Safety and Pharmacokinetics of Halix(TM) Albuterol Unit Dose Disposable Inhaler Versus Albuterol MDI

An Open-label, Single-Center, Single-Dose, 3-Way Crossover Study of the Safety and Pharmacokinetics of Albuterol Administered by the Halix(TM) Albuterol Unit Dose Disposable Inhaler

Healthy male and female volunteers without asthma will be recruited to enroll in a single dose 3-way crossover study of the safety and pharmacokinetics of albuterol when administered using the Halix (TM) albuterol unit dose disposable dry powder inhaler (DPI) and the albuterol HFA (hydrofluoroalkane) MDI inhaler.

The study objective is to compare the safety of albuterol in a dry powder inhaler (DPI) and albuterol in an HFA metered dose inhaler (MDI) after single albuterol doses of 90mcg and 180mcg delivered by the DPI and 180mcg delivered by the MDI. Another study objective is to compare the pharmacokinetics (metabolism) of albuterol with the two inhalers in all subjects treated. To participate in the study, subjects must provide written informed consent, washout any prohibited medications and pass all the screening criteria. Once this is done, there will be 3 treatment visits for each subject. At each of these visits, the subject will inhale from either the DPI or the MDI. Assignment of subjects to one of six (6) unique sequences of treatment will be according to a randomized scheme. The subject will inhale albuterol either once from the DPI (90mcg), twice from the DPI (180mcg) and twice from the MDI (180mcg). Following inhalation of the study drug, there will be a series of assessments taken at times postdose with spirometry (FEV1) measured up to 2 hours postdose, vital signs measured up to 10 hours post dose, ECGs obtained up to 5 hours postdose, blood taken to measure potassium and glucose up to 6 hours postdose, and blood for pharmacokinetic evaluation obtained up to 10 hours postdose. A washout period of 60 to 192 hours will separate each of the 3 treatment visits. Following these visits, there will be a study concluding visit 3 to 10 days later.

Inclusion Criteria:Subjects are required to meet ALL of the following inclusion criteria to be eligible for enrollment in the study.

1. Has provided written informed consent
2. Speaks and understands the English language
3. Males or females 18 to 55 years of age (inclusive) at the Consent Visit
4. Nonsmoker or ex-smoker who has abstained from smoking for at least 1 year prior to the Consent Visit and who has a ≤ 15 pack/year history of lifetime cigarette use
5. Has no history of use of nicotine gum, nicotine patch, e-cigarettes/vaping preparations in the 3 months before the Consent Visit
6. Has a body mass index (BMI) of 18.5 to 35.0 (calculated as kg/m2)
7. Has never had a diagnosis of asthma, exercise-induced bronchospasm, chronic obstructive pulmonary disease, or other chronic respiratory disease or chronic upper airway condition (seasonal or perennial allergic rhinitis is not exclusionary; however, nasal polypectomy within the 12 months prior to the Screening Visit is exclusionary
8. Has a FEV1 ≥ 80% of predicted normal for age, gender, height and ethnicity (percent of predicted normal values for FEV1 will be calculated using National Health and Nutrition Examination Survey III [NHANES III]) calculation at the Screening Visit
9. Has a FEV1/FVC ratio ≥ 0.70 at the Screening Visit
10. Ability to maintain a peak inspiratory flow rate of at least 60 L/min measured by the In-check DIAL device at the medium resistance setting.
11. At the Screening Visit, demonstrates adequate understanding of and ability to successfully inhale from an MDI as determined by the investigator and through demonstrated successful use of the Vitalograph® aerosol inhalation monitor (AIM™) (training/validation device for MDI) using a placebo MDI canister.

[Note: potential subjects who cannot demonstrate successful MDI technique using with the AIM device (with placebo canister) after in-clinic training at the Screening Visit will not be eligible for continued participation in the study.] 12. At the Screening Visit, demonstrates adequate understanding of and ability to successfully inhale when using the Halix™ UDDI [Note: a placebo UDDI not containing any drug powder will be supplied for each potential subject to become familiar with the inhaler and practice inhalation technique] [Note: potential subjects who cannot demonstrate successful inhalation technique using the Halix™ UDDI after in-clinic training at the Screening Visit will not be eligible for continued participation in the study].

13. Willing and able to comply with all aspects of the study protocol including avoiding use of certain concomitant medications and attending the required clinic visits (ie, has no conflicting plans that would prohibit attendance at scheduled study visits including each of the threeTreatment Day Visits)

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Exclusion Criteria:Subjects will be excluded from participation in the study if ANY of the following criteria are present:

1. Female subjects of childbearing potential (CBP) who are not using reliable contraception (eg, abstinence, double barrier method, oral/implantable/transdermal contraception, Depo-Provera, intrauterine device); a woman is of CBP unless she is premenarchal, is at least 2 years postmenopausal, is without a uterus and/or both ovaries, has had a bilateral tubal ligation, or has undergone the Essure procedure with confirmation of tubal blockage.

   [Note: If a female is identified as less than 2 years postmenopausal, a serum follicle-stimulating hormone (FSH) determination will be performed as a part of screening laboratory assessments. If a FSH result of < 40 mIU/mL is obtained, the female will be determined to be of CBP and her unwillingness to use reliable contraception as defined above will be exclusionary for the study.]

2. A woman who is pregnant (has a positive serum pregnancy test at Screening), is lactating, or is likely/planning to become pregnant during the study

3. Vital signs at the Screening Visit (after at least 2 minutes seated at rest) showing SBP either < 80 mmHg or >150 mmHg; DBP > 90 mmHg; or HR either < 40 bpm or > 100 bpm (vital signs outside these criteria may be repeated once after an additional seated rest period of at least 2 minutes- if vital signs exclusion criteria are not met after the repeat measurements of SBP, DBP, or HR, screening may continue)

4. Emergency room visit or hospitalization for any acute respiratory condition in the 3 months prior to the Screening Visit

5. Currently receiving pharmacologic treatment for diabetes or hypertension

6. History of any acute or chronic hepatobiliary disorder or documented elevation of alanine transaminase (ALT) or aspartate transaminase (AST) 2 or more times the upper limit of the normal (ULN) laboratory reference range in the 12 months prior to the Consent Visit,

7. Clinical laboratory results (after ≥4 hours fasting) at the Screening Visit that show any one or more of the following:

   • hemoglobin < 13.5 g/dL in male subjects; < 12 g/dL in female subjects
   • hematocrit < 38 % in male subjects; <35% in female subjects
   • total white blood cell count (WBC) < 2500 cells/mm3
   • platelet count < 150,000 cells/mm3
   • serum glucose < 80 mg/dL or > 120 mg/dL
   • serum potassium < 3.5 mmol/L or > 5.2 mmol/L
   • ALT or AST > 2.0 times ULN
   • alkaline phosphatase (ALP) > 1.5 times ULN
   • serum creatinine > 1.5 times ULN
   • positive serum hCG (female subjects only)
   • positive serologic test for HBsAg, anti-HCV antibody, or HIV antibody
   • in the opinion of the investigator, a urinalysis result showing medically significant abnormality
   • positive urine drug screen [Exception: urine drug screen detects evidence of an authorized prescribed medication]
   • positive urine cotinine test

8. Presence of any uncontrolled (in the Investigator's medical opinion) systemic disease, including, but not limited to renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, or psychiatric disease

9. Electrocardiogram obtained at Screening Visit that shows medically significant abnormalities (e.g., left bundle branch block, frequent premature ventricular contractions, chronic atrial fibrillation, or QTc interval prolongation > 450 msec for males and > 470 msec for females)

10. Has a FEV1 < 80% of that predicted for age, gender, height, and ethnicity at the Screening Visit based on NHANES III calculation.

11. Has a FEV1 / FVC ratio < 0.70

12. Inability to maintain a peak inspiratory flow rate of 60 L/min or higher

13. Presence of a current condition (e.g., alcoholism [or consumption of substantial quantities of alcohol], drug abuse, or psychiatric condition) making it unlikely that the requirements of the subject's participation in the protocol will be met

14. History of allergic reaction (known hypersensitivity) to albuterol sulfate and/or lactose, in any formulation, or history of severe hypersensitivity to milk proteins

15. Current participation in a drug, drug/device or biologic investigational research study or participation in a drug, drug/device or biologic investigational research study within the 30 days prior to the Screening Visit

16. An elective surgical or medical procedure currently is planned or scheduled to be performed during the study (this excludes routine immunotherapy/desensitization procedures that are being performed on a regular schedule and have been unchanged for at least 3 months prior to the Screening Visit)

17. Presence of a clinically diagnosed upper respiratory tract infection within the 14 days prior to the Screening Visit

18. Has undergone nasal polypectomy within the 12 months prior to the Screening Visit

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