PK/PD Study of IN-001 Sublingual Spray in Healthy Adults

• Epinephrine Auto-Injector 0.3 mg/0.3 mL (Drug), also known as Epipen: Epinephrine injection
• Epinephrine 0.3 mg intramuscular manual injection via a syringe and needle (Drug), also known as Adrenalin: Epinephrine injection
• IN-001 9.06 mg Sublingual Spray (Drug), also known as IN-001: Sublingual Spray
• IN-001 13.59 mg Sublingual Spray (Drug), also known as IN-001: Sublingual Spray

Primary outcomes

• Cmax [0 to 360 minutes post dose]: Maximum Epinephrine Plasma Concentration occurring at Tmax (Time to reach maximum concentration)
• Tmax [0 to 360 minutes postdose]: Time to reach maximum epinephrine plasma concentration

Secondary outcomes

• Systolic Blood Pressure [0 to 120 minutes postdose]: PD
• Diastolic Blood Pressure [0 to 120 minutes postdose]: PD
• Pulse Rate [0 to 120 minutes postdose]: PD

Sex: All, ages: 18 Years to 45 Years, accepts healthy volunteers

Inclusion Criteria:

* To participate in this trial, volunteers must meet all of the inclusion criteria listed below:

  1. Age > 18 years of age and < 45 years of age.
  2. Women of childbearing potential or men with childbearing potential partners must agree that the participant and/or their partner will use the following effective methods of birth control from screening visit until 14 days after the last dose of study drug:

     1. Abstinence
     2. Hormonal contraceptives for at least one month prior to Screening
     3. Double barrier (e.g., diaphragm with spermicide, condom with spermicide)
     4. Intrauterine device (IUD)
     5. Surgically sterile (e.g., bilateral tubal ligation, total or partial hysterectomy, or bilateral oophorectomy)

        * Note: Females will be considered post-menopausal if they

          * are at least 45 years of age with amenorrhea for at least one year, or
          * received bilateral oophorectomy with or without a hysterectomy.
  3. BMI > 18.50 and < 29.90 kg/m2 (using formula BMI = weight (kg)/height (m2).
  4. All clinical laboratory test results (e.g., hematology, chemistry, urinalysis) are within normal limits or considered not clinically significant by Investigator.
  5. Serum pseudocholinesterase activity is within normal limits or considered not clinically significant by Investigator.
  6. Physical examination (excluding genital and rectal exams) is normal or considered not clinically significant by Investigator.
  7. Vital signs measurements (pulse rate, blood pressure, temperature, and respiratory rate) are normal or considered not clinically significant by Investigator, while seated or semi-recumbent and after 5 minutes of rest. Normal vital sign ranges are listed below:

     1. Systolic blood pressure: 90 - 140 mmHg
     2. Diastolic blood pressure: 50 - 90 mmHg
     3. Pulse rate: 45 - 100 beats per minute (bpm)
     4. Oral body temperature: 35.0°C - 37.5°C
  8. 12-lead electrocardiogram (ECG) is normal or considered not clinically significant by Investigator.
  9. Participants must agree to not consume caffeine and/or xanthine containing products (i.e., coffee, tea, chocolate, caffeine-containing sodas, etc.), grapefruit and grapefruit containing products, and poppyseed containing foods within 48 hours prior to Period 1 check-in.
  10. Able to comply with study procedures, in the opinion of the Investigator(s).
  11. Willing to provide written consent for screening procedures. Legally authorized representatives will not be allowed to sign on behalf of participants in this trial.

Exclusion Criteria:

* To participate in this trial, volunteers must not meet any of the exclusion criteria listed below:

  1. Resident of a care facility, incarcerated individual, or individual in residential treatment facilities.
  2. Pregnant and/or breastfeeding.

     1. Females of childbearing potential should have a negative pregnancy test.
     2. Females must agree to refrain from breastfeeding from screening visit through 14 days after the last dose of study drug.
  3. Known history of Human Immunodeficiency Virus (HIV) 1 \& 2 and hepatitis B \& C virus.
  4. Clinically significant history of alcoholism within the last 12 months, per Investigator's discretion. Participants must

     a. have a negative breath alcohol test at screening. b. agree to abstain from using alcohol for 7 days prior to dosing in Period 1 until the end of study.
  5. Clinically significant history of addiction, abuse, and misuse of any drug, per the Investigator's discretion. Participants must

     a. have a negative drug test for substances of abuse at screening. b. agree to abstain from using drugs for 7 days prior to dosing in Period 1 until the end of study.
  6. Use of tobacco/nicotine containing products (e.g., chewing tobacco, smoking cigarettes, and/or electronic cigarettes) within the last 12 months. Participants must agree to abstain from using tobacco/nicotine containing products from the screening visit until the end of study.
  7. Use of or planned use of any investigational products (i.e., dosing in any clinical investigation) within 30 days prior to Period 1 dosing or within 10 half-lives of the investigational agent previously taken (whichever is longer).
  8. Use of or planned use of any prescription medications, except hormonal contraceptives, within 14 days prior to Period 1 dosing.
  9. Use of or planned use of any over-the-counter medications (e.g., aspirin, ibuprofen, antacids, etc.) within 5 days prior to Period 1 dosing.
  10. Use of or planned use of hormone replacement therapy within 90 days prior to Period 1 dosing.
  11. Use of or planned use of any of the following medications within 30 days prior to Period 1 dosing:

      1. Ergot alkaloids
      2. Cardiac glycosides
      3. Diuretics
      4. Anti-arrhythmic medications
      5. Tricyclic antidepressants
      6. Monoamine oxidase inhibitors
      7. Levothyroxine sodium
      8. Antihistamines, including chlorpheniramine and diphenhydramine
      9. Tripelennamine
      10. Propranolol
      11. Phentolamine
      12. Proton pump inhibitors
      13. Antihypertensives
      14. Chlorpromazine
      15. Ethosuximide
      16. Haloperidol
      17. Lithium carbonate
      18. Meperidine
      19. Methenamine therapy
      20. Norepinephrine
      21. Phenobarbital
      22. Phenytoin
      23. Propoxyphene
      24. Veratrum alkaloids
  12. Any major illness in the last 3 months or any significant ongoing chronic medical illness as determined by the Investigator.
  13. Presence or history of clinically significant disorders involving cardiovascular (e.g., cardiac arrhythmias, coronary artery or organic heart disease, or hypertension), respiratory, renal, hepatic, dermatologic, musculoskeletal, gastrointestinal, immunologic, hematologic, endocrine (e.g., hyperthyroidism, hypoglycemia, or diabetes) or neurologic systems (e.g., Parkinson's disease), or psychiatric disease (e.g., depression), as determined by the Investigator.
  14. History of complaints of frequent dizziness or lightheadedness occurring more than once every week.
  15. Existence of any surgical or medical condition which, in the judgment of the Investigator, might interfere with the absorption, distribution, metabolism, or elimination of the study drug or is likely to compromise the safety of the participant.
  16. Evidence of allergy or known hypersensitivity to epinephrine, sodium metabisulfite, or to any of the components of its formulation.
  17. History or presence of difficult venipuncture for blood sampling.
  18. History or presence of open sores or areas of irritation, redness, swelling, bleeding, lesions, piercings, or mucous membranes within the mouth.
  19. Below normal serum pseudocholinesterase levels, defined as:

      a. Males i. All ages: < 5,320 U/L b. Females i. Not taking hormonal contraceptives

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  1. Ages 18-39 years: < 4,260 U/L
  2. Ages > 40 years: < 5,320 U/L ii. Taking hormonal contraceptives

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  1. Ages 18-41 years: < 3,650 U/L
  2. Ages > 42 years: < 5,320 U/L

  20\. Any blood donation, or excess blood loss, within 30 days prior to Period 1 dosing and throughout the duration of the study. Participant agrees to continue to abstain from blood donation, outside of study activities, through end of study.

  21\. Any plasma donations or plans to donate plasma within 14 days prior to Period 1 dosing and throughout the duration of the study. Participant agrees to continue to abstain from plasma donation, outside of study activities, through end of study.

• Nancy Sweitzer, Principal investigator, WashU Medical School