E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Obstructive Pulmonary Disease (COPD) |
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E.1.1.1 | Medical condition in easily understood language |
Chronic Obstructive Pulmonary Disease (COPD) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10009033 |
E.1.2 | Term | Chronic obstructive pulmonary disease |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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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 |
The primary objective of this study is to assess and compare the pharmacokinetics (PK) of Tiotropium delivered via BAI (4.5 mcg or 9.0 mcg), SPIRIVA HandiHaler (18 mcg) and Respimat SMI (5.0 mcg) following repeat dosing for 7 days in subjects with COPD. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
• To evaluate the efficacy of Tiotropium HFA inhalation aerosol delivered via BAI (4.5 mcg or 9.0 mcg) compared with Tiotropium bromide delivered via SPIRIVA HandiHaler (18 mcg tiotropium) and Respimat SMI (5.0 mcg tiotropium) in subjects with COPD following repeat dosing for 7 days.
• To evaluate the safety and tolerability of Tiotropium HFA BAI
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent signed and dated by the subject before conducting any study related procedure
2. Male or female subjects 40 -80 years of age, as of the Screening Visit
3. Diagnosis of COPD as defined by the GOLD (Global Initiative for Chronic Obstructive Lung Disease) Guidelines
4. A pre-bronchodilator Peak Inspiratory Flow (PIF) rate≥ 30 L/ min as measured with the In-CheckTM DIAL training device.
5. A measured post-bronchodilator (ipratropium bromide) FEV1 >30% and <80% of predicted normal for height, age and gender at the Screening Visit (SV). NHANES III predicted values will be used and adjustments to predicted values will be made for African-American subjects [1].
6. A measured post-bronchodilator (ipratropium bromide) FEV1/FVC <0.70 at the Screening Visit (SV)
7. If female, is currently not pregnant, breast feeding, or attempting to become pregnant (for 4 weeks before the Screening Visit (SV) and throughout the duration of the study), and is of
• Non-childbearing potential, defined as:
o ≥1 year post-menopausal or
o Surgically sterile (tubal ligation, bilateral oophorectomy, salpingectomy, or hysterectomy)
or is of
• Childbearing potential, has a negative serum pregnancy test, and is willing to commit to using a consistent and acceptable method of birth control as defined below for the duration of the study:
o Systemic contraception used for ≥1 month prior to screening, including birth control pills, transdermal patch, vaginal ring, implants, or injectables or
o Double barrier methods (condoms, cervical cap, diaphragm, and vaginal contraceptive film with spermicide) or
o Intrauterine device (IUD) with a low failure rate defined as <1% per year (use of copper IUDs are excluded)
or is of
• Childbearing potential and not sexually active, has a negative serum pregnancy test, and is willing to commit to using a consistent and acceptable method of birth control as defined above for the duration of the study, in the event the subject becomes sexually active
8. Current or ex-smoker with ≥10 pack-year smoking history
9. Subject is free of any concomitant conditions or treatment that could interfere with study conduct, influence the interpretation of study observations/results, or put the subject at increased risk during the study
10. Able to perform technically acceptable and reproducible spirometry per study guidelines as defined in the protocol and study procedures manual.
11. Able to demonstrate the proper inhalation techniques required for correct use of all delivery devices required in the study
12. Capable of understanding the requirements, risks, and benefits of study participation, and, as judged by the investigator, capable of giving informed consent and being compliant with all study requirements |
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E.4 | Principal exclusion criteria |
1 Pregnancy, nursing, or plans to become pregnant or donate gametes (ova or sperm) for in vitro fertilization during the study period or for 30 days following the subject’s last study related visit
2 History or current evidence of a clinically significant or uncontrolled disease including, but not limited to: cardiovascular, hepatic, renal, haematological, neuropsychological, endocrine, gastrointestinal or pulmonary (other than COPD such as asthma, sarcoidosis, non-CF bronchiectasis , cystic fibrosis, bronchopulmonary dysplasia or a diagnosis of alpha 1-antitrypsin deficiency). 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 which could affect the endpoint analysis if the disease/condition exacerbated during the study
3 History of and/or current diagnosis of asthma
4 History of a life-threatening COPD exacerbation
5Thoracotomy with pulmonary resection
6 Current congestive heart failure, history or current evidence of myocardial infarction (within 3 yrs of the Screening Visit [SV]), or history or current evidence of ischemic heart disease, including a diagnosis on screening ECG
7 History or current evidence of clinically significant cardiac arrhythmia, including a diagnosis on screening ECG
8 Presence of angle-closure glaucoma
9 History of malignancy (excluding basal cell carcinoma) within the past 5 years, regardless of the clinical significance or current stability of the disease
10 Known history or any current evidence of renal impairment or urinary retention. This includes abnormal renal function test results at screening
11 Presence of symptomatic prostatic hyperplasia
12 History of silent infections, including positive tests for HIV1, HIV2, Hepatitis B, Hepatitis C, or tuberculosis
13 Occurrence of any upper or lower respiratory infection, including but not limited to the common cold and flu, sinusitis, tonsillitis, pneumonia, bronchitis, or an ear infection (including otitis media and externa) which is not resolved by 14 days prior to randomization
14 Occurrence of a COPD exacerbation which is not resolved by 14 days prior to randomization
15 Subjects who require oxygen therapy and in the investigator’s opinion, will be unable to abstain from the use of oxygen therapy during testing
16 Subjects who have started or stopped an exercise rehabilitation program within 4 weeks of SV
17 Known or suspected hypersensitivity or idiosyncratic reaction to tiotropium, or to any ingredients used in the study medication formulations
18 Severe allergy to milk protein
19 Significant adverse drug reactions, including allergy or hypersensitivity reactions, to atropine or any anticholinergic substance related pharmacologically to atropine
20 Use of any prohibited concomitant medications within the prescribed (per protocol) withdrawal periods prior to SV
21 Treatment with orally administered (excluding orally inhaled) β-adrenergics
22 Treatment with β–adrenergic receptor antagonists administered by any route. The single exception is that cardioselective β1–adrenergic receptor antagonists are permitted provided that subjects have been on a stable dose for at least 1 week prior to SV and subjects are expected to be able to maintain the same dose throughout the study
23 Treatment with drugs commonly recognized to prolong the QTc interval
24 Treatment with any known CYP2D6 or CYP3A4 inhibitors within 30 days prior to SV
25 Initiation or change in dose of inhaled corticosteroids within the last 6 weeks prior to the SV, and /or not expected to maintain a stable dose of inhaled corticosteroids during the course of the study
26 Initiation or change in dose of oral or systemic corticosteroids within the last 6 weeks prior to the SV, unable to maintain a stable dose of oral or systemic corticosteroids during the course of the study, or a dose of oral or systemic corticosteroids in excess of the equivalent of 10 mg of prednisone per day
27 Exposure to any investigational drug within 30 days or six half-lives (whichever is greater) prior to SV
28 Plans to donate or has donated plasma or blood within 1 month prior to SV. This does not include small blood volumes taken for diagnostic purposes. Plans to donate plasma or blood within 3 months following study completion
29 Has a history of alcohol and/or substance abuse within the past 5yrs
30 Vulnerable subjects (e.g. persons kept in detention)
31The subject is an employee of the study site or has an immediate family member or household member involved with the conduct of the study (including participation in the study)
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Pharmacokinetic Outcome Measures (on Day 7 following 7 days of repeat dosing):
• Area under the plasma concentration-time curve on day 7 from time 0 to 24 hours (AUC0-24) for tiotropium
• Maximum observed plasma concentration (Cmax) for tiotropium
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Day 7-Day 8, following 7 days repeat dosing |
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E.5.2 | Secondary end point(s) |
Secondary Pharmacokinetic Outcome Measure (on Day 7 following 7 days of repeat dosing):
• Area under the plasma concentration-time curve on day 7 from time 0 to the time of the last quantifiable concentration as measured up to 24 hrs (AUC 0-t) for tiotropium
• Time at which the maximum plasma concentration was observed (tmax)for tiotropium
Other Pharmacokinetic Outcomes:
• The cumulative amount of urinary excretion of tiotropium, over 24 hours post-dose on Day 7.
• The plasma and urine levels of tiotropium on Day 1, at the start of each dosing period/end of each washout period
Efficacy
The following efficacy endpoints will be assessed on Day 8 (23-24 hours post-dosing on day 7) of each Treatment Period:
• Trough FEV1, defined as the average of the values at 23-24 hours post-Day 7 dose
• Trough FVC, defined as the average of the values at 23-24 hours post-Day 7 dose
The following efficacy endpoints will be assessed on Day 7 of each Treatment Period:
• Time to onset of measured effect (>10% improvement in FEV1 from pre-dose baseline on Day 7)
• Time to peak FEV1
• Forced expiratory volume in one second (FEV1) area under the curve for the time period 0 to 24 hours post-dose (FEV1 AUC(0-24h))
• Forced Vital Capacity (FVC) AUC(0-24h)
• Peak FEV1
• Peak FVC
The following efficacy-related endpoints will be assessed: Rescue medication use within 24 hours prior to study visit assessments and throughout the assessment period on Days 1 and 7 of each Treatment Period.
Safety and Tolerability
The following endpoints will be measured / recorded to evaluate safety and tolerability.
• Serial FEV1 measures during 60 minutes post-dose on Day 1 of each Treatment Period (to assess paradoxical bronchoconstriction)
• Rescue medication use during 60 minutes post-dose on Day 1 to use in assessing paradoxical bronchoconstriction.
• Treatment-emergent adverse events throughout the study
At times defined in the study schedule of events:
• Vital signs (blood pressure and pulse rate)
• Safety laboratory assessments
• ECGs
• Physical examinations |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Pharmacokinetic: Day 7, following 7 days repeat dosing
Other Pharmacokinetic: Day 7
Efficacy: Day 8 (23-24 hours post-dosing on day 7) of each Treatment Period OR Day 7, as detailed above
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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 | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerability, intra-subject variability |
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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) | No |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |