Chronic Dosing Cross-Over Study to Assess the Efficacy and Safety of Glycopyrronium (PT001) in Adult Subjects With Intermittent Asthma or Mild to Moderate Persistent Asthma

Study Overview
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Brief Summary
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A Randomized, Double-Blind, Chronic Dosing (14 days), 5-Period, 7-Treatment, Placebo-Controlled, Incomplete Block, Cross-Over, Multi-center, Dose-ranging Study to Assess the Efficacy and Safety of Glycopyrronium MDI (PT001) Relative to Placebo MDI and Open-Label Serevent Diskus in Adult Subjects With Intermittent Asthma or Mild to Moderate Persistent Asthma

Official Title
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A Randomized, Double-Blind, Chronic-Dosing (14 Days), 5-Period, 7-Treatment, Placebo-Controlled, Incomplete Block, Cross-Over, Multicenter, Dose-ranging Study to Assess the Efficacy and Safety of PT001 Relative to Placebo Metered Dose Inhaler and Open-Label Serevent® Diskus® in Adult Subjects With Intermittent Asthma or Mild to Moderate Persistent Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Glycopyrronium MDI
* Drug: Serevent Diskus 50 μg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Give their signed written informed consent to participate Males and females ranging in age between 18 to 70 years, inclusive, before Screening (Visit 1a) A female is eligible to enter and participate in the study if she is of: Non-child bearing potential (ie., physiologically incapable of becoming pregnant, including any female who is 2 years post-menopausal); or Child bearing potential, has a negative serum pregnancy test at Screening (Visit 1a), and agrees to 1 of the following acceptable contraceptive methods used consistently and correctly (ie., in accordance with the approved product label and the instructions of the physician for the duration of the study, from Screening [Visit 1a] until 14 days after Visit 12): Complete abstinence from intercourse; or Implants of levonorgestrel inserted for at least 1 month prior to the study drug administration, but not beyond the third successive year following insertion; or Injectable progestogen administered for at least 1 month prior to study drug administration and administered for 1 month following study completion; or Oral contraceptive (combined or progestogen only) administered for at least one monthly cycle prior to study drug administration; or Double barrier method: condom or occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository); or An intrauterine device inserted by a qualified physician, with published data showing that the highest expected failure rate is less than 1% per year; or Estrogenic vaginal ring; or Percutaneous contraceptive patches Asthma History: Have a diagnosis of intermittent asthma or mild to moderate persistent asthma, diagnosed at least 6 months prior to Screening (Visit 1a) Reversibility: Diagnosis of asthma confirmed at Screening (Visits 1 and 2) with demonstration of reversibility to a bronchodilator defined as an FEV1 increase of at least 12% and at least 200 mL, 30 to 60 minutes after the inhalation of 4 puffs of salbutamol/albuterol (Ventolin HFA) Pulmonary Function: Must have a pre-bronchodilator FEV1 ≥60% and ≤90% of predicted normal value at Visit 1a/b and Visit 2a/b Asthma Maintenance Therapy: For those subjects receiving asthma maintenance therapy, they must be on a stable dose of ICS or non-ICS therapy (eg., LTRA) for at least 4 weeks prior to Screening (Visit 1a). Results of clinical laboratory tests conducted at Screening (Visit 1a) must be acceptable to the Investigator. Exclusion Criteria: Life-Threatening Asthma: A subject must not have life-threatening asthma. Lifethreatening asthma is defined as a history of significant asthma episode(s) requiring intubation associated with hypercapnia, respiratory arrest, hypoxic seizures, or asthma related syncopal episode(s) within the 12 months prior to Visit 1a (Screening). Worsening Asthma: A subject must not have experienced a worsening of asthma that involved an emergency department visit, hospitalization, or use of oral/parenteral corticosteroids within 6 weeks of Screening (Visit 1a). Seasonal or Exercise-Induced Asthma Alone: Subjects with only seasonal or exerciseinduced asthma are excluded from participation. Concurrent Respiratory Disease: A subject must not have current evidence or diagnosis of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, chronic bronchitis, emphysema, COPD, or other respiratory abnormalities other than asthma. Concurrent Conditions/Diseases: A subject with historical or current evidence of any clinically significant, or comorbid or uncontrolled condition or disease state that, in the opinion of the Investigator, would put the safety of the subject at risk through study participation or would confound the interpretation of the results if the condition/disease exacerbated during the study. Smoking History: Current smokers or former smokers who have stopped smoking within 6 months prior to enrollment or with a >10 pack year history of cigarettes, cigars, or pipe smoking. E-cigarettes and inhaled marijuana should be treated in the same manner as tobacco products. Inhaled Anticholinergic Use: Subjects must not have used inhaled anticholinergics for at least the 2 weeks prior to Screening (Visit 1a). Pregnant women or nursing mothers Respiratory Tract Infection: Subjects who have had a respiratory tract infection within 6 weeks prior to Screening (Visit 1a). Subjects who develop a respiratory tract infection during the Screening Period must discontinue from the trial, but will be permitted to reenroll at a later date (at least 6 weeks after the resolution of the respiratory tract infection). Uncontrolled Hypertension: Subjects who, in the opinion of the Investigator, have clinically significant uncontrolled hypertension. Liver Function: Subjects with abnormal liver function tests defined as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, or total bilirubin ≥1.5 times the upper limit of normal on repeat testing. Renal: a. Subjects with symptomatic prostatic hypertrophy that is clinically significant in the opinion of the Investigator (if treated and asymptomatic, the subject is eligible for enrollment). Subjects with a trans-urethral resection of prostate or full resection of the prostate within 6 months prior to Visit 1a are excluded from the study. b. Subjects with bladder neck obstruction or urinary retention that is clinically significant in the opinion of the Investigator. c. Subjects with a calculated creatinine clearance ≤30 mL/minute using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula [Levey, 2009] at Visit 1a and on repeat testing prior to Visit 3. Note: Subjects with overactive bladder syndrome treated with oral anticholinergics that have been on treatment for at least one month are allowed in the study. Glaucoma: Subjects with a diagnosis of angle closure glaucoma will be excluded, regardless of whether or not they have been treated. Subjects with a diagnosis of glaucoma (non-angle closure), that in the opinion of the Investigator, has not been adequately treated will also be excluded. Subjects with previously diagnosed glaucoma who have intraocular pressure controlled with medication(s) are eligible. All medications approved for control of intraocular pressures are allowed including topical ophthalmic non-selective β-blockers such as betaxolol, carteolol, levobunolol, metipranolol, or timolol. Cancer: Subjects who have cancer that has not been in complete remission for at least 5 years. Note: Subjects with squamous cell carcinoma and basal cell carcinoma of the skin that have been resected for cure are not considered exclusionary. Subjects with localized prostate cancer that in the opinion of the Investigator, has been adequately worked up, is clinically controlled, and the subject's participation in the study would not represent a safety concern, are eligible. Drug Allergy: Subjects who have a history of hypersensitivity to lactose, milk proteins, or to any component of the MDI or dry powder inhaler (DPI) Substance Abuse: Subjects with a known or suspected history of alcohol or drug abuse within the last 2-year period prior to Screening (Visit 1a). Cardiac Conditions/Disease: Subjects with documented myocardial infarction within a year from the Screening (Visit 1a) are to be excluded. Subjects with a recent history of acute coronary syndrome, or who have undergone percutaneous coronary intervention or coronary artery bypass graft within 3 months of Screening (Visit 1a) are to be excluded.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GP MDI 28.8 μg<br>GP MDI (PT001) 28.8 μg | Drug: Glycopyrronium MDI<br>* GP MDI<br>|
| Experimental: GP MDI 14.4 μg<br>GP MDI (PT001) 14.4 μg | Drug: Glycopyrronium MDI<br>* GP MDI<br>|
| Experimental: GP MDI 7.2 μg<br>GP MDI (PT001) 7.2 μg | Drug: Glycopyrronium MDI<br>* GP MDI<br>|
| Experimental: GP MDI 3.6 μg per<br>GP MDI (PT001) 3.6 μg | Drug: Glycopyrronium MDI<br>* GP MDI<br>|
| Experimental: GP MDI 1.9 μg<br>GP MDI (PT001) 1.9 μg | Drug: Glycopyrronium MDI<br>* GP MDI<br>|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br> <br> |
| Active Comparator: Serevent® Diskus® 50 μg per inhalation<br>Serevent® Diskus® 50 μg per inhalation | Drug: Serevent Diskus 50 μg<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Change From Baseline in FEV1 Within 3 Hours Post-dosing on Day 15 | Forced Expiratory Volume in 1 second (FEV1) within 3 hours post-dosing on Day 15 | From Day 1 to Within 3 hours post dosing on Day 15 in each of 5 treatment periods | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Morning Pre-dose Trough FEV1 on Day 15 | Change from baseline in morning pre-dose trough FEV1 on Day 15 | Day 1-Day 15 in each of 5 treatment periods | 
| FEV1 AUC0-3 on Day 15 | FEV1 AUC0-3 is the area under the curve for the change from baseline in FEV1 calculated using the trapezoidal rule. All observed data will be used with the trapezoidal rule to calculate AUC. To aid in interpretation, all AUC values will be normalized by dividing the AUC by the time from the first to the last non-missing value (typically 3 hours). | Day 1-Day 15 in each of 5 treatment periods | 
| Change From Baseline in Average Daily Pre-dose PEFR Over 14 Days | Change from baseline in average daily pre-dose peak expiratory flow rate (PEFR) over 14 days Daily pre-dose PEFR and daily post-dose PEFR will each be calculated as the average of the AM and PM measurements recorded for a given day. If either the AM or PM assessment is missing, only the single measurement will be used. Analyses of average daily pre-dose PEFR, average daily post-dose PEFR, and rescue Ventolin HFA usage will use the average of the non-missing daily values recorded in the subject diaries over each week and over the last week of treatment within each period. | Day 1-Day 15 in each of 5 treatment periods | 
| Change From Baseline in Average Daily Post-dose PEFR Over 14 Days | Daily pre-dose PEFR and daily post-dose PEFR will each be calculated as the average of the AM and PM measurements recorded for a given day. If either the AM or PM assessment is missing, only the single measurement will be used. Analyses of average daily pre-dose PEFR, average daily post-dose PEFR, and rescue Ventolin HFA usage will use the average of the non-missing daily values recorded in the subject diaries over each week and over the last week of treatment within each period. | Day 1-Day 15 in each of 5 treatment periods | 
| Change From Baseline in Average Daily Rescue Medication Use Over 14 Days | Daily pre-dose PEFR and daily post-dose PEFR will each be calculated as the average of the AM and PM measurements recorded for a given day. If either the AM or PM assessment is missing, only the single measurement will be used. Analyses of average daily pre-dose PEFR, average daily post-dose PEFR, and rescue Ventolin HFA usage will use the average of the non-missing daily values recorded in the subject diaries over each week and over the last week of treatment within each period. | Day 1-Day 15 in each of 5 treatment periods | 
| Change From Baseline in Asthma Control Questionnaire (ACQ-5) on Day 15 | The ACQ-5 measures 5 symptoms (woken at night by symptoms, wake in the morning with symptoms, limitation of daily activities, shortness of breath, and wheeze). The scale is 0-6, where 0=minimum and 6=maximum | Day 1-Day 15 in each of 5 treatment periods |