CCD-05993AB2-02

Chiesi Farmaceutici S.p.A

Via Palermo 26/A, Parma, Italy, 43122

Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., +39 05212791, clinicaltrials_info@chiesi.com

Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., +39 05212791, clinicaltrials_info@chiesi.com

No

No

No

Final

30 Jan 2019

Yes

28 May 2018

Yes

28 May 2018

No

The primary objectives of the trial were: - To demonstrate the superiority of CHF 5993 pressurised metered dose inhaler (pMDI) 200/6/12.5 μg compared to CHF 1535 pMDI 200/6 μg in terms of change from baseline in pre-dose forced expiratory volume in the 1st second (FEV1) at Week 26; - To demonstrate the reduction of moderate and severe asthma exacerbation rate with CHF 5993 pMDI 200/6/12.5 μg compared to CHF 1535 pMDI 200/6 μg during the entire 52-week treatment period.

The trial was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines and all other requirements of local laws. At all visits from screening onwards, concomitant medications and adverse events were recorded, physical examination of patients was carried out and asthma exacerbations were assessed. Vital signs and 12-lead electrocardiograms (ECGs) were recorded at all visits (pre-dose at screening, pre- and post-dose during the treatment period). 24-hour Holter ECGs were recorded at screening, Week 0, Week 12 , Week 26 and Week 52 on a subset of at least 10% of randomised patients. Spirometry was performed at all visits (pre-dose FEV1 and forced vital capacity from screening to Week 52, pre-dose inspiratory capacity and vital capacity, and serial post-dose spirometry [FEV1, FVC] from randomisation to Week 52). Subjects were provided with salbutamol as rescue medication. Patients completed the electronic diary (eDiary)/electronic peak flow meter (ePeakflowmeter) (same device) twice daily at home from screening to Week 52, recording asthma symptoms, treatment compliance, rescue intake and peak expiratory flow (PEF). The Asthma Control Questionnaire© (ACQ)-7 was completed at all visits from screening to Week 52. The EuroQuality of Life-5-Dimensional-3-Level (EQ-5D-3L™) questionnaire was completed at all visits from randomisation to Week 52. Health economic information was collected during the study. Blood collection for routine haematology and blood chemistry was performed at screening, Week 26 and Week 52. Heart rate, Fridericia-corrected QT interval, PR interval and QRS interval were evaluated on 12-lead ECGs. Electrocardiographic and arrhythmia analyses were performed on 24-hour Holter ECGs. An independent Data Safety Monitoring Board was established for independent scrutiny of the study and impartial safety insurance of patients. An Adjudication Committee was established to evaluate Major Adverse Cardiovascular Events.

06 Apr 2016

No

Yes

Argentina: 60

Belarus: 29

Italy: 1

Russian Federation: 325

Turkey: 5

Ukraine: 215

Poland: 289

Portugal: 2

Romania: 119

Slovakia: 24

Spain: 1

United Kingdom: 4

Bulgaria: 171

Czech Republic: 91

Germany: 31

Hungary: 69

Lithuania: 1

1437

803

0

0

0

0

0

0

1173

264

0

Treatment period (overall period)

Randomised - controlled

An Interactive Response Technology (IRT) system was used to generate the randomisation list. This was a double-blind study with an open-label arm (CHF 1535 pMDI 200/6 μg + tiotropium 2.5 μg arm).

Yes

CHF 5993 pMDI 200/6/12.5 μg

Pressurised inhalation, solution

Inhalation use

Test product: CHF 5993 pMDI containing 200 μg BDP/6 μg FF/12.5 μg GB per metered dose. Double-blind study design: During study visits patients randomised to the CHF 5993 pMDI 200/6/12.5 μg treatment group received two kits of study treatment at randomisation, Week 12, Week 26 and Week 40, each consisting of one box containing two CHF 5993 pMDI inhalers numbered 1 and 2. Patients administered 1 puff from each inhaler in the morning and evening. Dose: 2 inhalations BID (total daily dose: 800 μg BDP/24 μg FF/50 μg GB).

CHF 1535 pMDI 200/6 μg

Pressurised inhalation, solution

Inhalation use

Test product: CHF 1535 pMDI containing 200 μg BDP/6 μg FF per metered dose. Double-blind study design: During study visits patients randomised to the CHF 1535 pMDI 200/6 μg treatment group received two kits of study treatment at randomisation, Week 12, Week 26 and Week 40, each consisting of one box containing two CHF 1535 pMDI inhalers numbered 1 and 2. Patients administered 1 puff from each inhaler in the morning and evening. Dose: 2 inhalations BID (total daily dose: 800 μg BDP/24 μg FF).

CHF 1535 pMDI 200/6 μg

Pressurised inhalation, solution

Inhalation use

Test product: CHF 1535 pMDI containing 200 μg BDP/6 μg FF per metered dose. During study visits patients randomised to the CHF 1535 pMDI 200/6 μg + tiotropium 2.5 μg treatment group received two kits of pMDI at randomisation, Week 12, Week 26 and Week 40, each consisting of one box containing two CHF 1535 pMDI inhalers numbered 1 and 2. Patients administered 1 puff from each inhaler in the morning and evening. Dose: 2 inhalations BID (total daily dose: 800 μg BDP/24 μg FF). Patients randomised to this arm also received SPIRIVA® Respimat® for administration of tiotropium 2.5 μg.

Tiotropium 2.5 μg

Inhalation solution

Inhalation use

Test product: Tiotropium 2.5 μg per dose equivalent to 3.124 μg tiotropium bromide. During study visits patients randomised to the CHF 1535 pMDI 200/6 μg + tiotropium 2.5 μg treatment group received 2 kits of SPIRIVA® Respimat® at randomisation, Week 12, Week 26 and Week 40, each consisting of one box containing two tiotropium inhalers. These inhalers were to be used in the morning only; patients administered 1 puff from each SPIRIVA® Respimat® in the morning. Dose: 2 inhalations OD (total daily dose: 5 μg tiotropium). Patients randomised to this arm also received CHF 1535 pMDI inhalers for administration of CHF 1535 pMDI 200/6 μg.

CHF 5993 pMDI 200/6/12.5 μg

CHF 1535 pMDI 200/6 μg

CHF 1535 pMDI 200/6 μg + tiotropium 2.5 μg

CHF 5993 pMDI 200/6/12.5 μg - ITT

The Intention-to-treat (ITT) population was defined as all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after baseline.

CHF 1535 pMDI 200/6 μg - ITT

The ITT population was defined as all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after baseline.

CHF 1535 pMDI 200/6 μg + tiotropium 2.5 μg - ITT

The ITT population was defined as all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after baseline.

CHF 5993 pMDI 100/6/12.5 μg and 200/6/12.5 μg - ITT

A pre-specified pooled analysis of the rate of severe asthma exacerbations over the 52-week treatment period was performed in the ITT population in two pivotal studies - CCD-05993AB1-03 (TRIMARAN) and CCD-05993AB2-02 (TRIGGER). The ITT population in each study was defined as all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy (primary or secondary variables) after baseline. The present analysis set included patients from the CHF 5993 pMDI 100/6/12.5 μg (“CHF 5993 pMDI”) arm in Study CCD-05993AB1-03 (ITT population) and the CHF 5993 pMDI 200/6/12.5 μg (“CHF 5993 pMDI high strength [HS]") arm in Study CCD-05993AB2-02 (ITT population).

CHF 1535 pMDI 100/6 μg and 200/6 μg - ITT

A pre-specified pooled analysis of severe asthma exacerbations over the 52-week treatment period was performed in the ITT populations of two pivotal studies - CCD-05993AB1-03 (TRIMARAN) and CCD-05993AB2-02 (TRIGGER). The ITT population in each study was defined as all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy (primary or secondary variables) after baseline. The present analysis set included the CHF 1535 pMDI 100/6 μg ("CHF 1535 pMDI”) arm in Study CCD-05993AB1-03 (ITT population) and the CHF 1535 pMDI 200/6 μg (“CHF 1535 pMDI HS”) arm in Study CCD-05993AB2-02 (ITT population).

CHF 5993 pMDI 200/6/12.5 μg

CHF 1535 pMDI 200/6 μg

CHF 1535 pMDI 200/6 μg + tiotropium 2.5 μg

CHF 5993 pMDI 200/6/12.5 μg - ITT

The Intention-to-treat (ITT) population was defined as all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after baseline.

CHF 1535 pMDI 200/6 μg - ITT

The ITT population was defined as all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after baseline.

CHF 1535 pMDI 200/6 μg + tiotropium 2.5 μg - ITT

The ITT population was defined as all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after baseline.

CHF 5993 pMDI 100/6/12.5 μg and 200/6/12.5 μg - ITT

A pre-specified pooled analysis of the rate of severe asthma exacerbations over the 52-week treatment period was performed in the ITT population in two pivotal studies - CCD-05993AB1-03 (TRIMARAN) and CCD-05993AB2-02 (TRIGGER). The ITT population in each study was defined as all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy (primary or secondary variables) after baseline. The present analysis set included patients from the CHF 5993 pMDI 100/6/12.5 μg (“CHF 5993 pMDI”) arm in Study CCD-05993AB1-03 (ITT population) and the CHF 5993 pMDI 200/6/12.5 μg (“CHF 5993 pMDI high strength [HS]") arm in Study CCD-05993AB2-02 (ITT population).

CHF 1535 pMDI 100/6 μg and 200/6 μg - ITT

A pre-specified pooled analysis of severe asthma exacerbations over the 52-week treatment period was performed in the ITT populations of two pivotal studies - CCD-05993AB1-03 (TRIMARAN) and CCD-05993AB2-02 (TRIGGER). The ITT population in each study was defined as all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy (primary or secondary variables) after baseline. The present analysis set included the CHF 1535 pMDI 100/6 μg ("CHF 1535 pMDI”) arm in Study CCD-05993AB1-03 (ITT population) and the CHF 1535 pMDI 200/6 μg (“CHF 1535 pMDI HS”) arm in Study CCD-05993AB2-02 (ITT population).

FEV1 is the volume of air that can be forced out in the first second after taking a deep breath. Change from baseline (CFB) in pre-dose morning FEV1 at Week 26 was analysed. Data are presented as adjusted means (least square means) with their 95% confidence intervals (CIs).

Primary

Baseline (pre-dose at the randomisation visit, Week 0) to Week 26.

The CFB in pre-dose FEV1 at Week 26 was analysed using a linear mixed model for repeated measures (MMRM) including treatment, visit, treatment by visit interaction and country as fixed effects, and baseline value (pre-dose, Week 0) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. The adjusted (adj.) means in each treatment group, adj. mean differences between treatments, their 95% CIs and p-values were estimated by the model.

CHF 5993 pMDI 200/6/12.5 μg - ITT v CHF 1535 pMDI 200/6 μg - ITT

1098

Pre-specified

0.073

2-sided

The rate of moderate and severe asthma exacerbations (defined below) was evaluated over 52 weeks of treatment. Severe: asthma worsening requiring initiation of treatment with systemic corticosteroids for at least 3 days (corticosteroid courses separated by ≥ 1 week treated as separate exacerbations). Moderate: ≥ 1 of the following criteria fulfilled and leading to a change in treatment (sustained increase of ≥ 1 puff of short-acting β2-agonist [SABA] for 2 consecutive days): - Nocturnal awakening(s) due to asthma requiring SABA for 2 consecutive nights/increase of ≥ 0.75 from baseline in daily symptom score on 2 consecutive days; - Increase from baseline (minimum: 4 puffs/day) in occasions of SABA use on 2 consecutive days; - ≥ 20% decrease in PEF from baseline on at least 2 consecutive mornings/evenings or ≥ 20% decrease in FEV1 from baseline; - Visit to Emergency Room/study site, no corticosteroids.

Primary

Baseline to 52 weeks.

The number of moderate and severe asthma exacerbations over the 52-week treatment period was analysed using a negative binomial model including treatment, country and number of exacerbations in the previous year (1 or > 1) as fixed effects, and log-time on study as an offset. The adj. asthma exacerbation rates in each treatment group and the adj. rate ratios with their 95% CIs and p-values were estimated by the model.

CHF 5993 pMDI 200/6/12.5 μg - ITT v CHF 1535 pMDI 200/6 μg - ITT

1142

Pre-specified

0.88

2-sided

Peak0-3h FEV1 is the peak forced expiratory volume in the first second within 3 hours post-dose. The CFB in peak0-3h FEV1 at Week 26 was analysed. This was a key secondary efficacy endpoint. Data are presented as adjusted means (least squares means) with their 95% CIs.

Secondary

Baseline to Week 26.

The CFB in peak0-3h FEV1 at Week 26 was analysed using a linear MMRM including treatment, visit, treatment by visit interaction and country as fixed effects; baseline value (Week 0, pre-dose) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adj. means in each treatment group, adj. mean difference between treatments, their 95% CIs and p-values were estimated.

CHF 5993 pMDI 200/6/12.5 μg - ITT v CHF 1535 pMDI 200/6 μg - ITT

1087

Pre-specified

0.105

2-sided

Patients monitored PEF (litres/minute) twice a day (morning and evening) during the run-in period (baseline measurement) and the entire treatment period at home, using a portable ePeakflowmeter which was customised with a specific program according to the parameters required by the study protocol. Patients were trained on the purpose and technique of PEF home monitoring. During each measurement session, patients performed three blows before intake of run-in or study medication (as applicable). Data were recorded on the device and automatically transmitted from home to the Vitalograph database on a daily basis. The CFB in the average morning PEF over the 26-week treatment period was analysed. This was a key secondary efficacy endpoint. Data are presented as adjusted means (least squares mean) with their 95% CIs.

Secondary

26-week treatment period.

The CFB in average morning PEF over the 26-week treatment period was analysed using a linear MMRM which included treatment, inter-visit period, treatment by inter-visit period interaction and country as fixed effects, and baseline value (run-in) and baseline by inter-visit period interaction as covariates. Adj. means in each treatment group, adj. mean difference between treatments, their 95% CIs and p-values were estimated.

CHF 5993 pMDI 200/6/12.5 μg - ITT v CHF 1535 pMDI 200/6 μg - ITT

1125

Pre-specified

7.805

2-sided

A pre-specified pooled analysis of the rate of severe asthma exacerbations over the 52-week treatment period was performed in the ITT populations of two pivotal studies CCD-05993AB1-03 (TRIMARAN) and CCD-05993AB2-02 (present study, TRIGGER). The pooled analysis of the two studies was based on the following treatment groups: 1. CHF 5993 pMDI + CHF 5993 pMDI High Strength (HS), for which data from the CHF 5993 pMDI 100/6/12.5 μg (“CHF 5993 pMDI”) arm in Study CCD-05993AB1-03 and the CHF 5993 pMDI 200/6/12.5 μg (“CHF 5993 pMDI HS") arm in Study CCD-05993AB2-02 were pooled; 2. CHF 1535 pMDI + CHF 1535 pMDI HS, for which data from the CHF 1535 pMDI 100/6 μg ("CHF 1535 pMDI”) arm in Study CCD-05993AB1-03 and the CHF 1535 pMDI 200/6 μg (“CHF 1535 pMDI HS”) arm in Study CCD-05993AB2-02 were pooled. This was a key secondary efficacy endpoint.

Secondary

52-week treatment period.

The number of severe asthma exacerbations during the 52-week treatment period was analysed in the pooled data of the two pivotal studies using a negative binomial model including treatment, country, and number of exacerbations in the previous year (1 or > 1) as fixed effects, and log-time on study as an offset. The adj. asthma exacerbation rates in each treatment group and the adj. rate ratios with their 95% CIs and p-values were estimated by the model.

CHF 5993 pMDI 100/6/12.5 μg and 200/6/12.5 μg - ITT v CHF 1535 pMDI 100/6 μg and 200/6 μg - ITT

2291

Pre-specified

0.77

2-sided

An ACQ-7 response was defined as CFB (Week 0, pre-dose) in ACQ-7 score ≤ -0.5. Non-response was defined as CFB in ACQ-7 score > -0.5 or missing data. The ACQ-7 allows the 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 had been 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 (related to FEV1, completed by the clinical staff) was populated with 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 visits during the treatment period. The ACQ-7 was completed from screening to Week 52.

Secondary

Baseline to Week 52.

ACQ-7 response was compared between treatment groups using a logistic model including treatment and country as factors and the baseline value (Week 0) as covariate. The odds ratio for the treatment effects with their 95% CIs and corresponding p-values were estimated by the model.

CHF 5993 pMDI 200/6/12.5 μg - ITT v CHF 1535 pMDI 200/6 μg - ITT

1074

Pre-specified

1.161

2-sided

The number of patients at risk of a moderate or severe asthma exacerbation is presented.

Secondary

Baseline to Week 52.

Time to first moderate or severe asthma exacerbation was analysed using a Cox proportional hazards model including treatment, country and number of exacerbations in the previous year (1 or > 1) as factors.

CHF 5993 pMDI 200/6/12.5 μg - ITT v CHF 1535 pMDI 200/6 μg - ITT

1142

Pre-specified

0.799

2-sided

The number of patients at risk of a severe asthma exacerbation is presented.

Secondary

Baseline to 52 weeks for both studies in the pooled analysis.

Time to first severe asthma exacerbation in the pooled data of the two pivotal studies CCD-05993AB1-03 and CCD-05993AB2-02 was analysed using a Cox proportional hazards model including treatment, country and number of exacerbations in the previous year (1 or > 1) as factors.

CHF 5993 pMDI 100/6/12.5 μg and 200/6/12.5 μg - ITT v CHF 1535 pMDI 100/6 μg and 200/6 μg - ITT

2291

Pre-specified

0.788

2-sided

Patients recorded asthma symptom scores and use of rescue medication (puffs/day) in the eDiary twice a day at home during the run-in (baseline values) and treatment periods. Data were automatically transmitted daily to the Vitalograph database. Asthma symptoms (i.e. overall symptoms, cough, wheeze, chest tightness and breathlessness) were scored as follows: Morning (night-time asthma symptoms): 0 (no symptoms), 1 (mild - symptoms not causing awakening), 2 (moderate - discomfort enough to cause awakenings) and 3 (severe - causing awakenings for most of the night/did not sleep at all); Evening (daytime asthma symptoms): 0 (no symptoms), 1 (mild - aware of symptoms which could be easily tolerated), 2 (moderate - discomfort enough to cause interference with daily activity), 3 (severe - incapacitating with inability to work/take part in usual activity). Asthma control days were calculated as days (i.e. night-time + daytime) with a total asthma score of 0 and no rescue medication use.

Secondary

52-week treatment period.

The CFB in percentage of asthma control days over the entire treatment period (Weeks 1-52) was analysed using a linear MMRM including treatment, inter-visit period, treatment by inter-visit period interaction and country as fixed effects, and baseline value (run-in period) and baseline by inter-visit period interaction and country as covariates.

CHF 5993 pMDI 200/6/12.5 μg - ITT v CHF 1535 pMDI 200/6 μg - ITT

1139

Pre-specified

3.513

2-sided

Adverse events were reported from the time of patient informed consent until study completion or discontinuation.

Treatment-emergent AEs (TEAEs) were defined as AEs with date of first randomised study treatment intake ≤ AE onset date ≤ date of completion/discontinuation.

18.1

CHF 5993 pMDI 200/6/12.5 μg - Safety

CHF 1535 pMDI 200/6 μg - Safety

CHF 1535 pMDI 200/6 μg + tiotropium 2.5 μg - Safety