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Trial registered on ANZCTR


Registration number
ACTRN12623000296639
Ethics application status
Approved
Date submitted
28/02/2023
Date registered
17/03/2023
Date last updated
2/11/2023
Date data sharing statement initially provided
17/03/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1, Randomised, Double-Blind, Placebo-Controlled, First-in-Human Study of the Safety, Tolerability and Pharmacokinetics of AXN-001 in Healthy Volunteers.
Scientific title
A Phase 1, Randomised, Double-Blind, Placebo-Controlled, First-in-Human Study of the Safety, Tolerability and Pharmacokinetics of AXN-001 in Healthy Volunteers.
Secondary ID [1] 308968 0
AXN-001-01
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Migraine 328981 0
Condition category
Condition code
Neurological 325965 325965 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a randomised, double-blind, placebo-controlled, single ascending dose, multi-cohort study. The study will evaluate approximately 5 dose levels of AXN-001 administered subcutaneously with potentially 1 additional dose level administered intravenously. Up to 8 healthy volunteers will be enrolled in each study cohort (6 volunteers will receive the investigational product and 2 volunteers will receive placebo). Dose levels will be evaluated in a sequential manner starting at the lowest dose level with the decision to escalate between dose levels based upon review, by the Safety Review Committee (SRC), of the safety data up to and including study Day 2 assessments in each cohort and any available PK data from the current or preceding cohorts. Any safety data from the previous cohort(s) that are pertinent to the decision for dose escalation will be included in the review.

Dosing in each cohort will start with 2 sentinel participants with one of the 2 sentinels randomised to receive AXN-001 and the other randomised to receive placebo. The safety and tolerability of each sentinel participant will be monitored in the clinic until Day 2 and will be reviewed prior to dosing the remainder of participants in each cohort. The study Investigator will review safety/tolerability information available on the sentinel participants on Day 2 and will make the decision to dose the remaining 6 participants in the cohort.

• Cohort 1: 1 mg (subcutaneous bolus administration)
• Cohort 2: 2 mg (subcutaneous bolus administration)
• Cohort 3: 4 mg (subcutaneous bolus administration)
• Cohort 4: 8 mg (subcutaneous bolus administration)
• Cohort 5: 16 mg (subcutaneous bolus administration)
---------------------------------------------------------------
• Cohort 6: Optional (intravenous bolus administration). To enable determination of the bioavailability of the investigational product (IP) following SC administration, an optional Cohort 6 may be conducted by the IV route. Dose level to be determined based on the safety and pharmacokinetics of the previously studied subcutaneous cohorts. The expected dose level is between 0.5 mg and 2 mg.

• Cohort 7: Optional (subcutaneous bolus administration). Based on emerging safety and efficacy data from the previous study cohorts, an optional cohort (Cohort 7) may be performed where the population may be more defined based on the proportion of males and females. The exact ratio of each gender and the decision to proceed will be upon the Sponsor's review of all available data. The dose will not exceed 16 mg (maximum dose already administered).

Participants will be confined at the clinical facility from Day -1 through to Day 2. Participants will be discharged following completion of all safety assessments and collection of blood samples on Day 2. Site staff will conduct a follow-up telephone call to each study participant on Day 4. Participants will return to the clinical facility for End of Study (EoS) assessments and blood sample collection on study Day 7.

Clinical facility staff will administer the study drug which will be recorded in the appropriate drug accountability records and the 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] 325411 0
Treatment: Drugs
Comparator / control treatment
Healthy volunteers will be enrolled to receive single ascending doses of AXN-001 or placebo subcutaneously on Day 1. At each dose level, participants will be randomised to receive a single dose of AXN-001 (6 participants) or placebo (2 participants).

The placebo solution will be prepared as an aqueous solution at pH 4.5-5.5, containing mannitol.
Control group
Placebo

Outcomes
Primary outcome [1] 333860 0
To investigate the safety and tolerability of a single dose of AXN-001 in healthy adult volunteers.

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 (including changes from baseline in SpO2);
• Change from baseline in electrocardiogram (ECG) parameters;
• Change from baseline in clinical laboratory parameters (haematology, serum chemistry, and urinalysis).
Timepoint [1] 333860 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 on Day -1 through to Day 7 (End of Study/Early Termination Visit).

Vital Signs: Blood pressure and heart rate is assessed using a sphygmomanometer, respiratory rate by manual breath count and temperature by thermometer. Oxygen saturation levels will be measured using pulse oximetry. Assessed at Screening, Day -1, Day 1 pre-dose, 0.5 hrs, 1 hr, 3 hrs, 6hrs, 12 hrs post-dose, Day 2 24 hrs post-dose and Day 7 post-dose (End of Study/Early Termination Visit).

12-Lead ECG: ECG recordings will be obtained in triplicate at Screening, Day -1, Day 1 pre-dose, 0.5 hrs, 1 hr, 3 hrs post-dose, Day 2 24 hrs post-dose and Day 7 post-dose (End of Study/Early Termination Visit).

Clinical Laboratory Evaluations: Blood and Urine samples collected at Screening, Day -1, Day 1 6 hrs post-dose, Day 2 24 hrs post-dose and Day 7 post-dose (End of Study/Early Termination Visit).
Secondary outcome [1] 418561 0
To measure the pharmacokinetics (PK) of AXN-001 in plasma following a single dose in healthy adult volunteers.

PK endpoints include (but are not limited to):
• Maximum observed concentration (Cmax);
• Time to Cmax (Tmax);
• Time to 10 nM (T10nM), 30 nM (T30nM), and 100 nM (T100nM) for each dose;
• Area under the concentration-time curve from 0 to time of last quantifiable concentration (AUC0-t);
• Area under the concentration-time curve from 0 to infinity (AUC0-inf);
• Apparent terminal elimination half-life (t1/2);
• Terminal elimination rate constant (Lambda z);
• Total apparent body clearance (CL/F, or CL for IV);
• Apparent volume of distribution (Vz/F, or Vz for IV);
• Bioavailability of SC dose (Fsc) (%).
Timepoint [1] 418561 0
Plasma samples will be collected as follows:
Day 1 pre-dose, 5 mins, 10 mins, 15 mins, 20 mins, 0.5 hrs, 0.75 hrs, 1 hr, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8 hrs, 12 hrs post-dose, Day 2 24 hrs post-dose.

Eligibility
Key inclusion 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. Adult males and females, 18 to 55 years of age (inclusive) at Screening;
3. Body mass index greater than or equal to 18.0 and less than or equal to 32.0 kg/m2, with a body weight (to 1 decimal place) greater than or equal to 50.0 kg less than or equal to 120 kg;
4. Be non-smokers (including tobacco, e-cigarettes and marijuana) for at least 3 months prior to first study drug administration and have a negative test for cotinine at the screening visit and at check-in on Day -1. Participants who smoke up to 10 cigarettes per week and have a negative cotinine test will be eligible;
5. Medically healthy without clinically significant abnormalities (in the opinion of the Investigator), including:
a. Physical examination without any clinically significant findings;
b. Systolic blood pressure in the range of 90 to 140 mmHg (inclusive) and diastolic blood pressure in the range of 40 to 90 mmHg (inclusive) after 5 minutes in supine (or semi-supine) position;
c. Heart rate in the range of 50 to 100 bpm (inclusive) after 5 minutes rest in supine (or semi-supine) position;
d. Body temperature (tympanic) in the range 35.5°C to 37.7°C (inclusive);
e. No clinically significant findings in serum chemistry, haematology, coagulation, and urinalysis tests;
f. Estimated glomerular filtration rate greater than or equal to 70mL/min/1.73m2;
g. Triplicate 12-lead ECG (taken after the volunteer has been supine (or semi-supine) for at least 5 minutes) with a QT interval corrected using the Fridericia method (QTcF) less than or equal to 450 msec for males and less than or equal to 470 msec for females and no clinically significant abnormalities;
h. Oxygen saturation (SpO2) greater than or equal to 95%.
6. Female volunteers must:
a. Be of nonchildbearing potential i.e., be surgically sterilised (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before screening) or be postmenopausal, where menopause is defined as 12 months of amenorrhea in the absence of other biological causes. Females under the age of 55 years must have a documented serum follicle-stimulating hormone (FSH) level > 40mIU/mL to confirm menopause (females who are taking Hormone Replacement Therapy (HRT) should provide evidence that they are post-menopausal or should be excluded as their post-menopausal status cannot be confirmed by measuring FSH - alternatively they would need to stop HRT to allow FSH to be measured);
b. If of childbearing potential (defined as any female who has experienced menarche and who has not undergone surgical sterilisation and is not postmenopausal), the participant:
• Must have a negative serum test at the screening visit and a negative urine pregnancy test within 24 hours prior to the start of study drug;
• Must not be breastfeeding, lactating or planning pregnancy during the study period;
• Must agree not to attempt to become pregnant;
• If not exclusively in same-sex relationships, 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 by the female partner after signing consent, during the study, and at least 30 days after the EoS visit;
• Must agree to not donate ova for at least 30 days after EoS visit.
7. Male participants, if not surgically sterilised, must agree to:
a. Not donate sperm after signing consent, during the study, and at least 90 days after the EoS visit;
b. If engaging in sexual intercourse with a female partner who could become pregnant, use a condom in addition to having the female partner use a highly effective contraceptive method after signing consent, during the study, and at least 90 days after the EoS visit.
8. Have suitable venous access for blood sampling;
9. Be willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Previous diagnosis/history to migraine(s ) in the last 5 years as assessed by the Investigator. Where there is a history of headache, it is up to the investigator’s discretion if the description of the headaches fits with a diagnosis of migraine;
2. History or presence of significant cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic or neurological disease, including any acute illness or major surgery within the past 3 months determined by the Investigator to be clinically significant (participants with resolved childhood asthma may be included in the study). Conditions reported in the past 3 months considered by the Investigator to be clinically significant but not exclusionary should be discussed and be in agreement with the Sponsor;
3. Current or history of psychiatric disease in the last 5 years. Cases of untreated depression may be included in the study in agreement with the Sponsor;
4. Current infection that requires systemically absorbed antibiotic, antifungal, antiparasitic or antiviral medications;
5. Suffer from frequent or recurrent infections (defined as greater than or equal to 3 occurrences in the 12 months preceding first study drug administration or 2 occurrences in the 6 months preceding first study drug administration);
6. Any history of malignant disease in the last 10 years (excludes surgically resected skin squamous cell or basal cell carcinoma);
7. Prior diagnosis or family history of Addison’s disease, any other adrenal, pituitary or autoimmune disease;
8. Presence of clinically relevant immunosuppression from, but not limited to, immunodeficiency conditions such as common variable hypogammaglobulinemia;
9. Use of or plans to use systemic immunosuppressive (e.g., corticosteroids, methotrexate, azathioprine, cyclosporine) or immunomodulating medications (e.g., interferon) during the study or within 3 months prior to the first study drug administration (prior use of nasal sprays for hayfever may be permitted if used > 30 days prior to study drug administration or alternatively at the discretion of the Investigator);
10. History of risk factors for torsade de pointes (including a family history [in first-degree relatives] of long QT syndrome or sudden cardiac death) or a known arrythmia;
11. Liver function test results elevated more than 1.5-fold above the upper limit of normal (ULN) for gamma glutamyl transferase (GGT), bilirubin (total, conjugated and unconjugated), alkaline phosphatase (ALP), aspartate aminotransferase (AST) or alanine aminotransferase (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;
12. Positive test results for active human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibodies at the screening visit;
13. Presence or having sequelae of gastrointestinal, 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). Cholecystectomy and Gilbert’s Syndrome are not exclusionary;
14. Serum creatinine more than 1.5-fold above the ULN;
15. History of substance abuse or alcohol abuse within 12 weeks prior to the screening visit (defined as more than an average of 14 standard drinks per week or regular consumption of more than 4 standard drinks on any one day; 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]);
16. Positive drugs of abuse or alcohol breath test results at the screening visit or at check-in (Day -1).
17. Use of any prescription or over-the-counter medication (including herbal products, and hormone supplements) within 10 days or 5 half-lives of the medication (whichever is longer) prior to the first study drug administration – exceptions include hormone replacement therapy (eg, estrogen, thyroid), hormonal contraceptives and 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), ibuprofen (doses of 400 mg up to every 6 hours or 1.2 g per day maximum for no more than 3 consecutive days), topical ointments, and vitamins or dietary supplements used to manage AEs. Vitamins, herbal medications and dietary supplements and medications prescribed by a Healthcare Provider are permitted if taken for > 3 months on a stable prescribed dose. All non-prescribed medications are not permitted from Day -10 to EOS. Any exceptions will require approval from the Sponsor Medical Representative if, in the Investigator’s opinion, continued medication use is required;
18. Demonstrated clinically significant (required intervention, e.g., emergency room visit, epinephrine administration) allergic reactions (e.g., food, drug, or atopic reactions, asthmatic episodes) which, in the opinion of the Investigator, would interfere with the volunteer’s ability to participate in the trial;
19. In the investigator's opinion, known significant hypersensitivity to any drugs in the last 5 years
20. Use of any vaccinations within 14 days (within 4 weeks for live virus vaccines) prior to the first study drug administration;
21. The presence of tattoos or skin conditions at the injection site that would obstruct the visibility and assessment of injection site reactions;
22. For women of childbearing potential, a positive serum pregnancy test at the screening visit or a positive urine pregnancy test (with confirmatory serum pregnancy test) at check-in (Day -1);
23. Females who are breastfeeding or planning to breast feed at any time during the study;
24. Donation or loss of blood or plasma (>500mL) within 30 days prior to first study drug administration or receipt of a blood transfusion within 1 year of first study drug administration;
25. Treatment with an investigational drug in another clinical trial within 60 days or 5 half-lives of the other investigational drug (whichever is longer) prior to the first administration of study drug in this trial;
26. Any other condition or prior therapy that in the opinion of the Investigator would make the volunteer 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 pre-dose on Day 1, which corresponds to a study treatment (AXN-001 or placebo). Sealed participant-specific code break envelopes will be produced by the unblinded statistician(s) and will be retained at the clinical facility in a secure, accessible location.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The allocation to AXN-001 or placebo 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
This is a randomised, double-blind, placebo-controlled, single ascending dose, multi-cohort study. The study will evaluate approximately 5 dose levels of AXN-001 administered subcutaneously with potentially 1 additional dose level administered intravenously. Up to 8 healthy volunteers will be enrolled in each study cohort (6 volunteers will receive the investigational product and 2 volunteers will receive placebo). Dose levels will be evaluated in a sequential manner starting at the lowest dose level with dose escalation being based on all available safety and pharmacokinetic data obtained from the previously administered dose levels.
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
This study is the First in Human (FIH) study with AXN-001 and as such no formal sample size calculation was performed.

The full analysis set (FAS) will include all participants who receive AXN-001 or placebo and will be analysed according to treatment randomisation.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/05/2023
Actual
19/05/2023
Date of last participant enrolment
Anticipated
Actual
18/08/2023
Date of last data collection
Anticipated
Actual
28/08/2023
Sample size
Target
56
Accrual to date
Final
36
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 24044 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 39547 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 313183 0
Commercial sector/Industry
Name [1] 313183 0
Axon Therapeutics Inc.
Country [1] 313183 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Avance Clinical Pty Ltd
Address
Level 1, 2 Ann Nelson Drive,
Thebarton, South Australia 5031
Country
Australia
Secondary sponsor category [1] 315098 0
None
Name [1] 315098 0
Address [1] 315098 0
Country [1] 315098 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312418 0
Bellberry Limited Human Research Ethics Committee
Ethics committee address [1] 312418 0
123 Glen Osmond Road,
Eastwood, South Australia, 506
Ethics committee country [1] 312418 0
Australia
Date submitted for ethics approval [1] 312418 0
28/02/2023
Approval date [1] 312418 0
17/04/2023
Ethics approval number [1] 312418 0
2021-10-1223

Summary
Brief summary
This is a double-blind, randomised, placebo-controlled study evaluating the safety, tolerability, and pharmacokinetics (PK) of a single administration of AXN-001 at increasing dose levels in the range of 1 mg to 16 mg. Evaluation of dose levels will be conducted in a sequential fashion with lower dose levels evaluated first in the sequence.

Dose administration will be performed by the subcutaneous (SC) route for Cohorts 1 to 5. To enable determination of the bioavailability of the investigational product following SC administration, dose administration for Cohort 6 may be performed by the intravenous (IV) route. Cohort 7 may proceed via subcutaneous injection upon completion of cohort 5.
The decision by the Safety Review Committee (SRC) to escalate between dose levels will be based on review of all available safety and PK data from previous cohorts.

Up to 56 healthy male and female volunteers aged 18 to 55 years of age (inclusive) and with a body mass index between 18.0 kg/m2 and 32.0 kg/m2 are planned to be enrolled.

Healthy volunteers will be screened between Day -28 and Day -2, inclusive. Participants will be admitted to the clinical facility on Day -1 with dosing to occur on the following day (Day 1). All participants will be dosed under fasted conditions.

Seeking to address unmet medical needs for the acute treatment of migraine, Axon Therapeutics is developing AXN-001, a peptide CGRP-R antagonist as a subcutaneous (SC) formulation for the acute self-administered treatment of migraine.
Trial website
Trial related presentations / publications
Public notes
Inclusion Criteria:
10. Must have received at least double vaccination against COVID-19 (vaccines must be approved by the local Regulatory Authority in the country of administration);

Exclusion Criteria:
27. A diagnosis of COVID-19 within 1 month prior to screening;
28. Symptoms of long COVID, as determined by the Investigator;
29. Evidence of an active infection, including symptoms of COVID-19;

Contacts
Principal investigator
Name 124590 0
Dr Michele de Sciscio
Address 124590 0
CMAX Clinical Research Pty Ltd
Level 5, 21 North Terrace, Adelaide, South Australia 5000
Country 124590 0
Australia
Phone 124590 0
+61 0422447902
Fax 124590 0
Email 124590 0
[email protected]
Contact person for public queries
Name 124591 0
Michele de Sciscio
Address 124591 0
CMAX Clinical Research Pty Ltd
Level 5, 21 North Terrace, Adelaide, South Australia 5000
Country 124591 0
Australia
Phone 124591 0
+61 0422447902
Fax 124591 0
Email 124591 0
[email protected]
Contact person for scientific queries
Name 124592 0
Michele de Sciscio
Address 124592 0
CMAX Clinical Research Pty Ltd
Level 5, 21 North Terrace, Adelaide, South Australia 5000
Country 124592 0
Australia
Phone 124592 0
+61 0422447902
Fax 124592 0
Email 124592 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
Privacy and intellectual property considerations


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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