Triple in Asthma Dose Finding (Triskel)

A MULTICENTRE, RANDOMISED, DOUBLE-BLIND, ACTIVE-CONTROLLED, 3-WAY CROSS-OVER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF A FREE COMBINATION OF 3 DOSES OF CHF 5259 (GLYCOPYRROLATE) PLUS FOSTER® 100/6 µg (FIXED COMBINATION OF BECLOMETHASONE DIPROPIONATE PLUS FORMOTEROL) IN A METERED DOSE INHALER FOR THE TREATMENT OF PATIENTS WITH UNCONTROLLED ASTHMA UNDER MEDIUM DOSES OF INHALED CORTICOSTEROIDS PLUS LONG-ACTING β2-AGONISTS.

Primary objective

The primary objective was to evaluate the efficacy of a free combination of CHF 5259 at 3 dose levels plus Foster® 100/6 μg in a pMDI by comparison with Foster® 100/6 μg in terms of forced expiratory volume in the first second (FEV1) area under the curve between time 0 and 12 hours (AUC0-12h) normalised by time on Day 42.

Key secondary objective

The key secondary objective was to evaluate the efficacy of the free combination CHF 5259 plus Foster® 100/6 μg by comparison with Foster® 100/6 μg in terms of peak FEV1 on Day 42.

Secondary objectives

The secondary objectives were:

• To evaluate the effect of the free combination of CHF 5259 plus Foster® 100/6 μg on other lung function parameters and on clinical outcome measures;
• To assess the safety and the tolerability of the study treatments.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Drug: CHF 5259 plus Foster 100/6 µg; Drug: Foster 100/6 µg (four puffs BID)

Detailed Description

This was a dose-finding, phase II, multicentre, randomised, double-blind, active-controlled, 3-way cross-over of 6 weeks, balanced incomplete block and multiple dose study.

Since each patient serves as his/her own control, the cross-over design reduces the effect of potentially confounding variables and allows for greater statistical power with fewer subjects.

This study was designed to evaluate the efficacy of a free combination of CHF 5259 at 3 dose levels (25 μg, 50 μg or 100 μg daily) plus Foster vs. Foster alone, administered via pMDI over a 6-week treatment period in patients with uncontrolled asthma.

A total of 220 patients were targeted for randomisation to ensure that a minimum of 164 completed the study (assuming an estimated non-evaluable rate of 25%). There were 4 treatments, but as it was a cross-over incomplete block design, each patient took only 3 treatments out of 4, according to the randomisation list of sequences: A-C-B; B-D-C; C-A-D and D-B-A.

.

The four treatments were:

• Treatment A = CHF 5259 (GB 25 μg/day) plus Foster (BDP 400/FF 24 μg/day);
• Treatment B = CHF 5259 (GB 50 μg/day) plus Foster (BDP 400/FF 24 μg/day);
• Treatment C = CHF 5259 (GB 100 μg/day) plus Foster (BDP 400/FF 24 μg/day);
• Treatment D = Foster (BDP 400/FF 24 μg/day) alone.

Foster was used during the study as the control despite an indication in "patients not adequately controlled with inhaled corticosteroids and 'as needed' inhaled rapid-acting β2-agonist" (and not in patients with uncontrolled asthma). No risks for the patients were foreseen owing to the short study duration (6 weeks), the possibility of using salbutamol as rescue medication and the close medical monitoring during the entire study period.

The Foster dose (400/24 μg daily) for the run-in and wash-out periods was selected as this is a standard dosing regimen marketed for the use of Foster in the treatment of asthma.

This study comprised a total of 11 visits and a follow-up phone call:

• A Pre-Screening visit (Visit 0 [V0]), carried out in order to fully explain the study to potential patients, to obtain their written informed consent and to instruct them on Screening visit procedures (such as fasting and medication restrictions). This visit occurred one week maximum prior to the Screening visit.A Screening visit (V1), carried out to establish the eligibility of patients for inclusion in the study and to instruct them on study procedures (such as fasting, medication restrictions, recognition of asthma exacerbations and use of the pMDI device, of the e-diary and of the e-peakflow meter). This visit was followed by a 2-week (±2 days) open-label run-in period on Foster. A 2-week run-in period on Foster prior to randomisation was deemed sufficient to standardise the patient population on the same concomitant treatment without leading to a deterioration of the disease.

• An investigational phase, which lasted approximately 21 weeks and comprised 3 treatment periods (Period [P] 1, P2 and P3) of 6 weeks each (±2 days) separated by an open-label wash-out period of 1 week on Foster. Each 6-week treatment period allowed for adequate assessment of efficacy variables. Each treatment period comprised 3 visits (Day [D] 1, Day 14 and Day 42) during which efficacy and safety assessments were performed. Patients were also re-instructed on study procedures. Patients underwent the following visits:

  • A Randomisation visit at Visit P1D1 (V2);
  • Eight subsequent visits:

Day 1 of the second and third treatment period (day of the first dosing):

Visit P2D1 (V5) and Visit P3D1 (V8); Day 14 of each treatment period: Visit P1D14 (V3), Visit P2D14 (V6) and Visit P3D14 (V9); Day 42 of each treatment period (day of last dosing): Visit P1D42 (V4), Visit P2D42 (V7) and Visit P3D42 (V10). These visits were followed by a 1-week wash-out period with Foster.

• A safety follow-up phone call was made one week after Visit P3D42 (V10) (or 1 week after the last dose intake and/or last visit in case of premature discontinuation of the patient) to check any unresolved or new adverse events (AEs)/serious adverse events (SAEs).

• Study Type: Interventional
• Enrollment (Actual): 211
• Phase: Phase 2

Contacts and Locations

Study Locations

• Bulgaria
  • Dupnitsa, Bulgaria, 2600
    • Chiesi Clinical Trial Site 0105
  • Rousse, Bulgaria, 7002
    • Chiesi Clinical Trial Site 0101
  • Sevlievo, Bulgaria, 5400
    • Chiesi Clinical Trial Site 0106
  • Sofia, Bulgaria, 1233
    • Chiesi Clinical Trial Site 0107
  • Sofia, Bulgaria, 1336
    • Chiesi Clinical Trial Site 0108
  • Sofia, Bulgaria, 1407
    • Chiesi Clinical Trial Site 0102
  • Sofia, Bulgaria, 1431
    • Chiesi Clinical Trial Site 0110
  • Sofia, Bulgaria, 1432
    • Chiesi Clinical Trial Site 0109
  • Stara Zagora, Bulgaria, 6003
    • Chiesi Clinical Trial Site 0103
  • Troyan Municipality, Bulgaria, 5600
    • Chiesi Clinical Trial Site 0104
• Germany
  • Berlin, Germany, 10787
    • Chiesi Clinical Trial Site 0208
  • Berlin, Germany, 12165
    • Chiesi Clinical Trial Site 0207
  • Großhansdorf, Germany, 22927
    • Chiesi Clinical Trial Site 0206
  • Leipzig, Germany, 04357
    • Chiesi Clinical Trial Site 0201
  • Lübeck, Germany, 23552
    • Chiesi Clinical Trial Site 0203
  • Magdeburg, Germany, 39112
    • Chiesi Clinical Trial Site 0202
  • Radebeul, Germany, 01445
    • Chiesi Clinical Trial Site 0204
  • Witten, Germany, 58452
    • Chiesi Clinical Trial Site 0210
• Hungary
  • Balassagyarmat, Hungary, 2660
    • Chiesi Clinical Trial Site 0307
  • Budapest, Hungary, 1122
    • Chiesi Clinical Trial Site 0302
  • Deszk, Hungary, 6772
    • Chiesi Clinical Trial Site 0304
  • Gödöllő, Hungary, 2100
    • Chiesi Clinical Trial Site 0305
  • Komárom, Hungary, 2900
    • Chiesi Clinical Trial Site 0303
  • Siófok, Hungary, 8600
    • Chiesi Clinical Trial Site 0301
  • Szarvas, Hungary, 5540
    • Chiesi Clinical Trial Site 0306
• Italy
  • Brescia, Italy, 25123
    • Chiesi Clinical Trial Site 0403
  • Parma, Italy, 43125
    • Chiesi Clinical Trial Site 0402
  • Pisa, Italy, 56124
    • Chiesi Clinical Trial Site 0401
  • Trieste, Italy, 34149
    • Chiesi Clinical Trial Site 0408
  • Verona, Italy, 37134
    • Chiesi Clinical Trial Site 0404
• Poland
  • Bialystok, Poland, 15-430
    • Chiesi Clinical Trial Site 0510
  • Gdansk, Poland, 80-847
    • Chiesi Clinical Trial Site 0507
  • Giżycko, Poland, 11-500
    • Chiesi Clinical Trial Site 0502
  • Krakow, Poland, 31-637
    • Chiesi Clinical Trial Site 0511
  • Lodz, Poland, 90-141
    • Chiesi Clinical Trial Site 0505
  • Lodz, Poland, 90-153
    • Chiesi Clinical Trial Site 0509
  • Lublin, Poland, 20-718
    • Chiesi Clinical Trial Site 0512
  • Ostróda, Poland, 14-100
    • Chiesi Clinical Trial Site 0503
  • Oświęcim, Poland, 32-600
    • Chiesi Clinical Trial Site 0501
  • Proszowice, Poland, 32-100
    • Chiesi Clinical Trial Site 0506
  • Rzeszów, Poland, 35-241
    • Chiesi Clinical Trial Site 0508
  • Wroclaw, Poland, 51-162
    • Chiesi Clinical Trial Site 0504
• United Kingdom
  • London, United Kingdom, W1G 8HU
    • Chiesi Clinical Trial Site 0602
  • Manchester, United Kingdom, M23 9QZ
    • Chiesi Clinical Trial Site 0601

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

For inclusion into the study, patients were required to fulfil all of the following criteria:

1. Patient's written informed consent obtained prior to any study-related procedures;
2. Male or female patients aged ≥18;

3. Patients with uncontrolled asthma on medium doses of ICS+LABA (>500-1000 μg daily dose BDP non-extrafine or equivalent plus formoterol 24 μg or salmeterol 100 μg) at a stable dose for at least 4 weeks prior to Screening; Drug* Medium daily dose BDP non-extrafine >500 - 1000 μg BDP extrafine >250 - 500 μg Budesonide >400 - 800 μg Ciclesonide >160 - 320 μg Fluticasone >250 - 500 μg Mometasone ≥400 μg - < 800 μg

   *In this table (adapted from GINA 2012) the recommendations for doses of inhaled glucocorticosteroids are given as "μg/day budesonide or equivalent"

4. Patients with a pre-bronchodilator FEV1 ≥40% and <80% of their predicted normal value, after appropriate wash-out from bronchodilators, at Screening and at the end of the run-in period;
5. Patients with a positive response to the reversibility test at Screening within 30 minutes after administration of 400 μg of salbutamol pMDI, defined as ΔFEV1 ≥12% and ≥200 mL over Baseline; Note: In case the reversibility threshold is not met, the test can be performed once before randomisation.
6. Patients with uncontrolled asthma evidenced by a score at the Asthma Control Questionnaire® (ACQ) ≥1.5 (criterion must be met at Screening and at the end of the run-in period);
7. Patients with a co-operative attitude and ability to be trained to correctly use the pMDI.

At pre-Screening visit (V0) the patient's written informed consent (criterion 1) was obtained and then at the Screening visit (V1), all the above-mentioned inclusion criteria were checked. At the Randomisation visit (Visit P1D1 [V2]), the following inclusion criteria were re-checked: 4, 6 and 7.

Exclusion Criteria:

Patients were not enrolled if one or more of the following criteria were present:

1. Inability to carry out pulmonary lung function testing, to comply with study procedures or with study treatment intake;
2. History of near fatal asthma or of a past hospitalisation for asthma in intensive care unit or of frequent exacerbations which, in the judgement of the Investigator, may have placed the patient at undue risk;
3. Hospitalisation, emergency room admission or use of systemic corticosteroids for asthma exacerbation in the 4 weeks prior to Screening visit and during the run-in period;
4. Lower respiratory tract infection in the 4 weeks before the Screening visit or during the run-in period;
5. Patients who were in therapy for gastroesophageal reflux disease (GERD) and/or patients with a medical history of GERD that led to asthma symptoms;
6. Patients with a seasonal worsening of asthma and who were not able to complete the study outside the relevant allergen season;
7. History of cystic fibrosis, bronchiectasis or alpha-1 antitrypsin deficiency, or any other significant lung disease which may have interfered with data evaluation;
8. Patients who suffered from COPD as defined by the current Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines;
9. Current smokers or ex-smokers with total cumulative exposure equal or more than 10 pack-years and /or having stopped smoking one year or less prior to Screening visit;
10. Any change in dose, schedule, formulation of ICS + LABAs in the 4 weeks prior to Screening visit;
11. Patients used to be or treated with inhaled long-acting antimuscarinic drugs;
12. Patients treated with anti-IgE antibodies;

13. Pregnant or lactating women and all women physiologically capable of becoming pregnant (i.e. women of childbearing potential) UNLESS were using one or more of the following reliable methods of contraception:

    • Placement of an intra uterine device (IUD) or intra uterine system (IUS);
    • Hormonal contraception (implantable, patch, oral);
    • Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical vaults/caps) with spermicidal foam/gel/film/cream/suppository. Reliable contraception was maintained throughout the study. Pregnancy tests were performed at study entry (a serum one at Screening visit and a urine one at Screening and Randomisation visits) in all women of childbearing potential. Any postmenopausal women (physiologic menopause defined as "12 consecutive months of amenorrhea") or women permanently sterilized (e.g. tubal occlusion, hysterectomy or bilateral salpingectomy) were allowed to be enrolled in the study.
14. Patients who have received an investigational drug within 2 months before Screening visit;
15. Patients who had clinically significant (CS) cardiovascular condition according to Investigator's judgement, such as but not limited to: congestive heart failure (New York Heart Association [NYHA] class >3), acute ischemic heart disease in the last year prior to study Screening, history of sustained cardiac arrhythmias or sustained and nonsustained cardiac arrhythmias diagnosed in the last 6 months (sustained means lasting more than 30 seconds and or ending only with external action, and or leads to hemodynamic collapse; non-sustained means > 3 beats < 30 seconds, and or ending spontaneously, and or asymptomatic), impulse conduction blocks. Similarly, patients affected by permanent or paroxysmal atrial fibrillation were not considered for enrolment;
16. An abnormal and CS 12-lead electrocardiogram (ECG) that resulted in active medical problem which may have impacted the safety of the patient according to Investigator's judgement;
17. Patients whose electrocardiogram (12-lead ECG) showed Fridericia-Corrected QTc (QTcF) >450 millisecond (ms) for males or QTcF >470 ms for females at Screening or at Randomisation visits;
18. Medical diagnosis of narrow-angle glaucoma, clinically relevant prostatic hypertrophy or bladder neck obstruction that, in the opinion of the Investigator, would have prevented use of anticholinergic agents;
19. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may have increased the risk associated with study participation or study drug administration and, in the judgment of the Investigator, would have made the patient inappropriate for entry into this study, placed the patients at undue risk or potentially compromised the results or interpretation of the study;
20. Patients having received a live-attenuated virus vaccination within two weeks prior to Screening or during the run-in (inactivated influenza vaccination was acceptable provided it was not administered less than 48 hours prior to Screening);
21. Patients mentally or legally incapacitated;
22. Patients with a history of alcohol or drug abuse;
23. Patients with known intolerance/hypersensitivity or contra-indication to treatment with ß2-agonists, inhaled corticosteroids, anti-cholinergics or propellant gases/excipients;
24. Patients with major surgery in the 3 months prior to Screening visit and/or planned surgery during the trial;
25. Patients treated with non-potassium sparing diuretics (association with potassium sparing diuretics was allowed), non-selective β-blocking drugs, quinidine, quinidine-like anti arrhythmics, or any medication with a QTc prolongation potential or a history of QTc prolongation;
26. Patients treated with monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants;
27. Patients who were receiving any therapy that could have interfered with the study drugs according to Investigator's opinion.

At the Screening visit (V1), all the above-mentioned exclusion criteria were checked. At the Randomisation visit (Visit P1D1 [V2], the following exclusion criteria were re-checked: 1, 3, 4, 5, 13, 16, 17, 19, 20, 24 and 27.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sequence A-C-B; Each subject was allocated to 3 out of the 4 possible treatments performed in sequence during a cross over design (incomplete block). Treatment A (CHF 5259 12.5 μg + Foster 100/6 μg): total daily dose of GB 25 μg + BDP 400 μg/FF 24 μg; patients followed a schedule of one puff of CHF 5259 12.5 μg BID, one puff of CHF 5259 placebo BID, two puffs of Foster 100/6 μg BID. Treatment C (CHF 5259 25 μg + Foster 100/6 μg): total daily dose of GB 100 μg + BDP 400 μg/FF 24 μg; Patients followed a schedule of two puffs of CHF 5259 25 μg BID and two puffs of Foster 100/6 μg BID. Treatment B (CHF 5259 25 μg + Foster 100/6 μg): total daily dose of GB 50 μg + BDP 400 μg/FF 24 μg; patients followed a schedule of one puff of CHF 5259 25 μg BID, one puff of CHF 5259 placebo BID, two puffs of Foster 100/6 μg BID.	Drug: CHF 5259 plus Foster 100/6 µg; Comparison of different doses of CHF 5259 (on top of Foster 100/6 µg) versus Foster 100/6 µg over a treatment period of 6 weeks. Each subject was allocated to 3 out of the 4 possible treatments performed in sequence during a cross over design (incomplete block). All treatment medications were administered via pMDI. During each treatment period, treatment was administered as four puffs BID (morning and evening) approximately at the same time of the day.; Other Names: glycopyrrolate + beclometasone/formoterol; Drug: Foster 100/6 µg (four puffs BID); Active comparator Treatment D = Foster 400 μg/24 μg (daily dose): patients followed a schedule of two puffs of CHF 5259 placebo BID and two puffs of Foster 100/6 μg BID. All treatment medications were administered via pMDI. During each of the 3 treatment periods, treatment was administered as four puffs BID (morning and evening) approximately at the same time of the day.; Other Names: beclometasone dipropionate/formoterol
Experimental: Sequence B-D-C; Each subject was allocated to 3 out of the 4 possible treatments performed in sequence during a cross over design (incomplete block). Treatment B (CHF 5259 25 μg + Foster 100/6 μg): total daily dose of GB 50 μg + BDP 400 μg/FF 24 μg; patients followed a schedule of one puff of CHF 5259 25 μg BID, one puff of CHF 5259 placebo BID, two puffs of Foster 100/6 μg BID. Treatment D, Foster 400 μg/24 μg (daily dose): Patients followed a schedule of two puffs of CHF 5259 placebo BID and two puffs of Foster 100/6 μg BID. Treatment C (CHF 5259 25 μg + Foster 100/6 μg): total daily dose of GB 100 μg + BDP 400 μg/FF 24 μg; Patients followed a schedule of two puffs of CHF 5259 25 μg BID and two puffs of Foster 100/6 μg BID.	Drug: CHF 5259 plus Foster 100/6 µg; Comparison of different doses of CHF 5259 (on top of Foster 100/6 µg) versus Foster 100/6 µg over a treatment period of 6 weeks. Each subject was allocated to 3 out of the 4 possible treatments performed in sequence during a cross over design (incomplete block). All treatment medications were administered via pMDI. During each treatment period, treatment was administered as four puffs BID (morning and evening) approximately at the same time of the day.; Other Names: glycopyrrolate + beclometasone/formoterol; Drug: Foster 100/6 µg (four puffs BID); Active comparator Treatment D = Foster 400 μg/24 μg (daily dose): patients followed a schedule of two puffs of CHF 5259 placebo BID and two puffs of Foster 100/6 μg BID. All treatment medications were administered via pMDI. During each of the 3 treatment periods, treatment was administered as four puffs BID (morning and evening) approximately at the same time of the day.; Other Names: beclometasone dipropionate/formoterol
Experimental: Sequence C-A-D; Each subject was allocated to 3 out of the 4 possible treatments performed in sequence during a cross over design (incomplete block). Treatment C (CHF 5259 25 μg + Foster 100/6 μg): total daily dose of GB 100 μg + BDP 400 μg/FF 24 μg; Patients followed a schedule of two puffs of CHF 5259 25 μg BID and two puffs of Foster 100/6 μg BID. Treatment A (CHF 5259 12.5 μg + Foster 100/6 μg): total daily dose of GB 25 μg + BDP 400 μg/FF 24 μg; patients followed a schedule of one puff of CHF 5259 12.5 μg BID, one puff of CHF 5259 placebo BID, two puffs of Foster 100/6 μg BID. Treatment D, Foster 400 μg/24 μg (daily dose): Patients followed a schedule of two puffs of CHF 5259 placebo BID and two puffs of Foster 100/6 μg BID.	Drug: CHF 5259 plus Foster 100/6 µg; Comparison of different doses of CHF 5259 (on top of Foster 100/6 µg) versus Foster 100/6 µg over a treatment period of 6 weeks. Each subject was allocated to 3 out of the 4 possible treatments performed in sequence during a cross over design (incomplete block). All treatment medications were administered via pMDI. During each treatment period, treatment was administered as four puffs BID (morning and evening) approximately at the same time of the day.; Other Names: glycopyrrolate + beclometasone/formoterol; Drug: Foster 100/6 µg (four puffs BID); Active comparator Treatment D = Foster 400 μg/24 μg (daily dose): patients followed a schedule of two puffs of CHF 5259 placebo BID and two puffs of Foster 100/6 μg BID. All treatment medications were administered via pMDI. During each of the 3 treatment periods, treatment was administered as four puffs BID (morning and evening) approximately at the same time of the day.; Other Names: beclometasone dipropionate/formoterol
Experimental: Sequence B-D-A; Each subject was allocated to 3 out of the 4 possible treatments performed in sequence during a cross over design (incomplete block). Treatment B (CHF 5259 25 μg + Foster 100/6 μg): total daily dose of GB 50 μg + BDP 400 μg/FF 24 μg; patients followed a schedule of one puff of CHF 5259 25 μg BID, one puff of CHF 5259 placebo BID, two puffs of Foster 100/6 μg BID. Treatment D, Foster 400 μg/24 μg (daily dose): Patients followed a schedule of two puffs of CHF 5259 placebo BID and two puffs of Foster 100/6 μg BID. Treatment A (CHF 5259 12.5 μg + Foster 100/6 μg): total daily dose of GB 25 μg + BDP 400 μg/FF 24 μg; patients followed a schedule of one puff of CHF 5259 12.5 μg BID, one puff of CHF 5259 placebo BID, two puffs of Foster 100/6 μg BID.	Drug: CHF 5259 plus Foster 100/6 µg; Comparison of different doses of CHF 5259 (on top of Foster 100/6 µg) versus Foster 100/6 µg over a treatment period of 6 weeks. Each subject was allocated to 3 out of the 4 possible treatments performed in sequence during a cross over design (incomplete block). All treatment medications were administered via pMDI. During each treatment period, treatment was administered as four puffs BID (morning and evening) approximately at the same time of the day.; Other Names: glycopyrrolate + beclometasone/formoterol; Drug: Foster 100/6 µg (four puffs BID); Active comparator Treatment D = Foster 400 μg/24 μg (daily dose): patients followed a schedule of two puffs of CHF 5259 placebo BID and two puffs of Foster 100/6 μg BID. All treatment medications were administered via pMDI. During each of the 3 treatment periods, treatment was administered as four puffs BID (morning and evening) approximately at the same time of the day.; Other Names: beclometasone dipropionate/formoterol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
FEV1 AUC0-12h Normalised by Time on Day 42	FEV1 = Forced expiratory volume in the first second. AUC0-12h = area under the curve between the time 0 and 12 hours. Post-dose FEV1 on Day 42 of each treatment period was recorded at 15'; 30'; 45'; 1h; 2h; 3h, 4h,6h,8h, 11h30 and 12h post-study drug intake. The baseline FEV1 was the average FEV1 recorded on Day 1 at 45 and 10 minutes prior to study intake.	Day 42

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Peak FEV1 on Day 42	Change from Baseline in peak FEV1 on Day 42 is the study key secondary outcome. It represents the maximum value of all FEV1 assessments from 15 minutes to 12 hours post-dose of the respective day. Post-dose FEV1 on Day 42 of each treatment period was recorded at 15'; 30'; 45'; 1h; 2h; 3h, 4h, 6h, 8h, 11h30 and 12h post-study drug intake. Baseline is the average of the FEV1 pre-dose measurements on Day 1 of each period (recorded at 45 and 10 minuted prior to study drug intake).	Day 42
FEV1 AUC0-3h Normalised by Time on Day 1	AUC0-3h = area under the curve between time 0 and 3 hours. The pre-dose and post-dose lung function assessments were recorded under supervision at the following timing: Pre-dose FEV1 on Day 1 at 45 and 10 minutes prior to study drug intake (baseline FEV1);; Post-dose FEV1 on Day 1 of each treatment period: at 15'; 30'; 45'; 1h; 2h; 3h post-study drug intake.	Day 1
FEV1 AUC0-3h Normalised by Time on Day 42	AUC0-3h = area under the curve between time 0 and 3 hours. The pre-dose and post-dose lung function assessments were recorded under supervision at the following timings: Pre-dose FEV1 on Day 1 at 45 and 10 minutes prior to study drug intake (baseline FEV1);; Post-dose FEV1 on Day 42 of each treatment period: at 15'; 30'; 45'; 1h; 2h; 3h post-study drug intake.	Day 42
Change From Baseline in FEV1 Pre-dose on Day 14	The pre-dose morning FEV1 is defined as the mean of the two measurements at 45 and 10 minutes predose.	Day 14
Change From Baseline in FEV1 Pre-dose on Day 42	The pre-dose morning FEV1 is defined as the mean of the two measurements at 45 and 10 minutes predose.	Day 42
Change From Baseline in Through FEV1 at 12 h Post-dose on Day 1	Trough FEV1 at 12 hours is determined as the average of the 11.5 and 12 hours post-dose FEV1 assessments. Baseline value is the mean of the pre-dose measurement of FEV1 at Day 1 of each treatment period recorded at 45 and 10 minutes prior to study drug intake.	Day 1
Change From Baseline in Through FEV1 at 12 h Post-dose on Day 42	Trough FEV1 at 12 hours is determined as the average of the 11.5 and 12 hours post-dose FEV1 assessments. Baseline value is the mean of the pre-dose measurement of FEV1 at Day 1 of each treatment period recorded at 45 and 10 minutes prior to study drug intake.	Day 42
Change From Baseline in Peak FEV1 on Day 1	Peak FEV1 represents the maximum value of all FEV1 assessments from 15 minutes to 12 hours post-dose of the respective day (in this case on Day 1). Post-dose FEV1 on Day 1 of each treatment period was recorded at 15'; 30'; 45'; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h post-study drug intake. Baseline is the average of the FEV1 pre-dose measurements on Day 1 of each period (recorded at 45 and 10 minuted prior to study drug intake).	Day 1
FEV1 AUC0-12h Normalised by Time on Day 1	AUC0-12h = area under the curve between time 0 and 12 hours. Post-dose FEV1 on Day 1 of each treatment period was recorded at 15'; 30'; 45'; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h post-study drug intake. The baseline FEV1 was the average FEV1 recorded on Day 1 at 45 and 10 minutes prior to study intake.	Day 1
Change From Baseline in Asthma Control Questionnaire (ACQ) Total Score on Day 42	ACQ-7 allows identification of the adequacy of asthma control in individual patients. The first 6 items of the questionnaire refer to symptoms and rescue use in the previous 7 days (patients were asked to recall how their asthma was during the previous week and to respond to the symptom and bronchodilator use questions on a 7-point scale with 0 = no impairment and 6 = maximum impairment); the 7th item relates to FEV1 (completed by the clinical staff), used the value of FEV1 % of predicted when reversibility was met at screening (Week -2) and considering the pre-dose FEV1 % of predicted taken at -15 minutes at the visit. The 7th item ranges as well from 0 (best value) to 6 (worst value). The questions are equally weighted and the ACQ total score is the mean of the 7 questions and therefore between 0 (asthma totally controlled) and 6 (asthma severely uncontrolled).	Day 42
Change From Baseline in Pre-dose FVC on Day 14	FVC=Forced vital Capacity Pre-dose FVC was recorded on Day 14 at 45 minutes and 10 minutes prior to study drug intake.	Day 14
Change From Baseline in Pre-dose FVC on Day 42	FVC=Forced Vital Capacity. Pre-dose FVC was recorded on Day 42 at 45 minutes and 10 minutes prior to study drug intake.	Day 42
Change From Baseline in Peak FVC on Day 1	The peak FVC is the maximum FVC value obtained between 15 minutes and 12 hours post-dose. Post-dose FVC on Day 1 of each treatment period was recorded at 15'; 30'; 45'; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h post-study drug intake. Baseline is the average of the FVC pre-dose measurements on Day 1 of each period (recorded at 45 and 10 minuted prior to study drug intake).	Day 1
Change From Baseline in Peak FVC on Day 42	The peak FVC is the maximum FVC value obtained between 15 minutes and 12 hours post-dose. Post-dose FVC on Day 1 of each treatment period was recorded at 15'; 30'; 45'; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h post-study drug intake. Baseline is the average of the FVC pre-dose measurements on Day 1 of each period (recorded at 45 and 10 minuted prior to study drug intake).	Day 42
Change From Baseline in Forced Vital Capacity (FVC) 12h Post-dose on Day 1	The baseline FVC is the mean of the pre-dose measurements recorded on Day 1 of each treatment period. Post-dose FVC was recorded at 15'; 30'; 45'; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h post-study drug intake on Day 1. Only change from baseline at the last timepoint (12h post-dose) on Day 1 is reported in the system.	12h post-dose on Day 1
Change From Baseline in Forced Vital Capacity (FVC) at 2h Post-dose on Day 14	The baseline FVC is the mean of the pre-dose measurements recorded on Day 1 of each treatment period. Post-dose FVC was recorded at 2h on Day 14.	2h Post-dose on Day 14
Secondary: Change From Baseline in Forced Vital Capacity (FVC) 12h Post-dose on Day 42	The baseline FVC is the mean of the pre-dose measurements recorded on Day 1 of each treatment period. Post-dose FVC was recorded at 15'; 30'; 45'; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h post-study drug intake on Day 42. Only change from baseline at the last timepoint (12h post-dose) on Day 42 is reported in the system.	12h post-dose on Day 42
Mean Changes From Baseline in FEV1 Percentage of Predicted Normal Value 12h Post-dose on Day 1	Baseline is the average of the pre-dose measurements of FEV1 Percentage of Predicted Normal Value. Measurements were done: 15 min, 30 min, 45 min, 1h, 2h, 3h, 4h, 6h, 8h, 11h and 30 min, 12h post-dose on Day 1. Only data about the change from baseline at the last timepoint (12h post-dose) of the Day 1 are reported in the database.	12h post-dose on Day 1
Mean Changes From Baseline in FEV1 Percentage of Predicted Normal Value 2h Post-dose on Day 14	Baseline is the average of the pre-dose measurements of FEV1 Percentage of Predicted Normal Value. Measurements were done 2h post-dose on Day 14. Only the change from baseline (not the actual value) is reported in the database.	2h post-dose on Day 14
Mean Changes From Baseline in FEV1 Percentage of Predicted Normal Value 12h Post-dose on Day 42	Baseline is the average of the pre-dose measurements of FEV1 Percentage of Predicted Normal Value. Measurements were done: 15 min, 30 min, 45 min, 1h, 2h, 3h, 4h, 6h, 8h, 11h and 30 min, 12h postdose on Day 42. Only data about the change from baseline at the last timepoint (12h post-dose) of the Day 42 are reported in the database.	12h post-dose on Day 42
Average Daily Morning Peak Expiratory Flow (PEF)	PEF (L/min) was monitored by patients at home, twice daily using a portable e-peak flow meter, before the intake of the run-in medication or study medication: in the morning (between 7:00 am and 9:00 am) and in the evening (7:00 pm and 9:00 pm). An alarm reminded the patients to perform measurements. During each measure, 3 blows were performed and data recorded in the device. Average Daily PEF morning is the mean value of all morning measurements of Peak Expiratory Flow (PEF) = Σ all morning measurements of PEF / number of days with available data	From run-in (weeks 0-2±2 days) throughout the three treatment periods (Weeks 2-8, Weeks 9-15, and Weeks 16-22)
Average Daily Evening Peak Expiratory Flow (PEF)	PEF (L/min) was monitored by patients at home, twice daily using a portable e-peak flow meter, before the intake of the run-in medication or study medication: in the morning (between 7:00 am and 9:00 am) and in the evening (7:00 pm and 9:00 pm). An alarm reminded the patients to perform measurements. During each measure, 3 blows were performed and data recorded in the device. Average Daily PEF evening is the mean of all evening measurements of Peak Expiratory Flow (PEF) = Σ all evening measurements of PEF / number of days with available data	From run-in (weeks 0-2±2 days) throughout the three treatment periods (Weeks 2-8, Weeks 9-15, and Weeks 16-22)
Total Average Daily Asthma Symptoms, Morning	Asthma symptoms (cough, wheeze, chest tightness and breathlessness) were recorded, always before PEF measurements, twice daily - morning and evening - through the [ as follows: Morning (nighttime) asthma symptom score (ranging 0-3, where the lower the score the better the outcome): 0=No symptom; Mild: symptoms not causing awakening; Moderate: discomfort causing awakenings; Severe: causing awakenings for most of the night / don't allow to sleep at all. The average score of each symptom is the mean value of all measurements. Total average Daily Asthma Symptoms score nighttime = Σ [Cough nighttime score + Wheeze nighttime score + Chest Tightness nighttime score + Breathlessness nighttime score] / Number of days with available data. The average of nighttime asthma symptoms is the mean value of all nighttime measurements, ranging from 0 (no symptoms) to 12 (maximum severity). The lower the score, the better the symptom.	Daily, from Screening Visit (V1, week 0) till end of the third treatment period (V10, week 22)
Average Total Daily Asthma Symptoms, Evening	Asthma symptoms (cough, wheeze, chest tightness and breathlessness) were recorded, always before PEF measurements, twice daily - morning and evening - on the ediary as follows: Evening (daytime) asthma symptom score (ranging 0-3, where the lower the score the better the outcome): 0=No symptom; Mild: symptoms which can be easily tolerated; Moderate: discomfort causing interference with daily activity; Severe: incapacitating with inability to work/take part in usual activity. The average score of each symptom is the mean value of all measurements. Total average Daily Asthma Symptoms score daytime = Σ [Cough daytime score + Wheeze daytime score + Chest Tightness daytime score + Breathlessness daytime score] / Number of days with available data. The average of daytime asthma symptoms is the mean value of all daytime measurements, ranging from 0 (no symptoms) to 12 (maximum severity). The lower the score, the better the symptom.	From Screening Visit (V1, week 0) till end of the third treatment period (V10, week 22)
Percentage of Asthma Control Days During the Treatment Period	The percentage is calculated as the number of asthma control days / number of days with available data. If there are less than 20 non-missing values, the percentage of control days was considered missing. "Asthma control day", derived from patient diary data, is defined as any day during the treatment period that fulfils criteria: Days with a total asthma score of 0;; No rescue medication use. The adjusted mean percentage (of asthma control days) is reported.	Between V1 (D1) and V3 (D42) of the 6-week treatment period
Average Use of Rescue Medication (Number of Puffs/Day)	The average use of rescue medication (number of puffs per day) is determined as the total number of puffs of rescue mediation taken / number of days with available data.	Daily during run-in/wash-out & treatment periods (from V1 [week 0] to V10 [week 22])
Average Use of Rescue Medication (Number of Times/Day)	The average use of rescue medication (number of times per day) is determined as the total number of times of rescue medication taken/ number of days with available data.	Daily during run-in/wash-out & treatment periods (from V1 [week 0] to V10 [week 22])
Number of Participants With at Least One Adverse Event (TEAE) or Adverse Drug Reaction (ADR)	AE=An untoward medical occurrence after exposure to a medicine, which is not necessarily caused by that medicine. Serious AE= An adverse event that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a birth defect. ADR=A response to a medicinal product which is harmful and unintended. Response in this context means that a causal relationship between the medicinal product and an adverse event is at least a reasonable possibility Serious ADR=An adverse reaction that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a birth defect. Severe AE= "Severe" refers to the intensity of an AE; the event itself may be of relatively minor medical significance but intense.	Throughout the study up to Week 24 (end of study)

Collaborators and Investigators

• Sponsor: Chiesi Farmaceutici S.p.A.
• Investigators: Principal Investigator: Dave SINGH, MD, University Hospital of South Manchester, MANCHESTER M23 9 QZ, UK

Publications and helpful links

Helpful Links

• Study Record on EU Clinical Trials Register including results

Study record dates

Study Major Dates

• Study Start (Actual): April 11, 2014
• Primary Completion (Actual): March 8, 2015
• Study Completion (Actual): March 8, 2015

Study Registration Dates

• First Submitted: April 9, 2014
• First Submitted That Met QC Criteria: April 29, 2014
• First Posted (Estimated): May 1, 2014

Study Record Updates

• Last Update Posted (Actual): April 14, 2026
• Last Update Submitted That Met QC Criteria: March 25, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Asthma, anticholinergics; CHF5259 pMDI; glycopirrolate; Asthma, Foster; Asthma, ICS plus LABA
• Additional Relevant MeSH Terms: Immune System Diseases; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Asthma; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Therapeutics; Polycyclic Compounds; Amines; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Patient Care; Health Services; Health Care Facilities Workforce and Services; Community Health Services; Alcohols; Pregnadienetriols; Amino Alcohols; Ethanolamines; Quaternary Ammonium Compounds; Onium Compounds; Pyrrolidines; Steroids, Chlorinated; Formoterol Fumarate; Beclomethasone; Glycopyrrolate; Foster Home Care
• Other Study ID Numbers: CCD-1206-PR-0088; 2013-003043-36 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Chiesi commits to sharing with qualified scientific and medical Researchers, conducting legitimate research, Patient-level Data, Study-level Data, the Clinical Protocol and the full CSR, providing access to clinical trial information consistently with the principle of safeguarding commercially confidential information and patient privacy. Any shared Patient-level Data is anonymized to protect personally identifiable information.

Chiesi access criteria and complete process for clinical data sharing is available on the Chiesi Group website.

• IPD Sharing Access Criteria: Chiesi access criteria and complete process for clinical data sharing is available on the Chiesi Group website.