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Trial registered on ANZCTR


Registration number
ACTRN12619001745134
Ethics application status
Approved
Date submitted
13/08/2019
Date registered
9/12/2019
Date last updated
9/12/2019
Date data sharing statement initially provided
9/12/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
A pilot study of the bioavailability and pharmacokinetics of epinephrine after administration of ARS-1 and intramuscular epinephrine to healthy volunteers
Scientific title
A pilot, three-treatment dose escalation, followed by a two-period, two-treatment,
randomised crossover study of the bioavailability and pharmacokinetics of epinephrine after administration of ARS-1 and intramuscular epinephrine to healthy volunteers
Secondary ID [1] 299009 0
None
Universal Trial Number (UTN)
U1111-1238-5799
Trial acronym
EPI-02
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anaphylaxis 314017 0
Condition category
Condition code
Inflammatory and Immune System 312406 312406 0 0
Allergies

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a Phase 1, dose escalation followed by two 12 subject open-label, randomized, single dose, two-treatment, two-period, crossover studies that will consist of a screening period, baseline period, and an open-label treatment period. Screening, dosing and monitoring will be conducted under the supervision of trained study staff and medical professionals (where appropriate). Adherence to the administration of the study drug will be documented and any adverse reactions will be recorded and treated appropriately in line with GCP and safety standards.

Part 1: Dose escalation in three subjects to determine the optimal dose of epinephrine. Screening Period: Subjects will undergo screening within 28 days prior to entering into the Part 1 of the study.

Three (3) subjects will be enrolled and receive ARS-1 doses of 0.5 mg, 1.0 mg and 2.0 mg epinephrine by intranasal administration after an overnight fast. Blood samples will be collected for 360 minutes after dosing. Treatments will be separated by a minimum 24 hours wash out period.

Part 2: Comparative bioavailability with intramuscular injection in twelve subjects in an open label, randomized, single-dose, two-treatment, two-period, crossover study that will consist of a screening period, baseline period, and an open-label treatment period.

Screening Period: Subjects will undergo screening within 28 days prior to entering into the Part 2 of the study.

Open-Label Treatment Period: Twelve (12) eligible subjects will be randomized to the optimal
dose of ARS-1 determined in Part 1 of this study or a 0.3 mg dose of epinephrine injection by
intramuscular administration after an overnight fast to receive single doses. Blood samples will be collected for 360 minutes after dosing. Treatments will be separated by a minimum 24 hours wash out period.

Part 3: Comparative bioavailability with intramuscular injection to test two pH conditions of
ARS-1 in twelve subjects (six per group) in an open-label, randomized, single-dose,
two-treatment, two-period, crossover study that will consist of a screening period, baseline
period, and an open-label treatment period.

Screening Period: Subjects will undergo screening within 28 days prior to entering into the Part 3 of the study.

Open-Label Treatment Period: Twelve (12) eligible subjects will be randomized, 6 per group,
to a 1 mg per 100 microliters spray of ARS-1 at one of two pH conditions or a 0.3 mg dose of
epinephrine injection by intramuscular administration after an overnight fast to receive single doses. Blood samples will be collected for 360 minutes after dosing. Treatments will be separated by a minimum 24 hours wash out period.


For Part 1, 2 and 3: Safety assessments will be performed at each of the study day and subjects can be released after discharge assessment on Day 2 for Part 1 and Day 1 for Part 2 and Part 3. Subjects will be followed for 6 hours after the administration of the last dose of study drug.

A total of twenty-seven (27) males will be enrolled in Part 1, Part 2 and Part 3 combined.
Plasma samples from all subjects that complete the study will be analyzed. This is a pilot
comparative bioequivalence study and thus there is no statistical basis for the number of
subjects being enrolled. The number of subjects is considered to be adequate to assess the
bioavailability and power a more definitive bioequivalence study.

Blood samples for the measurement of plasma concentrations of Epinephrine will be collected
before (0, pre-dose) and at 2, 4, 6, 8, 10, 12.5, 15, 20, 25, 45, 60, 90, 120, 150, 180, 240 and 360 minutes after dosing. Actual blood collection times can vary as follows: 1) ± 1 minutes for the 2 to 20 minute samples, 2) ± 2 minutes for the 25 to 90 minute samples, and 3) ± 5 minutes for the 120 to 360 minute samples. Actual sampling times will be recorded.
Intervention code [1] 315276 0
Treatment: Drugs
Comparator / control treatment
The effects of increasing doses of the treatment drug administered in part 2 and 3 of the study will be compared.
Control group
Active

Outcomes
Primary outcome [1] 321054 0
Pharmacokinetic Plasma Sampling
The primary endpoint is to determine the optimal dose of ARS-1 to be used in Part 1 to assess the bioavailability of epinephrine after intranasal administration as ARS-1 in healthy volunteers under fasted conditions
Timepoint [1] 321054 0
Pharmacokinetic Plasma Sampling
Blood samples for the measurement of plasma concentrations of epinephrine will be collected as follows: before (0, pre-dose) and at 2, 4, 6, 8, 10, 12.5, 15, 20, 25, 45, 60, 90, 120, 150, 180, 240 and 360 minutes after dosing.
Bioanalytical Method
Plasma samples will be evaluated by a validated LC/MS/MS method capable of detecting
epinephrine.
Pharmacokinetic parameters that will be assessed are
- maximum plasma concentration (Cmax),
- time to Cmax (tmax),
- area under the curve to the final time with a concentration equal to or greater than the lower limit of quantitation [AUC(0-t)] and to infinity [AUC(inf)],
- elimination rate constant (lambda z) and half-life (t½),
- for epinephrine only, clearance (CL/F) and volume of distribution (Vz/F) uncorrected for
bioavailability (F).
Primary outcome [2] 322196 0
The primary endpoint is to determine the optimal dose of ARS-1 to be used in Part 2 to assess the comparative bioavailability of epinephrine after intranasal administration as ARS-1 and intramuscular administration as intramuscular epinephrine injection in healthy volunteers under fasted conditions.
Timepoint [2] 322196 0
Pharmacokinetic Plasma Sampling
Blood samples for the measurement of plasma concentrations of epinephrine will be collected as follows: before (0, pre-dose) and at 2, 4, 6, 8, 10, 12.5, 15, 20, 25, 45, 60, 90, 120, 150, 180, 240 and 360 minutes after dosing.
Bioanalytical Method
Plasma samples will be evaluated by a validated LC/MS/MS method capable of detecting
epinephrine.
Pharmacokinetic parameters that will be assessed are
- maximum plasma concentration (Cmax),
- time to Cmax (tmax),
- area under the curve to the final time with a concentration equal to or greater than the lower limit of quantitation [AUC(0-t)] and to infinity [AUC(inf)],
- elimination rate constant (lambda z) and half-life (t½),
- for epinephrine only, clearance (CL/F) and volume of distribution (Vz/F) uncorrected for
bioavailability (F).
Primary outcome [3] 322198 0
The primary endpoint is to determine the optimal dose of ARS-1 to be used in Part 3 comparative bioavailability with intramuscular injection to test two pH conditions of
ARS-1 in healthy volunteers under fasted conditions.
Timepoint [3] 322198 0
Pharmacokinetic Plasma Sampling
Blood samples for the measurement of plasma concentrations of epinephrine will be collected as follows: before (0, pre-dose) and at 2, 4, 6, 8, 10, 12.5, 15, 20, 25, 45, 60, 90, 120, 150, 180, 240 and 360 minutes after dosing.
Bioanalytical Method
Plasma samples will be evaluated by a validated LC/MS/MS method capable of detecting
epinephrine.
Pharmacokinetic parameters that will be assessed are
- maximum plasma concentration (Cmax),
- time to Cmax (tmax),
- area under the curve to the final time with a concentration equal to or greater than the lower limit of quantitation [AUC(0-t)] and to infinity [AUC(inf)],
- elimination rate constant (lambda z) and half-life (t½),
- for epinephrine only, clearance (CL/F) and volume of distribution (Vz/F) uncorrected for
bioavailability (F).
Secondary outcome [1] 373810 0
The secondary endpoints are to evaluate the safety and tolerability of ARS-1 in healthy volunteers in all 3 Parts of the study.
Timepoint [1] 373810 0
Adverse events will be collected and reviewed to evaluate the safety and tolerability of ARS-1.
Other safety measures will include vital sign measurements (temperature, pulse, respiratory rate and blood pressure) are to be obtained just prior to dosing, and at 30 minutes, 1 , 2, 4, 6 hours post dosing on Day 0, Day 1, and Day 2 as well as discharge assessment for Part 1 and on Day 0 and Day 1 as well as at discharge for Part 2 and Part 3 .

Objective evaluations of nasal irritation will be assessed after each administration of study drug using a 6-point (0 - 5) score. The scoring will be done by a medically trained observer based on an assessment of the nasal mucosa prior to dosing (baseline) and at 30 minutes,
and 1 , 2, 4 , and 6 hours post dose. Irritation will be assessed by evaluating the degree of mucosal inflammation and bleeding. The subjects will also be required to report any incident of bleeding or inflammation in-between the actual evaluation time points.

An unconstrained visual analog scale (VAS) that consists of a 10 cm (100 mm)
horizontal straight line will be used to assess acute pain following each administration of the intranasal ARS-1 drug product. The ends of the scale are defined as extreme limits of pain sensation: 0 =no pain, 10 = extreme pain. The subjects will be asked to mark a point on the scale which best describes their intensity of pain and discomfort just prior to dosing (baseline) and at 15 and 30 minutes, and 1 hour post dose. The location of the marking at each time point will be measured and noted as the reported score.

Eligibility
Key inclusion criteria
The study population will be healthy male adult volunteers who have consented to participate in this study.
For a subject to be eligible for this study, he must meet all of the following criteria:
1. Male subjects between the ages of 18 and 30 years, inclusive.
2. Written informed consent to participate in the study.
3. Body weight more than 50 kg and mass index between 18 and 28 kg/m², inclusive.
4. No family and medical history of hypertension and cardiovascular disease within the past 10 years, and the blood pressure is within normal range (i.e. blood pressure less than
140/90 mmHg) at screening.
5. No clinically significant abnormal findings in the medical history, on the physical
examination, electrocardiogram (QTcF<450 msec), or clinical laboratory results during
screening.
6. Subjects must agree to remain confined in house until Day 2 for Part1 and Day 1 for Part
2 and Part 3, and must be willing to comply with all required study procedures.
Minimum age
18 Years
Maximum age
30 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
Subjects must NOT meet any of the following Exclusion criteria to be eligible for enrollment:
1. A history of clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic,
endocrine, oncologic, pulmonary, immunologic, psychiatric, or cardiovascular disease,
severe seasonal or non seasonal allergies, nasal polyps, or any nasal passage abnormality
that could interfere with nasal spray administration, or any other condition which, in the
opinion of the Principal Investigator, would jeopardize the safety of the subject or impact
the validity of the study results.
2. Subject who has smoked within 6 months prior to screening
3. Subject has had significant traumatic injury, major surgery or open biopsy within 30 days
prior to study screening.
4. A history of allergic or adverse responses to epinephrine or any comparable or similar
product.
5. Subjects who (for whatever reason) have been on an abnormal diet (such as one that
severely restricts specific basic food groups [e.g., ketogenic diet], limits calories [e.g.,
fast], and/or requires the use of daily supplements as a substitute for the foods typically
eaten at mealtimes), during the four (4) weeks preceding the study.
6. Subjects who donated blood or plasma within 30 days of the first dose of study drug.
7. Participation in a clinical trial within 30 days prior to the first dose of study drug.
Participation in an observational (non-interventional) study is not excluded as long as
there are no scheduling conflicts with this study.
8. Inadequate or difficult venous access that may jeopardize the quality or timing of the PK
samples.
9. Positive blood screen for HIV, Hepatitis B surface antigen (HbSAg), or Hepatitis C, or a
positive urine screen for alcohol, drugs of abuse, or cotinine.

Restrictions
Subjects who meet any of the following criteria will be excluded from participation in the study:
1. Subject may not take OTC products, including vitamins and supplements, for the seven
(7) days prior to dosing study medication.
2. Use of any prescription medication within 14 days prior to the first dose of study drug or
during the study unless approved by the Principal Investigator and medical monitor.
3. Use of oral and/or nasal decongestants within 14 days prior to the first dose of study drug or during the study.
4. Smoking and the use of tobacco products are not permitted for six (6) months prior to the first dose of Study Drug and for the duration of the study.
5. Subjects should not engage in strenuous exercise during the confinement period of the
study.

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)
In Part 2 and Part 3, each subject who is determined to be eligible for the study will be randomly assigned to one of the two treatments. Each subject will cross-over to the alternate treatment as defined by the treatment assignment.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
In Part 2 and Part 3, once subjects are confirmed to be eligible, they will be randomized to one of the treatment groups based on the randomization schedule.
Simple randomisation using a randomisation table created by computer software will be used.
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
Sample Size Determination
This is a pilot comparative bioequivalence study and thus there is no statistical basis for the
number of subjects being enrolled.

Analysis Data Sets
Subjects who receive at least one dose of ARS-1 will be included in the safety analyses. Subjects who complete at least two treatments, one of which must be ARS-1, during this study will be included in the primary PK analyses.

Pharmacokinetic Data Analyses
The pharmacokinetic parameters Cmax, AUC(0-t), and AUC(inf) for epinephrine will be compared among treatments using an analysis of variance (ANOVA) model with treatment, period, sequence, and subject within sequence as the classification variables using the natural logarithms of the data. Confidence intervals (90%) will be constructed for the geometric mean ratios, ARS- 1-to-Epinephrine of the three parameters using the log-transformed data and the two one-sided ttests procedure. The point estimates and confidence limits will be exponentiated back to the original scale. Comparability between ARS-1 and epinephrine will be assessed from the geometric mean ratios and 90% confidence intervals for the three parameters.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
22/11/2017
Date of last participant enrolment
Anticipated
Actual
23/05/2018
Date of last data collection
Anticipated
Actual
29/05/2018
Sample size
Target
27
Accrual to date
Final
27
Recruitment in Australia
Recruitment state(s)
SA

Funding & Sponsors
Funding source category [1] 303544 0
Commercial sector/Industry
Name [1] 303544 0
ARS Pharmaceuticals PTY LTD
Country [1] 303544 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
ARS Pharmaceuticals PTY LTD
Address
6-10 O’Connell Street, Level 21
Sydney NSW, 2000
Australia
Country
Australia
Secondary sponsor category [1] 303615 0
None
Name [1] 303615 0
Address [1] 303615 0
Country [1] 303615 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304072 0
Bellberry Human Research Ethics Committee A TGA HREC Code: EC00372
Ethics committee address [1] 304072 0
129 Glen Osmond Rd
Eastwood SA 5063
Phone: 08 8361 3222
Ethics committee country [1] 304072 0
Australia
Date submitted for ethics approval [1] 304072 0
04/10/2017
Approval date [1] 304072 0
15/11/2017
Ethics approval number [1] 304072 0
2017-10-751

Summary
Brief summary
Intramuscular epinephrine injection is the most commonly used epinephrine injection indicated for the treatment of anaphylaxis.
An epinephrine nasal spray is being developed for patients who experience anaphylaxis to
provide an alternative more convenient and acceptable route of epinephrine administration.
The purpose of this pilot study is to determine the optimal dose of ARS-1 to be used in Part 2 and Part 3 to compare the bioavailability of epinephrine after intranasal administration as ARS-1 and the intramuscular administration as IM epinephrine injection as well as evaluate the safety and tolerability of ARS-1 in healthy volunteers.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 95726 0
Dr Daniel Scherer
Address 95726 0
CMAX Clinical Research
Level 5
18A North Terrace
Adelaide SA 5000
Country 95726 0
Australia
Phone 95726 0
+61 422 122 112
Fax 95726 0
+61 8 7088 7999
Email 95726 0
[email protected]
Contact person for public queries
Name 95727 0
Daniel Scherer
Address 95727 0
CMAX Clinical Research
Level 5
18A North Terrace
Adelaide SA 5000
Country 95727 0
Australia
Phone 95727 0
+61 422 122 112
Fax 95727 0
+61 8 7088 7999
Email 95727 0
[email protected]
Contact person for scientific queries
Name 95728 0
Daniel Scherer
Address 95728 0
CMAX Clinical Research
Level 5
18A North Terrace
Adelaide SA 5000
Country 95728 0
Australia
Phone 95728 0
+61 422 122 112
Fax 95728 0
+61 8 7088 7999
Email 95728 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
Subject medical information obtained as a result of this study is considered confidential.
Disclosure to third parties other than those noted below is prohibited. All reports and
communications relating to subjects in this study will identify each subject only by their initials and number. Medical information resulting from a subject’s participation in this study may be given to the subject’s personal physician or to the appropriate medical personnel responsible for the subject’s welfare. Data generated as a result of this study are to be available for inspection on request by FDA or other government regulatory agency auditors, the Sponsor clinical monitor (ordesignee), and the IRB/EC.


What supporting documents are/will be available?

No Supporting Document Provided



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