CCD-05993AB1-03

Chiesi Farmaceutici S.p.A.

Via Palermo 26/A, Parma, Italy, 43122

Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., +39 0521 2791, clinicaltrials_info@chiesi.com

Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., +39 0521 2791, clinicaltrials_info@chiesi.com

No

No

No

Final

24 Jan 2019

Yes

17 May 2018

Yes

17 May 2018

No

- To demonstrate the superiority of CHF 5993 pressurised metered dose inhaler (pMDI) 100/6/12.5 μg compared to CHF 1535 pMDI 100/6 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 exacerbations rate with CHF 5993 pMDI 100/6/12.5 μg compared to CHF 1535 pMDI 100/6 μg during the entire 52-week treatment period.

The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines and following all other requirements of local laws. From screening to end of treatment, vital signs were recorded pre-dose at screening and pre- and post-dose at all visits during the treatment period; physical examination was performed at all visits; concomitant medications and adverse events (AEs) were recorded, and asthma exacerbations were assessed at all visits; lung function tests were performed (pre-dose for FEV1 and forced vital capacity from screening to end of treatment visits, pre-dose for inspiratory capacity and vital capacity and post-dose serial spirometry at all visits during the treatment period); 12-lead single electrocardiograms were recorded pre-dose at screening and pre- and post-dose at all visits during the treatment period (parameters evaluated included heart rate, PR interval, QRS interval and Fridericia-corrected QT interval). Patients completed the electronic diary from home twice daily from screening until the end of treatment to record asthma symptoms, treatment compliance and use of rescue medication, and used the electronic peakflowmeter to record peak expiratory flow twice daily from home from screening until the end of treatment. The Asthma Control Questionnaire© (ACQ)-7 was completed at screening and all visits during the treatment period. The EuroQuality of Life-5-Dimensional-3-Level questionnaire, and health economic and outcome assessments were competed at all visits during the treatment period. Blood samplings for haematology and blood chemistry were performed at screening, Week 26 and Week 52. Rescue medication (salbutamol 100 μg per inhalation) was used throughout the treatment period in case of absolute need; the maximum allowed dose was 8 inhalations/day (800 μg). An independent Data Safety Monitoring Board was established for independent scrutiny of the study and impartial safety insurance of patients.

17 Feb 2016

No

Yes

Poland: 131

Portugal: 1

Romania: 41

Slovakia: 15

Bulgaria: 96

Czech Republic: 107

Germany: 36

Hungary: 83

Argentina: 21

Belarus: 13

Italy: 8

Russian Federation: 361

Ukraine: 242

1155

518

0

0

0

0

0

0

950

205

0

Treatment period (overall period)

Randomised - controlled

An Interactive Response Technology (IRT) system was used to assign patients to the treatment arms. The randomisation list was provided to the labelling facility. An additional copy of the Master Randomisation List was provided to the analytical laboratory performing the pharmacokinetic analyses on biological samples, that was unblinded.

Yes

CHF 5993 pMDI 100/6/12.6 μg

Pressurised inhalation, solution

Inhalation use

Test product: CHF 5993 pMDI, fixed-dose combination of BDP/FF/GB. Dose: BDP 100 μg, FF 6 μg, GB 12.5 μg per actuation, 2 puffs BID. Total daily dose: BDP/FF/GB 400/24/50 μg. Mode of administration: pMDI using a standard actuator. Patients were trained in the proper use of the pMDI device. At Week 0, Week 12, Week 26 and Week 40, 2 kits of study treatment were dispensed to each patient, each consisting of one box containing two inhalers (numbered 1 and 2) which were to be used in the morning and in the evening. Each day during the 52-week treatment period, patients administered 1 puff from each pMDI inhaler in the morning and in the evening. If patients were used to inhaling their pMDI asthma medications with a spacer device, they used the AeroChamber Plus™ for inhaling the study treatment. Patients were trained in the proper use of this device, which was dispensed at screening, Week 0 and Week 26.

CHF 1535 pMDI 100/6 μg

Pressurised inhalation, solution

Inhalation use

CHF 1535 pMDI 100/6 μg containing BDP 100 μg and FF 6 μg. Dose: BDP 100 μg and FF 6 μg per actuation, 2 puffs BID. Total daily dose: BDP/FF 400/24 μg. Mode of administration: pMDI using a standard actuator. Patients were trained in the proper use of the pMDI device. At Week 0, Week 12, Week 26 and Week 40, 2 kits of study treatment were dispensed to each patient, each kit consisting of one box containing two inhalers (numbered 1 and 2) which were to be used in the morning and in the evening. Each day during the 52-week treatment period, patients administered 1 puff from each pMDI inhaler in the morning and in the evening. If patients were used to inhaling their pMDI asthma medications with a spacer device, they used the AeroChamber Plus™ for inhaling the study treatment. Patients were trained in the use of the AeroChamber Plus™ device, and this was dispensed at screening, Week 0 and Week 26.

CHF 5993 pMDI 100/6/12.5 μg

CHF 1535 pMDI 100/6 μg

CHF 5993 pMDI 100/6/12.5 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 100/6 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 5993 pMDI 100/6/12.5 μg - Safety

The Safety population was defined as all randomised patients who received at least one dose of study treatment.

CHF 1535 pMDI 100/6 μg - Safety

The Safety population was defined as all randomised patients who received at least one dose of study treatment.

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 100/6/12.5 μg

CHF 1535 pMDI 100/6 μg

CHF 5993 pMDI 100/6/12.5 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 100/6 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 5993 pMDI 100/6/12.5 μg - Safety

The Safety population was defined as all randomised patients who received at least one dose of study treatment.

CHF 1535 pMDI 100/6 μg - Safety

The Safety population was defined as all randomised patients who received at least one dose of study treatment.

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 forced expiratory volume in the first second. Change from baseline (CFB) in pre-dose morning FEV1 at Week 26 was analysed. Data are presented as adjusted means (least squares means) with their 95% confidence intervals (CIs).

Primary

Baseline 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 (Week 0, pre-dose) and baseline by visit interaction as covariates. An unstructured covariance matrix was assumed. Adjusted means in each treatment group, adjusted mean difference between treatments with 95% CIs and p-values were estimated.

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

1110

Pre-specified

0.057

2-sided

Severe asthma exacerbation - asthma worsening requiring initiation of treatment with systemic corticosteroids for at least 3 days (courses of corticosteroids separated by ≥ 1 week treated as separate severe exacerbations); requirement of an emergency room (ER) visit or hospitalisation was documented. Moderate asthma exacerbation - defined as ≥ 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 in occasions of SABA use on 2 consecutive days (minimum increase 4 puffs/day); ≥ 20% decrease in peak expiratory flow from baseline on at least 2 consecutive mornings/evenings or ≥ 20% decrease in FEV1 from baseline; visit to the ER/trial site for asthma treatment not requiring systemic corticosteroids.

Primary

52-week treatment period.

The number of moderate and severe exacerbations during 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. Adjusted asthma exacerbation rates in each treatment group, adjusted rate ratios with their 95% CIs and p-values were estimated by the model.

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

1149

Pre-specified

0.846

2-sided

Peak0-3h FEV1 is the peak forced expiratory volume in the first second within 3 hours post-dose. The change from baseline 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. Adjusted means in each treatment group, adjusted mean difference between treatments, their 95% CIs and p-values were estimated.

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

1106

Pre-specified

0.084

2-sided

Patients monitored peak expiratory flow (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 change from baseline 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 from Weeks 1 to 26.

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 and baseline by inter-visit period interaction as covariates. Adjusted means in each treatment group, adjusted mean difference between treatments, 95% CIs and p-values were estimated.

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

1135

Pre-specified

8.456

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 (present study, TRIMARAN) and CCD-05993AB2-02 (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 adjusted asthma exacerbation rates in each treatment group and the adjusted 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 change from baseline (Week 0, pre-dose) in ACQ-7 score ≤ -0.5; non-response was defined as change from baseline 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 at screening, and during the treatment period from Week 0 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 100/6/12.5 μg - ITT v CHF 1535 pMDI 100/6 μg - ITT

1149

Pre-specified

1.072

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 100/6/12.5 μg - ITT v CHF 1535 pMDI 100/6 μg - ITT

1149

Pre-specified

0.842

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 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 100/6/12.5 μg - ITT v CHF 1535 pMDI 100/6 μg - ITT

1148

Pre-specified

1.286

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 100/6/12.5 μg - Safety

CHF 1535 pMDI 100/6 μg - Safety