A Bioequivalence Pivotal Study of SYN010 HFA Inhaler and Symbicort® 160/4.5 in Healthy Volunteers Without Charcoal Block

A Single-Dose, Randomized, Open-Label, Two-Treatment, Three-Period, Three-Sequence, Three-Way Crossover, Partial Replicate, Oral BE Pivotal Study of SYN010 HFA 160/4.5 Inhaler and Symbicort® 160/4.5 in Healthy Volunteers Without Charcoal Block

The objective of this pivotal study is to evaluate the relative bioavailability of SYN010 HFA Inhaler and Symbicort 160/4.5μg in healthy volunteers without charcoal block.

A pivotal, single-dose, randomized, open-label, partial replicate, three-period, three-sequence, two-treatment, three-way crossover, comparative bioavailability study.

Ninety-nine, male and female volunteers, 20-45 years of age, with a body mass index (BMI) within 18.5-30.0 kg/m2, inclusive, will be enrolled. (The body weight should be over 50 kg, inclusive, respectively)

A single dose of 8 puffs (eq. to budesonide 1280 μg /formoterol fumarate dihydrate 36 μg) in each study period.

Inclusion Criteria:

1. Healthy male and female volunteers, aged 20-45, inclusive.

2. BMI that is within 18.5-30.0 kg/m², inclusive. (The body weight should be over 50 kg, inclusive, respectively)

3. Healthy or Non Clinical Significant, according to the medical history, Electrocardiography (ECG), Chest X-ray and physical examination as determined by the Principal Investigator/Sub-Investigator.

4. Systolic blood pressure between 90-139 mmHg, inclusive, and diastolic blood pressure between 50-90 mmHg, inclusive, and pulse rate between 50-100 bpm, inclusive and temperature between 35.0-37.4°C.

5. Clinical laboratory values within reference range or Non-Clinical Significance (NCS) judged by the Principal Investigator/Sub-Investigator.

6. Ability to comprehend and be informed of the nature of the study. Capable of giving written informed consent prior to receiving any study medication. Must be able to communicate effectively with clinic staff.

7. Ability to fast for at least 14 hours and to consume standard meals.

8. Availability to volunteer for the entire study duration and willing to adhere to all protocol requirements.

9. Agree not to have a tattoo or body piercing until the end of the study.

10. Female subjects must fulfill at least one of the following:

    1. Be surgically sterile for a minimum of 6 months;
    2. Post-menopausal for a minimum of 1 year;
    3. Agree to avoid pregnancy and use medically acceptable method of contraception from screening day until 30 days after study has ended (last study procedure). Medically acceptable methods of contraception include non-hormonal intrauterine device or double barrier method (condom with foam or vaginal spermicidal suppository, diaphragm with spermicide). Complete abstinence alone can be used as a method of contraception.

Exclusion Criteria:

1. Known history or presence of any clinically significant hepatic (e.g. active liver disease, hepatic impairment), renal/genitourinary (e.g. renal impairment), gastrointestinal, cardiovascular, cerebrovascular, pulmonary, endocrine (e.g. hypothyroidism), immunological, musculoskeletal (e.g. myopathy, rhabdomyolysis), neurological, psychiatric, dermatological or hematological disease or condition unless determined as not clinically significant by the Principal Investigator/Sub-Investigator.

2. Clinically significant history or presence of any clinically significant gastrointestinal pathology (e.g. chronic diarrhea, inflammatory bowel disease), unresolved gastrointestinal symptoms (e.g. diarrhea, vomiting), or other conditions known to interfere with the absorption, distribution, metabolism or excretion of the drug experienced within 7 days prior to first drug administration, as determined by the Principal Investigator/Sub- Investigator.

3. Presence of any clinically significant illness within 30 days prior to first dosing, as determined by the Principal Investigator/Sub-Investigator.

4. Presence of any significant physical or organ abnormality as determined by the Principal Investigator/Sub-Investigator.

5. A positive test result for any of the following: Human immunodeficiency virus (HIV), Hepatitis B surface antigen, Hepatitis C, drugs of abuse (amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine, tetrahydrocannabinol), breath alcohol test. Positive pregnancy test for female subjects.

6. Known history or presence of:

   1. Alcohol abuse or dependence within one year prior to first drug administration;
   2. Drug abuse or dependence;
   3. Hypersensitivity or idiosyncratic reaction to budesonide, formoterol fumarate dihydrate , its excipients, and/or related substances;
   4. Food allergies and/or presence of any dietary restrictions;
   5. Severe allergic reactions (e.g. anaphylactic reactions, angioedema).

7. Intolerance to and/or difficulty with blood sampling through venipuncture.

8. Abnormal diet patterns (for any reason) during the four weeks preceding the study, including fasting, high protein diets etc.

9. Individuals who have donated, in the days prior to first drug administration:

   1. Less than 250 mL of blood in the previous 60 days
   2. 300 mL or more in the previous 90 days

10. Donation of plasma by plasmapheresis within 7 days prior to first drug administration.

11. Individuals who have participated in another clinical trial and received an investigational drug within 30 days prior to first drug administration.

12. Consumption of food or beverages containing caffeine/methylxanthines, poppy seeds and/or alcohol within 48 hours before dosing and containing grapefruit and/or pomelo within 10 days prior to first drug administration.

13. Use of any prescription medication within 30 days prior to first drug administration.

14. Use of any over-the-counter medications (including oral multivitamins, herbal and/or dietary supplements) within 30 days prior to first drug administration (except for spermicidal/barrier contraceptive products).

15. Females taking oral or transdermal hormonal contraceptives within 30 days prior to first drug administration.

16. Females having used implanted, injected, intravaginal, or intrauterine hormonal contraceptive within 6 months prior to first drug administration.

17. Individuals having undergone any major surgery within 6 months prior to the start of the study, unless deemed otherwise by Principal Investigator/Sub-Investigator.

18. Known history of smoking or using tobacco products, nicotine products (patches, gum etc.) within 6 months prior to first drug administration.

19. Pregnant/lactating women.

20. Subjects will be given training to ensure that subjects are able to correctly use the investigational products in screening. The subjects who are unable to operate the investigational products proficiently will not be included in this study.