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
Condition: Asthma
MeSH terms: Asthma
Intervention: Glycopyrronium MDI; Serevent Diskus 50 μg; Placebo
Intervention description: GP MDI
Intervention MeSH terms: Glycopyrrolate; Salmeterol Xinafoate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 248.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No

Summary:

      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
    

Eligibility criteria:

        Inclusion Criteria:

          1. Give their signed written informed consent to participate

          2. Males and females ranging in age between 18 to 70 years, inclusive, before Screening
             (Visit 1a)

          3. 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

          4. Asthma History: Have a diagnosis of intermittent asthma or mild to moderate persistent
             asthma, diagnosed at least 6 months prior to Screening (Visit 1a)

          5. 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)

          6. Pulmonary Function: Must have a pre-bronchodilator FEV1 ≥60% and ≤90% of predicted
             normal value at Visit 1a/b and Visit 2a/b

          7. 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).

          8. Results of clinical laboratory tests conducted at Screening (Visit 1a) must be
             acceptable to the Investigator.

        Exclusion Criteria:

          1. 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).

          2. 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).

          3. Seasonal or Exercise-Induced Asthma Alone: Subjects with only seasonal or
             exerciseinduced asthma are excluded from participation.

          4. 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.

          5. 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.

          6. 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.

          7. Inhaled Anticholinergic Use: Subjects must not have used inhaled anticholinergics for
             at least the 2 weeks prior to Screening (Visit 1a).

          8. Pregnant women or nursing mothers

          9. 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).

         10. Uncontrolled Hypertension: Subjects who, in the opinion of the Investigator, have
             clinically significant uncontrolled hypertension.

         11. 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.

         12. 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.

         13. 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.

         14. 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.

         15. 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)

         16. 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).

         17. 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.