The primary objective of the study is to evaluate the efficacy of dupilumab on the lung function in patients with ABPA.The secondary objectives of the study are:• To evaluate the effects of dupilumab on exacerbations in patients with ABPA • To…
ID
Source
Brief title
Condition
- Allergic conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint in the study is change from baseline in pre-bronchodilator
forced expiratory volume in one second (FEV1) compared to placebo.
Secondary outcome
The secondary endpoints are:
1. Annualized rate of severe respiratory exacerbations, defined as new onset of
symptoms or clinical worsening of respiratory symptoms requiring systemic
corticosteroid treatment for >=3 consecutive days; for
patients who are on maintenance systemic corticosteroids, at least double the
dose of maintenance systemic corticosteroids for >=3 consecutive days (with or
without antibiotic therapy if indicated).
2. Annualized rate of ABPA-related exacerbations, defined as severe respiratory
exacerbations (as defined above) that are associated with a doubling of serum
total IgE from the prior pre-exacerbation value, over the 52 week treatment
period compared to placebo
3. Annualized rate of severe respiratory exacerbations requiring either
hospitalization or observation for >24 hours in an ED/urgent care facility
during the 52 week treatment period compared to placebo
4. Change from baseline in ACQ-5 compared to placebo over the 52-week treatment
period
5. Change from baseline in SGRQ total score compared to placebo over the 52
week treatment period
6. Percentage of participants achieving a reduction in the SGRQ score of 4
points or greater from baseline to weeks 12, 24, 36, and 52 compared to placebo
7. Percent change from baseline in total IgE in serum compared to placebo over
the 52 week treatment period
8. Percent change from baseline in A fumigatus-specific IgE in serum compared
to placebo over the 52-week treatment period
9. Percent and absolute change from baseline in FeNO compared to placebo over
the 52 week treatment period
10. Incidence of treatment-emergent adverse events (TEAEs)
11. Immunogenicity of dupilumab, as determined by the incidence, titer, and
clinical impact of treatment emergent ADA to dupilumab
12. Concentrations of functional dupilumab in serum by treatment regimen
Background summary
Allergic bronchopulmonary aspergillosis (ABPA) is a progressive, immunologic
lung disease caused by hypersensitivity to the fungus Aspergillus fumigatus (A
fumigatus) that occurs in patients with asthma or cystic fibrosis. The
prevalence of ABPA is estimated to be 1% to 3% in patients with severe asthma
referred for specialty care. Clinically, asthma patients with ABPA have a more
severe clinical course with poorly controlled asthma, poor response to
treatment, and frequent episodes of exacerbations compared to patients with
asthma who do not have ABPA. In addition, ABPA is often associated with thick
mucoid secretions that can lead to obstruction of large and small airways,
bronchiectasis (which does not otherwise occur in asthma), and lung function
impairment beyond that seen in a typical asthma patient.
The current mainstay of treatment for ABPA is administration of systemic
corticosteroids, with many patients becoming corticosteroid-dependent to
control the disease. However, not all patients respond to systemic
corticosteroids. Long-term use of systemic corticosteroids is not recommended
due to the lack of evidence supporting prevention of progressive bronchial
destruction and the potential for serious side effects associated with chronic
use. ABPA complicating asthma does not respond clinically to conventional
asthma therapy including high doses of inhaled corticosteroids (ICS). Various
antifungal agents (eg, itraconazole, voriconazole, ketoconazole, amphotericin
B) are used as adjunctive treatments for ABPA in patients who respond poorly to
corticosteroids in an effort to reduce the fungal antigenic stimulus. However,
clinical response to antifungals is variable, antifungal therapy is not
curative, and the side effects of antifungals - which include nausea, vomiting,
diarrhea, fever, rash, headache, and hepatotoxicity * limit their use.
Long-term studies to evaluate the effect of treatment with these agents to
modify the progressive decline in lung function in ABPA are lacking.
Thus, there is an unmet need for more effective and safe treatments that target
the immunological underpinnings of ABPA to prevent irreversible airway and
parenchymal disease, improve clinical symptoms, and obviate the need for
systemic corticosteroids with their accompanying safety concerns.
Dupilumab is a human monoclonal IgG4 antibody that inhibits IL-4 and IL-13
signaling by specifically binding to the IL-4Rα subunit shared by the IL-4 and
IL-13 receptor complexes. Dupilumab inhibits IL-4 signaling via the type I
receptor and both IL-4 and IL-13 signaling through the type II receptor.
Blocking IL-4Rα with dupilumab inhibits IL-4 and IL-13, key cytokines that
drive the type 2 inflammatory response, including the release of
proinflammatory cytokines, chemokines, nitric oxide, and IgE. Dupilumab,
therefore, may have the potential to treat ABPA, a disease driven by type 2
inflammation.
This study is designed to provide evidence of the efficacy and safety of
dupilumab in patients with ABPA who remain uncontrolled despite ICS.
Study objective
The primary objective of the study is to evaluate the efficacy of dupilumab on
the lung function in patients with ABPA.
The secondary objectives of the study are:
• To evaluate the effects of dupilumab on exacerbations in patients with ABPA
• To evaluate the effects of dupilumab on ABPA-related exacerbations
• To evaluate the effects of dupilumab on hospitalization/emergency department
(ED)/urgent care visits in patients with ABPA
• To evaluate the effects of dupilumab on asthma control in patients with ABPA
• To evaluate the effects of dupilumab on health-related quality of life
(HRQoL) in patients with ABPA
• To evaluate the effects of dupilumab on serum total IgE and
Aspergillus-specific IgE concentrations
• To evaluate the effects of dupilumab on FeNO levels
• To evaluate safety and tolerability of dupilumab in patients with ABPA
• To evaluate dupilumab concentrations in serum and the incidence of
anti-dupilumab antibodies in patients with ABPA
Study design
Phase 2, global, multicenter, randomized, double-blind, placebo-controlled,
parallel group study to evaluate efficacy and safety of dupilumab in patients
with ABPA. The 3 study periods include a screening period, a randomization
period and post-treatment follow-up period. Patients will be randomized 1:1 to
receive either dupilumab 300 mg given subcutaneously (SC) after a loading dose
of 600 mg, or matching placebo given SC every 2 weeks (Q2W).
Intervention
Dupilumab, as 150 mg/mL solution for SC injection. Loading dose of 600 mg on
day 1, followed by 300 mg SC, Q2W
Placebo, matching dupilumab formulation without addition of protein.
Administered SC, Q2W
Study burden and risks
Please refer to appendix D of the subject information sheet for an overview of
the side effects and possible risks of the study.
Old Saw Mill River Road 777
Tarrytown, NY 10591
US
Old Saw Mill River Road 777
Tarrytown, NY 10591
US
Listed location countries
Age
Inclusion criteria
•Males and females >=12 years of age at screening
Diagnoses of both ABPA and asthma.
•On a maintenance therapy for their asthma with controller medication which
must include ICS and may include 1 or more additional controller medications
including a LABA, LTRA, and/or LAMA, etc for at least 12 weeks, with a stable
dose and regimen with no change in the dose or frequency of administration for
at least 4 weeks prior to the screening visit, and between the screening and
baseline/randomization visits
•For patients on OCS: must be on a chronic stable dose (no change in the dose)
of OCS of up to 10 mg/day (for patients taking daily corticosteroids) or 30 mg
every alternate day (for patients taking alternate day corticosteroids) of OCS
(prednisone/prednisolone or the equivalent) for at least 4 weeks prior to the
screening visit and between the screening and the baseline/randomization visit.
In addition, patients must agree to switch to study-required
prednisone/prednisolone as their OCS at visit 1 and use it per protocol for the
duration of the study. The number of patients receiving OCS at baseline will be
capped at approximately 25% of the study population.
•Must have experienced >=1 severe respiratory exacerbation requiring treatment
with systemic corticosteroids or hospitalization or treatment in ED/urgent care
within 12 months prior to the screening visit, or must have received systemic
corticosteroids during 5 of the 6 months prior to the screening visit and
between the screening and baseline visits.be receiving chronic stable low-dose
OCS
NOTE: Other protocol defined inclusion criteria apply
Exclusion criteria
•Weight less than 30.0 kilograms
• Current smoker or e-cigarette user, cessation of smoking or e-cigarette use
within 6 months prior to randomization, or >10 pack-years smoking history
•Post-bronchodilator FEV1 <30% predicted normal at screening
•For those receiving OCS at baseline: Considered to be at high risk for adverse
events due to tapering of OCS, in the opinion of the investigator
• Respiratory exacerbation requiring systemic corticosteroids within 4 weeks
prior to screening and between screening and baseline visit (for patients on
daily or alternate day OCS, exacerbation requiring at least double the
maintenance dose of corticosteroids)
• Upper or lower respiratory tract infection within the 4 weeks prior to
screening (visit 1) or between the screening and randomization visits
• Significant chronic pulmonary disease other than asthma complicated with ABPA
(eg, physician-diagnosed bronchiectasis due to a condition other than ABPA or
with a history of a positive lower respiratory culture for P aeruginosa or
other multi-drug-resistant, gram-negative bacilli; cystic fibrosis;
sarcoidosis; interstitial lung disease not due to ABPA; chronic obstructive
pulmonary disease [COPD] not due to ABPA; hypereosinophilic syndrome; etc) or a
diagnosed pulmonary or systemic disease associated with elevated peripheral
eosinophil counts
• Diagnosis or suspected diagnosis of eosinophilic granulomatosis with
polyangiitis (EGPA; also called Churg-Strauss Syndrome)
NOTE: Other protocol defined exclusion criteria apply
Design
Recruitment
Medical products/devices used
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
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 | EUCTR2019-002619-24-NL |
| CCMO | NL73438.018.20 |