive hepatitis B virus or hepatitisC virus serology may be enrolled if quantitative polymerase chain reaction for hepatitis B virus or hepatitisC virus ribonucleic acid is negative.
9. Has a fever at screening* or has a positive COVID-19 test or a fever at Period 1 Day -1.
10. Had major surgery or donated or lost 1 unit of blood or blood products (approximately 500 mL) within 4weeks prior to Period 1 Day -1.
11. Is unable to refrain from the use of prescription or non-prescription drugs, including vitamins, herbal anddietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzymeinducer) or 5 half-lives (whichever is longer) prior to the fi rst dose of study medication and through thecompletion of study participation at the Follow-Up visit. Exceptions are noted below..
12. Has excessive consumption of alcohol within 6 months prior to screening (greater than 14 drinks/week for males and greater than 7 drinks/week for females, where 1 drink is equal to 5 ounces [150 mL] of wine or 12ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor) or use of soft drugs (such as marijuana) within 3 months prior to Screening, or hard drugs (such as cocaine) within 6 months prior to Screening.
13. Is unwilling or unable to refrain from study alcohol restrictions:
- Subjects must not consume any alcohol from 3 days (at least 72 hours) prior to check-in throughdischarge from the unit in each period, and from 3 days (at least 72 hours) prior to the poststudy visit.
- At all other times, alcohol consumption is limited to less than or equal to 14 drinks/week for males and less than or equal to 7 drinks/week for females where l drink equal to 5 ounces [150 mL] of wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] ofhard liquor.
14. Is unable or unwilling to refrain from consuming caffeinated products from 24 hours prior to check-inthrough discharge from the unit in each period, and 24 hours prior to the follow up visit.
15. Has a substance abuse disorder.
16. Had a previous major psychotic disorder.
17. Has a corrected QT interval to Fridericia's formula (QTcF) greater than 450 milliseconds (msec) for malesand greater than 470 msec for females at screening or predose on Period 1 Day 1.
18. Has a mean value for triplicate semi-recumbent systolic blood pressure greater than 140 mmHg and/ordiastolic blood pressure greater than 90 mmHg measured after at least 10 minutes at rest at the ScreeningVisit or on Period 1 Day -1. If subject’s BP is over the limits, then one triplicate repeat may be taken after atleast another 10 minutes of rest.
19. Has a mean value for triplicate semi-recumbent heart rate less than 60 bpm measured after at least 10minutes at rest at the Screening Visit or on Period 1 Day -1. If this criterion is met, then one triplicate repeatmay be taken after at least another 10 minutes of rest.
20. Has an estimated glomerular filtration rate (eGFR by the Chronic Kidney Disease Epidemiology [CKD-EPI] equation) less than 70 mL/min/1.73m2 at the Screening Visit or Period 1 Day -1.
21. Has alanine aminotransferase or aspartate aminotransferase (ALT or AST) of greater than 1.0X upper limit of normal (ULN) or total bilirubin greater than 1.5 multiplied by ULN upper limit of normal (ULN) (isolated bilirubingreater than 1.5X ULN is acceptable if bilirubin is fractionated and direct bilirubin is within the laboratory normal range) at the Screening Visit or Period 1 Day -1.
22. Thyroid stimulating hormone (TSH) at screening is outside (above or below) the laboratory referencerange.
23. Has a history of clinically signifi cant endocrine, gastrointestinal, cardiovascular, hematological, hepatic,immunological, renal, respiratory, neurologic disorder, neoplastic, or genitourinary abnormalities ordiseases.
24. Family history of congenital hypogonadotropic hypogonadism in a fi rst-degree relative unless a specifi cgenetic cause has been confi rmed which does not involve mutation of TAC3R (the NK3R gene).
25. Subject meets any of the following:
- Any history of, or signs/symptoms consistent with a clinically signifi cant ocular disease/condition(including eye injury).
- Myopia with refractive error greater than or equal to 3D in either eye, or myopia previously treated with refractivesurgery (e.g. LASIK). Note: Other routine refractive errors are not exclusionary.
- Any history of ocular surgery, including refractive surgery (e.g. LASIK).
- Current routine use of any topical ophthalmic agents (including artifi cial tears) and/or planned/potentialuse during study participation.
- Personal or family history of any genetic condition that may predispose to retinal detachment includingStickler Syndrome, Marfan Syndrome, Ehler-Danlos Syndrome, Wagner Syndrome, and Familial ExudativeVitreoretinopathy. Note: A family history of such a condition is not exclusionary if results of genetic testingare provided which confi rm the participant does not have the condition.
26. Has a history of any illness that, in the opinion of the study investigator, might confound the results ofthe study or poses an additional risk to the subject by their participation in the study.
27. Has a pregnant partner.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
No formal sample size calculations were made, as no formal hypothesis testing is planned for this study.

The Safety Analysis Set will consist of all subjects who are enrolled and receive study drug. No formal statistical tests or inference will be performed for safety analyses. All summaries will be reported and performed by K-3505 dose level.

The PD Analysis Set will include all subjects who received study drug and have at least one value for the biomarker test of interest. Pupil diameter will be summarized for each eye by panels and dose levels over time.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
10/09/2024
Actual
Date of last participant enrolment
Anticipated
28/02/2025
Actual
Date of last data collection
Anticipated
13/03/2025
Actual
Sample size
Target
12
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 26867 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment postcode(s) [1] 42928 0
4007 - Herston

Funding & Sponsors
Funding source category [1] 317054 0
Commercial sector/Industry
Name [1] 317054 0
KALLYOPE, Inc.
Country [1] 317054 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
KALLYOPE, Inc.
Address
Country
United States of America
Secondary sponsor category [1] 319302 0
Commercial sector/Industry
Name [1] 319302 0
Avance Clinical Pty Ltd
Address [1] 319302 0
Country [1] 319302 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315805 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 315805 0
Ethics committee country [1] 315805 0
Australia
Date submitted for ethics approval [1] 315805 0
03/07/2024
Approval date [1] 315805 0
29/07/2024
Ethics approval number [1] 315805 0

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

Contacts
Principal investigator
Name 135858 0
Dr Dr Richard Friend
Address 135858 0
Q-Pharm Pty Ltd, Level 5, 300C Herston Road, Herston, Queensland, 4006
Country 135858 0
Australia
Phone 135858 0
+61 737072720
Fax 135858 0
Email 135858 0
[email protected]
Contact person for public queries
Name 135859 0
Gabrielle Robb
Address 135859 0
Q-Pharm Pty Ltd, Level 5, 300C Herston Road, Herston, Queensland, 4006
Country 135859 0
Australia
Phone 135859 0
+61 737072784
Fax 135859 0
Email 135859 0
[email protected]
Contact person for scientific queries
Name 135860 0
Dr Richard Friend
Address 135860 0
Q-Pharm Pty Ltd, Level 5, 300C Herston Road, Herston, Queensland, 4006
Country 135860 0
Australia
Phone 135860 0
+61 737072720
Fax 135860 0
Email 135860 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No other documents available


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.