COPD

The overall objective of this study is to assess the efficacy and safety of treatment with Glycopyrronium and Formoterol Fumarate MDI (GFF MDI, 14.4/9.6 μg ex-actuator, BID), Formoterol Fumarate MDI (FF MDI, 9.6 μg ex-actuator, BID), and Glycopyrronium MDI (GP MDI, 14.4 μg ex-actuator, BID) compared with each other and with Placebo MDI over 24 weeks in subjects with moderate to very severe COPD.

Glycopyrronium and Fomoterol Fumarate Inhalation Aerosol

Formoterol Fumarate
Glycopyrronium
Glycopyrronium and Fomoterol Fumarate

Metered Dose Inhaler

4.8
7.2
7.2/4.8

Efficacy Assessments:
All efficacy assessments are relative to pre-dose baseline obtained at Visit 4. Lung
function measurements and symptom-based endpoints will be evaluated. The primary
endpoint differs by approach but is always based on morning pre-dose trough FEV1.
However, in some regions co-primary endpoints are required for registration purposes.
The four different registration approaches will be called: 1) US/China, 2) Japan 3) EU,
and 4) Hybrid.
In the US/China and Japan approaches, co-primary endpoints are not required.
Evaluation of treatment efficacy at a landmark time point is required for the US and
China, and the primary endpoint is identical for these two countries. However in Japan,
the primary endpoint is assessed over Weeks 12 to 24.
The EU approach is for registration purposes in countries or regions such as Europe
where co-primary endpoints are required.
The Hybrid approach is for countries or regions where co-primary endpoints are only
required for comparisons to Placebo MDI and not for the comparison of GFF MDI to its
components. The delineation of multiplicity controls for the primary and secondary
measures are separated by approach.
All inferential results will be based on analyses using the Intent-to-Treat (ITT)
Population.

Inclusion Criteria
Subjects eligible for enrollment in the study must meet all of the following criteria:
1. Give their signed written informed consent to participate.
2. Are at least 40 years of age and no older than 80 at Visit 1.
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 Visit 1, and agrees to
one of the following acceptable contraceptive methods used consistently and correctly
as outlined below (ie, in accordance with the approved product label and the
instructions of the physician for the duration of the study – from Visit 1 (Screening)
until 14 days after Visit 11:
- 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; 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 (IUD), 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. COPD Diagnosis: Subjects with an established clinical history of COPD as defined by
the American Thoracic Society (ATS)/European Respiratory Society (ERS) (Celli, 2004)
characterized by:
- Airflow limitation that is not fully reversible. Progressive airflow limitation
associated with an abnormal inflammatory response of the lungs to noxious particles
or gases, primarily caused by cigarette smoking.
5. Tobacco Use: Current or former smokers with a history of at least 10 pack-years of
cigarette smoking. [Number of pack-years = (number of cigarettes per day / 20) x
number of years smoked (eg, 20 cigarettes per day for 10 years, or 10 cigarettes per day
for 20 years represent 10 pack-years)].
6. Severity of Disease: Subjects with an established clinical history of COPD and severity
defined as:
- At Visit 1, FEV1/FVC ratio of <0.70.
- At Visit 2, and 3, pre- and post-bronchodilator FEV1/FVC ratio of <0.70.
- At Visit 1, FEV1 must be <80% predicted normal value calculated using the Third
National Health and Nutrition Examination Survey (NHANES III) reference
equations. (Or reference norms applicable to other regions, e.g. for Japan, use Japan
Respiratory Society (JRS) reference equations;[JRS, 2013].
- At Visit 2, post-bronchodilator FEV1 must be <80% predicted normal value,
calculated using NHANES III reference equations (Or reference norms applicable to
other regions, e.g. for Japan, use Japan Respiratory Society (JRS) reference
equations;[JRS, 2013]and the measured FEV1 must also be ≥750 mL if FEV1 <30%
of predicted normal value.
- At Visit 4, pre-bronchodilator FEV1/FVC ratio of <0.70.
- At Visit 4, the average of the -60 min and -30 min pre-dose FEV1 assessments must be
<80% predicted normal value calculated using NHANES III reference equations (Or
reference norms applicable to other regions, e.g. for Japan, use Japan Respiratory
Society (JRS) reference equations;[JRS, 2013].
7. Subject is willing and, in the opinion of the Investigator, able to adjust current COPD
therapy as required by the protocol
8. Screening clinical laboratory tests must be acceptable to the Investigator.
9. Screening ECG must be acceptable to the Investigator.
10. Chest X-ray or computed tomography (CT) scan of the chest/lungs within 6 months prior
to Visit 1 must be acceptable to the Investigator. Subjects who have a chest X-ray
(or CT scan) that reveals clinically significant abnormalities not believed to be due to the
presence of COPD should not be included. A chest X-ray must be conducted if the most
recent chest X-ray or CT scan are more than 6 months old at the time of Visit 1 except in
countries with restrictive radiology assessment practice (e.g. Germany) where only
subjects who have had an x-ray or CT scan (thorax) performed outside of the study in the
last 6 months are allowed to be enrolled. Alternatively, in these countries, an MRI may
be used instead of a CT scan or x-ray as per local practice assessment.
11. Compliance: Subjects must be willing to remain at the study center as required per
protocol to complete all visit assessments.

Exclusion Criteria
Subjects meeting any of the following criteria are to be excluded:
1. Significant diseases other than COPD, ie, disease or condition which, in the opinion of
the Investigator, may put the subject at risk because of participation in the study or may
influence either the results of the study or the subject’s ability to participate in the study
2. Pregnancy: Women who are pregnant or lactating or women of childbearing potential
who are not using an acceptable method of contraception.
3. Respiratory
a) Asthma: Subjects, who in the opinion of the Investigator, have a current diagnosis
of asthma.
b) Alpha-1 Antitrypsin Deficiency: Subjects who have alpha-1 antitrypsin deficiency
as the cause of COPD.
c) Other Respiratory Disorders: Subjects who have other active pulmonary disease
such as active tuberculosis, lung cancer, bronchiectasis (High Resolution CT
evidence of bronchiectasis that cause repeated acute exacerbations), sarcoidosis,
idiopathic interstitial pulmonary fibrosis (IPF), primary pulmonary hypertension,
or uncontrolled sleep apnea (ie, in the opinion of the Investigator severity of the
disorder would impact the conduct of the study). Note: Allergic rhinitis is not
exclusionary.
d) Lung Volume Reduction: Subjects who have undergone lung volume reduction
surgery, lobectomy or bronchoscopic lung volume reduction (endobronchial
blockers, airway bypass, endobronchial valves, thermal vapor ablation, biological
sealants, and airway implants) within 1 year of Visit 1.
e) Hospitalization: Subjects who have been hospitalized due to poorly controlled
COPD within 3 months prior to Visit 1 (Screening) or during the Screening Period
(Visit 1 to Visit 4).
f) Poorly Controlled COPD: Subjects who have poorly controlled COPD, defined as
acute worsening of COPD that requires treatment with oral corticosteroids or
antibiotics within 6 weeks prior to Visit 1 (Screening) or during the Screening
Period (Visit 1 to Visit 4). Note: Subjects who are steroid dependent and
maintained on an equivalent of 5 mg prednisone per day or 10 mg every other day
for at least 3 months prior to Visit 1 are eligible for enrollment providing the dose
of oral steroids remains stable during the screening period (V1-V4).
g) Lower Respiratory Tract Infection: Subjects who had lower respiratory tract
infections that required antibiotics within 6 weeks prior to Visit 1 (Screening) or
during the Screening Period (Visit 1 to Visit 4).
h) Spirometry Performance:
a. Acceptability: Subjects who cannot perform acceptable spirometry,
ie, meet ATS/ERS acceptability criteria
b. Repeatability: Subjects who cannot perform technically acceptable
spirometry with at least three acceptable flow-volume curves with two or
more meeting ATS repeatability criteria for FEV1during at least one of the
pre-bronchodilator assessments at Visit 2 (-60 minute or -30 minute) and at
the post-bronchodilator assessment at Visit 2
c. FEV1 Baseline Stability: Subjects who cannot meet protocol-specified
reproducible criteria. FEV1 Baseline Stability is defined as the average of
the -60 min and -30 min pre-dose FEV1 assessments at Visit 4 being within
±20% or 200 mL of the mean of the pre-bronchodilator FEV1 assessments
obtained at the two preceding visits (average of pre-dose FEV1
assessments obtained at Visit 2 and Visit 3).
i) Oxygen: Subjects receiving long-term-oxygen therapy (LTOT) or nocturnal
oxygen therapy required for greater than 12 hours a day. Note: As needed oxygen
use is not exclusionary.
j) Subject use of any non-invasive positive pressure ventilation (NIPPV).device
Note: Subjects using continuous positive airway pressure (CPAP) or bilevel
positive airway pressure (BiPAP) for Sleep Apnea Syndrome are allowed in the
study.
k) Change in smoking status (ie, start or stop smoking,) or initiation of a smoking
cessation program within 6 weeks of Visit 1 and throughout the Screening Period
(Visit 1 to Visit 4).
l) Pulmonary Rehabilitation: Subjects who have participated in the acute phase of a
pulmonary rehabilitation program within 4 weeks prior to Visit 1 (Screening) or
who will enter the acute phase of a pulmonary rehabilitation program during the
study. Subjects who are in the maintenance phase of a pulmonary rehabilitation
program are not to be excluded.
m) Subjects who have initiated or altered the dose regimen of intranasal
corticosteroids, intranasal antihistamines, or a combination thereof within 7 days
prior to Visit 1 or during the Screening Period (Visit 1 to Visit 4)
4. Cardiac disease
a) Subjects who have unstable ischemic heart disease, left ventricular failure, or
documented myocardial infarction within 12 months of enrollment. Subjects with
a recent history of acute coronary syndrome, or who have undergone
percutaneous coronary intervention or coronary artery bypass graft within the past
3 months are to be excluded.
b) Subjects with congestive heart failure (CHF NYHA Class III/IV)
c) Clinically significant abnormal ECG: A clinically significant abnormal ECG is
defined as (but not limited to) any of the following:
1. Clinically significant conduction abnormalities [eg, left bundle branch
block, Wolff-Parkinson-White syndrome or evidence of second degree
(Mobitz Type II) or third degree atrioventricular (AV) block]
2. Clinically significant arrhythmias (eg, atrial fibrillation with irregular
ventricular response, atrial flutter, ventricular tachycardia). Note: atrial
fibrillation that has been clinically stable for at least 6 months is
appropriately treated with anticoagulation and controlled with a rate
control strategy (ie, selective beta blocker, calcium channel blocker,
digoxin or ablation therapy) for at least 6 months is allowed for inclusion.
In such subjects, atrial fibrillation must be present at pre-randomization
visits, with a resting ventricular rate < 100/min. At screening, the atrial
fibrillation must be confirmed by central reading.
3. A mean corrected QT interval using Fridericia’s correction factor (QTcF)
value at screening >450 ms for males and >470 ms for females or an ECG
that is not suitable for QT measurements (eg, poorly defined termination
of the T wave) at Visit 1 that remains elevated on repeat testing prior to
Visit 2.
4. Ventricular rate <45 beats per minute (bpm)
5. Pathological Q waves of ≤1 year
6. ST- T wave abnormalities deemed to be clinically significant by the
Investigator. Note: Subjects with non-specific ST-T wave abnormalities
that are not deemed clinically significant (per Investigator) are allowed.
7. Any other ECG abnormalities not listed above that in the opinion of the
Investigator are clinically significant.
d) Clinically Uncontrolled Hypertension: Subjects who have clinically significant
uncontrolled hypertension.
5. Neurological
• Subjects with seizures requiring anticonvulsants within 12 months prior to Visit 1
(Screening). Note: Subjects treated with anticonvulsant medication for 12 months
or more with no seizure events are eligible.
• Subjects taking selective serotonin reuptake inhibitors (SSRIs) or serotonin–
norepinephrine reuptake inhibitors (SNRIs) whose dose has not been stable for at
least four weeks prior to Visit 1 or is altered at any point during the Screening
Period (Visit 1 to Visit 4), or exceeds the maximum recommended dose
6. Renal
a) Subjects with symptomatic prostatic hypertrophy that is clinically significant in
the opinion of the Investigator. Subjects with a trans-urethral resection of prostate
(TURP) or full resection of the prostate within 6 months prior to Visit 1 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 ≤ 50 mL/minute using CKD-EPI
(Chronic Kidney Disease Epidemiology Collaboration) formula (Levey 2009) at
Visit 1 and on repeat testing prior to Visit 2.
Note: Subjects with overactive bladder syndrome treated with oral
anticholinergics who have been on treatment for at least 1 month are allowed in
the trial.
7. Endocrine
a) Subjects, who in the opinion of the Investigator, have uncontrolled hypo-or
hyperthyroidism, hypokalemia or hyperadrenergic state
b) Subjects, who in the opinion of the Investigator, have uncontrolled Type I or II
diabetes
8. Liver: Subjects with abnormal liver function tests defined as AST, ALT, or total bilirubin
≥ 1.5 times upper limit of normal at Visit 1 and on repeat testing prior to Visit 2.
9. Cancer: Subjects who have cancer that has not been in complete remission for at least
five years. Note: Subjects with squamous cell carcinoma of the skin, basal cell
carcinoma of the skin, or localized prostate cancer are eligible, if in the opinion of the
Investigator, the condition has been adequately worked up, is clinically controlled and the
subject’s participation in the study would not represent a safety concern.
10. 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 open
angle 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.
11. Drug Allergy: Subjects who have a history of hypersensitivity to β2-agonists,
glycopyrronium or other muscarinic anticholinergics, or any component of the MDI.
12. Substance Abuse: Subjects, who in the opinion of the Investigator, significantly abuse
alcohol or drugs (Refer to exclusion criterion 1).
13. Medication prior to spirometry: Subjects who are medically unable to withhold their
short-acting bronchodilators for the 6-hour period required prior to spirometry testing at
each study visit will be excluded.
14. Prohibited Medications: Subjects who, in the opinion of the Investigator, would be
unable to abstain from protocol-defined prohibited medications during the screening
period and treatment phases of this study (Refer to Tables 1-4 in Section 5.4).
15. Vaccinations: Subjects who received a live attenuated vaccination within 30 days prior
to Visit 1 (Screening) or during the Screening Period (between Visit 1 to Visit 4).
Note: Inactivated influenza vaccination, pneumococcal vaccination or any other
inactivated vaccine is acceptable provided it is not administered within 48 hours prior to
Visit 1 (Screening) or Visit 4 (randomization).
16. Non-compliance: Subjects unable to comply with study procedures including noncompliance with diary completion (ie, <70% subject completion of diary assessments in
the last 7 days preceding Visit 4).
17. Affiliations with Investigator site: Study Investigators, sub-Investigators, study
coordinators, employees of a participating Investigator or immediate family members of
the aforementioned are excluded from participation in this study.
18. Questionable Validity of Consent: Subjects with a history of psychiatric disease,
intellectual deficiency, poor motivation, substance abuse (including drug and alcohol), or
other conditions that will limit the validity of informed consent to participate in the study.
19. Subjects using prohibited medications (Refer to Table 4)
20. Investigational Drugs or Devices: Treatment with investigational study drug or device in
another clinical trial within the last 30 days or five half-lives prior to Visit 1 (Screening),
whichever is longer. Note: Subject participation in observational studies (ie, studies that
do not require change to medication or an additional intervention) is not exclusionary.
21. Hand-to-Breath Coordination: Subjects who requires the use of a spacer device to
compensate for poor hand-to-breath coordination with a MDI. Note: Use of a nebulizer
to deliver COPD medications is prohibited throughout the trial
22. Previous Participation: Subjects who were previously enrolled in any Pearl Therapeutics
trial.