Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 60
Healthy volunteers: yes

Brief summary:
This study was designed to assess the bioequivalence between the test products (Albuterol Sulfate Inhalation Aerosol 108 mcg Per Actuation) and the reference products (Proair HFA \[Albuterol Sulfate\] Inhalation Aerosol 90 mcg Per Actuation) in healthy volunteers under fasting conditions. The test product was considered bioequivalent to the reference product if the T/R ln-transformed AUC(0-t), AUC(0-inf), and Cmax were within 80.00-125.00% of those of the reference.

Detailed description:
A single-dose, randomized, open-label, two-period, two-sequence, two-treatment, single-centre, crossover bioequivalence study was carried out under fasting conditions in healthy adults, aged 20-60 years. For each period, each subject received a single dose as equivalent to 180 mcg of albuterol of the study drugs according to the pre-determined randomization scheme. Each subject was drawn 22 times over the period of 24 hours. Plasma samples were collected and analyzed for albuterol concentrations by using LC-MS/MS. For each subject, there were 2 dosing periods separated by a 14-day washout period. During the study, standardized meals were provided to all subjects while institutionalized.

Arms:
arm 1: Albuterol Sulfate inhalation aerosol arm 2: Proair HFA (albuterol sulfate) Inhalation Aerosol

Interventions: intervention 1: Albuterol Sulfate inhalation aerosol 108mcg per actuation intervention 2: Proair HFA (albuterol sulfate) Inhalation Aerosol 90 mcg per actuation
Intervention descriptions: intervention 1: MDI, 2 puffs, single dose, fasting intervention 2: MDI, 2 puffs, single dose, fasting

Protocol document:
Prot_000.pdf: 
 
 
Official Title: 
A Randomized, Single-dose, Open-label, Two-way Crossover Pivotal 
Study to Assess the Bioequivalence between Albuterol Sulfate 
inhalation aerosol 108mcg per actuation (MDI, eq. to albuterol 
90mcg/puff) and Proair HFA (albuterol sulfate) Inhalation Aerosol 90 
mcg per actuation (MDI, eq. to albuterol 90mcg/puff) in Healthy 
Volunteers under Fasting Conditions 
 
NCT Number: 
NCT04803734 
 
Document Date: 
Protocol Version 2.0: May-02-2021 
 
 
 
 
 


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Clinical Study Protocol 
Protocol No.: TW20-4502 
Version/Date: V2.0/ May-02-2021 
 
Page 1 of 42 
 
 
~CONFIDENTIAL~ 
 
 
1. 
TITLE PAGE 
 
 
 
A Randomized, Single-dose, Open-label, Two-way Crossover Pivotal Study to Assess the 
Bioequivalence between Albuterol Sulfate inhalation aerosol 108mcg per actuation (MDI, eq. 
to albuterol 90mcg/puff) and Proair HFA(albuterol sulfate) Inhalation Aerosol 90 mcg per 
actuation (MDI, eq. to albuterol 90mcg/puff) in Healthy Volunteers under Fasting Conditions 
 
Protocol No.: TW20-4502 
Protocol Version: 1.0 
Protocol Version Date: Jan-08-2021 
 
 
Sponsor 
Intech Biopharm Ltd.  
3F., No.36, Ln. 358, Ruiguang Rd., Neihu Dist., 
Taipei City 114, Taiwan  
Phone: +886-2-7721-8877 
Fax: +886-2-7721-8800 
Contract Research Organization 
Protech Pharmaservices Corporation 
11F., No.3, Park St., Nangang District, 
Taipei City 11503, Taiwan 
Phone: +886-2-5558-0000 
Fax: +886-2-5558-0055 
 
 
 
 
 
 
 
 
 
 
 
 
 


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~CONFIDENTIAL~ 
 
 
1.1 PROTOCOL REVISION CONTROL 
Version # (Version Date) 
Affected Sections 
1.0 (Jan-08-2021) 
N/A (New protocol) 
2.0 (May-02-2021) 
9.6 
 
1.2 AMENDMENT 
Version #  
(Version Date) 
Modifications 
2.0 (May-02-2021) 
Change the rule of echelons 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






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2. 
INVESTIGATORS AND FACILITIES 
2.1 FACILITIES 
Sponsor 
Intech Biopharm Ltd. 
3F., No.36, Ln. 358, Ruiguang Rd., Neihu Dist., Taipei City 114, Taiwan  
Phone: +886-2-7721-8877 
Fax: +886-2-7721-8800 
CRO 
Protech Pharmaservices Corporation 
11F., No.3, Park St., Nangang District, Taipei City 11503, Taiwan 
Phone: +886-2-5558-0000 
Fax: +886-2-5558-0055 
Clinical Facility 
Clinical Pharmacology Unit,Mackay Memorial Hospital  
No.45, Minsheng Rd., Tamshui District, New Taipei City 25160, Taiwan 
Phone: +886-2-2809-3000 
Fax: +886-2-2809-3082 
Clinical 
Laboratory 
Tamshui Mackay Memorial Hospital 
No. 45, Minsheng Rd., Tamshui District, New Taipei City 25160, Taiwan 
Phone: +886-2-2809-4661 
Fax: +886-2-2809-4679 
 
Protech Pharmaservices Corporation 
11F., No.3, Park St., Nangang District, Taipei City 11503, Taiwan 
Phone: +886-2-5558-0000 
Fax: +886-2-5558-0055 
 
or any other certified lab in case of emergency 
Bioanalytical 
Laboratory 
Protech Pharmaservices Corporation 
11F., No.3, Park St., Nangang District, Taipei City 11503, Taiwan 
Phone: +886-2-5558-0000 
Fax: +886-2-5558-0055 
Pharmacokinetic/ 
Statistical 
Facility 
Protech Pharmaservices Corporation 
11F., No.3, Park St., Nangang District, Taipei City 11503, Taiwan 
Phone: +886-2-5558-0000 
Fax: +886-2-5558-0055 
Institutional 
Mackay Memorial Hospital Institutional Review Board (MMHIRB) 


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Review Board 
(IRB) 
8F, No. 92, Sec. 2, Zhongshan N. Rd., Zhongshan District, Taipei City 
10449, Taiwan 
Phone: +886-2-2543-3535 
Fax: +886-2-2521-9529 
 
2.2 INVESTIGATORS AND PARTICIPANTS 
Name 
Affiliation / Address 
Responsibility 
 M.D. 
 
Tamshui Mackay Memorial Hospital 
No.45, Minsheng Rd., Tamshui District, New 
Taipei City 25160, Taiwan 
Principal Investigator 
 
 M.D.  
 
Tamshui Mackay Memorial Hospital  
No.45, Minsheng Rd., Tamshui District, New 
Taipei City 25160, Taiwan 
Sub-Investigator 
, M.D. 
 
Tamshui Mackay Memorial Hospital  
No.45, Minsheng Rd., Tamshui District, New 
Taipei City 25160, Taiwan 
Sub-Investigator 
 M.D.  
 
Tamshui Mackay Memorial Hospital  
No.45, Minsheng Rd., Tamshui District, New 
Taipei City 25160, Taiwan 
Sub-Investigator 
 M.S. 
 
Protech Pharmaservices Corporation 
11F., No.3, Park St., Nangang District, Taipei 
City 11503, Taiwan 
Pharmacokineticist 
 Ph.D.  
 
Protech Pharmaservices Corporation 
11F., No.3, Park St., Nangang District, Taipei 
City 11503, Taiwan 
Pharmacokineticist 
 
 
 
 
 
 


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3. 
SYNOPSIS 
Protocol Title 
A Randomized, Single-dose, Open-label, Two-way Crossover 
Pivotal Study to Assess the Bioequivalence between Albuterol 
Sulfate inhalation aerosol 108mcg per actuation (MDI, eq. to 
albuterol 90mcg/puff) and Proair HFA(albuterol sulfate) Inhalation 
Aerosol 90 mcg per actuation (MDI, eq. to albuterol 90mcg/puff) 
in Healthy Volunteers under Fasting Conditions. 
Objective 
The objective of this study is to evaluate the bioequivalence 
between two formulations of MDI, eq. to albuterol 90mcg/puff in 
healthy volunteers under fasting conditions. 
Study Design and Study 
Population 
A single-dose, randomized, open-label, two-period, two-sequence, 
two-treatment, two-way crossover, bioequivalence pivotal study.  
 
Sixty healthy volunteers, 20-60 years of age, inclusive, with a 
body mass index (BMI) within 18.0-30.0 kg/m2, inclusive, will be 
randomized.  
Test Drug (T) 
Albuterol Sulfate inhalation aerosol 108mcg per actuation 
(equivalent to 90mcg of Albuterol) 
Reference Drug (R) 
Proair HFA(albuterol sulfate) Inhalation Aerosol 90 mcg per 
actuation 
Treatment 
A single dose of albuterol inhalation aerosol (2 puffs) in each 
period. 
Duration of Confinement 
For each period, subject will be confined from at least 10.5 hours 
prior to dosing until at least 24-hours post-dose, for a total of at 
least 34.5 hours. 
Washout 
At least 14 days between each dosing. 
Safety Monitoring  
 
Vital signs (blood pressure [BP], pulse rate [PR] and body 
temperature) will be obtained at pre-dose and at 0.5, 16 and 
24 hours after dosing in each study period. 
 
The Investigator will be present from approximately 30 
minutes prior to dosing until 4 hours after dosing in each 
study period. The Investigator will remain on-call throughout 
the duration of the study. 


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Blood Sampling 
Time-points 
Blood samples will be collected at 0-hour (pre-dose), and at 2, 5, 
10, 15, 20, 30, 45 minutes, and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 4, 
6, 8, 12, 16 and 24 hours post-dose (a total of 22 sampling points) 
after dosing in each study period for analysis. 
Total Blood Volume 
Approximately 328 ml of blood, including 20 ml for pre- and post- 
study procedures and 308 ml for pharmacokinetic analysis. 
Analyte(s) to be Measured 
Plasma samples will be assayed for albuterol using a validated 
analytical method according to the principles of FDA GLP Title 21 
Part 58.  
Statistical Analysis 
For albuterol analysis of variance (ANOVA) for log-transformed 
AUC0-t, AUC0- and Cmax, and untransformed Tmax, kel and T1/2. 
Tmax will be analyzed using an additional non-parametric test 
(Wilcoxon test). The 90% confidence intervals (CI) for the 
Test/Reference ratios of geometric means for AUC0-t, AUC0- and 
Cmax will be calculated based on the least square means 
(LSMEANS) and ESTIMATE of the ANOVA. 
Bioequivalence Criteria 
To establish bioequivalence, the calculated 90% CI for the ratio of 
geometric means for AUC0-t, AUC0- and Cmax for albuterol should 
fall within 80.00%-125.00%. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4. 
LIST OF ABBREVIATIONS 
AE 
Adverse Event(s) 
AMP 
Adenosine monophosphate 
ANOVA 
Analysis of variance 
AUC0-t 
Area under the plasma concentration-time curve from zero to last concentration time 
AUC0- 
Area under the plasma concentration-time curve extrapolated to infinity 
BLQ 
Below the lower limit of quantitation 
BMI 
Body Mass Index 
BP 
Blood Pressure 
bpm 
Beats per minute 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
Cmax 
Maximum plasma concentrations 
COPD 
Chronic obstructive pulmonary disease 
CRO 
Contract Research Organization 
CV 
Coefficient of variability 
CYP 
Cytochrome P450 
ECG 
Electrocardiogram 
eq. 
Equivlent to  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
-GT 
Gamma-Glutamyl-Transpeptidase 
h or hr 
Hour(s) 
HBsAg 
Hepatitis B Surface Antigen 
hCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form(s) 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
kel(λ) 
Plasma elimination rate constant determined by simple linear regression 


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based on the terminal phase of plasma concentration 
Max 
Maximum 
MDI 
Metered-Dose Inhaler 
Mean 
Arithmetic mean 
mg 
Milligram(s) 
Min 
Minimum(s) 
ml  
Milliliter(s) 
mmHg 
Millimeters of Mercury 
MMHIRB 
Mackay Memorial Hospital Institutional Review Board 
MRT 
Mean residence time 
N/A 
Not applicable 
pH 
Negative log hydrogen ion concentration 
PK 
Pharmacokinetic(s) 
PPC 
Protech Pharmaservices Corporation 
PR 
Pulse Rate 
PTE 
Pretreatment event 
R 
Reference or Reference drug(s) 
RBC 
Red Blood Cell 
RLD 
Reference Listed Drug 
SAE 
Serious Adverse Event(s) 
SAS® 
Statistical Analysis System 
SD 
Standard deviation 
SGOT 
Serum Glutamic Oxaloacetic Transaminase (same as AST) 
SGPT 
Serum Glutamic Pyruvic Transaminase (same as ALT) 
SOP 
Standard Operating Procedure(s) 
T 
Test or Test drug 
T1/2 
Half-life 
TFDA 
Taiwan Food and Drug Administration 
TG 
Triglycerides 
Tmax 
Time to reach maximum plasma concentrations 
WBC 
White Blood Cell 


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~CONFIDENTIAL~ 
 
 
5. 
TABLE OF CONTENT 
1. 
TITLE PAGE ................................................................................................................ 1 
1.1 
PROTOCOL REVISION CONTROL .......................................................................... 2 
1.2 
AMENDMENT ............................................................................................................ 2 
1.3 
PROTOCOL APPROVAL/SIGNATURE PAGE-SPONSOR ...................................... 3 
1.4 
PROTOCOL APPROVAL/SIGNATURE PAGE-PRINCIPLE INVESTIGATOR ...... 4 
2. 
INVESTIGATORS AND FACILITIES ....................................................................... 5 
2.1 
FACILITIES ................................................................................................................. 5 
2.2 
INVESTIGATORS AND PARTICIPANTS ................................................................. 6 
3. 
SYNOPSIS ................................................................................................................... 7 
4. 
LIST OF ABBREVIATIONS ....................................................................................... 9 
5. 
TABLE OF CONTENT .............................................................................................. 11 
6. 
BACKGROUND AND PHARMACOKINETICS[1] ................................................. 14 
6.1 
INDICATION AND USAGE ..................................................................................... 14 
6.2 
CLINICAL PHARMACOLOGY ............................................................................... 14 
6.3 
PHARMACOKINETICS ........................................................................................... 15 
6.4 
ADVERSE EVENTS ................................................................................................. 15 
6.5 
PREGNANCY CATEGORY ...................................................................................... 16 
7. 
STUDY OBJECTIVE AND RATIONALE ................................................................ 16 
7.1 
PRIMARY OBJECTIVE ............................................................................................ 16 
7.2 
SECONDARY OBJECTIVE ...................................................................................... 16 
8. 
STUDY DESIGN ....................................................................................................... 16 
8.1 
DISCUSSION OF STUDY DESIGN ......................................................................... 16 
8.2 
STUDY CONFINEMENT AND WASHOUT ........................................................... 17 
8.3 
RANDOMIZATION AND BLINDING ..................................................................... 17 
9. 
SUBJECT SELECTION ............................................................................................ 18 
9.1 
PRE-STUDY PROCEDURES ................................................................................... 18 
9.2 
CLINICAL LABORATORY ASSESSMENT ............................................................ 19 
9.3 
INCLUSION/EXCLUSION CRITERIA ................................................................... 20 
9.3.1 
INCLUSION CRITERIA .................................................................................... 20 
9.3.2 
EXCLUSION CRITERIA ................................................................................... 21 
9.4 
CONCOMITANT MEDICATIONS ........................................................................... 22 
9.5 
STUDY RESTRICTIONS .......................................................................................... 22 
9.6 
SAMPLE SIZE ........................................................................................................... 24 
9.7 
DROPOUT AND WITHDRAWAL/TERMINATION ............................................... 24 


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10. 
DRUG PRODUCTS ................................................................................................... 25 
10.1 
DRUG INFORMATION ............................................................................................ 25 
10.2 
LABELING, MAINTENANCE, AND RETENTION OF STUDY DRUGS ............ 25 
11. 
STUDY PROCEDURES ............................................................................................ 26 
11.1 
STUDY PERIOD CHECK-IN PROCEDURES ........................................................ 29 
11.2 
FOOD AND FLUID INTAKE ................................................................................... 29 
11.3 
VITAL SIGNS MEASUREMENTS .......................................................................... 30 
11.4 
CHEST X-RAY AND ECG MONITORING ............................................................. 30 
11.5 
ADDITIONAL TESTING .......................................................................................... 30 
11.6 
DOSING ..................................................................................................................... 31 
11.7 
PHYSICAL ACTIVITY ............................................................................................. 31 
11.8 
BLOOD SAMPLING SCHEDULE, SAMPLE COLLECTION, PROCESSING AND 
STORAGE .................................................................................................................. 31 
11.9 
HEALTHY STATUS MONITORING ........................................................................ 33 
11.10 
POST-STUDY TESTS ............................................................................................... 33 
11.11 
SAMPLE SHIPMENT ............................................................................................... 33 
12. 
ADVERSE EVENT ................................................................................................... 33 
12.1 
ADVERSE EVENT RECORDING AND FOLLOW-UP .......................................... 33 
12.2 
ASSESSING RELATIONSHIP TO STUDY DRUG ................................................. 34 
12.3 
PROCEDURES FOR REPORTING ADVERSE EVENTS....................................... 35 
12.4 
PREGNANCY REPORTING ..................................................................................... 36 
13. 
BIOANALYTICAL ANALYSIS ................................................................................ 36 
13.1 
ANALYTICAL PROCEDURES ................................................................................ 37 
13.1.1 
SAMPLES TO BE ASSAYED ............................................................................ 37 
13.1.2 
ANALYTE(S) IN BIOLOGICAL MATRIX ....................................................... 37 
14. 
PHARMACOKINETIC AND STATISTICAL ANALYSIS ...................................... 37 
14.1 
PHARMACOKINETIC ANALYSIS DATA SET ...................................................... 37 
14.2 
ANALYSIS OF DATA ............................................................................................... 37 
14.2.1 
PHARMACOKINETIC ANALYSIS .................................................................. 38 
14.2.2 
STATISTICAL ANALYSIS ................................................................................ 39 
14.2.3 
MISSING DATA ................................................................................................. 39 
14.3 
BIOEQUIVALENCE CRITERIA .............................................................................. 39 
15. 
ETHICAL CONSIDERATIONS ................................................................................ 40 
15.1 
BASIC PRINCIPLES ................................................................................................. 40 
15.2 
INSTITUTIONAL REVIEW BOARD ...................................................................... 40 


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15.3 
INFORMED CONSENT FORM ............................................................................... 40 
15.4 
REVISIONS AND/OR AMENDMENTS TO THE PROTOCOL ............................. 40 
15.5 
INVESTIGATOR RESPONSIBILITIES ................................................................... 41 
15.6 
STUDY COMPLETION/TERMINATION ................................................................ 41 
15.7 
SPONSOR VISITS ..................................................................................................... 41 
15.8 
CONFIDENTIALITY ................................................................................................ 41 
16. 
DATA MANAGEMENT/RECORD KEEPING ......................................................... 42 
16.1 
SOURCE DATA ......................................................................................................... 42 
16.2 
QUALITY OF DATA ................................................................................................. 42 
16.3 
RETENTION OF DOCUMENTS .............................................................................. 42 
17. 
REFERENCES ........................................................................................................... 42 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6. 
BACKGROUND AND PHARMACOKINETICS[1] 
6.1 INDICATION AND USAGE 
Bronchospasm 
Albuterol is indicated for the treatment or prevention of bronchospasm in patients 4 years of age and 
older with reversible obstructive airway disease.  
Exercise-Induced Bronchospasm 
Albuterol is indicated for the prevention of exercise-induced bronchospasm in patients 4 years of 
age and older.  
6.2 CLINICAL PHARMACOLOGY 
Albuterol sulfate is a beta2-adrenergic agonist. The pharmacologic effects of albuterol sulfate are 
attributable to activation of beta2-adrenergic receptors on airway smooth muscle. Activation of 
beta2-adrenergic receptors leads to the activation of adenylcyclase and to an increase in the 
intracellular concentration of cyclic-3′,5′-adenosine monophosphate (cyclic AMP). This increase of 
cyclic AMP is associated with the activation of protein kinase A, which in turn inhibits the 
phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in muscle 
relaxation. Albuterol relaxes the smooth muscle of all airways, from the trachea to the terminal 
bronchioles. Albuterol acts as a functional antagonist to relax the airway irrespective of the 
spasmogen involved, thus protecting against all bronchoconstrictor challenges. Increased cyclic 
AMP concentrations are also associated with the inhibition of release of mediators from mast cells in 
the airway. While it is recognized that beta2 adrenergic receptors are the predominant receptors on 
bronchial smooth muscle, data indicate that there are beta-receptors in the human heart, 10% to 50% 
of which are cardiac beta2-adrenergic receptors. The precise function of these receptors has not been 
established. 
Albuterol has been shown in most controlled clinical trials to have more effect on the respiratory 
tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses 
while producing fewer cardiovascular effects. However, inhaled albuterol, like other beta-adrenergic 
agonist drugs, can produce a significant cardiovascular effect in some patients, as measured by pulse 
rate, blood pressure, symptoms, and/or electrocardiographic changes.  


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6.3 PHARMACOKINETICS 
The systemic levels of albuterol are low after inhalation of recommended doses. In a crossover study 
conducted in healthy male and female volunteers, high cumulative doses of PROAIR HFA 
Inhalation Aerosol (1,080 mcg of albuterol base administered over one hour) yielded mean peak 
plasma concentrations (Cmax) and systemic exposure (AUCinf) of approximately 4,100 pg/mL and 
28,426 pg/mL*hr, respectively compared to approximately 3,900 pg/mL and 28,395 pg/mL*hr, 
respectively following the same dose of an active HFA-134a albuterol inhaler comparator. The 
terminal plasma half-life of albuterol delivered by PROAIR HFA Inhalation Aerosol was 
approximately 6 hours. Comparison of the pharmacokinetic parameters demonstrated no differences 
between the products.  
The pharmacokinetic profile of PROAIR HFA Inhalation Aerosol was evaluated in a two-way 
cross-over study in 11 healthy pediatric volunteers, 4 to 11 years of age. A single dose 
administration of PROAIR HFA Inhalation Aerosol (180 mcg albuterol base) yielded a least square 
mean (SE) Cmax and AUC0- of 1,100 (1.18) pg/mL and 5,120 (1.15) pg/mL*hr, respectively. The 
least square mean (SE) terminal plasma half-life of albuterol delivered by PROAIR HFA Inhalation 
Aerosol was 166 (7.8) minutes. 
Information available in the published literature suggests that the primary enzyme responsible for 
the metabolism of albuterol in humans is SULTIA3 (sulfotransferase). When racemic albuterol was 
administered either intravenously or via inhalation after oral charcoal administration, there was a 3- 
to 4-fold difference in the area under the concentration-time curves between the (R)- and (S) 
albuterol enantiomers, with (S)-albuterol concentrations being consistently higher. However, 
without charcoal pretreatment, after either oral or inhalation administration the differences were 8- 
to 24-fold, suggesting that the (R)-albuterol is preferentially metabolized in the gastrointestinal tract, 
presumably by SULTIA3. 
The primary route of elimination of albuterol is through renal excretion (80% to 100%) of either the 
parent compound or the primary metabolite. Less than 20% of the drug is detected in the feces. 
Following intravenous administration of racemic albuterol, between 25% and 46% of the 
(R)-albuterol fraction of the dose was excreted as unchanged (R)-albuterol in the urine. 
6.4 ADVERSE EVENTS 
Because clinical trials are conducted under widely varying conditions, adverse reaction rates 
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of 
another drug and may not reflect the rates observed in practice. The adverse reaction information 
from clinical trials does, however, provide a basis for identifying the AE that appear to be related to 


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drug use and for approximating the incidence. There is a chance that in this clinical trial, new, 
unexpected adverse events may occur. 
Most common adverse reactions (incidence ≥ 3%) are: Asthma: nasopharyngitis, headache, upper 
respiratory tract infection, pharygolaryngeal pain, sinusitis, influenza, back pain, nasal congestion, 
stomach discomfort, vomiting, and oral candidiasis. COPD: nasopharyngitis, oral candidiasis, 
bronchitis, sinusitis, upper respiratory tract infections. 
6.5 PREGNANCY CATEGORY 
Pregnancy Category C 
7. 
STUDY OBJECTIVE AND RATIONALE 
The objective of this study is to evaluate PK profile of the test product of Albuterol Sulfate 
inhalation aerosol 108mcg per actuation (equivalent to 90mcg of Albuterol base) and to determine 
its bioequivalence to the RLD in healthy volunteers under fasting conditions.  
7.1 PRIMARY OBJECTIVE 
This study is designed to assess the bioequivalence of the test product and the reference products 
under fasting conditions. Test product will be considered bioequivalent to reference product if the 
T/R ln-transformed AUC0-t, AUC0- and Cmax are within 80.00-125.00% of those of the reference. 
7.2 SECONDARY OBJECTIVE  
The other PK-variables will be assessed for descriptive purposes. As for safety parameters, AE and 
vital signs (BP, PR and body temperature) will be recorded. 
8. 
STUDY DESIGN 
8.1 DISCUSSION OF STUDY DESIGN 
This pivotal study will be conducted by a way of single-dose, randomized, open-label, two-period, 
two-sequence, two-treatment, single-centre, two-way crossover design to examine the 
bioequivalence of Albuterol Sulfate inhalation aerosol 108mcg per actuation (equivalent to 90mcg 
of Albuterol base) (MDI, eq. to albuterol 90mcg/puff) [Test, T] and Proair HFA(albuterol sulfate) 
Inhalation Aerosol 90 mcg per actuation (MDI, eq. to albuterol 90mcg/puff) [Reference, R]. The 
investigational drugs will be studied using a crossover design with 60 healthy volunteers being 
administered a single dose as equivalent to 180 mcg of albuterol under fasting conditions. Each 


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subject will be drawn at 0-hour (sampling before dosing as baseline), and at 2, 5, 10, 15, 20, 30, 45 
minutes, and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 4, 6, 8, 12, 16 and 24 hours post-dose in each study 
period. Blood samples will be collected and analyzed for albuterol concentrations by using 
LC-MS/MS 
Subjects who meet the eligibility criteria will be randomly assigned to receive the study drugs 
according to the two-treatment, two-period, two-sequence randomization scheme (T-R or R-T). The 
randomization scheme will be generated by using SAS® version 9.2 or higher prior to first dosing 
period. For example: if subjects are randomized to the T-R sequence, they will receive the test 
product in Period 1, and then, following at least 14-day washout period, receive the reference 
product in Period 2. 
At least 14-day was estimated to be adequate to avoid carry-over effects of the preceding treatments. 
The trial will be performed as an open-label study as the PK profile should not be expected to be 
affected by having the knowledge of which study drug was administered. Blinding of the 
Investigator/clinical staff and subjects is not considered necessary. 
8.2 STUDY CONFINEMENT AND WASHOUT 
Subjects will be confined to the clinic site from at least 10.5 hours prior to dosing until at least 
24-hours post-dose, for a total of at least 34.5 hours for each study period. This study will consist of 
two study periods with one washout period of at least 14 days between each dosing. 
8.3 RANDOMIZATION AND BLINDING 
In this study, the assignment of treatment groups, known as the randomization scheme will be 
generated by a computer program, writer and run in SAS® Version 9.2 or higher at PPC to produce a 
balanced (if possible) random allocation of subjects into treatment sequences. Subjects will be 
assigned consecutive subject numbers in an ascending order. This number will identify the subject 
and determine the treatment sequence the subject will undergo. Treatment assignment will be 
described in the randomization scheme. 
Subjects who meet the eligibility criteria will be randomly assigned to receive the study drugs 
according to the randomization schedule prior to dosing of period 1. Subjects will be assigned 
consecutive subject numbers in an ascending order. After randomization, any subjects withdrew due 
to any reason will not be replaced. 
This is an open-label study and subjects as well as clinical staff will not be blinded to the 


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randomization. The analytical laboratory will not have access to the randomization scheme until the 
bioanalytical analysis is complete. Subjects will be randomized equally into one of the following 
two sequence groups:  
 
Period 1 
Washout 
Period 2 
Sequence 1 
T 
≥ 14 days 
R 
Sequence 2 
R 
T 
Each subject is scheduled to receive a total of two treatments by the end of the study. 
9. 
SUBJECT SELECTION 
9.1 PRE-STUDY PROCEDURES 
The following screening procedures will be conducted on each potential subject: 
 
Obtain written informed consent for screening.  
 
Record medical/medication history and demographic information based on the interview with 
the potential subject.  
 
Review of inclusion/exclusion criteria for each potential subject.  
 
Obtain height and body weight to calculate BMI.  
 
Obtain vital signs (seated BP, PR as well as temperature). 
 
Perform electrocardiogram (ECG) and chest X-ray. (The results of ECG and chest X-ray within 
previous 30 days will be accepted for evaluation.) 
 
Collect blood and urine samples for hematology, biochemistry, serology, urinalysis, screening 
for drugs of abuse. Perform breath alcohol test. Pregnancy test will be performed only for 
female subjects. For a complete listing of all tests to be performed, please refer to Section 9.2 
Assessment. (The results of laboratory test within previous 30 days will be accepted for 
evaluation.) 
 
Perform a physical examination.  
 
Principal Investigator’s/Sub-Investigator’s review of inclusion/exclusion criteria and all 
screening results/data to assess eligibility of each potential subject. 
Screening procedures will be conducted within thirty (30) days prior to dosing in Period 1 (Day -30 
to Day -1). 


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9.2 CLINICAL LABORATORY ASSESSMENT 
TYPE OF TEST 
COMPONENTS 
Hematology 
 Hemoglobin 
 Hematocrit 
 RBC count 
 Platelet count  
 WBC and differential  
Biochemistry 
 Total protein 
 γ-GT 
 SGOT 
 SGPT 
 Albumin 
 Creatinine 
 Glucose 
 BUN 
 TG 
 Uric Acid 
 Total cholesterol 
 Alkaline Phosphatase 
 Total Bilirubin 
Urinalysis 
 Urine Bilirubin 
 Occult blood  
 Glucose 
 pH  
 Ketone body 
 Leukocytes 
 Urobilinogen 
 Protein 
 Specific gravity 
 Nitrite 
Urine Tests for 
Drugs of Abuseα 
 Amphetamines 
 Barbiturates 
 Benzodiazepines 
 Cocaine 
 Opiates 
 Phencyclidine 
 Tetrahydrocannabinol 
Other Tests 
 Breath alcohol testα 
 Pregnancy testβ 
Serologyγ 
 Anti-HIV 
 HBsAg 
 Anti-HCV 
α Urine tests for drugs of abuse and breath alcohol tests will be performed at screening and check-in of each period. 
β For females, serum hCG will be performed only at screening. Urine hCG will be performed at check in of each period 
and post examination.  
γ Serology test will only be performed at screening 
 
 


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9.3 INCLUSION/EXCLUSION CRITERIA 
9.3.1 INCLUSION CRITERIA 
Potential subjects meeting all of the following criteria may be included in the study: 
1. 
Healthy male and female volunteers, aged 20-60, inclusive.  
2. 
BMI of 18.0-30.0 kg/m², inclusiv e. The body weight should be over 50 kg, inclusive. (BMI will 
be calculated as weight in kilogram [kg]/height in meters2 [m2]). 
3. 
Healthy or Non Clinical Significant, according to the medical history, 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℃. 
5. 
Screening laboratory values within reference range or NCS as determined by the Principal 
Investigator/Sub-Investigator. 
6. 
Ability to comprehend and be informed of the nature of the study, as assessed by clinical staff. 
Capable of giving written informed consent prior to receiving any study medication. Must be 
able to communicate effectively with clinical staff. 
7. 
Willing 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, body piercing, or any invasive procedure and blood donation until 
the end of the study. 
10. Never-smokers; or former smokers who have smoked ≥ 100 cigarettes in their lifetime and 
have not consumed any tobacco or tobacco containing products for at least 12 months prior to 
screening. 
11. Subjects who are non-asthmatic, defined as no clinical history of asthma, allergy or atopy. 
12. Able to perform special breathing using nebulizer correctly as per the required standard.  
13. Subjects must fulfill at least one of the following:  
 
Be surgically sterile for a minimum of 6 months;  
 
Post-menopausal for a minimum of 1 year;  
 
Agree to avoid pregnancy and use medically acceptable method of contraception from 
screening day until 30 days after the study ends (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. 


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9.3.2 EXCLUSION CRITERIA 
Potential subjects meeting any of the following criteria will be excluded: 
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, hematological 
disease, or any other medical conditions, unless determined as not clinically significant by the 
Principal Investigator/Sub-Investigator.  
2. Presence of any clinically significant illness within 30 days prior to first dosing, as determined 
by the Principal Investigator/Sub-Investigator.  
3. Presence of any significant physical or organ abnormality as determined by the Principal 
Investigator/Sub-Investigator.  
4. A positive test result for any of the following: 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. 
5. Known history or presence of:  
 Alcohol abuse within one year prior to first drug administration; 
 Drug abuse or dependence; 
 Hypersensitivity or idiosyncratic reaction to albuterol, its excipients, and/or related 
substances; 
 Allergy to standardized meal provided by site and/or presence of any dietary restrictions; 
6. Intolerance to and/or difficulty in blood sampling through venipuncture. 
7. Abnormal diet patterns (for any reason) during the 4 weeks preceding the study, including 
fasting, high protein diets etc.  
8. Except for screening procedures, blood donation that results in blood loss of not more than 250 
ml in the past 2 months prior to first dosing; blood loss of more than 250 ml within 3 months 
prior to first dosing. 
9. Donation of plasma by plasmapheresis within 7 days prior to first drug administration.  
10. Individuals who receives an investigational drug from 2 months prior to first drug 
administration. 
11. Consumption of products containing caffeine/methylxanthines, poppy seeds and/or alcohol 
within 48 hours before dosing and products containing grapefruit and/or pomelo (shown to 
inhibit cytochrome P450 [CYP] 3A4 activity) within 10 days prior to first drug administration.  
12. Use of any medication, including oral multivitamins, herbal and/or dietary supplements within 
30 days prior to first drug administration (except topical agents without systemic absorption as 


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determined by the Principal Investigator/Sub-Investigator). 
13. Females taking oral or transdermal hormonal contraceptives within 30 days prior to first drug 
administration.  
14. Females having used implanted, injected, intravaginal, or intrauterine hormonal contraceptive 
within 6 months prior to first drug administration. 
15. Individuals having undergone any major surgery within 6 months prior to the start of the study, 
unless deemed otherwise by Principal Investigator/Sub-Investigator. 
16. Using tobacco products, nicotine products (patches, gum etc.) within 6 months prior to first 
drug administration. 
17. Lactating women. 
9.4 CONCOMITANT MEDICATIONS 
Any concomitant medication (prescription or over-the-counter, except for spermicidal/barrier 
contraceptive products), any herbal and/or dietary supplements will not be permitted during the 
study unless deemed otherwise by the Principal Investigator/Sub-Investigator.  
Each case where concomitant medication or herbal/dietary supplement is used during the restriction 
period will be reported as soon as possible to the PPC Pharmacokineticist and/or the Sponsor and 
will be reviewed on a case by case basis to determine the subject’s further participation in the study. 
9.5 STUDY RESTRICTIONS 
If any subject does not comply with these restrictions, at any time prior to or during the study, 
continued participation will be re-assessed by the Principal Investigator/Sub-Investigator, PPC 
Pharmacokineticist and/or the Sponsor. 
If drug therapy other than those specified in the protocol is required during the study, the decision 
whether to continue or discontinue the subject’s participation in the study will be made by the 
Principal Investigator/Sub-Investigator, Pharmacokineticist, and/or the Sponsor. 
Concomitant drug or non-drug treatment administered to subjects as per instructions from physicians 
for treatment of any AE (as required) will be permitted. Clinical staff will provide the subjects with 
the treatment (e.g. medication, fluids) and will document all substances given outside of the protocol 
specified requirements. All cases of concomitant medication or herbal/dietary supplement 
administration will be reported as soon as possible to the PPC Pharmacokineticist and/or the 
Sponsor and will be reviewed on a case by case basis to determine the subject’s further participation 
in the study. 


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Restriction Period 
Item Restricted 
Examples 
6 months prior to first drug 
administration until the last blood 
draw in the final study period 
Smoke or use tobacco 
products, nicotine products 
(patches, gum etc.) 
Females: implanted, injected, 
intravaginal, or intrauterine 
hormonal contraceptive 
 
30 days prior to first drug 
administration until the last blood 
draw in the final study period 
Prescription medication, 
vaccination 
Prescription pills, topical 
systemic creams, 
inhalants, sprays 
Over-the-counter medication, 
dietary and/or herbal 
supplements 
Acetaminophen, St. 
John´s Wort, Ricola, oral 
multivitamins 
Oral or transdermal hormonal 
contraceptives 
 
Note: Spermicidal/barrier 
contraceptive products may be 
permitted. 
 
10 days prior to first drug 
administration until the last blood 
draw in the final study period 
Products containing grapefruit 
and/or pomelo (shown to 
inhibit cytochrome P450 
[CYP] 3A4 activity)  
Grapefruit, grapefruit 
juice, grapefruit candies, 
pomelo, etc. 
48 
hours 
prior 
to 
drug 
administration until after the last 
blood draw in each study period 
Products containing poppy 
seeds, caffeine/ 
methylxanthines 
Coffee, tea, chocolate, 
caffeine-containing soft 
drinks (e.g. Coke, Pepsi, 
Red Bull) 
Alcohol of any kind 
Wine, beer, liquor, 
cocktails 
Subject should avoid driving a car or operating dangerous machinery after dosing until the last blood 
draw in each study period. The subjects will be advised to use contraceptive methods from at least 
screening day until 30 days after study has ended (last study procedure). The subjects will be 
advised to avoid any strenuous exercises within 48 hours before the first administration of the first 
study period until the final examination. Using tobacco or nicotine products, having a tattoo or body 
piercing, any invasive procedure, and blood donation will be prohibited during the study. 


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9.6 SAMPLE SIZE 
For the pivotal study, a sufficient number of healthy adults will be screened with volunteer’s consent 
and 60 subjects will be randomized under fasting conditions. 
When possible, subjects will be enrolled in three echelons for all the planned number of subjects. If 
the capability/capacity of the clinical study facility is limited during the enrollment, the planned 
subjects may be split into 3 or more echelons with minimal 18 subjects in each echelon. If the 
minimal subject number per echelon fails to meet the requirement, it is acceptable to split 
more echelons to achieve the designated sample size, as specified in the protocol. In the 
circumstance the subjects are enrolled in split groups, statistical analysis will NOT be carried out 
before all the planned subjects have completed the study. Details for considerations of potential 
group effects will be stipulated separately in the statistical analysis plan. 
9.7 DROPOUT AND WITHDRAWAL/TERMINATION 
After administration, dropouts should not be replaced for any reason. 
The following circumstances may lead to discontinuation of the study by an individual subject who 
will then be recorded as a drop-out: 
- 
Withdrawal at any time for any reason 
- 
AE necessitating withdrawal from the study 
- 
Circumstances in which the health of the subject would be endangered upon continued 
participation in the study 
- 
Protocol violation which could jeopardize the conduct of the study as judged by principal 
investigator  
- 
For female with positive pregnancy test prior dosing 
- 
Incorrect use of investigational product while dosing (e.g. any leak of investigational product 
from mouth while dosing) 
Removal of a subject from the study will only be permitted prior to commencement of bioanalysis. 
If a subject’s participation is terminated prematurely, the cause for the early termination date and 
time of the termination will be documented on the source documents and in the final study report. 
Withdrawn and dismissed subjects are not required to adhere to the study specific procedures (e.g. 
food and fluid restrictions, sample collections). If withdrawn or dismissed after drug administration, 
these subjects will be asked to adhere to the study restrictions in regards to the safety, prescription 
medication, over-the-counter medication, dietary and/or herbal supplements for the expected 


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duration of the restrictions relevant to the study period which the subject withdraws or is dismissed 
from (that period will be the subject’s last study period). Subjects will be asked to adhere to the 
requirements of not becoming pregnant and using a medically acceptable method of contraception 
for 30 days after discontinuation in the study (if applicable). 
If a subject withdraws or is dismissed from the study, a post-study physical examination and 
post-study testing will be completed, where possible. 
10. DRUG PRODUCTS 
10.1 DRUG INFORMATION 
Treatment Code 
T 
R 
Drug Name: 
Albuterol Sulfate inhalation aerosol 
108mcg per actuation (equivalent to 
90mcg of Albuterol) 
Proair HFA(albuterol sulfate) 
Inhalation Aerosol 90 mcg per 
actuation 
Active ingredient: 
Albuterol sulfate 
Albuterol sulfate 
Strength: 
eq. to albuterol 90mcg/puff 
eq. to albuterol 90mcg/puff 
Dosage Form: 
MDI 
MDI 
Manufactured by: 
Intech Biopharm Ltd. 
IVAX Pharmaceuticals Ireland 
Waterford, Ireland 
Dose: 
Single dosing, 180mcg (2 puffs) 
Single dosing, 180mcg (2 puffs) 
Mode of 
administration: 
Inhalation 
Inhalation 
Batch Number 
ALMB040 
DAE50A 
 
10.2 LABELING, MAINTENANCE, AND RETENTION OF STUDY DRUGS 
The Sponsor will supply a sufficient quantity of the study formulation(s) to allow completion of this 
study. Records will be made of receipt and dispensing of study drugs supplied and will be 
maintained by the Pharmacy staff. It is the responsibility of the Sponsor to ensure that all drug 
supplies provided for the study are manufactured under current Good Manufacturing Practices and 


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are suitable for human use.  
The pharmacist will randomly select the boxes or bottles or containers to be used in the study. An 
inventory record of the drugs received and dispensed will be maintained by the Pharmacy staff. Each 
investigational study drug will be tagged with a statement indicating that the drug is an 
investigational drug to be used only by a Qualified Investigator as well as, Drug Name, Protocol 
Number, Strength, Sponsor’s Name, the recommended storage conditions for the drug, Expiry Date 
(when available) and Lot/Batch Number. Study drugs will be locked in a temperature controlled 
room with restricted access. The study drugs will be prepared by pharmacy staff into individual 
unit-dose containers. Each unit-dose container will contain the Protocol Number, Period Number, 
Subject Number, Drug Name, Strength and Treatment Code. 
11. STUDY PROCEDURES 
Efficacy and Safety Measurements and Flow Chart 


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Procedure/Activity 
Screening 
Each Period 
Check-in 
Period 1 and 2 
Post study 
examinations 
ICF 
X 
 
 
 
Urine tests for drugs of abuse 
X 
X 
 
 
Breath alcohol test 
X 
X 
 
 
Medical History 
X 
 
 
 
Physical Exam 
X 
 
 
X 
Chest X-rayα 
X 
 
 
 
ECGα 
X 
 
 
 
BMI 
X 
 
 
 
Vital signβ 
(BP, PR and Temperature) 
X 
 
X 
 
AE Reporting (including PTE)ε 
X 
X 
X 
X 
Laboratory testsγ 
 
 
 
 
    Hematology 
X 
 
 
X 
    Biochemistry 
X 
 
 
X 
    Urinalysis 
X 
 
 
X 
    Serology 
X 
 
 
 
Pregnancy testδ 
X 
X 
 
X 
Inclusion/Exclusion Assessment 
X 
 
 
 
Restrictions Compliance Check 
 
X 
X 
 
Drug administration 
 
 
X 
 
PK Sampling 
 
 
X 
 
Meals 
 
 
X 
 
α The results of ECG and chest X-Ray within previous 30 days will be accepted for evaluation. 
β Details refer to Section 11. Dosing Procedures and Sampling Time Schedule. 
γ Details refer to Section 9.2. 
δ For females subjects, serum hCG will be performed only at screening. Urine hCG will be performed at check in of 
each period and post examination.  
ε This study will collect pretreatment event (PTE) and adverse event (AE) after subjects provide written consent in the 
ICF. Only AE occur after first dosing will be analyzed for safety assessment. 
The following section describes the scheduled intervals for this study, whereas the planned time 


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listed herein is to serve as examples only. The actual time executed for each individual subject will 
be advanced or postponed for several hours. 
Dosing Procedures and Sampling Time Scheduleα 
Day 
Time 
Events 
Corresponding time after 
dosing 
Number of 
Samplingε 
Vital Signs 
Measuringζ 
Hours  
hh:mm 
-1 
21:00 Subjects Check-in 
- 
 
- 
 
 
21:30 
Start of fasting 
- 
 
- 
 
1 
07:00 
 
 Pre-doseγ 
1 
δ 
 
07:30 
Dosingβ 
0 
+00:00 
- 
 
 
07:32 
 
0.033 
+00:02 
2 
 
 
07:35 
 
0.083 
+00:05 
3 
 
 
07:40 
 
0.167 
+00:10 
4 
 
 
07:45 
 
0.25 
+00:15 
5 
 
 
08:50 
 
0.333 
+00:20 
6 
 
 
08:00 
 
0.5 
+00:30 
7 
δ 
 
08:15 
 
0.75 
+00:45 
8 
 
 
08:30 
 
1.0 
+01:00 
9 
 
 
08:45 
 
1.25 
+01:15 
10 
 
 
09:00 
 
1.5 
+01:30 
11 
 
 
09:15 
 
1.75 
+01:45 
12 
 
 
09:30 
 
2.0 
+02:00 
13 
 
 
09:45 
 
2.25 
+02:15 
14 
 
 
10:00 
 
2.5 
+02:30 
15 
 
 
10:30 
 
3.0 
+03:00 
16 
 
 
11:30 
End of fasting and 
start of lunch 
4.0 
+04:00 
17 
 
 
13:30 
 
6.0 
+06:00 
18 
 
 
15:30 
 
8.0 
+08:00 
19 
 
 
17:30 
Dinner 
10 
+10:00 
- 
 
 
19:30 
 
12.0 
+12:00 
20 
 
 
23:30 
 
16.0 
+16:00 
21 
δ 
2 
07:30 
 
24.0 
+24:00 
22 
δ 
α Time schedule listed herein is to serve as examples. For each individual subject, the execution of subsequent sampling 


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time will be corresponding to the actual dosing time in relation to the ascending order of random number. 
β Subjects will be administered an orally inhaled dose of 2 puffs (eq. to albuterol 180 mcg) under fasting conditions. 
Both start time and end time of inhalation will be recorded.  
γ Pre-dose sample will be collected within 60 minutes before dosing and shown as 0 hour sample in bioanalytical and 
statistical analysis report.  
δ Vital signs: BP, PR and body temperature.  
ε The suggested time windows for sampling time are listed as follows (Sampling deviation within time window will not 
apply to protocol deviation): 
Sample No. 
No. 2-9 
No. 10-21 
No. 22 
Time window 
+2 minutes 
+5 minutes 
+60 minutes 
ζ Pre-dose vital signs will be measured within 2 hours of administration. On dosing day, the acceptable window of vital 
sign is ± 30 minutes. The non-administration day acceptable window will be measured within ± 60 minutes at a 
predetermined time. (Measurement of vital sign within time window or vital sign rechecked time exceeding the time 
window will not be considered as a protocol deviation.) 
11.1 STUDY PERIOD CHECK-IN PROCEDURES 
At check-in for each study period, subjects will be questioned about whether they have complied 
with the study restrictions. 
If drug therapy other than that specified in the protocol is used, a decision to continue or discontinue 
the subject’s participation will be made by the Principal Investigator/Sub-Investigator and/or by the 
PPC Pharmacokineticist and/or by the Sponsor. 
Urine tests for drugs of abuse and a breath alcohol test will be performed on all subjects at each 
study period check-in. In addition, urine hCG testing will be performed on all female subjects at 
each study period check-in. 
Clinical staff reserves the right to conduct random testing (urine drugs of abuse, urine hCG [females 
only], or breath alcohol) on any subject at any time during the study to ensure subject compliance 
and/or safety. 
Any subjects with a positive test for urine drugs of abuse, or breathe alcohol or urine hCG (females 
only) will be withdrawn from the study immediately. 
11.2 FOOD AND FLUID INTAKE 
The day before the study (Day -1), subjects must arrive at clinical facility by 21:00. Subjects will 


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remain fasted at least 10 hours before dosing and a minimum of 4 hours thereafter. Subjects will be 
given standardized meals and caffeine/methylxanthine-free beverages at scheduled times. Meals will 
be served at approximately 4 and 10 hours after dosing on Day 1, and any other food is prohibited. 
Meals and beverages during confinement will be identical (if feasible) for each study period. 
Water will be prohibited 1 hour prior to dosing and restricted until 2 hour after inhalation. No fluids 
other than water and those served for administration/with meals will be permitted during the 
confinement. 
11.3 VITAL SIGNS MEASUREMENTS 
In the interest of subject safety, staff will monitor vital signs (BP, PR, and temperature) at pre-dose 
and at 0.5, 16 and 24 hours post-dose in each study period. 
Pre-Dose and Post-Dose: 
All subjects with vital signs outside of acceptable range of systolic blood pressure between 90-139 
mmHg, inclusive, diastolic blood pressure between 50-90 mmHg, inclusive, and pulse rate between 
50-100 bpm, inclusive, will have their vital signs repeated up to two times. If vital signs are still 
outside of acceptable range Principal Investigator/Sub-Investigator will determine appropriate 
course of action. 
Additional vital signs measurements will be taken if deemed necessary by the Principal 
Investigator/Sub-Investigator. Blood draws will take precedence over vital signs measurements and 
other scheduled activities, should a timing conflict arise unless deemed necessary by the Principal 
Investigator/Sub-Investigator. 
11.4 CHEST X-RAY AND ECG MONITORING 
Chest X-ray and ECG measurements will be performed at screening. For each period, Chest X-ray 
and ECG measurements are not required unless deemed necessary by the Principal 
Investigator/Sub-Investigator. 
11.5 ADDITIONAL TESTING 
Additional tests are not required during the study unless deemed necessary by the Principal 
Investigator/Sub-Investigator. 


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11.6 DOSING 
Subjects will take their assigned formulation, designated by the randomization scheme, after at least 
a 10-hour fasting period at their scheduled time-point. 
Two puffs (eq. to albuterol 180 mcg) of test product and reference product will be inhaled per orally. 
The investigational product will be inhaled with adequate time intervals between subjects to ensure 
correct blood sampling. 
11.7 PHYSICAL ACTIVITY 
Subjects will stay awake and remain seated in an upright position for the first 4 hours following drug 
administration, and allowed to rise under supervision only for brief periods of time, in order to 
comply with study-related activities and to use the washroom. After the first 4 hours they will be 
allowed to ambulate freely within the clinic. However, if a medical event (i.e. AE) occurs, subjects 
may be placed in an appropriate position at any time. Subjects will be required to abstain from 
strenuous activities for the duration of the study period(s).  
11.8 BLOOD SAMPLING SCHEDULE, SAMPLE COLLECTION, PROCESSING AND 
STORAGE 
Samples will be collected through an indwelling cannula (if possible) placed in a vein. The pre-dose 
samples will be collected prior to drug dosing. Intravenous indwelling cannula would be kept in 
place up to 24 hours post-dose by injecting adequate amount but not more than 0.5 ml of normal 
saline solution during the collection of multiple samples. In such case, the blood sample would be 
collected after discarding the first 0.5 ml of blood from the tubing. Blood may also be withdrawn by 
a fresh clean venipuncture either by using sterile syringe and needle or disposable sterilized needle 
and vacutainer if the cannula is blocked.  
If the blood sample collection time coincides with the other study events like vitals, subject 
well-being questionnaire and meal, the sequence of the events would be followed as: blood sample 
collection / vitals > subject well-being questionnaire > meal / water.  
During the study, blood sample are collected from vein. Subject may suffer the common AE with 
donating blood, including vasovagal syncope (including temporary weakness, dizzy and nausea) and 
ecchymoma. 


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Number of Samples 
For each subject, the total number of blood 
draws will be 44 (22 samplings x 2 periods).  
Total Volume of Blood (for all periods, 
including approximately 20 ml for pre-, and 
post-study procedures) 
7 ml of venous blood samples will be collected 
according to time-point schedule. The total 
volume 
of 
blood 
withdrawn 
will 
be 
approximately 328 ml, (Up to 10 ml for 
screening, approximately 308 ml for the two 
periods and up to 10 ml for post study 
laboratory test at the end of last period). 
Blood Sampling Time Points 
0-hour (Pre-dose), and at 2, 5, 10, 15, 20, 30, 
45 minutes, and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 
3, 4, 6, 8, 12, 16 and 24 hours post-dose in each 
study period.  
Type of specimens: plasma 
Each blood sample will be collected into a pre-labeled tube containing an applicable anti-coagulant 
(e.g., heparin sodium or EDTA, depending on the analytic methods to be used). The label includes 
the trial number, random number, sampling time point, and study period number. The samples 
collected at each time point will be centrifuged (1900g and 4°C for 10 minutes or other applicable 
conditions) to separate the plasma from the whole blood within 30 minutes after drawing the blood 
samples from the subjects. 
The separated plasma will be aliquoted into two batches (if feasible), transferred to appropriately 
labeled tubes, and then stored in a freezer with a temperature of -20°C or lower at the clinical facility. 
After the collection and centrifugation procedures, the samples will be maintained in an ice-bath 
container until stored in the freezer at the clinical facility.  
The time between the blood centrifugation and the freezer storage should, in general, not exceed 1 
hour. However, exception can be made to allow the above processing time up to 2 hours if the 
prolonged time period will not interfere with the stability of the analyte(s). 
The first of the plasma samples will be packaged with dry ice and delivered from the clinical facility 
to bioanalytical lab with temperature recording. This first batch will be stored in a freezer with a 
temperature of -20°C or lower at the bioanalytical lab until further analysis; the other batch as 


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back-up will be stored in the freezer of clinical facility and will be delivered separately thereafter if 
required. 
11.9 HEALTHY STATUS MONITORING 
Health monitoring will be conducted throughout the study or as needed. AE will be reported and 
monitored after the first dose of the study drug. 
11.10 POST-STUDY TESTS 
An exit physical examination will be conducted upon completion of the study or after 
withdrawal/dismissal of a subject from the study, where possible. 
Within 7 days after completion of the clinical part, a clinical laboratory tests (hematology, 
biochemistry and urinalysis), as per section 9.2 Clinical Laboratory Assessment, will be performed 
in order to determine possible changes in the subject’s state of health. Study personnel should 
contact those subjects who do not come back for the post study examinations within a week, and 
then a 3-day grace period will be given. The subjects will be considered as lost to follow-up after the 
grace period, and all communication should be recorded. In addition, urine hCG testing will be 
performed on all female subjects at post-study. 
11.11 SAMPLE SHIPMENT 
The samples from all subjects will be delivered to the analytical facility packed on dry ice. All 
shipments will be accompanied by an inventory list and delivered to the analytical laboratory. 
Clinical personnel will notify the analytical laboratory prior to shipment by phone, fax or e-mail. 
12. ADVERSE EVENT 
PPC has established SOP in conformity with regulatory requirements to ensure the timely, accurate, 
and complete reporting of safety information. This study will collect PTE and AE after subjects 
provide written consent in the ICF. Only AE occur after first dosing will be analyzed for safety 
assessment.  
12.1 ADVERSE EVENT RECORDING AND FOLLOW-UP 
Subjects will be instructed to inform clinical personnel of any untoward medical symptoms and/or 
events that may arise during the course of the study.  


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Prior to the subsequent study period, subjects will be questioned concerning symptoms that may 
have occurred after the previous administration of the study drug(s). The incidence, severity and 
duration of all AE will be recorded according to the following scale: 
Mild 
AE resulting in discomfort, but not sufficient to cause interference in 
normal daily activities. 
Moderate 
AE resulting in discomfort that is sufficient to cause interference in 
daily activities.  
Severe 
AE resulting in discomfort causing an inability to carry out normal 
daily activities.  
AE monitoring and reporting will be followed up until resolution or stabilization at an acceptable 
level and thereafter the Principal Investigator or Sub-investigator will decide the course of action. 
12.2 ASSESSING RELATIONSHIP TO STUDY DRUG 
The Principal Investigator/Sub-Investigator will assess the relationship of all adverse reactions to the 
drug, using the following scale: 


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Certain: 
A clinical event, including laboratory test abnormality, occurring in 
a plausible time relationship to drug administration, and which 
cannot be explained by concurrent disease or other drugs or 
chemical. The response to withdrawal of the drug (de-challenge) 
should be clinically plausible. The event must be definitive 
pharmacological 
or phenomenological, 
using a satisfactory 
re-challenge procedure if necessary. 
Probable/ 
likely: 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely to 
be attributed to concurrent disease or other drugs or chemicals, and 
which follows an clinically reasonable response to an withdrawal 
(de-challenge). Re-challenge information is not required to fulfill 
this definition 
Possible: 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, but which 
could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or 
unclear. 
Unlikely: 
A clinical event, including laboratory test abnormality, with a 
temporal relationship to drug administration which makes a causal 
relationship improbable, and in which other drugs, chemicals or 
underlying disease provides plausible explanation. 
Unrelated: A report suggesting an adverse reaction which cannot be judged 
because information is insufficient or contradictory, and which 
cannot be supplemented or verified.  
12.3 PROCEDURES FOR REPORTING ADVERSE EVENTS 
Subjects will be instructed to inform clinic personnel of AE that may arise during the course of the 
study. Treatment of any AE will be administered under the direction of a physician at Tamshui 
Mackay Memorial Hospital. 
All symptoms will be recorded by clinical staff and will be reviewed by the Principal 
Investigator/Sub-Investigator prior to any subsequent dosing. 


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When appropriate, medical tests and examinations will be performed to document resolution of the 
event(s). 
All SAE, whether or not the event is deemed drug-related, will be reported to the Sponsor by 
telephone within twenty-four hours of PPC’s being aware of SAE, followed by a written report 
within seven days. PPC will be responsible for notifying the IRB and regulatory agencies, if 
applicable. 
The following Sponsor personnel are to be contacted at the occurrence of a SAE: 
General Manager, 
 / Intech Biopharm Ltd. 
3F., No.36, Ln. 358, Ruiguang Rd., Neihu Dist., Taipei City 114, Taiwan 
ROC 
Phone: +(02)7721-8877 
Fax: +(02)7721-8800 
12.4 PREGNANCY REPORTING 
If the female subject or the partner of a male subject becomes pregnant while receiving the 
investigational drugs or within 30 days after the completion of the last dose of study drug, a 
pregnancy report form should be completed and expeditiously submitted to the sponsor to facilitate 
the outcome follow-up. Information on the status of the mother and child will be forwarded to the 
sponsor. Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any premature termination of the pregnancy will be reported. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE and will 
be followed as described in Section 12. 
An abortion, whether accidental, therapeutic, or spontaneous, should be always reported as an SAE. 
Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the study drug 
should be recorded and reported as an SAE. 
13. BIOANALYTICAL ANALYSIS 
Bioanalytical procedures will be performed according to PPC SOP. 


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13.1 ANALYTICAL PROCEDURES 
Data management, quality review and reporting of study data pertaining to laboratory analysis of 
study data will be the responsibility of PPC. 
13.1.1 SAMPLES TO BE ASSAYED 
In general, single batch of each sample will be all analyzed for drug concentration. Samples from 
subjects being analyzed will be defined prior to sample analysis 
13.1.2 ANALYTE(S) IN BIOLOGICAL MATRIX 
Plasma samples will be assayed and reported at the actual sampling time points (or scheduled 
sampling time points) for albuterol using a validated analytical method according to the principles of 
FDA GLP Title 21 Part 58. 
14. PHARMACOKINETIC AND STATISTICAL ANALYSIS 
14.1 PHARMACOKINETIC ANALYSIS DATA SET 
The data from the following subjects will be included in the final PK and statistical analysis: 
1. 
Subjects who complete all study periods without major/suspect protocol deviation. 
2. 
Subjects who have missed samples that have been determined prior to the start of bioanalytical 
analysis as not significantly impacting the overall outcome of the study. 
Data from subjects who are dismissed or withdraw due to AE will not be included in the final PK 
and statistical analysis. The data for these subjects will be presented separately. 
Any decision to exclude data from the final data set will be provided with a detailed explanation and 
will be properly recorded and dated. 
The final data set will be defined prior to sample analysis. 
14.2 ANALYSIS OF DATA 
PK and statistical analysis will be performed on all data from all subjects in the final data set. 


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14.2.1 PHARMACOKINETIC ANALYSIS 
The following PK parameters shall be estimated (where possible and appropriate) included in the PK 
and statistical analyses for the subjects in the final data set: 
Cmax: 
The maximal observed plasma concentration. 
Tmax: 
Time when the maximal plasma concentration is observed. 
AUC0-t: 
Area under the concentration-time curve from time zero 
until the last measurable concentration or last sampling 
time t, whichever occurs first. AUC0-t is estimated using 
the trapezoidal method. 
AUC0-: 
Area under the concentration-time curve from time zero to 
infinity, calculated as AUC0-t + Clast/λ, where Clast is the 
last measurable concentration. 
kel(λ): 
Terminal elimination rate constant, estimated by linear 
regression analysis of the terminal portion of the 
ln-concentration vs. time plot. 
T1/2: 
Terminal elimination half-life, estimated as ln(2)/λ. 
MRT: 
Mean residence time 
If a subject’s pre-dose concentration is less than or equal to 5% of the Cmax value for that subject in 
the given period, then the subject’s data without any adjustments can be included in all PK 
measurements and calculations. If the pre-dose value is greater than 5% of the Cmax, data from that 
subject will be dropped from the PK and statistical analysis. Data for subjects dropped due to higher 
than 5% of Cmax pre-dose concentrations will be included in a separate appendix in the final study 
report. 
During PK and statistical analyses, drug concentrations below the lower limit of quantitation (BLQ) 
of an assay will be considered as zero except when they occur between two non-BLQ 
concentrations. 
Missed samples and non-reportable concentrations (e.g. quantity not sufficient) from the analytical 
laboratory will be treated in the PK analysis as if they had not been scheduled for collection. 


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The kel, T1/2, and AUC0- parameters will not be estimated for plasma concentration-time profiles 
where the terminal linear phase is not clearly defined. 
For subjects with missing or non-reportable concentrations for three or more of the last samples, 
only the AUC0-t, Cmax and Tmax will be presented and included in the statistical analysis (if 
applicable).  
14.2.2 STATISTICAL ANALYSIS 
PK and statistical analyses will be performed using SAS® Version 9.2 or higher by PPC. 
Descriptive statistics of all PK parameters (min, max, median, mean, SD and CV) will be provided 
for the test and reference products. 
ANOVA including sequence, subjects nested within sequence, period and treatment will be 
performed on the log-transformed data for AUC0-t, AUC0- and Cmax and on the raw data for Tmax, kel 
and T1/2. Tmax will be analyzed using an additional non-parametric test (Wilcoxon test). 
For albuterol, the 90% CI of the Test/Reference ratios of geometric means for AUC0-t, AUC0- and 
Cmax will be calculated based on the LSMEANS and ESTIMATE of the ANOVA. 
Additional statistical and alternate tests will be performed if necessary. 
14.2.3 MISSING DATA 
During PK and statistical analyses, treatment of missing data will follow PPC’s SOP.  
14.3 BIOEQUIVALENCE CRITERIA 
Bioequivalence will be demonstrated under fasting conditions if the 90% CI for the Test/Reference 
ratios of geometric means for AUC0-t, AUC0- and Cmax are completely contained within the FDA 
defined acceptance range of 80.00%-125.00%.  


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15. ETHICAL CONSIDERATIONS 
15.1 BASIC PRINCIPLES 
This research will be carried out in accordance with GCP as set out by the ICH, the basic principles 
defined in the U.S. Code of Federal Regulations (21 CFR Part 320), Guideline for GCP and the 
principles enunciated in the most recent version of the World Medical Association Declaration of 
Helsinki. 
15.2 INSTITUTIONAL REVIEW BOARD 
This Protocol and the ICF will be reviewed and approved by the IRB prior to the initiation of the 
study. The board is constituted and operates in accordance with ICH Harmonized Tripartite 
Guideline (GCP Consolidated Guideline). 
15.3 INFORMED CONSENT FORM 
The ICF will be approved by the IRB and a copy will be included in the final report. The ICF will be 
signed by each subject prior to the study procedure. Each subject will be provided with verbal and 
written information, in non-technical terms, which will describe the nature and duration of the study. 
Prior to signing the ICF, subjects will be allowed adequate time to consider the potential benefits and 
risks associated with their participation in the study. Signed and dated ICFs will be retained with the 
study records. Subjects/Volunteers will be provided a copy of their signed and dated ICF. 
15.4 REVISIONS AND/OR AMENDMENTS TO THE PROTOCOL 
Revisions and/or amendments to the protocol must be documented and approved by the Principal 
Investigator and Sponsor. If the revision/amendment will affect subject safety and/or study design, 
then the amendment will be re-submitted to the IRB for approval. Administrative changes (i.e., 
change of analytical facility, typographical errors, discrepancies, clarifications) will also be 
submitted to the IRB. A copy of the IRB’s approval documents will be included in the final report. 
For revisions or amendments to the protocol that substantially alter the study design after initiation 
of the study, the Principal Investigator and Sponsor will decide whether a revised ICF will be needed 
for continued participation. 
It is the Sponsor’s responsibility to submit, or to assign responsibility to submit, all revisions and 
amendments to the appropriate regulatory authorities when necessary. 


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If an amended or revised version of the ICF is introduced during the study, each subject’s further 
consent should be obtained. 
15.5 INVESTIGATOR RESPONSIBILITIES 
The Principal Investigator is responsible for ensuring that the clinical study is performed in 
accordance with the protocol, the current revision of the Declaration of Helsinki, ICH GCP 
guidelines and applicable regulatory requirements. 
15.6 STUDY COMPLETION/TERMINATION 
PPC and/or the Sponsor reserve the right to terminate the study at any time, and for any reason. 
15.7 SPONSOR VISITS 
The Sponsor is encouraged to visit PPC and clinical facility, if desired, and at their convenience. The 
Principal Investigator and staff will provide, if requested, all source documents and/or other 
study-related documents. The Principal Investigator will maintain regular written and telephone 
communication with the Sponsor. 
15.8 CONFIDENTIALITY 
The information in this study protocol is confidential. This document contains trade secrets and 
commercial information that is confidential and may not be disclosed to third parties (except to the 
IRB, TFDA, FDA, and/or relevant regulatory agencies). These restrictions will apply as well to all 
future communications if deemed privileged or confidential. 
Sponsor, study monitors, auditors, the IRB and applicable regulatory authorities will be granted 
direct access to the subject’s original medical records for verification of clinical trial procedure 
and/or data, without violating the confidentiality of the subject, to the extent permitted by applicable 
laws and regulations and that, by signing a written ICF, the subject or the subjects legally acceptable 
representative authorizes such access. 
All documentation collected by the Sponsor or by PPC and clinical facility personnel will be kept 
confidential. The name and identity of the subjects will remain confidential. If documents containing 
the subjects’ names are photocopied, the name will be redacted from the photocopied version. 


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16. DATA MANAGEMENT/RECORD KEEPING 
16.1 SOURCE DATA 
All data will be recorded in accordance with GCP, to ensure accuracy, completeness, legibility, and 
timeliness of the data reported. All data will be recorded directly on the source documents and will 
be considered source data. PPC standard CRF will be supplied. All the evaluations conducted in this 
study for each subject will be recorded in the CRF. A hardcopy of each CRF prepared using a data 
management system with an audit trail, signed by the investigator, will be regarded as the original. 
All raw data generated in connection with this study, together with the original copy of the final 
report, will be retained.  
Electronic data capture software TrialOne will be available in this study. Partial data will be entered 
directly onto the CRF to be considered to be source data (e.g. tracking of biosample/data collection, 
vital signs, investigational drugs administration, meals/fluids uptake status, etc.) 
16.2 QUALITY OF DATA 
All source documents and laboratory reports will be Quality Control reviewed to ensure accuracy 
and completeness. AE will be reviewed and assessed for severity and causality by the Principal 
Investigator/Sub-Investigator. Specific processes of the study, its source documentation and any 
reports (if applicable) will be audited by the Quality Assurance unit of PPC. 
16.3 RETENTION OF DOCUMENTS 
All records and documents pertaining to the study will be retained by PPC for at least 2 years after 
the date of approval of the application or at least 5 years after the date of study termination, and will 
be available for inspection by the Sponsor and/or Regulatory Agencies. 
17. REFERENCES 
1. US FDA label of PROAIR HFA (albuterol sulfate) inhalation aerosol (02/2019) 
 
 

SAP_001.pdf: 
 
 
Official Title: 
A Randomized, Single-dose, Open-label, Two-way Crossover Pivotal 
Study to Assess the Bioequivalence between Albuterol Sulfate 
inhalation aerosol 108mcg per actuation (MDI, eq. to albuterol 90mcg 
/puff) and Proair HFA (albuterol sulfate) Inhalation Aerosol 90 mcg per 
actuation (MDI, eq. to albuterol 90mcg /puff) in Healthy Volunteers 
under Fasting Conditions 
 
NCT Number: 
NCT04803734 
 
Document Date: 
Statistical Analysis Plan Version 1.0: May-13-2021 
 
 
 
 
 


PPC 
 
Statistical Analysis Plan 
Protocol No.: TW20-4502 
Page 1 of 11 
 
 
 
CONFIDENTIALITY STATEMENT 
This document contains proprietary information. Do not disclose this information to third 
party without the prior consent of PPC. 
 
 
Statistical Analysis Plan 
 
 
TITLE OF STUDY: 
A Randomized, Single-dose, Open-label, Two-way 
Crossover Pivotal Study to Assess the Bioequivalence 
between Albuterol Sulfate inhalation aerosol 108mcg 
per actuation (MDI, eq. to albuterol 90mcg/puff) and 
Proair HFA(albuterol sulfate) Inhalation Aerosol 90 
mcg per actuation (MDI, eq. to albuterol 90mcg/puff) 
in Healthy Volunteers under Fasting Conditions 
 
PROTOCOL NO.: 
TW20-4502 
PROTOCOL VERSION : 
1.0 
PROTOCOL VERSION 
DATE: 
Jan-08-2021 
PPC STUDY NO.: 
TW20-4502 
SPONSOR: 
Intech Biopharm Ltd.  
3F., No.36, Ln. 358, Ruiguang Rd., Neihu Dist., 
Taipei City 114, Taiwan  
Phone: +886-2-7721-8877 
Fax: +886-2-7721-8800 
 
CRO: 
Protech Pharmaservices Corporation 
11F., No.3, Park St., Nangang District, 
Taipei City 11503, Taiwan 
Phone: +886-2-5558-0000 
Fax: +886-2-5558-0055 
 
STATUS: 
Final 
DATE/VERSION: 
May-13-2021 v1.0 
AUTHOR: 
 
Protech Pharmaservices Corporation 
 






PPC 
 
Statistical Analysis Plan 
Protocol No.: TW20-4502 
Page 4 of 11 
 
 
Center Laboratories, Inc. 
Prepared by PPC 
－ CONFIDENTIAL － 
Date/Version: May-13-2021 v1.0 
 
 
TABLE OF CONTENTS 
 
1. 
SIGNATURE PAGE ............................................................................................................................................ 2 
2. 
STUDY DESIGN .................................................................................................................................................. 5 
3. 
STUDY OBJECTIVES ........................................................................................................................................ 5 
3.1 
PRIMARY OBJECTIVE..................................................................................................................................... 5 
3.2 
SECONDARY OBJECTIVE ................................................................................................................................ 6 
4. 
SPONSOR ............................................................................................................................................................ 6 
5. 
STATISTICAL ANALYSIS FACILITY ........................................................................................................... 6 
6. 
STUDY PERSONNEL ......................................................................................................................................... 6 
7. 
SUBJECT POPULATIONS ................................................................................................................................ 6 
8. 
STATISTICAL METHODOLOGY ................................................................................................................... 6 
8.1 
OBJECTIVE .................................................................................................................................................... 7 
8.2 
GENERAL CONSIDERATIONS .......................................................................................................................... 7 
8.2.1 
Continuous Variables .............................................................................................................................. 7 
8.2.2 
Categorical Variables ............................................................................................................................. 7 
8.3 
PHARMACOKINETIC ANALYSIS ...................................................................................................................... 7 
8.4 
STATISTICAL ANALYSIS FOR PHARMACOKINETIC PARAMETERS .................................................................... 8 
8.5 
BIOEQUIVALENCE CRITERIA .......................................................................................................................... 9 
8.6 
SAFETY PARAMETERS .................................................................................................................................... 9 
8.6.1 
Adverse event ........................................................................................................................................... 9 
8.6.2 
Vital signs ................................................................................................................................................ 9 
9. 
RECORD AND ARCHIVE ................................................................................................................................. 9 
10. 
CHANGES TO PLANNED ANALYSES FROM CLINICAL PROTOCOL ............................................ 9 
11. 
STATISTICAL ANALYSIS PLAN AMENDMENT ................................................................................... 9 
12. 
PROGRAMMING CONSIDERATIONS ..................................................................................................... 9 
STATISTICAL SOFTWARE .............................................................................................................................................. 9 
FORMAT OF TABLE AND FIGURE ................................................................................................................................ 10 
FORMAT OF LISTING ................................................................................................................................................... 10 
13. 
REFERENCE(S) ........................................................................................................................................... 11 
 


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Center Laboratories, Inc. 
Prepared by PPC 
－ CONFIDENTIAL － 
Date/Version: May-13-2021 v1.0 
 
 
2. STUDY DESIGN 
Using a single-dose, randomized, open-label, single-centre, two-way crossover study design, 
is examined after administration to 60 healthy volunteers under fasting conditions on this study. 
The subjects are assigned to one of the treatment sequences as follows: 
Sequence 
Period 1 
Washout 
Period 2 
1 
T 
≥ 14 days 
R 
2 
R 
T 
 
 
The following tables show the information about study treatments: 
Test Product (T) 
Drug name: 
Albuterol Sulfate inhalation aerosol 108mcg per actuation 
(equivalent to 90mcg of Albuterol) 
Active ingredient: 
Albuterol sulfate 
Strength: 
eq. to albuterol 90mcg/puff 
Dosage form: 
MDI 
Manufactured by: 
Intech Biopharm Ltd. 
Mode of administration: Inhalation 
Reference Product (R) 
Drug name: 
Proair HFA(albuterol sulfate) Inhalation Aerosol 90 mcg per 
actuation 
Active ingredient: 
Albuterol sulfate 
Strength: 
eq. to albuterol 90mcg/puff 
Dosage form: 
MDI 
Manufactured by: 
IVAX Pharmaceuticals Ireland Waterford, Ireland 
Mode of administration: Inhalation 
 
The scheduled sampling times for drug’s concentration analysis are pre-dose and at 2, 5, 10, 
15, 20, 30, 45 minutes, and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 4, 6, 8, 12, 16 and 24 hours after 
dosing, a total of 22 sampling points are drawn for each study period. 
3. STUDY OBJECTIVES 
3.1 Primary Objective 


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Center Laboratories, Inc. 
Prepared by PPC 
－ CONFIDENTIAL － 
Date/Version: May-13-2021 v1.0 
 
This study is designed to assess the bioequivalence of Albuterol sulfate of the Test product vs. the 
Reference product under fasting conditions. Bioequivalence will be assumed if the 90% 
confidence interval of the AUC0-t, AUC0- and Cmax ratio are within the 80-125% interval for ln-
transformed values. 
3.2 Secondary Objective 
The other PK-variables will be assessed for descriptive purposes. As for safety parameters, AE 
and vital signs (BP, PR and body temperature) will be recorded. 
4. SPONSOR 
Intech Biopharm Ltd.  
3F., No.36, Ln. 358, Ruiguang Rd., Neihu Dist., Taipei City 114, Taiwan  
Phone: +886-2-7721-8877 
Fax: +886-2-7721-8800 
5. STATISTICAL ANALYSIS FACILITY 
Protech Pharmaservices Corporation 
11F., No.3, Park St., Nangang District, Taipei City 11503, Taiwan 
Phone: +886-2-5558-0000    Fax: +886-2-5558-0055 
6. STUDY PERSONNEL 
Biostatistician: 
, Biostatistics & Data Management Department 
7. SUBJECT POPULATIONS 
The data from the following subjects will be included in the final pharmacokinetic and statistical 
analysis: 
1. 
Subjects who complete all study periods. 
2. 
Subjects who have missed samples that have been determined prior to the start of 
bioanalytical analysis as not significantly impacting the overall outcome of the study. 
Data from subjects who were dismissed or withdrew due to AE(s) will not be included in the 
pharmacokinetic and statistical analysis.  
8. STATISTICAL METHODOLOGY 


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Statistical Analysis Plan 
Protocol No.: TW20-4502 
Page 7 of 11 
 
 
Center Laboratories, Inc. 
Prepared by PPC 
－ CONFIDENTIAL － 
Date/Version: May-13-2021 v1.0 
 
8.1 Objective  
In this bioequivalence study, the concentration value of Albuterol sulfate for the Test product 
[Albuterol Sulfate inhalation aerosol 108mcg per actuation (equivalent to 90mcg of Albuterol)] 
and the Reference product [Proair HFA(albuterol sulfate) Inhalation Aerosol 90 mcg per actuation] 
will be used to calculate the pharmacokinetic parameters, to perform the statistical analysis, to 
compare the bioavailability between Test product and Reference product, and will be used to 
assess the bioequivalence between Test product and Reference product. 
8.2 General Considerations 
8.2.1 Continuous Variables 
The raw data will be summarized with the number of available observations, mean, standard 
deviation, minimum and maximum on visit basis. 
8.2.2 Categorical Variables 
The raw data will be summarized with the number of available observations, frequency of each 
class on visit basis.   
8.3 Pharmacokinetic Analysis 
The following pharmacokinetic parameters will be estimated (where possible) for Albuterol 
sulfate included in the pharmacokinetic and statistical analysis for the subjects in the final data set: 
Cmax: 
The maximal observed plasma concentration. 
Tmax: 
Time when the maximal plasma concentration is observed. 
AUC0-t: 
Area under the concentration-time curve from time zero until the last measurable 
concentration or last sampling time t, whichever occurs first. AUC0-t is estimated 
using the trapezoidal method. 
AUC0-: 
Area under the concentration-time curve from time zero to infinity, calculated as 
AUC0-t + Clast/λ, where Clast is the last measurable concentration. 
kel(λ): 
Terminal elimination rate constant, estimated by linear regression analysis of the 
terminal portion of the ln-concentration vs. time plot. 
T1/2: 
Terminal elimination half-life, estimated as ln(2)/λ. 
MRT: 
Mean residence time 
If a subject’s pre-dose concentration is less than or equal to 5% of the Cmax value for that subject 
in the given period, then the subject’s data without any adjustments can be included in all 
pharmacokinetic measurements and calculations. If the pre-dose value is greater than 5% of the 
Cmax, data from that subject will be dropped from the pharmacokinetic and statistical analysis.  


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During pharmacokinetic and statistical analyses, drug concentrations below the lower limit of 
quantitation (<LLOQ) of an assay will be considered as zero except when they occur between two 
measurable concentrations where they will be considered as missing during pharmacokinetic 
calculations and estimations. 
Missed samples and non-reportable concentrations (e.g. quantity not sufficient) from the analytical 
laboratory will be treated as they had not been scheduled for collection in the pharmacokinetic 
analysis. 
The AUC0-, kel(λ), T1/2 and MRT parameters will not be estimated for plasma concentration-time 
profiles where the terminal linear phase is not clearly defined, only the AUC0-t, Cmax and Tmax will 
be presented and included in the statistical analysis. 
8.4 Statistical Analysis for Pharmacokinetic Parameters 
Pharmacokinetic and statistical analysis will be performed by PPC. The actual sampling times will 
be used in the pharmacokinetic calculations. 
Descriptive statistics of all pharmacokinetic parameters (min, max, median, mean, standard 
deviation and coefficient of variability) will be provided for Albuterol sulfate for the Test and 
Reference products. Parameter differences will be tabulated without coefficient of variability and 
geometric mean. 
ANOVA including sequence, subjects nested within sequence, period and treatment will be 
performed on the ln-transformed data for AUC0-t, AUC0- and Cmax, and on the raw data for kel 
and T1/2. Tmax will be analyzed using an additional non-parametric test (Wilcoxon test). 
The 90% CI of the Test/Reference ratios of geometric means for AUC0-t, AUC0- and Cmax will be 
calculated based on the LSMEANS and ESTIMATE of the ANOVA. Schuirmann’s two one-sided 
test procedures will be evaluated. 
For Albuterol sulfate, the 90% CI of the Test/Reference ratios of geometric means for AUC0-t, 
AUC0- and Cmax will be calculated based on the LSMEANS and ESTIMATE of the ANOVA. 
Schuirmann’s two one-sided test procedures will be evaluated. 
If study is carried out in two or more groups of subjects, the model should reflect the fact that the 
periods for the first group are different from the periods for the second group. 
The model of ANOVA including Group, Sequence, Treatment, Subject (nested within Group × 
Sequence), Period (nested within Group), Group-by-Treatment Interaction will be performed on 
the ln-transformed data for AUC0-t, AUC0- and Cmax. 
Subject (nested within Group×Sequence) is a random effect, and all other effects are fixed effects. 
If the Group-by-Treatment interaction test or Group test is not statistically significant (p ≥0.05), 
the bioequivalence will be demonstrated by pooled group of all subjects. 
If the Group-by-Treatment interaction test or Group test is statistically significant (p<0.05), the 
bioequivalence will be demonstrated by pooled group of all subjects and separated group. 
Additional statistical and alternate tests will be performed if necessary. 


PPC 
 
Statistical Analysis Plan 
Protocol No.: TW20-4502 
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Center Laboratories, Inc. 
Prepared by PPC 
－ CONFIDENTIAL － 
Date/Version: May-13-2021 v1.0 
 
8.5 Bioequivalence Criteria 
Bioequivalence will be demonstrated under fasting conditions if the 90% CI for the 
Test/Reference ratios of geometric means for AUC0-t, AUC0- and Cmax are completely contained 
within the FDA defined acceptance range of 80.00%-125.00% for Albuterol sulfate. 
8.6 Safety parameters 
The safety data for each subject will be included in subject listings, separate from the statistical 
analysis report. 
8.6.1 Adverse event 
Subjects will be instructed to inform clinical personnel of any untoward medical symptoms and/or 
events that may arise during the course of the study. Prior to subsequent study periods, subjects 
will be questioned concerning symptoms that may have occurred after the previous administration 
of the study drug(s).  
This study will collect pretreatment event(s) and adverse event after subjects provide written 
consent in the ICF. Only AE occur after first dosing will be analyzed for safety assessment. 
8.6.2 Vital signs 
Vital signs (blood pressure [BP], pulse rate [PR] and body temperature) will be obtained at pre-
dose and at 0.5, 16 and 24 hours after dosing in each study period. Additional vital signs 
measurements will be taken if deemed necessary by the Principal Investigator/Sub-Investigator. 
9. RECORD AND ARCHIVE 
After completing this study, the statistical analysis plan, statistical analysis report, and the storage 
media (if necessary) should be archived in PPC for 2 years following the date on which the study 
is completed, then returned according to the sponsor’s demand. 
10. CHANGES TO PLANNED ANALYSES FROM CLINICAL PROTOCOL 
There is no change section. 
11. STATISTICAL ANALYSIS PLAN AMENDMENT 
Changes to the statistical analysis plan must be authorized by the biostatistician, and the sponsor. 
Any sentences, reasons and content of the modification will be attached to the statistical analysis 
plan as an amendment and signed by the biostatistician. The head of division and the sponsor 
should keep a copy version of amendment. 
12. PROGRAMMING CONSIDERATIONS 
Statistical Software 


PPC 
 
Statistical Analysis Plan 
Protocol No.: TW20-4502 
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Center Laboratories, Inc. 
Prepared by PPC 
－ CONFIDENTIAL － 
Date/Version: May-13-2021 v1.0 
 
The calculation of pharmacokinetic parameters will be obtained from software WinNonlin version 
6.4 or higher. All tables, listing and analyses of pharmacokinetic parameters will be produced 
using the SAS® version 9.2 or higher.  
Format of Table and Figure 
The following is the table and figure list for the format of output, they will be adjusted when 
perform real analytical figures in these table. 
Statistical Table and Figure Name 
Table 14.2.1.1. The concentration vs. time value for Test product  
Table 14.2.1.2. The concentration vs. time value for Reference product  
Table 14.2.1.3. The actual sampling time for test product 
Table 14.2.1.4. The actual sampling time for reference product 
Table 14.2.2.1. The individual pharmacokinetic parameters for Test product  
Table 14.2.2.2. The individual pharmacokinetic parameters for Reference product  
Table 14.2.3.1. The summary of AUC0-t and ln-transformed AUC0-t - Test vs Reference 
Table 14.2.3.2. The summary of AUC0- and ln-transformed AUC0-- Test vs Reference 
Table 14.2.3.3. The summary of Cmax and ln-transformed Cmax - Test vs Reference 
Table 14.2.4. Statistical analysis for pharmacokinetic parameters  
Figure 14.2.1.1. The individual concentration-time profile on linear scale  
Figure 14.2.1.2. The mean concentration-time profile on linear scale  
Figure 14.2.2.1. The individual concentration-time profile on semi-logarithmic scale  
Figure 14.2.2.2. The mean concentration-time profile on semi-logarithmic scale 
Format of listing 
The following is the subject listing for the format of output, they will be adjusted if required. The 
output of subject listing will be separate from the statistical analysis report.  
Subject Listing Name 
Listing 16.1. Subject disposition 
Listing 16.2. Study termination 
Listing 16.3. Date of consent and demography 
Listing 16.4. Vital signs 
Listing 16.5. Medical history 
Listing 16.6. Physical examination 
Listing 16.7. Drugs of Abuse 


PPC 
 
Statistical Analysis Plan 
Protocol No.: TW20-4502 
Page 11 of 11 
 
 
Center Laboratories, Inc. 
Prepared by PPC 
－ CONFIDENTIAL － 
Date/Version: May-13-2021 v1.0 
 
Listing 16.8. Breath Alcohol Test 
Listing 16.9. 12-lead ECG 
Listing 16.10. Study drug administration and blood sampling 
Listing 16.11. Urine pregnancy test 
Listing 16.12. Adverse event 
Listing 16.13. Inclusion criteria 
Listing 16.14. Exclusion criteria. 
Listing 16.15. Concomitant medication 
 
13. REFERENCE(S) 
1. Guidance for Industry. Statistical Approaches to Establishing Bioequivalence. U.S. 
Department of Health and Human Services, Food and Drug Administration, Center for Drug 
Evaluation and Research (CDER), January 2001. 
2. Chow, S.C., and Liu, J.P. (2009) Design and Analysis of Bioavailability and Bioequivalence 
Studies, Third Edition. Marcel Dekker, Inc. New York.