A pilot study of the bioavailability and pharmacokinetics of epinephrine after administration of ARS-1 and intramuscular epinephrine to healthy volunteers
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
ARS Pharmaceuticals PTY LTD
27 participants
Nov 22, 2017
Interventional
Conditions
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.
Eligibility
Inclusion Criteria12
- 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:
- Male subjects between the ages of 18 and 30 years, inclusive.
- Written informed consent to participate in the study.
- Body weight more than 50 kg and mass index between 18 and 28 kg/m², inclusive.
- 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
- /90 mmHg) at screening.
- No clinically significant abnormal findings in the medical history, on the physical
- examination, electrocardiogram (QTcF<450 msec), or clinical laboratory results during
- screening.
- Subjects must agree to remain confined in house until Day 2 for Part1 and Day 1 for Part
- and Part 3, and must be willing to comply with all required study procedures.
Exclusion Criteria33
- 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.
- Subject who has smoked within 6 months prior to screening
- Subject has had significant traumatic injury, major surgery or open biopsy within 30 days
- prior to study screening.
- A history of allergic or adverse responses to epinephrine or any comparable or similar
- product.
- 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.
- Subjects who donated blood or plasma within 30 days of the first dose of study drug.
- 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.
- Inadequate or difficult venous access that may jeopardize the quality or timing of the PK
- samples.
- 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:
- Subject may not take OTC products, including vitamins and supplements, for the seven
- (7) days prior to dosing study medication.
- 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.
- Use of oral and/or nasal decongestants within 14 days prior to the first dose of study drug or during the study.
- 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.
- Subjects should not engage in strenuous exercise during the confinement period of the
- study.
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Interventions
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.
Locations(1)
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ACTRN12619001745134