Primary Objective:To evaluate the effect of INS1007 compared with placebo on time to first pulmonary exacerbation over the 24-week treatment period.Secondary Objectives:1. To evaluate the effect of INS1007 compared with placebo on quality of life (…
ID
Source
Brief title
Condition
- Bronchial disorders (excl neoplasms)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the time to the first pulmonary exacerbation over the
24-week treatment period.
A pulmonary exacerbation in this study is defined as having 3 or more of the
following symptoms for at least 48 hours resulting in a physician*s decision to
prescribe antibiotics:
1 Increased cough;
2 Increased sputum volume or change in sputum consistency;
3 Increased sputum purulence;
4 Increased breathlessness and/or decreased exercise tolerance;
5 Fatigue and/or malaise;
6 Hemoptysis.
Subjects on chronic macrolide therapy whose only change in therapy is dose or
frequency adjustment will not meet the definition of exacerbation.
Secondary outcome
Secondary Endpoints:
1. Change from Baseline in QOL-B Respiratory Symptoms Domain score over the
24-week treatment period.
2. Change from Screening in post-bronchodilator FEV1 over the 24-week treatment
period.
3. Change in concentration of active NE in sputum from pre-treatment (defined
as the average of Screening and Day 1 concentrations) to on-treatment (defined
as the average of Week 12 and Week 24 concentrations).
4. Rate of pulmonary exacerbations (number of events per person-time) over the
24-week treatment period.
Safety Endpoints:
The safety endpoints will include AEs, 12-lead ECG measurements, clinical
laboratory testing results, vital sign measurements, physical examination
results, and PFT measurements. Adverse events of special interest (AESIs) which
will be reported include hyperkeratosis, periodontitis/gingivitis, and other
infections.
Pharmacokinetic Endpoints:
The PK parameters, as estimated using non-compartmental analysis methods, will
include maximum plasma concentration (Cmax), time to maximum plasma
concentration (Tmax), average plasma concentration at steady state (Css),
maximum plasma concentration at steady state (Cmaxss), time to maximum plasma
concentration at steady state (Tmaxss), minimum plasma concentration at steady
state (Cminss), and area under the plasma concentration curve from 0 to 8 hours
(AUC0-8).
Background summary
Bronchiectasis is a disease characterized by localized, irreversible
enlargement of bronchi and bronchioles that may lead to obstructed breathing
caused by abnormal mucus production. Bronchiectasis symptoms typically include
a chronic dry or wet cough. Other symptoms include shortness of breath,
coughing up blood, and chest pain. Wheezing and nail clubbing may also occur.
People with the disease often get frequent lung infections.
Subjects having NCFBE experience pulmonary exacerbations with an average
frequency ranging from 1.5 to 6 per year. Currently, there is no
standard-of-care for prophylactic pharmacological treatment of NCFBE. The
primary goal of treatment is to treat the underlying cause, prevent disease
progression, maintain or improve lung function, and improve the symptoms and
quality of life.
INS1007 is a potent, selective, competitive and reversible DPP1 inhibitor that
was shown to inhibit the formation of all 3 active NSPs in maturing neutrophils
in vitro and in vivo.
It is hypothesized that the functional inhibition of NSPs by a DPP1 inhibitor
such as INS1007 will decrease inflammation and mucus hypersecretion, leading to
slowing down lung tissue destruction, and decreasing the exacerbation rate in
subjects with neutrophilic lung conditions with a protease-driven pathology
such as NCFBE.
This study will evaluate whether this hypothesis is confirmed.
It is postulated that administration of INS1007 may result in beneficial
effects for patients suffering from NCFBE via decreasing inflammation and mucus
hypersecretion, leading to an improvement in respiratory symptoms (eg, cough
and sputum production) and lung function (eg, FEV1) and a decrease in
exacerbation rate. Since INS1007 acts upstream of NE and inhibits two other
NSPs regulated by DPP1, it may have a larger impact on slowing lung damage
progression in NCFBE patients compared to inhibition of NE alone.
Considering the potential benefits to subjects with NCFBE, all the available
data for INS1007 from the nonclinical toxicity studies, the 2 Phase 1 studies,
and the risk mitigation strategies to be put in place, this study, in the
opinion of the Sponsor, is considered to have a favorable risk-benefit ratio.
Study objective
Primary Objective:
To evaluate the effect of INS1007 compared with placebo on time to first
pulmonary exacerbation over the 24-week treatment period.
Secondary Objectives:
1. To evaluate the effect of INS1007 compared with placebo on quality of life
(QOL), as assessed by the Quality of Life Questionnaire-Bronchiectasis (QOL-B),
Respiratory Symptoms Domain score, over the 24-week treatment period.
2. To evaluate the effect of INS1007 compared with placebo on lung function, as
measured by forced expiratory volume in 1 second (FEV1), over the 24-week
treatment period.
3. To evaluate the effect of INS1007 compared with placebo on the concentration
of active neutrophil elastase (NE) in sputum, as measured by the difference
between the pre-treatment concentration and on-treatment concentration.
4. To evaluate the effect of INS1007 compared with placebo on the rate of
pulmonary exacerbations over the 24-week treatment period.
Safety Objective:
To assess the safety and tolerability of INS1007 relative to placebo based on
adverse events (AEs), vital signs and electrocardiogram (ECG) measurements,
physical exams, pulmonary function tests (PFTs), and clinical laboratory
evaluations.
Pharmacokinetic Objectives:
1. To evaluate the pharmacokinetics (PK) of INS1007.
2. To assess the relationship between PK measures for INS1007 and efficacy,
safety and biomarker measures (eg, concentrations of active NE in sputum and
reagent-stimulated blood).
Study design
This is a Phase 2, randomized, double-blind, placebo-controlled,
parallel-group, multicenter, multi-national study to assess the efficacy,
safety and tolerability, and PK of INS1007 administered once daily (QD) for 24
weeks in subjects with non-cystic fibrosis bronchiectasis (NCFBE).
This multi-center study will be conducted at approximately 120 sites;
enrollment is competitive across all sites. Across these sites, it is planned
to randomize approximately 240 subjects with NCFBE. Subjects will be randomized
in a 1:1:1 ratio to 3 treatment arms (80/arm) to receive either 10 mg or 25 mg
of INS1007 or matching placebo. Randomization will be stratified based on
whether the Screening sputum is culture positive for P aeruginosa and whether
the subject is on a maintenance use of macrolides for preventing pulmonary
exacerbation.
There will be a screening period of up to 6 weeks per subject. During the
screening period, the subject*s demographic information, medical history, and
smoking history will be obtained, a physical exam will be performed and the
vital signs will be evaluated and a sputum sample for sputum culture will be
collected. Biomarkers will be collected, and clinical laboratory test,
pregnancy test, ECG, pulmonary function test (PFT), and periodontal cleaning
and examination will be conducted. Subjects whose past chest radiographic image
records are not available will undergo a chest CT scan during screening
(Visit1). Subjects who meet all the inclusion but none of the exclusion
criteria, except for the dental exclusion criteria, will proceed to have a
dental examination for dental criteria screening. Subjects who meet all
eligibility criteria will undergo a periodontal cleaning procedure prior to
randomization.
Subjects will be randomized at Visit 2 (Day 1) and return thereafter for study
visits at 2 (Visit 3), 4 (Visit 4), 8 (Visit 5), 12 (Visit 6), 16 (Visit 7), 20
(Visit 8), 24 (Visit 9) and 28 (Visit 10) weeks. There will be a visit window
of ± 3 days for each of the scheduled visits. During each visit, all
assessments and procedures will be performed as described in Section 6 of this
protocol. Study treatment will occur between Visits 2 and 9.
Subjects will be required to have an end-of-study visit (Visit 10) at Week 28
to collect blood and sputum samples for biomarker assessment and to collect
information on AEs and concomitant medications use. A PK sample will be
collected from each subject participating in the PK sub-study.
Pharmacokinetic Sub-study:
A PK sub-study will be conducted at a select number of sites (NLD will not
participate). Subjects who enroll at the selected sites will undergo intensive
PK sampling. A maximum of 36 subjects will be included in the PK sub-study. For
subjects who participate in the PK sub-study, the visit window for Visit 4 will
be ± 5 days. Additionally, for subjects not participating in the PK sub-study,
sparse PK sampling will be conducted in subjects at all sites with PK sampling
processing capabilities. (see Section 7.6.1). Pharmacokinetic samples will be
analyzed in batches on an ongoing basis.
Intervention
Each subject will receive study treatment for 24 weeks. The entire study is
scheduled to take a maximum of 32 weeks for each individual subject from
Screening (Visit 1) to the End of Study (Visit 10).
Study burden and risks
Bronchiectasis is a disease with symptoms like a chronic dry or wet cough,
shortness of breath, coughing up blood, chest pain, wheezing and often frequent
lung infections. Subjects having NCFBE experience pulmonary exacerbations with
an average frequency ranging from 1.5 to 6 per year. Currently, there is no
standard-of-care for prophylactic pharmacological treatment of NCFBE. The
primary goal of treatment is to treat the underlying cause, prevent disease
progression, maintain or improve lung function, and improve the symptoms and
quality of life.
It is expected that administration of INS1007 may result in beneficial effects
for patients suffering from NCFBE via decreasing inflammation and mucus
hypersecretion, leading to an improvement in respiratory symptoms (eg, cough
and sputum production) and lung function (eg, FEV1) and a decrease in
exacerbation rate. Since INS1007 acts upstream of NE and inhibits two other
NSPs regulated by DPP1, it may have a larger impact on slowing lung damage
progression in NCFBE patients compared to inhibition of NE alone.
Considering the potential benefits to subjects with NCFBE, all the available
data for INS1007 from the nonclinical toxicity studies, the 2 Phase 1 studies,
and the risk mitigation strategies to be put in place, this study, in the
opinion of the Sponsor, is considered to have a favorable risk-benefit ratio.
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Age
Inclusion criteria
Subjects who have given their signed, informed consent, are male or female between 18 and 85 years of age (inclusive) with a body mass index > 18.5 at Screening (Visit 1) and have a clinical history consistent with NCFBE will be eligible for enrollment in the study.
Exclusion criteria
Subjects who have a primary diagnosis of chronic obstructive pulmonary disease or asthma, have bronchiectasis due to cystic fibrosis, hypogammaglobulinemia, common variable immunodeficiency, or *1-antitrypsin deficiency, are current smokers as defined per Centers for Disease Control and Prevention criteria, or currently being treated for a non tuberculous mycobacterial lung infection, allergic bronchopulmonary aspergillosis, tuberculosis or have a clinical diagnosis of Papillon-Lefèvre Syndrome will not be eligible for enrollment in the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-002533-32-NL |
| ClinicalTrials.gov | NCT03218917 |
| CCMO | NL63023.100.17 |