Effect of Glycopyrronium on Morning Symptoms and Pulmonary Function in Patients With Moderate to Severe COPD

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01959516
• Collaborator: (none)
• Enrollment: 124
• Locations: 21
• Arms: 2
• Duration (Months): 8
• Patients Per Site: 5.9
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

This study purpose is to further study the profiles of glycopyrronium (NVA237) and tiotropium during the first hours after dosing and their impact on pulmonary function, COPD symptoms and ability to perform daily activities by the patient.

Condition or Disease	Intervention/Treatment	Phase
COPD	Drug: Glycopyrronium; Drug: Tiotropium; Drug: Placebo to glycopyrronium; Drug: Placebo to tiotropium	Phase 4

Detailed Description

Randomized, multicenter, blinded, two-period cross-over design. Each treatment will last 28 days. All patients will receive both treatments in a cross-over design, with a wash-out period of 14-19 days in between. The total duration of the study for each patient is approximately 70 days (from randomization) plus 30 days of safety follow-up.

Study Design

• Study Type: Interventional
• Actual Enrollment: 124 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Multicenter, Randomized, Blinded, Two-period Cross-over Study to Assess the Effect of Glycopyrronium (44 Micrograms QD) Versus Tiotropium (18 Micrograms QD) on Morning Symptoms and Pulmonary Function in Patients With Moderate to Severe COPD
• Study Start Date: Feb 1, 2014
• Actual Primary Completion Date: Oct 1, 2014
• Actual Study Completion Date: Oct 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sequence A ⇒ B Participants will receive sequence A = glycopyrronium + placebo to tiotropium during 28 days, followed by a 14 day washout period, then sequence B= tiotropium + placebo to glycopyrronium for 28 days.	Drug: Glycopyrronium; Glycopyrronium capsule for inhalation once per day via SDDPI; Drug: Tiotropium; Tiotropium capsule for inhalation once per day via HandiHaler® device; Drug: Placebo to glycopyrronium; Placebo to glycopyrronium capsule for inhalation once per day via SDDPI; Drug: Placebo to tiotropium; Placebo to tiotropium capsule for inhalation once per day via HandiHaler® device
Experimental: Sequence B ⇒ A Participants will receive sequence B= tiotropium + placebo to glycopyrronium during 28 days, followed by a 14 day washout period, then sequence A= glycopyrronium + placebo to tiotropium for 28 days.	Drug: Glycopyrronium; Glycopyrronium capsule for inhalation once per day via SDDPI; Drug: Tiotropium; Tiotropium capsule for inhalation once per day via HandiHaler® device; Drug: Placebo to glycopyrronium; Placebo to glycopyrronium capsule for inhalation once per day via SDDPI; Drug: Placebo to tiotropium; Placebo to tiotropium capsule for inhalation once per day via HandiHaler® device

Outcome Measures

Primary Outcome Measures

1. Forced Expiratory Volume in 1 Second (FEV1) AUC0-4h After First Dose of Treatment. [Day 1]

   Forced Expiratory Volume in 1 second (FEV1) Area Under the Curve (AUC) will measured via spirometry and calculated from 0 to 4 hours post-dose on day 1 of study treatment.

Secondary Outcome Measures

1. Comparison of Glycopyrronium QD Versus Tiotropium QD on Symptoms Outcome [day 1 (baseline) and week 4]

   Comparison of symptoms outcome between glycopyrronium QD versus tiotropium QD will be conducted via the PROMorning COPD Symptoms questionnaire. This questionnaire will be completed by participants at waking-up, pre-inhalation of study treatment (at home), and they will complete Part 2 of PRO-Morning COPD Symptoms questionnaire at site, 3hours post-inhalation of study treatment. The PRO-Morning COPD Symptoms Questionnaire is a self-administered patient reported outcome (PRO) instrument developed by the sponsor to evaluate patients' experience of early morning symptoms of COPD. The questionnaire consists of two parts : predose and postdose. Each part has 6 questions and for each question a scale of 0 to 10 can be reached. For the predose and postdose part of the questionnaire you will have then each a total score of 0-60 by adding the sub-scores for each question, higher scores represent worse severity of COPD morning symptoms

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Male and female adults aged ≥ 40 years.

• Co-operative outpatients with a clinical diagnosis of moderate to severe COPD confirmed by spirometry according to GOLD criteria 2013 and including all of the following: a) Current or ex-smokers who have a smoking history of at least 10 pack years (e.g.10 pack years = 1 pack /day x 10 years or ½ pack/day x 20 years). An ex-smoker may be defined as a subject who has not smoked for ≥ 6 months at Screening.

1. Patients with airflow limitation indicated by a post-bronchodilator FEV1 < 80% and ≥ 40% of the predicted normal value at Visit 2 (Post- bronchodilator refers to within 10-15 min of inhalation of 400 µg (4x100 µg) of salbutamol). c) .Post-bronchodilator FEV1/FVC < 0.7 at Visit 2 (Post- bronchodilator refers to within 10-15 min of inhalation of 400 µg (4x100 µg) of salbutamol).

• Patients with a COPD Assessment Test (CAT) score ≥ 10 at Visit 2.

Exclusion criteria:

• Patients who have had a COPD exacerbation requiring systemic glucocorticosteroid treatment or antibiotics and/or hospitalization in the 6 weeks prior to Visit 1. In the event of an exacerbation occurring during the Screening period (Visits 1-2), the patient must be discontinued from the study. The patient may be re-enrolled once the inclusion/exclusion criteria are met. Only one re-enrollment is allowed.

• Patients who have had a respiratory tract infection within 6 weeks prior to Visit 1. Patients who develop a respiratory tract infection between Visit 1 and Visit 2 must discontinue from the trial, but may be permitted to re-enrol at a later date once the inclusion/exclusion criteria have been met. Only one re-enrollment is allowed.

• Patients on any long-acting bronchodilator therapy. Those patients may enter the study after bronchodilator withdrawal during a 10-day wash-out period (only rescue salbutamol allowed as bronchodilator therapy during wash-out). Patients on fixed combination of long acting β2-agonists/inhaled corticosteroid (LABA/ICS) therapy before screening must be switched to the equivalent dose of ICS monotherapy and salbutamol as rescue.

• Patients receiving any other prohibited COPD-related medications specified in Table 5-1 must undergo the required wash-out period prior to Visit 2.

• Patients who have had a clinical history of asthma.

• Patients with concomitant pulmonary disease, e.g. pulmonary tuberculosis or clinically significant bronchiectasis.

• Patients with alpha-1-antitrypsin deficiency.

• Patients with contraindications for LAMA treatment including medical history of symptomatic prostatic hypertrophy, bladder neck obstruction, narrow-angle glaucoma and severe renal impairment (estimated glomerular filtration rate below 30 ml/min/1.73 m2) documented in the previous 6 months.

• Patients with a history of unstable cardiovascular disease or arrhythmias including atrial fibrillation/flutter or long QT syndrome or whose resting QTcF (calculated according to Fridericia QT correction formula preferred, but Bazett acceptable) is prolonged (≥ 450 msec for males and ≥ 460 msec for females) at screening (Visit 1) or baseline (Visit 2, baseline 1).

• Concomitant use of agents known to prolong the QT interval unless it can be permanently discontinued for the duration of study.

• Patients contraindicated for treatment with, or having a history of reactions/ hypersensitivity to any of the following inhaled drugs, drugs of a similar class or any component thereof: -anticholinergic agents - long and short acting 2 agonists -sympathomimetic amines -excipients of the trial medication (lactose monohydrate and/or magnesium estearate)

• Patients whose body mass index (BMI) is less than 15 or greater than 40 kg/m2.

• History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.

Other exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Geesthacht	Schleswig Holstein	Germany	12502
2	Novartis Investigative Site	Berlin		Germany	10119
3	Novartis Investigative Site	Berlin		Germany	12099
4	Novartis Investigative Site	Berlin		Germany	13156
5	Novartis Investigative Site	Halle		Germany	06108
6	Novartis Investigative Site	Leipzig		Germany	04103
7	Novartis Investigative Site	Leipzig		Germany	04275
8	Novartis Investigative Site	Potsdam		Germany	14467
9	Novartis Investigative Site	Wiesbaden		Germany	65187
10	Novartis Investigative Site	Firenze	FI	Italy	50122
11	Novartis Investigative Site	Milano	MI	Italy	20138
12	Novartis Investigative Site	Orbassano	TO	Italy	10043
13	Novartis Investigative Site	Barcelona	Cataluña	Spain	08026
14	Novartis Investigative Site	Lugo	Galicia	Spain	27003
15	Novartis Investigative Site	Zaragoza		Spain	50009
16	Novartis Investigative Site	Blackpool		United Kingdom	FY3 7EN
17	Novartis Investigative Site	Bradford		United Kingdom	BD9 6RJ
18	Novartis Investigative Site	Cambridge		United Kingdom	CB7 5JD
19	Novartis Investigative Site	Cardiff		United Kingdom	CF5 4AD
20	Novartis Investigative Site	Watford		United Kingdom	WD25 7NL
21	Novartis Investigative Site	Wishaw		United Kingdom	ML2 0DP

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01959516
• Other Study ID Numbers: CNVA237A3401
• First Posted: Oct 10, 2013
• Last Update Posted: Apr 15, 2016
• Last Verified: Mar 1, 2016

• Keywords provided by Novartis Pharmaceuticals: COPD, early morning symptoms
• Additional relevant MeSH terms: Glycopyrrolate; Tiotropium Bromide

Study Results

Participant Flow

Recruitment Details	A total of 126 patients were randomized to one of the two treatment sequences in a ratio of 1:1. Due to misrandomization, two patients did not receive at least one dose of the study treatment. Both, safety and ITT population included 124 patients.

Arm/Group Title	Glycopyrronium First, Then Tiotropium"	Tiotropium First, Then Glycopyrronium
Arm/Group Description	Sequence A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto) to B (Tiotropium 18 μg QD + placebo of glycopyrronium) Sequence B (Tiotropium 18 μg QD + placebo of glycopyrronium) to A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto)	Sequence B (Tiotropium 18 μg QD + placebo of glycopyrronium) to A (Glycopyrronium 44 μg QD + placebo of tiotropiumto) Sequence A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto) to B (Tiotropium 18 μg QD + placebo of glycopyrronium)
Period Title: Epoch 1
STARTED	63	63
Safety Population	62	62
ITT Population	62	62
COMPLETED	53	58
NOT COMPLETED	10	5
Period Title: Epoch 1
STARTED	63	63
COMPLETED	61	62
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	All Participants (Intent To Treat Analysis,ITT)
Arm/Group Description	All participants who were randomized to one of the two treatment sequences in a ratio of 1:1. Participants will receive sequence A = glycopyrronium + placebo to tiotropium during 28 days, followed by a 14 day washout period, then sequence B= tiotropium + placebo to glycopyrronium for 28 days.
Overall Participants	124
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	65.7 (8.1)
Sex: Female, Male (Count of Participants)
Female	37 29.8%
Male	87 70.2%

Outcome Measures

1. Primary Outcome

Title	Forced Expiratory Volume in 1 Second (FEV1) AUC0-4h After First Dose of Treatment.
Description	Forced Expiratory Volume in 1 second (FEV1) Area Under the Curve (AUC) will measured via spirometry and calculated from 0 to 4 hours post-dose on day 1 of study treatment.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) population consisted of all randomized patients who received at least one dose of the study treatment and had at least one post-dose value of FEV1

Arm/Group Title	Glycopyronium From Sequence A to B and Sequence B to A	Tiotropium From Sequence A to B and Sequence B to A
Arm/Group Description	Sequence A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto) to B (Tiotropium 18 μg QD + placebo of glycopyrronium) Sequence B (Tiotropium 18 μg QD + placebo of glycopyrronium) to A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto)	Sequence B (Tiotropium 18 μg QD + placebo of glycopyrronium) to A (Glycopyrronium 44 μg QD + placebo of tiotropiumto) Sequence A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto) to B (Tiotropium 18 μg QD + placebo of glycopyrronium)
Measure Participants	124	124
Least Squares Mean (95% Confidence Interval) [Liters*hours]	1.7432 (0.5171)	1.7132 (0.5175)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Glycopyronium From Sequence A to B and Sequence B to A, Tiotropium From Sequence A to B and Sequence B to A
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0250
	Comments
	Method	Mixed Models Analysis
	Comments

2. Secondary Outcome

Title	Comparison of Glycopyrronium QD Versus Tiotropium QD on Symptoms Outcome
Description	Comparison of symptoms outcome between glycopyrronium QD versus tiotropium QD will be conducted via the PROMorning COPD Symptoms questionnaire. This questionnaire will be completed by participants at waking-up, pre-inhalation of study treatment (at home), and they will complete Part 2 of PRO-Morning COPD Symptoms questionnaire at site, 3hours post-inhalation of study treatment. The PRO-Morning COPD Symptoms Questionnaire is a self-administered patient reported outcome (PRO) instrument developed by the sponsor to evaluate patients' experience of early morning symptoms of COPD. The questionnaire consists of two parts : predose and postdose. Each part has 6 questions and for each question a scale of 0 to 10 can be reached. For the predose and postdose part of the questionnaire you will have then each a total score of 0-60 by adding the sub-scores for each question, higher scores represent worse severity of COPD morning symptoms
Time Frame	day 1 (baseline) and week 4

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) population consisted of all randomized patients who received at least one dose of the study treatment and had at least one post-dose value of FEV1

Arm/Group Title	Glycopyronium From Sequence A to B and Sequence B to A	Tiotropium From Sequence A to B and Sequence B to A
Arm/Group Description	Sequence A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto) to B (Tiotropium 18 μg QD + placebo of glycopyrronium) Sequence B (Tiotropium 18 μg QD + placebo of glycopyrronium) to A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto)	Sequence B (Tiotropium 18 μg QD + placebo of glycopyrronium) to A (Glycopyrronium 44 μg QD + placebo of tiotropiumto) Sequence A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto) to B (Tiotropium 18 μg QD + placebo of glycopyrronium)
Measure Participants	124	124
3h post-dose (Day 1)	9.7068 (8.8)	10.3974 (8.1)
3h post-dose (Week 4)	10.4641 (8.8)	10.3193 (9.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Glycopyronium From Sequence A to B and Sequence B to A, Tiotropium From Sequence A to B and Sequence B to A
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1439
	Comments
	Method	Mixed Models Analysis
	Comments

Adverse Events

Arm/Group Title	Glycopyronium From Sequence A to B and Sequence B to A		Tiotropium From Sequence A to B and Sequence B to A
Arm/Group Description	Sequence A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto) to B (Tiotropium 18 μg QD + placebo of glycopyrronium) Sequence B (Tiotropium 18 μg QD + placebo of glycopyrronium) to A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto)		Sequence B (Tiotropium 18 μg QD + placebo of glycopyrronium) to A (Glycopyrronium 44 μg QD + placebo of tiotropiumto) Sequence A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto) to B (Tiotropium 18 μg QD + placebo of glycopyrronium)
All Cause Mortality
	Glycopyronium From Sequence A to B and Sequence B to A		Tiotropium From Sequence A to B and Sequence B to A
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Glycopyronium From Sequence A to B and Sequence B to A		Tiotropium From Sequence A to B and Sequence B to A
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/124 (1.6%)		2/124 (1.6%)
Infections and infestations
Pneumonia	1/124 (0.8%)		0/124 (0%)
Injury, poisoning and procedural complications
Lumbar vertebral fracture	0/124 (0%)		1/124 (0.8%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/124 (0.8%)		0/124 (0%)
Pleurisy	0/124 (0%)		1/124 (0.8%)
Other (Not Including Serious) Adverse Events
	Glycopyronium From Sequence A to B and Sequence B to A		Tiotropium From Sequence A to B and Sequence B to A
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/124 (13.7%)		12/124 (9.7%)
Cardiac disorders
Bundle branch block left	1/124 (0.8%)		0/124 (0%)
Bundle branch block right	1/124 (0.8%)		0/124 (0%)
Eye disorders
Cystoid macular oedema	1/124 (0.8%)		0/124 (0%)
Gastrointestinal disorders
Abdominal pain	0/124 (0%)		1/124 (0.8%)
Constipation	0/124 (0%)		1/124 (0.8%)
Diarrhoea	0/124 (0%)		1/124 (0.8%)
General disorders
Chest pain	0/124 (0%)		1/124 (0.8%)
Oedema peripheral	0/124 (0%)		1/124 (0.8%)
Hepatobiliary disorders
Hepatic cyst	0/124 (0%)		1/124 (0.8%)
Immune system disorders
Food allergy	1/124 (0.8%)		0/124 (0%)
Infections and infestations
Dermatophytosis	1/124 (0.8%)		0/124 (0%)
Infected dermal cyst	0/124 (0%)		1/124 (0.8%)
Lower respiratory tract infection	1/124 (0.8%)		1/124 (0.8%)
Nasopharyngitis	3/124 (2.4%)		0/124 (0%)
Respiratory tract infection	1/124 (0.8%)		0/124 (0%)
Injury, poisoning and procedural complications
Limb injury	1/124 (0.8%)		0/124 (0%)
Meniscus injury	0/124 (0%)		1/124 (0.8%)
Skin abrasion	1/124 (0.8%)		0/124 (0%)
Musculoskeletal and connective tissue disorders
Ankylosing spondylitis	1/124 (0.8%)		0/124 (0%)
Arthralgia	1/124 (0.8%)		1/124 (0.8%)
Limb discomfort	0/124 (0%)		1/124 (0.8%)
Muscle spasms	1/124 (0.8%)		0/124 (0%)
Nervous system disorders
Headache	1/124 (0.8%)		1/124 (0.8%)
Presyncope	1/124 (0.8%)		1/124 (0.8%)
Sciatica	1/124 (0.8%)		0/124 (0%)
Renal and urinary disorders
Dysuria	0/124 (0%)		1/124 (0.8%)
Reproductive system and breast disorders
Balanoposthitis	0/124 (0%)		1/124 (0.8%)
Respiratory, thoracic and mediastinal disorders
Cough	2/124 (1.6%)		0/124 (0%)
Dyspnoea	0/124 (0%)		1/124 (0.8%)
Sputum discoloured	1/124 (0.8%)		0/124 (0%)
Skin and subcutaneous tissue disorders
Dry skin	1/124 (0.8%)		1/124 (0.8%)
Psoriasis	1/124 (0.8%)		0/124 (0%)
Vascular disorders
Peripheral arterial occlusive disease	0/124 (0%)		1/124 (0.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety