Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624001241527
Ethics application status
Approved
Date submitted
5/09/2024
Date registered
9/10/2024
Date last updated
9/10/2024
Date data sharing statement initially provided
9/10/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
A First-In-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of K-645 in Healthy Volunteers
Scientific title
A First-In-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of K-645 in Healthy Volunteers
Secondary ID [1] 312752 0
K-645 P001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Migraine 334788 0
Condition category
Condition code
Neurological 331350 331350 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a randomized, double-blind placebo-controlled, single ascending dose study of K-645 in healthy male participants. This will be the first administration of K-645 to humans.

This study will be composed of 2 panels of 8 participants (Panels A and B), each having Screening (up to 35 days prior to the first dose of study drug), Treatment, and Follow-up (approximately 14 days after their last dose of study medication) stages.

For each panel, the Treatment stage will include up to 4 dosing periods. There will be at least 5 days between the completion of dosing in one period and the start of dosing in the next period. The 14 day Follow-up stage will occur for each panel after completion of their final dosing period.

Participants will participate in either Panel A or Panel B which will be conducted sequentially. Therefore, the first 8 eligible subjects will be assigned to Panel A and the next 8 to Panel B. Panel A will complete all 4 dosing periods before Panel B begins the Treatment stage.

Within each panel, participants will be randomized to treatment with either K-645 or placebo in a 3:1 ratio (6 active: 2 placebo). Participants will be assigned to either K-645 or placebo for the entire study. Therefore, participants randomized to K-645 will receive K-645 in all 4 dosing periods, and those randomized to placebo will receive placebo in all 4 dosing periods. Dosing is double blind meaning that neither the study participants nor the unit staff will know whether a participant is receiving K-645 or placebo in a given treatment period.

All periods for both panels will involve a single administration of K-645 or placebo in the fasted state, except for the final dosing period for Panel B. In Panel B Period 4, one of the dose levels that was administered in the fasted state in a prior period, will be administered following a standardized medium fat breakfast consisting of approximately 750 calories comprised of approximately, 51% carbohydrates, around 18% protein, and 31% fat. The breakfast is expected to include toast, cereals and or hash browns. The standard breakfast will be administered 30 minutes prior to administration of study medication (K-645 or placebo). Participants will have 20 minutes to complete the breakfast.

In all treatment periods, participants will be admitted into the study unit on the day prior to K-645 or placebo administration (Day -1), remain domiciled for at least 24 hours after dosing for safety monitoring and blood sampling, and be discharged on Day 2.

Study medication (K-645 and placebo) will be orally administered as capsules in potencies of 1, 10 and 100mg K-645, and placebo, all of which are visually identical. Capsules are made of Swedish orange hydroxypropyl methylcellulose (HPMC). Compliance will be monitored by site staff witnessing of dosing and will be documented in participant study files.

Planned doses of K-645 are as follows:

Dosing Schedule

Panel A:
Period 1 - 2 mg or placebo
Period 2 - 6 mg or placebo
Period 3 - 18 mg or placebo
Period 4 - 50 mg or placebo

Panel B:
Period 1 - 150 mg or placebo
Period 2 - 300 mg or placebo
Period 3: 500 mg or placebo
Period 4 - 150 mg or placebo



Intervention code [1] 329283 0
Treatment: Drugs
Comparator / control treatment
Placebo capsules for oral administration will be used. These will be Swedish orange capsules which are visually identical to K-645 capsules and filled with microcrystalline cellulose.
Control group
Placebo

Outcomes
Primary outcome [1] 339106 0
To characterize the safety and tolerability of single rising oral doses of K-645 in healthy male participants.
Timepoint [1] 339106 0
TEAEs are AEs that start or worsen after the first dose of study medication.

For both panels (Panel A and Panel B), TEAEs will be assessed in Period 1 on Day 1 (after dosing) and Day 2, in Periods 2-4 on Day -1, Day 1 and Day 2, and at the post-study visit 14 days after the final dose.

For any subjects 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 in Period 1 and completion of dosing in Period 4.
Secondary outcome [1] 438580 0
To characterize the plasma pharmacokinetics (PK) of K-645
Timepoint [1] 438580 0
PK timepoints include-
Panel A and Panel B /All Periods: Day 1 predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24 (Day 2), and 48 (Day 3) hours post dose
Secondary outcome [2] 438916 0
To characterize the plasma pharmacokinetics (PK) of K-645
Timepoint [2] 438916 0
PK timepoints include-
Panel A and Panel B /All Periods: Day 1 predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24 (Day 2), and 48 (Day 3) hours post dose
Secondary outcome [3] 438917 0
To characterize the plasma pharmacokinetics (PK) of K-645
Timepoint [3] 438917 0
PK timepoints include-
Panel A and Panel B /All Periods: Day 1 predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24 (Day 2), and 48 (Day 3) hours post dose
Secondary outcome [4] 438918 0
To characterize the plasma pharmacokinetics (PK) of K-645
Timepoint [4] 438918 0
PK timepoints include-
Panel A and Panel B /All Periods: Day 1 predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24 (Day 2), and 48 (Day 3) hours post dose
Secondary outcome [5] 438940 0
To characterize the plasma pharmacokinetics (PK) of K-645
Timepoint [5] 438940 0
PK timepoints include-
Panel A and Panel B /All Periods: Day 1 - 24 hours post dose
Secondary outcome [6] 438941 0
To characterize the plasma pharmacokinetics (PK) of K-645
Timepoint [6] 438941 0
PK timepoints include-
Panel A and Panel B /All Periods: Day 1 predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24 (Day 2), and 48 (Day 3) hours post dose
Secondary outcome [7] 438942 0
To characterize the plasma pharmacokinetics (PK) of K-645
Timepoint [7] 438942 0
PK timepoints include-
Panel A and Panel B /All Periods: Day 1 predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24 (Day 2), and 48 (Day 3) hours post dose
Secondary outcome [8] 438943 0
To characterize the plasma pharmacokinetics (PK) of K-645
Timepoint [8] 438943 0
PK timepoints include-
Panel A and Panel B /All Periods: Day 1 predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24 (Day 2), and 48 (Day 3) hours post dose
Secondary outcome [9] 438944 0
To characterize the plasma pharmacokinetics (PK) of K-645
Timepoint [9] 438944 0
PK timepoints include-
Panel A and Panel B /All Periods: Day 1 predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24 (Day 2), and 48 (Day 3) hours post dose

Eligibility
Key inclusion criteria
1. Understand the trial procedures and agree to participate by providing written informed consent prior to trial related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial.
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 a male 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 other nicotine-containing products (eg, nicotine patch, e-cigarettes) for at least 1 month before administration of the initial dose of trial drug, has used no more than 5 tobacco/nicotine forms (ie. less than or equal to 5 cigarettes; less than or equal to 10 mg nicotine) per week within 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 Post study visit).
6. Be judged to be in good health by the Investigator, based on clinical evaluations including laboratory safety tests, medical history, physical examination, 12-lead ECG, and vital sign measurements performed at the Screening Visit and before administration of the initial dose of trial drug.
7. Meet the following requirements:
Is a male who meets all criteria under A and B
A. has Screening serum LH, FSH and total testosterone concentrations within the normal range established for the laboratory performing the tests. If Screening total testosterone is below the normal range and the test was performed after 10AM, it may be repeated once between 8AM and 10AM and be considered qualifying if this repeat value is within the laboratory normal range.
B. agrees to all of the following:
1. To use an appropriate method of contraception, including a condom, from the first dose of study drug until greater than or equal to 90 days after the last dose of study drug. A male participant who has had a vasectomy procedure must follow the same restrictions as a non-vasectomized male. This requirement is waived for male participants with male partners.
2. To not donate sperm from the first dose of study drug until greater than or equal to 90 days after the last dose of study drug.
Minimum age
18 Years
Maximum age
45 Years
Sex
Males
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 or twice the duration of the biological effect of the investigational product (whichever is longer or based on local regulations) prior to the Screening Visit. The window will be derived from the date of the last study procedure and/or AE related to the study procedure in the previous study to the Screening Visit of the current study.
2. Is an employee of the Sponsor or study site or an immediate family member (eg, spouse, parent, child, sibling) of any employee of the Sponsor or study site.
3. Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy) or has had an anaphylactic reaction or significant intolerance to prescription or nonprescription drugs or food.
4. Has a known hypersensitivity or contraindication to any component of K-645, its excipients, or related compounds.
5. Has a positive alcohol or drug screen at Screening or admission.
6. Has a positive test result for hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency antibody, at the Screening Visit. Note: Subjects with positive hepatitis B virus or hepatitis C virus serology may be enrolled if quantitative polymerase chain reaction for hepatitis B virus or hepatitis C virus ribonucleic acid is negative.
7. Has a fever at screening* or has a positive COVID-19 test or has a fever at Period 1 Day -1.
8. Had major surgery or donated or lost 1 unit of blood or blood products (approximately 500 mL) within 4 weeks prior to Period 1 Day -1.
9. Is unable to refrain from the use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication and through the completion of study participation at the Follow-Up visit. Exceptions are noted below:
Exceptions:
- The occasional use of non-steroidal anti-inflammatory agents (e.g. ibuprofen) that do not include paracetamol/acetaminophen is allowed. Note: chronic routine use of NSAIDs prior to the screening visit is exclusionary.
- Influenza vaccination and COVID vaccination are allowed.
- Other exceptions can be made, case by case, if the Investigator and Kallyope Medical Monitor agree that the medication in question will not interfere with the study procedures, compromise subject safety, or otherwise undermine study goals.
Note: CYP3A4 inhibitors and inducers, and P-glycoprotein (P-gp) inhibitors are strictly prohibited due to potential for drug interactions with K-645.
10. Has excessive consumption of alcohol within 6 months prior to screening (greater than 14 drinks/week, where l drink= 5 ounces [150 mL] of wine or 12 ounces [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.
11. Is unwilling or unable to refrain from study alcohol restrictions:
- Subjects will refrain from consuming alcohol from 5 days (at least 120 hours) prior to check-in through discharge from the unit in each period, and from 5 days (at least 120 hours) prior to the Poststudy visit.
- At all other times, alcohol consumption is limited to less than or equal to 14 drinks/week, where 1 drink equals to 5 ounces [150 mL] of wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor.
12. Is unable or unwilling to refrain from consumption of Seville oranges, grapefruit, grapefruit juice, pomelos, exotic citrus fruits, grapefruit hybrids from 2 weeks prior to administration of the first dose of study drug, throughout the study, and until the Follow-up Visit.
13. Is unwilling/unable to refrain from consumption of mustard green family (eg, kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, and mustard) or charbroiled (charcoal cooking) meats beginning approximately 48 hours prior to admission to the clinic in Period 1, if possible (if subject has consumed any of these items prior to admission, the subject may be included in the study and the food and amount should be recorded in the source documents). Subjects will not consume any of the above foods while in the clinical research unit and until the poststudy visit.
14. Is unable or unwilling to refrain from consuming caffeinated beverages 24 hours prior to check-in through 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 mean triplicate value for corrected QT interval to Fridericia's formula (QTcF) greater than 450 milliseconds (msec) at screening or on Period 1 Day 1.
18. Has a mean value for triplicate semi-recumbent systolic blood pressure (SBP) greater than 140 mmHg and/or diastolic blood pressure (DBP) greater than 90 mmHg measured after at least 10 minutes at rest at the Screening Visit or on Period 1 Day -1. If a subject’s BP is over the limits, then one triplicate repeat may be taken after at least another 10 minutes of rest.
19. Has an estimated glomerular filtration rate (eGFR by the Chronic Kidney Disease Epidemiology [CKD-EPI]) less than 70 mL/min/1.73m2 at the Screening Visit or Period 1 Day -1.
20. Has alanine aminotransferase or aspartate aminotransferase (ALT or AST) of greater than 1.0X upper limit of normal (ULN) or total bilirubin greater than 1.5X ULN upper limit of normal (ULN) (total bilirubin greater than 1.5X ULN is acceptable if bilirubin is fractionated and direct bilirubin is within the laboratory normal range) at the Screening Visit and Period 1 Day -1.
21. Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, neurologic, neoplastic, or genitourinary abnormalities or diseases.
- Note: Self-limited conditions/events that occurred and resolved greater than or equal to 1 year prior to screening are not exclusionary if both the Investigator and Kallyope Medical Monitor agree that these conditions were self-limited and do not compromise subject safety, or otherwise undermine study goals.
22. Family history of congenital hypogonadotropic hypogonadism in a first-degree relative unless a specific genetic cause has been confirmed which does not involve mutation of TAC3R (the NK3R gene) or TAC3 (the neurokinin B gene).
23. Has a history of any illness that, in the opinion of the study investigator, might confound the results of the study or poses an additional risk to the subject by their participation in the study.
24. Is biological female.
25. Has a pregnant partner.
*A subject may be included if they are able to return to the site within 7 days of initial screening and the exclusion criterion is no longer met.

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)
A Sponsor-generated, password protected allocation schedule will be emailed to unblinded pharmacy staff.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomization will occur, using a randomization table created by computer software.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Other
Other design features
Subjects will be assigned to Panel A or Panel B, then randomized to K-645 or placebo within the assigned panel in a 3:1 ratio.
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 by K-645 dose level.

The PK Analysis Set will consist of all subjects who receive study drug and have at least 1 measurable plasma concentration. PK parameters will be summarized using descriptive statistics.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
10/10/2024
Actual
Date of last participant enrolment
Anticipated
30/05/2025
Actual
Date of last data collection
Anticipated
30/06/2025
Actual
Sample size
Target
16
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 26966 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment postcode(s) [1] 43041 0
4007 - Herston

Funding & Sponsors
Funding source category [1] 317182 0
Commercial sector/Industry
Name [1] 317182 0
Kallyope, Inc
Country [1] 317182 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Kallyope, Inc.
Address
Country
United States of America
Secondary sponsor category [1] 319451 0
Commercial sector/Industry
Name [1] 319451 0
Avance Clinical Pty Ltd
Address [1] 319451 0
Country [1] 319451 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315926 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 315926 0
Ethics committee country [1] 315926 0
Australia
Date submitted for ethics approval [1] 315926 0
04/09/2024
Approval date [1] 315926 0
30/09/2024
Ethics approval number [1] 315926 0

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

Contacts
Principal investigator
Name 136242 0
Dr Richard Friend
Address 136242 0
Q-Pharm Pty Ltd, Level 5, 300C Herston Road, Herston, Queensland, 4006
Country 136242 0
Australia
Phone 136242 0
+61 7 3845 3620
Fax 136242 0
Email 136242 0
[email protected]
Contact person for public queries
Name 136243 0
Gabrielle Robb
Address 136243 0
Q-Pharm Pty Ltd, Level 5, 300C Herston Road, Herston, Queensland, 4006
Country 136243 0
Australia
Phone 136243 0
+61 7 3707 2784
Fax 136243 0
Email 136243 0
[email protected]
Contact person for scientific queries
Name 136244 0
Dr Richard Friend
Address 136244 0
Q-Pharm Pty Ltd, Level 5, 300C Herston Road, Herston, Queensland, 4006
Country 136244 0
Australia
Phone 136244 0
+61 7 370 72720
Fax 136244 0
Email 136244 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.