Main Phase:To demonstrate the superiority of medium-dose BDP/FF/GB pMDI compared to high-dose BDP/FF pMDI in terms of the proportion of subjects exhibiting on average NPAL over 26 weeks of treatment in the study sub-population with PAL at screening…
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Source
Brief title
Condition
- Bronchial disorders (excl neoplasms)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Main Phase
Main estimand
Population: Subjects with asthma meeting PAL criterion at screening.
Treatment: Randomised treatment (BDP/FF/GB 100/6/12.5 pMDI vs. BDP/FF 200/6
pMDI) including rescue medication and any other asthma treatments that may be
administered during the study.
Variable: Proportion of subjects exhibiting on average NPAL status over 26
weeks of treatment.
Population-level summary: Adjusted odds ratio comparing BDP/FF/GB 100/6/12.5
pMDI vs. BDP/FF 200/6 pMDI.
Strategy for intercurrent events:
• Early discontinuation from study treatment: FEV1/FVC values after the
discontinuation from the study treatment will be considered as missing and will
be imputed considering *Missing at Random* (MAR) assumption (i.e. targeting a
hypothetical strategy).
• Use of not allowed medication and other important protocol deviations: Data
will be used regardless of whether or not the intercurrent event occurs (i.e.
targeting a treatment policy strategy).
• Wrong study drug intake: Data will be used regardless of whether or not the
intercurrent event occurs (i.e. targeting a treatment policy strategy).
Strategy for events leading to missing data:
• FEV1/FVC value not available before the discontinuation from the study
treatment: Missing FEV1/FVC values will be imputed considering *Missing at
Random* (MAR) assumption (i.e. targeting a hypothetical strategy).
Sensitivity analyses - strategy for intercurrent events:
• Early discontinuation from study treatment: FEV1/FVC values after treatment
discontinuation will be considered as missing and will be imputed considering
*Missing not at Random* (MNAR) assumption:
o Copy Reference (CR) imputation based on BDP/FF 200/6 pMDI arm if reason for
treatment discontinuation is likely to be related to study treatment.
o CR imputation based on the relevant treatment arm if reason for treatment
discontinuation is not likely to be related to study treatment.
Alternative estimand
The attributes of the alternative estimand in terms of population, treatments,
variable and population-level summary are consistent with those for main
estimand provided above.
Strategy for intercurrent events:
• Early discontinuation from study treatment: FEV1/FVC values collected after
the treatment discontinuation will be included in the analysis (i.e. targeting
a treatment policy strategy).
• Use of not allowed medication and other important protocol deviations: Data
will be used regardless of whether or not the intercurrent event occurs (i.e.
targeting a treatment policy strategy).
• Wrong study drug intake: Data will be used regardless of whether or not the
intercurrent event occurs (i.e. targeting a treatment policy strategy).
Strategy for events leading to missing data:
• Early discontinuation from study: The collected off-treatment FEV1/FVC
observed on all subjectswill be considered for the imputation of missing
FEV1/FVC after the study discontinuation of both treatment groups (i.e.
targeting a hypothetical strategy). In case of few off-treatment FEV1/FVC
values collected, a CR imputation based on BDP/FF 200/6 pMDI arm will be
considered for all the treatment arms.
• FEV1/FVC value not available before the discontinuation of the study
treatment: Missing FEV1/FVC values will be imputed considering *Missing at
Random* (MAR) assumption.
Sensitivity analyses:
• No sensitivity analysis is planned for this alternative estimand.
Analysis
The proportion of subjects exhibiting on average NPAL status over 26 weeks of
treatment in the study sub-population meeting PAL criterion at screening will
be analysed on the ITT set using a logistic regression model including
treatment and region as factors and baseline FEV1/FVC value (i.e. Week 0,
pre-dose) as covariate. The odds ratio for the treatment effect (BDP/FF/GB
100/6/12.5 pMDI vs. BDP/FF 200/6 pMDI) with its 95% Wald CI and corresponding
p-value will be estimated by the model. Superiority of BDP/FF/GB 100/6/12.5
pMDI will be demonstrated by a statistically significant difference between
treatments (defined as p<0.05) favouring BDP/FF/GB 100/6/12.5 pMDI. A subject
will be considered as having on average a NPAL status over 26 weeks of
treatment if the mean of the 2h post-dose FEV1/FVC values is >= 0.7
OLE Phase
Main efficacy variables
The efficacy variable associated to the four main objectives of the OLE phase
is the proportion of subjects with *Adequately Controlled Asthma* in the four
afore mentioned cohorts of subjects (Cohort 1, 2, 3 and 4).
The attributes of the main estimand associated to the four main objectives are
summarised below. (cf protcol)
Secondary outcome
Main Phase
Main estimand
Population: Subjects with asthma meeting PAL criterion at screening.
Treatment: Randomised treatment (BDP/FF/GB 100/6/12.5 pMDI vs. BDP/FF 200/6
pMDI) including rescue medication and any other asthma treatments that may be
administered during the study.
Variable: Change from baseline in pre-dose FEV1 at Week 26.
Population-level summary: Adjusted between treatment difference comparing
BDP/FF/GB 100/6/12.5 pMDI vs. BDP/FF 200/6 pMDI.
Strategy for intercurrent events:
• Early discontinuation from study treatment: Pre-dose FEV1 values after the
discontinuation from the study treatment will be considered as missing and will
be managed by the mixed model for repeated measures, which relies on MAR
assumption for missing data (i.e. targeting a hypothetical strategy).
• Use of not allowed medication and other important protocol deviations: Data
will be used regardless of whether or not the intercurrent event occurs (i.e.
targeting a treatment policy strategy).
• Wrong study drug intake: Data will be used regardless of whether or not the
intercurrent event occurs (i.e. targeting a treatment policy strategy).
Strategy for events leading to missing data:
• Pre-dose FEV1 value not available before the discontinuation from the study
treatment: Missing pre-dose FEV1 values will be managed by the mixed model for
repeated measures, which relies on MAR assumption for missing data.
Sensitivity analyses - strategy for intercurrent events:
• Early discontinuation from study treatment: Missing FEV1 values after
treatment discontinuation will be considered as missing and will be imputed
considering MNAR assumption:
o CR imputation based on BDP/FF 200/6 pMDI arm if reason for treatment
discontinuation is likely to be related to study treatment.
o CR imputation based on the relevant treatment arm if reason for treatment
discontinuation is not likely to be related to study treatment.
Alternative estimand
The attributes of the alternative estimand in terms of population, treatments,
variable and population-level summary are consistent with those for main
estimand provided above.
Strategy for intercurrent events and events leading to missing data:
• Early discontinuation from study treatment: Pre-dose FEV1 values collected
after the treatment discontinuation will be included in the analysis (i.e.
targeting a treatment policy strategy).
• Use of not allowed medication and other important protocol deviations: Data
will be used regardless of whether or not the intercurrent event occurs (i.e.
targeting a treatment policy strategy).
• Wrong study drug intake: Data will be used regardless of whether or not the
intercurrent event occurs (i.e. targeting a treatment policy strategy).
Strategy for intercurrent events and events leading to missing data:
• Early discontinuation from study: The collected off-treatment pre-dose FEV1
observed on all subjects will be considered for the imputation of missing
pre-dose FEV1 after the study discontinuation of both treatment groups (i.e.
targeting a hypothetical strategy). In case of few off-treatment pre-dose FEV1
values collected; a CR imputation based on BDP/FF 200/6 pMDI arm will be
considered for all the treatment arms.
• Pre-dose FEV1 value not available before the discontinuation of the study
treatment: Missing pre-dose FEV1 values will be imputed considering *Missing at
Random* (MAR) assumption
Sensitivity analyses:
• No sensitivity analysis is planned for this alternative estimand.
Analysis
Change from baseline in pre-dose morning FEV1 at Week 26 in the study
sub-population meeting PAL criterion at screening will be analysed on the ITT
set using using a linear mixed model for repeated measures including treatment,
visit, treatment by visit interaction and region as fixed effects, and baseline
value (i.e. Week 0, pre-dose) and baseline by visit interaction as covariates.
An unstructured covariance matrix will be assumed. The adjusted means in each
treatment group, the adjusted mean difference between treatments and their 95%
CIs at Week 26 will be estimated by the model. Superiority of BDP/FF/GB
100/6/12.5 pMDI will be demonstrated by a statistically significant difference
between treatments at Week 26 (defined as p<0.05, in case the primary variable
analysis is successful) favouring BDP/FF/GB 100/6/12.5 pMDI.
OLE phase
Other efficacy and safety variables
• Analyses of other efficacy variables are planned to exclude off-treatment
data for subjects who discontinue the OLE phase study treatment prior to the
planned treatment completion (i.e. Week 50) and to target an hypothetical
strategy for the missing data as result of the event *Early discontinuation
from study treatment*.
• Safety analysis will be based on Safety set. For subjects who discontinue the
OLE phase study treatment but accept to remain in the study, assessments
conducted following 1 week after the last dose of study drug will not be
considered in analysis or presentation of safety data.
Details for other efficacy and safety variables are defined in the section 12
of protocol.
Background summary
Asthma is a serious, sometimes fatal disease affecting people of all ages,
characterized by chronic airway inflammation, respiratory symptoms (e.g.
wheeze, shortness of breath, cough, chest tightness), and variable expiratory
flow limitation, that is completely or partially reversible with treatment.
Asthma not only impacts the daily life of the affected individuals, but also
the life of their families. The number of disability adjusted life years
(DALYs) lost due to asthma amounts to 26.2 million representing about 1% of
DALYs lost by any disease and are similar to diabetes or Alzheimer*s disease.
Recent estimates suggest that about 350 million people suffer from asthma
worldwide, of which more than 30 million in Europe, with 0.4 million annual
deaths.
The goal of asthma management is to achieve and maintain disease control for
prolonged periods with regard to good symptom control and prevention of future
risk of exacerbations, persistent airflow limitation, asthma-related mortality,
and side-effects of treatment. A 5-step approach to the pharmacological
treatment of asthma has been established by the Global Initiative for Asthma
(GINA) and is widely accepted. Treatment with regular daily dose inhaled
corticosteroids (ICS) is highly effective in asthma management, and for many
patients the addition of a long-acting β2-agonist (LABA) to ICS has been shown
to improve symptom control, lung function and quality of life. A long-term,
daily treatment with ICS in combination with LABA is the preferred controller
option recommended in GINA for mild to severe asthma.
However, for a substantial proportion of patients, asthma remains uncontrolled
even with ICS/LABA, and this is a crucial point, as poorly controlled asthma
increases the risk of severe asthma exacerbations. With the 2021 revision GINA
guideline recommends added treatment "tracks" complementing the 5-step approach
to start the therapy. The Track 1 suggests using ICS/Formoterol combinations
either as maintenance and as reliver therapy at all steps. The Track 2 allows
to use SABA as a reliver complementing appropriate strength of ICS/LABA
maintenance treatment. However, GINA recognise the Track 1 as a preferred
reasoning it with additional reduction of exacerbations with ICS/Formoterol as
a reliver comparing to SABA and improved adherence. Starting from the 2015 GINA
update, an alternative and effective approach was introduced with the addition
of a long-acting muscarinic antagonist (LAMA) on top of ICS/LABA at GINA step
4-5, with a different pathway of action. Cholinergic tone is an independent
mechanism resulting in contraction of airway smooth muscle and release of mucus
from submucosal glands, and muscarinic receptor blockade (M3-receptors) results
in bronchodilation. The use of LAMA in asthma is well known, and their efficacy
and safety have been supported by several controlled clinical studies. They
produce a rapid onset of sustained bronchodilation, reduce airways
hyperresponsiveness and severe/moderate exacerbations, and increase the time to
first severe exacerbation in patients with inadequately controlled asthma.
Inhaled glycopyrronium bromide (GB) has been found to be an effective LAMA in
chronic obstructive pulmonary disease (COPD) and has been shown to induce
prolonged bronchodilation in patients with asthma and improve asthma control.
Trimbow is an extrafine fixed dose combination of the ICS beclometasone
dipropionate (BDP), the LABA formoterol fumarate (FF) and the LAMA
glycopyrronium bromide (GB), developed by Chiesi. The extrafine ICS/LABA
combination with BDP and FF has been approved for asthma, in Europe, since 2006
(Foster medium strength: 100/6 µg), and 2015 (Foster high strength: 200/6 µg).
Trimbow has been approved by the European Commission in July 2017 for treatment
of COPD, and has proven to be effective and safe also in asthma. It was
therefore authorized by the European Commission in January 2021 for maintenance
treatment of asthma, in adults not adequately controlled with a maintenance
combination of LABA and ICS (at medium or high dose, for Trimbow medium or high
strength, respectively), and who experienced one or more asthma exacerbations
in the previous year.
Two strengths of Trimbow are currently registered in Europe for asthma, namely
100/6/12.5 µg (medium strength, MS) and 200/6/12.5 µg (high strength, HS),
delivered with a single inhaler, with the advantage of reducing the burden of
using multiple inhalers that are often of a different type, with different
posology, and therefore may impact patient*s adherence to their inhaled
medication.
Study rationale
According to GINA 2021 recommendations, asthmatic patients not adequately
controlled with medium dose of ICS/LABA have the following treatment options:
1. Increase the dose of ICS;
2. add-on treatment with LAMA;
3. add-on treatment with other controllers (e.g. leukotriene receptor
antagonists, azithromycin);
4. administration of oral corticosteroids;
5. administration of biologic therapies, if available and appropriate after
phenotyping. Despite being authorized in several markets since 2014 and
recommended by GINA since 2015, the use of tiotropium as add-on LAMA is widely
variable, reported to be between 13 to 45% of patients with severe asthma
uncontrolled on medium-dose or high-dose ICS/LABA.
This in part may be due to absent availability of other LAMAs, and the need to
use multiple inhalers until the recent approval of fixed-dose triple
ICS/LABA/LAMA combinations (Trimbow, Enerzair Breezhaler) in Europe in 2020.
More importantly, a barrier to appropriate use of add-on LAMA has been the lack
of robust evidence to guide the decision of when to adding a LAMA to
medium-dose ICS/LABA is preferred overstepping up from medium-dose to high-dose
ICS/LABA.
Indeed, it is known that there are asthmatic patients who are low responders to
ICS (e.g. *low-Th2 phenotype*). These patients are unlikely to experience
better disease control following ICS dose step-up and would be unnecessarily
exposed to the risk of adverse effects associated with long-term exposure to
high-dose ICS.
Two pivotal trials evaluated the efficacy and safety of medium-dose BDP/FF/GB
vs mediumdose BDP/FF (TRIMARAN) and high-dose BDP/FF/GB vs high-dose BDP/FF
(TRIGGER).
As the two study populations differed with regards to their prior asthma
control medications (medium dose ICS/LABA in TRIMARAN, high-dose ICS/LABA in
TRIGGER) a comparison of the medium-dose BDP/FF/GB to the high-dose BDP/FF was
not possible. Moreover, two recently completed large RCTs (CAPTAIN, IRIDIUM)
that included both a medium-dose ICS/LABA/LAMA and a high-dose ICS/LABA
treatment arms failed to provide a conclusive answer to this question as well.
In these two RCTs, 33% and 37% of subjects enrolled, respectively, had
uncontrolled asthma on prior high-dose ICS/LABA which meant that they
experienced a step-down in their ICS dose when randomized to medium-dose triple
therapy (TT). In the IRIDIUM study, an evaluation of the results in the subset
uncontrolled on prior medium-dose ICS showed that treatment with medium-dose
MF/IND/GB resulted in better predose FEV1 (41 mL) at week 26 with no difference
in the annualized rate of moderate-severe asthma exacerbations compared to
high-dose MF/IND (RR 1.03), and a comparison in the overall study population
between medium-dose MF/IND/GB and high-dose FP/SLM showed a much a large
increase in lung function (+99 mL) and lower rate of mod/severe (-19%) and
severe exacerbations (-16%). No breakdown of results by prior treatment is
available from the CAPTAIN study which evaluated FluF/VIL/UMEC vs FluF/VIL.
There is evidence suggesting that subgroups with persistent airflow limitation
(PAL), defined by a post-salbutamol FEV1/FVC ratio < 0.7, might respond better
to LAMAs, with data suggesting improvements by adding a LAMA on top of medium
dose ICS/LABA, compared to stepping up to high dose of ICS, in lung function,
exacerbations, emergency department visits and hospitalizations, and use of
reliever therapy.
However, according to the latest European Respiratory Society/American Thoracic
Society guideline on management of severe asthma, further studies are needed to
confirm these findings and identify additional phenotypes, treatable traits and
associated biomarkers that may have a role in driving the best therapeutic
choice. Recently, the EMA evaluation of these three single-inhaler triple
therapies (SITT) resulted in the approval of ENERZAIR® Breezhaler® (MF/IND/GB)
only at the high-strength, the rejection of TRELEGY® ELLIPTA® (FluF/VIL/UMEC)
based on insufficient proof of efficacy, and the approval of TRIMBOW®
(BDP/FF/GB) at both medium and high-strength as maintenance treatment for
asthma.
Therefore, the market availability of the medium-dose BDP/FF/GB as well as the
availability of the high-strength FOSTER (BDP/FF) in the same pMDI device
provides a unique opportunity to design this study to evaluate, prospectively,
the treatment response of adding a LAMA compared to doubling the dose of ICS in
patients whose asthma is uncontrolled on medium-dose ICS/LABA and who show
persistent airflow limitation postsalbutamol.
The study will compare the efficacy and safety of the fixed-dose triple
ICS/LABA/LAMA combination BDP/FF/GB given at a medium ICS total daily dose
(BDP/FF/GB 400/24/50 µg) versus the fixed-dose ICS/LABA BDP/FF given at a high
ICS total daily dose (800/24 µg) for 26 weeks, in subjects with uncontrolled
asthma under medium doses of ICS/LABA.
The primary efficacy endpoint is chosen to be the proportion of subjects who on
average no longer exhibit persistent airflow limitation (NPAL) over the 26
weeks of the study treatment, and the key-secondary outcome will be the change
from baseline in pre-dose morning FEV1 at week 26. These will be evaluated
primarily in the subgroup of subjects who show PAL at screening which will
constitute approximately 65% of the overall enrolled population, closely
mimicking its prevalence in prior RCTs.
The choice of the primary efficacy outcome is supported considering the
positive correlation of PAL status with increased risk of asthma exacerbation
and with the increased likelihood that patients with PAL would normalize their
airflow following LAMA add-on.
In this study, we elected to apply the definition of PAL provided in the 2021
GOLD Report which specifies a post-bronchodilator FEV1/FVC ratio cut-off <0.7.
We defined PAL status at V1 (screening) as a FEV1/FVC < 0.7 within 30 min
post-salbutamol 400 mcg inhalation; and post-randomization as a FEV1/FVC < 0.7
at 2hr post study treatment dose at V2, V3, V4, V5 and V6 to correspond to peak
bronchodilator effect. Secondarily, we will evaluate PAL status using FEV1/FVC
< lower limit of normal (LLN) standard since it is helpful to avoid
underdiagnosis of abnormalities in younger, taller individuals and
over-diagnosis in those older or shorter. We expect the results between the two
methods to be concordant.
Furthermore, to mitigate the potential variability in PAL status over time, we
will measure this parameter at several time points during the 26 weeks of
treatment, and we will consider the average of values obtained at all visits.
Secondarily, we will also calculate the proportions of subjects who
consistently exhibit PAL status on treatment at every visit and those who don*t.
Chiesi believes that this study can shed light on the above-mentioned open
questions, in a context where the triple therapy (ICS/LABA/LAMA) is being
increasingly deployed to treat moderate to severe asthma, and personalized
medicine plays an important role in asthma, as new treatable traits are found
to be linked to asthma management.
Study objective
Main Phase:
To demonstrate the superiority of medium-dose BDP/FF/GB pMDI compared to
high-dose BDP/FF pMDI in terms of the proportion of subjects exhibiting on
average NPAL over 26 weeks of treatment in the study sub-population with PAL at
screening.
• A subject is defined as having PAL at screening if their post-bronchodilator
(salbutamol) FEV1/FVC ratio is < 0.7.
• A subject is defined as having NPAL during the treatment period if the mean
of their 2h post-dose FEV1/FVC ratios collected during the 26-week treatment
period is >= 0.7.
OLE Phase:
To assess the proportion of subjects whose asthma remains "Adequately
Controlled":
• On MS BDP/FF/GB at the end of the OLE phase in subjects with previously
"Adequately Controlled Asthma" (Cohort 1 on HS BDP/FF, Cohort 4 on MS
BDP/FF/GB).
• On HS BDP/FF/GB at end of the OLE phase in subjects with previously
"Uncontrolled Asthma" (Cohort 2 on MS BDP/FF/GB, cohort 3 on HS BDP/FF) at the
end of the main phase.
Study design
Main phase
The main phase is a phase IV, randomized, double-blind, active-controlled,
2-arm parallel group study.
The main phase entails three periods: a run-in period of 2-week duration, a
treatment period of 26 weeks duration, and a post-treatment follow-up period of
1 week (applicable only for subjects not enrolled in the OLE phase).
A total of 7 clinic visits (V0 to V6) plus a follow-up call will be performed
during the study, as follows:
• A pre-screening visit (V0) will be carried out in order to fully explain the
study to potential subjects and to obtain the written informed consent from the
subject and instruct the subject on screening visit procedures (such as
medication restrictions).
• A screening visit (V1) (within 7 days after V0) will help establishing the
subjects* eligibility for inclusion in the study. This visit will be followed
by a 2-week open-label run-in period during which the subjects will receive
BDP/FF 100/6 µg 2 inhalations BID (daily dose 400/24 µg).
• A randomization visit (V2), at which eligible subjects will be randomized to
one of the 2 treatment groups. All subjects will receive their 1st study drug
treatment.
• After randomization, subjects will be assessed after 4, 12, 22 and 26 weeks
of treatment (visits V3 to V6 respectively) at the clinic/hospital.
For the subjects who will not be enrolled in the OLE phase: A follow up (FU)
call will take place 1 week after the last study visit (V6 or ETD visit) of the
subject to check safety and the subjects* status.
The total duration of the main phase (V0 to FU call) is 30 weeks for any
subject completing the trial and not enrolled in the OLE phase.
The start of the trial is defined as the date of first site initiation visit in
the trial.
OLE phase
At the end of the main phase, subjects can opt to enroll into the OLE phase: An
Exploratory Open Label, non-randomised, Multinational, Multicentre, 2-arm
parallel group extension, up until the target sample size is reached.
The OLE phase will employ partially decentralized approach (Decentralized
Clinical Trial). The aim of the decentralization is to monitor subjects at home
in order to avoid travel to sites and consequently reduce patient*s burden
after completion of the main phase.
Decentralization is the preferred option and will follow local regulations.
Two out of the five visits of the OLE phase will be performed remotely by the
investigator using the decentralized (DCT) platformand the remote video call
application.
*Each subject who completed the main phase (i.e. at Week 26), will be
classified into *Adequately Controlled Asthma* or *Uncontrolled Asthma*.
If the subject cannot be included in one of the two categories at the end of
the main phase (e.g. due to missing data), he/she will not be considered for
the OLE phase.
If the subject discontinues from the study treatment before the end of the main
phase (i.e. Week 26), he/she will not be considered for the OLE phase.
A total of 5 clinic visits, (3 on site and 2 remote) from V6OLE to V10, and one
follow-up call will be performed.
The total duration of the OLE phase (V6OLE to FU call) is 25 weeks for any
subject who completes this phase, 24 weeks of open-label treatment plus one
week of follow-up.
• Visit 6/6OLE Investigator will fully explain the OLE phase objectives and
details to potential subjects as needed, and obtain the electronic (preferred
option) or written informed consent. The first visit of OLE phase (visit 6 OLE)
will occur the same day of visit 6 of the main phase to assess OLE
phase-specific screening assessments after all assessments for the MiSTIC main
phase have been performed.
When all the inclusion and exclusion criteria have been checked, eligible
subjects for the OLE phase will be categorized into one of two groups
*Adequately Controlled Asthma* (to receive open-label MS BDP/FF/GB for 24
weeks) and *Uncontrolled Asthma* (to receive open-label HS BDP/FF/GB for 24
weeks) as reported above in the figure 4.
• Visit V7 (at Week 30, occurring at 4 weeks after the start of OLE phase) will
be performed as a remote visit (in the form of video call through a DCT
platform by the investigator
• Visit V8 (at Week 38, occurring at 12 weeks after the start of OLE phase)
will be performed at clinic/hospital. Subjects will be provided with study
treatment resupply.
• Visit V9 (at Week 46, occurring at 22 weeks after the start of OLE phase)
will be performed as remote visit
• Visit V10 (at Week 50, occurring at 24 weeks after the start of OLE phase)
will be performed at clinic/hospital.
• A safety follow-up phone call will be done by the investigator 1 week after
the V10 or Early Treatment Discontinuation visit to check the status of
unresolved adverse events and to record any new AEs that have occurred after
the last visit as well as the related concomitant medications.
The end of the study is defined as the last contact with the last subject in
the OLE phase:
- Last follow-up contact if the last subject in the trial is discontinued from
the OLE phase;
- Last study visit if the last subject in the trial is discontinued from the
treatment of the OLE phase and agrees to remain in the study.
Intervention
Main Phase:
Treatment A: CHF 5993 100/6/12.5 µg (MS BDP/FF/GB)
Medium Strength (MS) Fixed combination of extrafine beclometasone dipropionate
100 µg plus formoterol fumarate 6 µg plus glycopyrronium bromide 12.5 µg /
metered dose
Dose regimen: BDP/FF/GB 100/6/12.5 µg per inhalation, 2 inhalations BID, total
daily dose 400/24/50 µg
Administration: pressurized metered dose inhaler (pMDI)
Note: Subjects used to inhale their asthma pMDI medications with a spacer or
experiencing difficulties when switching from different inhaler type (e.g. Dry
Powder Inhaler) should be using a spacer to take the pMDI study drugs.
OLE Phase:
CHF 5993 100/6/12.5 µg pMDI (MS BDP/FF/GB)
Medium Strength (MS) Fixed combination of extrafine beclometasone dipropionate
100 µg plus formoterol fumarate 6 µg plus glycopyrronium bromide 12.5 µg /
metered dose
Dose regimen: BDP/FF/GB 100/6/12.5 µg per inhalation, 2 inhalations BID, total
daily dose 400/24/50 µg
Administration: pressurized metered dose inhaler (pMDI)
Note: Subjects used to inhaling their asthma pMDI medications with a spacer
during the main phase should continue using a spacer to take the pMDI study
drugs.
CHF 5993 200/6/12.5 µg pMDI (HS BDP/FF/GB)
High Strength (HS) Fixed combination of extrafine beclometasone dipropionate
200 µg plus formoterol fumarate 6 µg plus glycopyrronium bromide 12.5 µg /
metered dose.
Dose regimen: BDP/FF/GB 200/6/12.5 µg per inhalation, 2 inhalations BID, total
daily dose 800/24/50 µg
Administration: pressurized metered dose inhaler (pMDI)
Note: Subjects used to inhaling their asthma pMDI medications with a spacer
during the main phase should continue using a spacer to take the pMDI study
drugs.
Study burden and risks
cf. E4 and E9
Via Palermo 26/A NA
Parma 43122
IT
Via Palermo 26/A NA
Parma 43122
IT
Listed location countries
Age
Inclusion criteria
Main phase
1.Informed consent: Subject*s written informed consent obtained prior to any
study related procedures;
2.Sex and age: Male or female subjects aged >= 18;
3.Diagnosis of asthma: A documented diagnosis of persistent asthma for at least
1 year according to GINA recommendations (Box 1-2, GINA report 2021), and with
diagnosis before the subject*s age of 40 years;
4.Stable asthma therapy: a stable treatment with medium dose of Inhaled
corticosteroids (ICS) (extrafine BDP daily dose > 200 and <=400 µg or
estimated clinically comparable dose, as described in GINA 2021 box 3-6) plus
a long-acting ß2-agonist (LABA) (formoterol 24 µg or salmeterol 100 µg or
vilanterol 25 µg or other approved dose of LABA as clinically comparable to the
others) for at least 4 weeks prior to screening;
5.Lung function: A prebronchodilator FEV1 < 80% of the predicted normal
value, after appropriate washout from bronchodilators, at the screening and
randomisation visits;
6.Bronchodilator responsiveness: A demonstrated increase in FEV1 > 12% and
> 200 mL over baseline within 30 minutes after inhaling 400 µg of salbutamol
pMDI (based on ATS/ERS guidelines);
7.A Post-bronchodilator FEV1/FVC ratio >= 0.5 within 30 minutes after inhaling
400 µg of salbutamol pMDI at screening (based on ATS/ERS guidelines);
8.Poor Asthma control: Evidence of poorly controlled or uncontrolled asthma as
based on an Asthma Control Questionnaire© (ACQ-7) score >= 1.5 at screening and
at randomisation;
9.History of asthma exacerbations: A documented history of one or more asthma
exacerbations requiring treatment with systemic corticosteroids or emergency
department visit or inpatient hospitalisation in the last 3 years prior to
screening;
10.A willingness and ability:
- to correctly use the pMDI inhalers;
- to perform all trial related procedures including technically acceptable
pulmonary function tests;
- to correctly use the e-Diary/e-Peak flow meter.
11.Female subjects:
a. Woman of Childbearing Potential or
b. Female patient of nonchildbearing potential: Please refer to the protocol.
OLE phase
1. Informed consent: Subject's electronic (preferred option) or written
informed consent obtained prior to any study related procedures;
2. Participation in MiSTIC study main phase: Subjects enrolled in MiSTIC main
phase, who did not discontinue from the main phase study treatment before Week
26 and with available data to allow classification into one of the two
categories "Adequately Controlled Asthma" or "Uncontrolled Asthma" at the end
of the main phase;
3. A willingness and ability:
-To correctly use the pMDI inhalers;
-To perform all trial related procedures including technically acceptable
pulmonary function tests;
-To correctly use the e-Diary;
-To correctly use the technology enabling remote visits and home supervised
spirometry assessments. This applies only to countries where remote visits are
allowed as per local regulations and for subjects willing to participate to
remote assessments. The home spirometry will be supervised by site personnel
during the remote visits.
4. Treatment compliance during main phase: Subjects with main phase study
treatment compliance = 70%
5.Female subjects:
a.Woman of Childbearing Potential or
b.Female patient of non childbearing potential: Please refer to the pPotocol.
Exclusion criteria
Main phase
1. Pregnant or lactating woman where pregnancy is defined as the state of a
female after conception and until termination of the gestation, confirmed by a
positive pregnancy test (serum pregnancy test to be performed at screening
visit and urine pregnancy test to be performed prior to randomisation);
2. Run-in compliance to study drug and e-Diary completion< 50% at randomisation;
3. History of *high risk* asthma: History of near fatal asthma or
hospitalisation for asthma in an intensive care unit which, in the judgement of
the Investigator, may place the subject at undue risk if enrolled in this study;
4. Recent exacerbation: hospitalisation, emergency room admission or use of
systemic corticosteroids for an asthma exacerbation in the 4 weeks prior to
screening visit or during the run-in period;
Note: Subjects experiencing an exacerbation during the run-in period may be
re-screened once, at least 4 weeks after recovery.
5. Non-persistent asthma: exercise-induced, seasonal asthma (as the only
asthma-related diagnosis) not requiring daily asthma control medicine;
6. Subjects using systemic corticosteroid medication in the 4 weeks or slow
release corticosteroids in the 12 weeks, prior to screening;
7. Asthma requiring use of biologics: Subjects receiving asthma treatment with
an injectable biologic drug such as monoclonal antibodies;
8. Respiratory disorders other than asthma: Subjects with known respiratory
disorders other than asthma. This can include but is not limited to: diagnosis
of COPD as defined by the current guidelines (e.g. GOLD Report), known *1-
antitrypsine deficiency, active tuberculosis, bronchiectasis, sarcoidosis,
interstitial lung diseases, idiopathic pulmonary fibrosis and pulmonary
hypertension;
9. Lung cancer or history of lung cancer: Subjects with an active diagnosis of
lung cancer
or a history of lung cancer;
10. Lung resection: Subjects with a history of lung volume resection;
11. Respiratory tract infection: subjects with respiratory tract infection
within 4 weeks prior to screening or during the run-in period;
Note: Subjects experiencing a respiratory tract infection during the run-in
period may be re-screened once, at least 4 weeks after recovery.
12. Smoking status: Current smokers, or ex-smokers with total cumulative
exposure equal or more than 10 pack-years; (pack-years = the number of
cigarette packs per day times the number of years). Ex- smokers must have
stopped smoking for >=1 year (>= 6 months for ecigarettes).
13. Cancer or history of cancer (other than lung): Subjects with active cancer
or a history of cancer with less than 5 years disease free survival time
(whether or not there is evidence of local recurrence or metastases). Localised
carcinoma (e.g. basal cell carcinoma, in situ carcinoma of the cervix
adequately treated, *) is acceptable;
14. Cardiovascular diseases: Subjects who have clinically significant (CS)
cardiovascular condition according to Investigator*s judgement, such as but not
limited to: congestive heart failure (NYHA class IV), unstable or acute
ischaemic heart disease in the last year prior to screening, history of
sustained and non-sustained cardiac arrhythmias diagnosed in the last 6 months
prior to screening (sustained meant lasting more than 30 seconds or ending only
with external action, or led to haemodynamic collapse; non-sustained meant > 3
beats < 30 seconds, and or ending spontaneously, and or asymptomatic), high
degree impulse conduction blocks (> 2nd degree atrioventricular block type 2),
persistent, long
standing or paroxysmal atrial fibrillation (AF);
Note: Subjects with permanent AF (for at least 6 months prior screening) with a
resting ventricular rate < 100/min, controlled with a rate control strategy
(i.e. selective β-blocker, calcium channel blocker, pacemaker placement,
digoxin or ablation therapy) can be considered for enrolment;
15. ECG criteria: Any abnormal and CS 12-lead ECG that in the investigator's
opinion would affect efficacy or safety evaluation or place the subjects at
risk.
16. ECG QTcF: Male subjects with a Fridericia*s corrected QT interval (QTcF)
>450 msec and female subjects with a QTcF >470 msec at screening are not
eligible (not applicable for subjects with permanent atrial fibrillation and
for subjects with pacemaker);
For full list please refer to the Protocol.
OLE phase:
1. Pregnant or lactating woman.
2. Subjects who have experienced an ADR during the main phase;
3. Subjects with ongoing SAEs from the main phase
4. Any clinically significant changes in subject's medical history, physical
examination (PE)/Vital Signs (VS)/laboratory analysis;
5. Changes in study treatments during the main phase
For complete criteria, please refer to the Protocol.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-002391-39-NL |
| ClinicalTrials.gov | NCT05018598 |
| CCMO | NL79925.091.22 |