To evaluate the effect of triple-therapy wih Budesonide, Glycopyrronium and Formoterol Fumarate (PT010) versus dual therapy with Budesonide and Formoterol Fumarate on asthma exacerbations in adult and adolescent subjects with inadequately controlled…
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Source
Brief title
Condition
- Bronchial disorders (excl neoplasms)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary objective is to assess the effect of BGF MDI relative to BFF MDI or
Symbicort pMDI on lung function in participants with inadequately controlled
asthma, using the primary endpoint of change from baseline in morning pre-dose
trough FEV1 over 24 Weeks
Secondary outcome
Secondary objectives are (1.) to assess the effect of BGF MDI relative to BFF
MDI or Symbicort pMDI on lung function in participants with inadequately
controlled asthma and (2.) to assess the effect of BGF MDI relative to BFF MDI
or Symbicort pMDI on lung function, PROs, and symptoms in participants with
inadequately controlled asthma.
Secondary endpoints are (1.) Change from baseline in FEV1 AUC0-3 over 24 Weeks,
(2.) Percentage of responders in ACQ-7 (*0.5 decrease equals response) at Week
24, over 24 Weeks or over 12 to 24 Weeks, (3.) Percentage of responders in
ACQ-5 (*0.5 decrease equals response) at Week 24, over 24 Weeks or over 12 to
24 Weeks, (4.) Percentage of responders in the Asthma Quality of Life
Questionnaire for 12 years and older (AQLQ +12) (*0.5 increase equals response)
at Week 24, over 24 Weeks or over 12 to 24 Weeks, (5.) Percentage of responders
in the St. George*s Respiratory Questionnaire (SGRQ) (*4.0 unit decrease equals
response) at Week 24, (6.) Onset of action on Day 1: Absolute change in FEV1 at
5 minutes on Day 1 and (7.) Rate of severe asthma exacerbations over the
Treatment Period
Background summary
Asthma is a heterogeneous disease that is characterized by chronic airway
inflammation and bronchial hyperreactivity. Worsening asthma symptoms/airway
obstruction can be severe, resulting in an asthma exacerbation that may be
life-threatening. Such events pose a significant burden to patients and result
in significant direct and indirect economic costs. Asthma affects approximately
339 million people in all regions of the world. Globally, there are roughly
1000 asthma-related deaths per day, and this condition is among the leading
causes of disability. There are adult and adolescent patients with asthma who
remain inadequately controlled despite treatment with a medium or high dose of
ICS/LABA, and the Global Initiative for Asthma (GINA) guidelines recommend a
step-up in therapy. The addition of LAMA to ICS/LABA is an appropriate
treatment option in this population. This addition could provide an important
step up in care before escalation to systemic or invasive therapies such as
bronchial thermoplasty, thus having a significant role in the management of
asthma when used in combination with other controller medications. The aim of
this study is to demonstrate benefit of the fixed-dose triple combination of
ICS/LAMA/LABA in reducing severe asthma exacerbations and improving lung
function and health-related quality of life measures.
Study objective
To evaluate the effect of triple-therapy wih Budesonide, Glycopyrronium and
Formoterol Fumarate (PT010) versus dual therapy with Budesonide and Formoterol
Fumarate on asthma exacerbations in adult and adolescent subjects with
inadequately controlled asthma.
Study design
This is a Phase III randomized, double-blind, double dummy, parallel group,
multicenter variable length efficacy and safety study comparing two doses of
Budesonide, Glycopyrronium, and Formoterol Fumarate (BGF) Metered-Dose Inhaler
(MDI) (320/28.8/9.6 *g and 320/14.4/9.6 *g) to Budesonide and Formoterol
Fumarate (BFF) MDI 320/9.6 *g (an ICS/LABA currently under development) and
Symbicort pMDI 320/9 *g in adult and adolescent participants who have asthma
which remains inadequately controlled (ACQ-7 total score *1.5) despite
treatment with a medium or high dose of ICS/LABA. Adult participants (but not
adolescents) must also have a documented history of at least one asthma
exacerbation in the 12 months prior to Visit 1. All doses represent the sum of
two actuations. All study interventions will be administered twice daily (BID)
for a minimum of 24 weeks and a maximum of 52 weeks. The study will end when
the last randomized participant completes 24 weeks on randomized study
intervention and a 2-week safety follow up, phone call. This study will be
conducted at approximately 560 sites worldwide and will randomize approximately
2800 adult and adolescent participants. The number of participants per
treatment arm may be increased based on a blinded sample size re-estimation
(BSSR).
Intervention
Subjects will be randomized in a 1:1:1:1 ratio to either BGF MDI
(320/57.6/9.6*g / day), BGF MDI (640/28.8/19.2*g / day), BFF MDI (640/19.2*g /
day) or Symbicort pMDI (320/18*g / day).
Study burden and risks
The subject is asked to visit the site maximal 15 times. The visit time will
last maximal 4 hours (although subjects that take part in the sub-studies will
have visit times up to 13 hours). The subject will be contacted by telephone at
least 1 time at the end of the study (2 weeks after the last dose). Blood and
urine samples will be collected for safety laboratory assessment or exploratory
biomarker sampling up to 4 times in this study. The total volume of blood that
will be collected is approximately 50 ml. The subject will undergo physical
examinations during 4 visits. The subject will undergo a spirometry test during
every visit and 4 times a serial spirometry up to 4 hours. The subject will
undergo a FeNO test twice during the study. Reversibility to albuterol will be
evaluated once during the study, with a potential repeated measurement in the
subsequent visit if reversibility criteria are not met the first time. An ECG
will be performed at 5 visits during the study. Woman of child bearing
potential have to provide a urine sample to test for pregnancy at all site
visits (15 times). The subject will be asked to fill out questionnaires at all
hospital visits with a maximum of 15 times. The subject must fill out
questionnaires every day (in the morning and evening) in an e-Diary.
The subject (only in the 12-hour spirometry sub-study) will undergo serial
spirometry 12 hours post-dose at 2 visits during the study. The subject (only
in the 12-hour pharmacokinetics sub-study) will undergo plasma sample
collection 11 times during 1 of the site visits (total of 110 mL blood). The
subject (only in the Holter sub-study) will undergo Holter monitoring for 24
hours initiated on 3 site visits during the study and the subject will be
instructed to return to the clinic the following day for removal of the Holter
Monitor.
The subject (only in the optional genetic analysis) will undergo blood sample
collection (6 mL) once.
Prinses Beatrixlaan 582
Den Haag 2595BM
NL
Prinses Beatrixlaan 582
Den Haag 2595BM
NL
Listed location countries
Age
Inclusion criteria
(1.) Female or male subjects between 12-80 years inclusive, at the time of
signing the ICF. (2.) Participants who have a documented history of
physician-diagnosed asthma *1 year prior to Visit 1, according to GINA
guidelines [GINA 2020]. Healthcare records for 1 year prior to Visit 1 must be
provided for adolescent participants (12 to <18 years of age) to ensure
consistent evaluation and follow-up of treatment in those participants. (3.)
Participants who have been regularly using a stable daily ICS/LABA regimen
(including a stable ICS dose), for at least 4 weeks prior to Visit 1. (4.) Have
a documented history of at least one asthma exacerbation requiring use of
systemic corticosteroids (oral or IV) for at least 3 days AND an associated
physician visit, hospitalization, or ER visit due to asthma (within 3 days of
the corticosteroid use) in the 12 months prior to Visit 1. (5.) ACQ-7 total
score *1.5 at Visits 1, 3, and 5 (pre-randomization). (6.) A pre-bronchodilator
FEV1 <80% predicted normal value at Visits 1, 2, 3, 4, and 5
(pre-randomization) for participants *18 years of age OR a pre-bronchodilator
FEV1 <90% predicted normal value at Visits 1, 2, 3, 4, and 5
(pre-randomization) for participants 12 to <18 years of age. (7.) Documented
reversibility to albuterol, which is defined as a post-albuterol increase in
FEV1 of *12% and *200 mL for participants *18 years of age OR a post-albuterol
increase of FEV1 of *12% for participants 12 to <18 years of age at Visit 2, or
at Visit 3 if repeat testing necessary. (8.) Willing and, in the opinion of the
Investigator, able to adjust current asthma therapy, as required by the
protocol. (9.) Received no asthma medication other than run-in BFF MDI BID and
albuterol as needed during screening, except for allowed medications defined in
Table 8 and systemic corticosteroid or ICS for the treatment of an asthma
exacerbation (see Section 5.5.2 regarding Screening extension). (10.) No
respiratory infection within 4 weeks of randomization, or asthma exacerbation
treated with systemic corticosteroid and/or additional ICS treatment within 4
weeks of randomization.
Exclusion criteria
(1.) Life-threatening asthma defined as a history of significant asthma
episode(s) requiring intubation associated with hypercapnia, respiratory
arrest, hypoxic seizures, or asthma-related syncopal episode(s). (2.) Completed
treatment for respiratory infection or asthma exacerbation with systemic
corticosteroids within 4 weeks of Visit 1. (3.) Hospitalization for asthma
within 2 months of Visit 1. (4.) Historical or current evidence of a clinically
significant disease including, but not limited to: cardiovascular, hepatic,
renal, hematological, neurological, endocrine, gastrointestinal, or pulmonary.
(5.) Narrow angle glaucoma not adequately treated and/or change in vision that
may be relevant, in the opinion of the Investigator, within 3 months of Visit
1. (6.) Symptomatic prostatic hypertrophy or bladder neck obstruction/urinary
retention that, in the opinion of the Investigator, is clinically significant.
(7.) Unresectable cancer that has not been in complete remission for at least 5
years prior to Visit 1. (8.) Oral and IV corticosteroid use (any dose) within 4
weeks of Visit 1. (9.) Depot corticosteroid use for any reason within 12 months
of Visit 1. (10.) Use of LAMA as maintenance treatment, either alone or as part
of an inhaled combination therapy, within 12 months prior to Visit 1. (11.) Use
of oral beta2-agonist within 3 months of Visit 1. (12.) Any marketed (e.g.,
omalizumab, mepolizumab, benralizumab, reslizumab) or investigational biologic
within 3 months or 5 half-lives of Visit 1 (13.) Regular use of a nebulizer or
a home nebulizer for receiving asthma medications. (14.) Use of any
immunomodulators or immunosuppressive medication within 3 months or 5
half-lives. (15.) Participants with a known hypersensitivity to beta2-agonists,
corticosteroids, anticholinergics, or any component of the MDI or pMDI. (16.)
Current smokers, former smokers with >10 pack-years history, or former smokers
who stopped smoking <6 months prior to Visit 1. (17.) Planned hospitalization
during the study. (18.) Previous or current randomization in any budesonide and
formoterol fumarate studies (PT009), budesonide, glycopyrronium, and formoterol
fumarate studies (PT010), or glycopyrronium studies (PT001). (19.) For women
only * currently pregnant (confirmed with positive pregnancy test),
breastfeeding, or planned pregnancy during the study or not using acceptable
contraception measures, as judged by the Investigator.
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 | EUCTR2020-001520-34-NL |
| ClinicalTrials.gov | NCT04609878 |
| CCMO | NL75439.100.20 |