| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects With Persistent Asthma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Subjects With Persistent Asthma |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the effect of 3 doses of GP MDI compared to Placebo MDI and Spiriva® Respimat® on lung function over 24 weeks in subjects with persistent asthma. |
|
| E.2.2 | Secondary objectives of the trial |
| To assess the effect of 3 doses of GP MDI compared to Placebo MDI and Spiriva Respimat on exacerbations, quality of life, and symptoms over 24 weeks in subjects with persistent asthma. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Give their signed written informed consent (and assent as appropriate) to participate
2. Are at least 12 years of age and no older than 80 years
3. Have a documented history of physician-diagnosed asthma
4. Require inhaled asthma maintenance therapy: has been regularly using an ICS/LABA on a stable regimen, with the ICS doses allowed in Table 5 1, for at least 4 weeks prior. Subjects may be included if also receiving tiotropium 2.5 µg QD for at least 4 weeks prior.
5. ACQ-5 total score ≥1.5 at Visit 2
6. Based on the average of 2 assessments, pre-bronchodilator FEV1 >40% and <85% of predicted normal value for subjects 18 to 80 years of age or >40% and <90% of predicted for subjects 12 to <18 years of age at Visits 1, 2 (if applicable), and 4
7. Documented reversibility to albuterol (defined as a post-albuterol increase in FEV1 of ≥12% and ≥200 mL) at either Visit 1 or Visit 2
8. At Visits 1, 2 (if applicable), and 4 (pre-randomization), demonstrate both:
- Acceptable spirometry performance (ie, meet American Thoracic Society [ATS]/European Respiratory Society [ERS] acceptability criteria; Appendix 3)
- FEV1 repeatability at one of the pre-dose measurements
9. Willing and, in the opinion of the Investigator, able to adjust current asthma therapy, as required by the protocol
10. Demonstrate acceptable MDI administration technique
Note: Use of a spacer device during the Screening and randomized Treatment Periods is not permitted.
11. Body mass index <40 kg/m2 (see calculators in Appendix 1)
12. Agree to 1 of the following to prevent pregnancy:
- Non-childbearing potential (ie, physiologically incapable of becoming pregnant, including any female who is 2 years post-menopausal, or surgically sterile [defined as having a bilateral oophorectomy, hysterectomy, or tubal ligation])
Note: For purposes of this protocol, menopausal women are defined as women ≥50 years old who are amenorrheic for 12 consecutive months or more following cessation of all exogenous hormonal treatment
- Practice abstinence
- If a female of childbearing potential and sexually active, agrees to prevent pregnancy by using 1 of the following methods of birth control from the date the ICF is signed until 2 weeks after the final dose of study drug is taken:
◦ Hormonal contraception (eg, oral contraceptive, contraceptive implant, or injectable hormonal contraceptive)
◦ Double-barrier birth control (eg, condom plus intrauterine device, diaphragm plus spermicide, or condom plus spermicide)
◦ Maintenance of a monogamous sexual relationship with a male partner who has been surgically sterilized by vasectomy
- If a female of childbearing potential, have a negative serum pregnancy test
13. Screening clinical laboratory tests must be acceptable to the Investigator
14. Screening ECG must be acceptable to the Investigator
15. Compliance: must be willing to remain at the study center as required per protocol to complete all visit assessments |
|
| E.4 | Principal exclusion criteria |
1. Oral corticosteroid use (any dose) within 4 weeks
2. Received any marketed (eg, omalizumab) or investigational biologic within 3 months or 5 half-lives, whichever is longer, or any other medication specifically prohibited by the protocol within the indicated exclusionary time periods (Table 5 4 and Table 5 5)
3. Current smokers, former smokers with >10 pack-years history, or former smokers who stopped smoking <6 months previously (including all forms of tobacco, e-cigarettes, and marijuana)
4. Life-threatening asthma as defined as a history of significant asthma episode(s) requiring intubation associated with hypercapnia, respiratory arrest, hypoxic seizures, or asthma related syncopal episode(s)
5. Completed treatment for lower respiratory infection or asthma exacerbation within 4 weeks
6. Upper respiratory infection not resolved within 7 days
7. Hospitalizations for asthma within 3 months
8. Historical or current evidence of a clinically significant disease including, but not limited to: cardiovascular (eg, congestive heart failure, known aortic aneurysm, clinically significant cardiac arrhythmia, coronary heart disease), hepatic, renal, hematological, neurological, endocrine (eg, uncontrolled diabetes mellitus, uncontrolled thyroid disorder, Addison’s disease, Cushing’s syndrome), gastrointestinal (eg, poorly controlled peptic ulcer, gastroesophageal reflux disease), or pulmonary (eg, chronic bronchitis, emphysema, bronchiectasis with the need of treatment, cystic fibrosis, bronchopulmonary dysplasia, chronic obstructive pulmonary disease). Significant is defined as any disease that, in the opinion of the Investigator, would put the safety of the subject at risk through participation, or that could affect the efficacy or safety analysis if the disease/condition exacerbated during the study
9. Pacemaker or implantable cardioverter-defibrillator/cardiac resynchronization therapy/cardiac resynchronization therapy-defibrillator devices
10. Narrow angle glaucoma not adequately treated. All medications approved for control of intraocular pressures are allowed, including topical ophthalmic non-selective β-blockers
11. Symptomatic prostatic hypertrophy that in the opinion of the Investigator is clinically significant and not adequately controlled with appropriate therapy
Note: Subjects with a trans-urethral resection of prostate or full resection of the prostate within 6 months prior to Visit 1 are excluded from the study.
12. Bladder neck obstruction or urinary retention that is clinically significant in the opinion of the Investigator
13. Calculated creatinine clearance ≤30 mL/minute using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula for subjects 19 to 80 years of age or the Schwartz formula for subjects 12 to <19 years of age and on repeat testing prior to Visit 4
14. Abnormal liver function tests, defined as aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin (TBL) ≥1.5 times the upper limit of normal (ULN) at Visit 1 and on repeat testing prior to Visit 2 (Note: Chronic stable hepatitis B or C is acceptable)
15. Cancer not in complete remission for at least 5 years
Note: Subjects with squamous cell carcinoma of the skin, basal cell carcinoma of the skin, in situ carcinoma of the cervix, or localized prostate cancer are eligible if, in the opinion of the Investigator, the condition has been adequately worked up and clinically controlled and the subject’s participation in the study would not represent a safety concern.
16. Hospitalized for psychiatric disorder or attempted suicide within 1 year
17. History of psychiatric disease, intellectual deficiency, poor motivation, or other conditions limiting informed consent validity
18. Hypersensitivity to β2-agonists, corticosteroids, anticholinergics, or any component of the investigational MDI, Spiriva Respimat (tiotropium), or ipratropium
19. Significant, in the opinion of the Investigator, abuse of alcohol or drugs
20. Unable to abstain from protocol-defined prohibited medications during Screening and Treatment Periods
21. Using any herbal products by inhalation or nebulizer within 2 weeks and does not agree to stop during the study duration
22. Received a live attenuated vaccination within 7 days
23. Study investigators, sub-investigators, coordinators, and their employees or immediate family members
24. Treatment with investigational study drug (or device) in another clinical study within the last 30 days or 5 half-lives, whichever is longer
25. Previously randomized in any PT001 study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 4 hours (AUC0-4) at Week 24 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| • Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 4 hours (AUC0-4) at Week 24 |
|
| E.5.2 | Secondary end point(s) |
• Change from baseline in morning pre-dose trough FEV1 at Week 24
• Time to first moderate/severe asthma exacerbation
• Change from baseline in Asthma Control Questionnaire (ACQ)–7 at Week 24
• Change from baseline in ACQ-5 at Week 24
• Change from baseline in Asthma Quality of Life Questionnaire for 12 years and older (AQLQ +12) at Week 24 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Change from baseline in morning pre-dose trough FEV1 at Week 24
• Time to first moderate/severe asthma exacerbation
• Change from baseline in Asthma Control Questionnaire (ACQ)–7 at Week 24
• Change from baseline in ACQ-5 at Week 24
• Change from baseline in Asthma Quality of Life Questionnaire for 12 years and older (AQLQ +12) at Week 24 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Open-label Spiriva® Respimat® |
|
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| Yes |
| E.8.4 | Will this trial be conducted at multiple sites globally? | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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