This study has been transitioned to CTIS with ID 2023-510175-60-00 check the CTIS register for the current data. The objective of the proposed study is to confirm the findings of the dose ranging trial by, primarily, assessing the effect of two…
ID
Source
Brief title
Condition
- Bronchial disorders (excl neoplasms)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To evaluate the efficacy of two doses of CHF6001 add-on to maintenance triple
therapy (ICS,
LABA, LAMA) to reduce the rate of moderate and severe exacerbations after 52
weeks of treatment in comparison with maintenance triple therapy (i.e. placebo
arm)
Secondary outcome
Key Secondary:
To evaluate the efficacy of the two doses of CHF6001 add-on to maintenance
triple therapy on health-related quality of life after 52 weeks of treatment
(change in SGRQ total score).
Secondary:
To evaluate
- the efficacy of the two doses of CHF6001 add-on to maintenance triple therapy
on lung function, health-related quality of life, severe exacerbations in the
pooled analysis of CLI-06001AA1-04 and CLI-06001AA1-05 studies and other
clinical outcome measures in comparison with maintenance triple therapy.
- the safety and tolerability of the two doses of CHF6001
Other:
- To evaluate the effect of the two doses of CHF6001 on blood biomarkers of
inflammation
- To evaluate the efficacy of CHF6001 to reduce exacerbations in subjects
categorized by their level of blood eosinophil count compared to maintenance
triple therapy
- To investigate the inter-subject variability in the drug exposure and the
effects of selected covariates on PK parameters by performing a population PK
analysis in a subset of subjects treated with CHF6001
- To assess the impact of study treatments on health economic outcomes
Background summary
The pathogenesis and progression of chronic obstructive pulmonary disease
(COPD) is, in part, due to chronic inflammation [2]. However, the nature and
severity of inflammation in COPD varies, and pharmacological anti-inflammatory
treatments are unlikely to be effective in all patients; a precision medicine
approach is needed to selectively target patients to increase the chance of
therapeutic success [3].
Phosphodiesterase-4 (PDE4) is an enzyme that mediates the breakdown of cyclic
adenosine monophosphate (cAMP), with PDE4 inhibition having anti-inflammatory
effects in a broad range of cell types [33]. The orally administered PDE4
inhibitor roflumilast prevents exacerbations in patients with COPD [4, 5].
However, systemic exposure after oral administration often causes side effects
such as nausea, weight loss and gastrointestinal disturbance, which limit its
use in clinical practice [5, 6]. CHF6001 is a novel inhaled PDE4 inhibitor [7],
currently in clinical development that has been specifically designed and
formulated as an extra-fine formulation to be delivered via inhalation and to
have a low systemic exposure. This allows CHF6001 to reach therapeutic
concentration in the target organ, the lung, yet reduces exposure in the
systemic circulation thus limiting systemic adverse effects.
CHF6001 has been developed up to the completion of Phase 2 showing significant
anti-inflammatory effects and relevant exacerbation reduction signal [13, 14].
The activity on sputum inflammatory cells and biomarkers was strongly evidenced
in the Biomarker study in which CHF6001 was administered on top of maintenance
triple therapy in COPD patients with chronic bronchitis for 32 days [14]. It
was demonstrated that CHF6001 significantly decreased a number of key
biomarkers of airway inflammation in sputum and in blood. This observed
anti-inflammatory effect of CHF6001 translated in a consistent and relevant
reduction of moderate or severe exacerbations of COPD in patients with chronic
bronchitis, on maintenance therapy with a LABA, in a 6-month dose finding trial
[13]. All doses of CHF6001 in both Phase 2 studies were safe and well
tolerated. The incidence of known *drug class* adverse effects (e.g.
gastrointestinal side effects) was low and similar across the dose groups and
comparable to that of placebo.
Study objective
This study has been transitioned to CTIS with ID 2023-510175-60-00 check the CTIS register for the current data.
The objective of the proposed study is to confirm the findings of the dose
ranging trial by, primarily, assessing the effect of two doses of CHF6001 on
the rate reduction of moderate and severe exacerbations, when added onto
maintenance triple therapy (ICS+LABA+LAMA) in symptomatic COPD patients with
chronic bronchitis, at risk of exacerbations, in comparison with triple therapy
(i.e. placebo arm).
For detailed information on preclinical and clinical data please refer to the
Investigator's Brochure
Study design
This is a phase III, randomized, double-blind, placebo-controlled, 3-arm
parallel group study.
Approximately 2985 subjects will be randomized in approximately 270 sites.
The study entails three periods: a run-in period of 2-week duration, a
treatment period of 52 weeks duration, and a post-treatment follow-up period of
1 week.
Intervention
Treatment A: CHF6001 400 µg/actuation - CHF6001 total daily dose 1600 µg
- 2 inhalations of CHF6001 400 µg in the morning and in the evening (giving a
total daily dose of 1600 µg)
Treatment B: CHF6001 800 µg/actuation - CHF6001 total daily dose 3200 µg
- 2 inhalations of CHF6001 800 µg in the morning and in the evening (giving a
total daily dose of 3200 µg)
Treatment C: Placebo
- 2 inhalations of CHF6001 matching Placebo in the morning and in the evening
Study burden and risks
The proposed study has been designed to confirm the efficacy and safety of two
doses of CHF6001 (1600µg and 3200µg daily) in COPD patients with chronic
bronchitis who are still symptomatic and at risk of exacerbations despite being
on maintenance triple therapy for at least one year in comparison with triple
therapy alone.
CHF6001 thus far, has been investigated in more than 1100 COPD patients
assessing doses up to 3200µg/day for 6 months in moderate- to -very severe
patients with COPD [13] and up to 4800µg in healthy subjects [10]. CHF6001
proved to be safe and well tolerated with no evidence of PDE4 inhibitors class
related side effects (e.g. gastrointestinal, psychiatric side effects, weight
loss) leading to treatment discontinuation [37]. Based on the number of
patients exposed to CHF6001 so far, the incidence of PDE4 inhibitor drug class
effects appeared low compared to that of roflumilast as reported in the
literature [34 -37]. This may be explained by the inhaled route of delivery of
the CHF6001 which limits the systemic exposure and thus the adverse effects.
The population in the proposed study i.e. moderate- to -very severe symptomatic
(CAT score >=10) COPD patients with chronic bronchitis and a history of at least
one moderate or severe exacerbation in the previous year, while on maintenance
triple therapy for at least 12 months prior to study entry, has the potential
to benefit from the effect of the IMPs on the reduction of exacerbations.
The exclusion criteria are defined in order to minimize potential risks for the
participants. Participants will have regular clinical assessments at the
clinical site during 1 year of observation. An electronic diary will be used to
record patients* symptoms, compliance and rescue use daily. Remote access to
these data will allow to closely monitor any disease worsening. Pre-specified
criteria for exacerbation will be set, alerts will be triggered when they are
met and patients will be advised to contact the site. In case of acute
exacerbation, patients will be treated according to the Investigator standard
clinical practice.
The decision to discontinue the patient from further participation to the study
will be at the investigator*s discretion if he/she deems continuing the study
will place the patient at undue risk. The efficacy and safety endpoints are
those recommended by the guidelines for assessing anti-inflammatory drugs in
COPD [18, 19, 22, 42].
The trial will be conducted in compliance with the Declaration of Helsinki
(1964 and amendments) current ICH E6 Good Clinical Practices and all other
applicable laws and regulations. Considering the expected therapeutic value,
the safety profile of the IMP, the measures in place to assure the patients*
safety, the overall risk/benefit assessment can be considered acceptable for
the proposed trial.
Via Palermo 26/A 26/A
Parma 43122
IT
Via Palermo 26/A 26/A
Parma 43122
IT
Listed location countries
Age
Inclusion criteria
1. Males and females aged >= 40 years with written informed consent obtained
prior to any study-related procedure.
2. Females are eligible to enter the study if they are of
a. non-childbearing potential i.e. physiologically incapable of becoming
pregnant (e.g. postmenopausal women defined as being amenorrhoeic for >=12
consecutive months without an alternative medical cause*) or women permanently
sterilized (e.g. bilateral oophorectomy, hysterectomy or bilateral
salpingectomy).
or
b. childbearing potential, they must have a negative pregnancy test at
screening and must agree to use one or more of the following acceptable
contraceptive measures:
i. Placement of an intrauterine device (IUD) or intrauterine hormone-releasing
system (IUS).
ii. Combined (oestrogen and progestogen containing) hormonal contraception
associated with inhibition of ovulation (oral, intravaginal, transdermal).
iii. Progesterone-only hormonal contraception associated with inhibition of
ovulation (oral, injectable, implantable).
iv. Bilateral tubal occlusion.
v. Vasectomized partner.
vi. Double barrier method: condom and an occlusive cap (diaphragm or
cervical/vault caps) with a vaginal spermicidal agent
Reliable contraception should be maintained throughout the study.
Abstinence is acceptable where it is in line with the subject*s preferred and
usual lifestyle. Pregnancy tests will be performed at screening (urine and
serum tests) and at randomization (urine test only) in all women of
childbearing potential.
3. Subjects with an established diagnosis of COPD (according to GOLD 2020), at
least 12 months before the screening visit with chronic bronchitis (defined as
productive cough for at least 3 months in each of the prior two consecutive
years) and/or with chronic productive cough >=12 months prior to screening
4. Current smokers or ex-smokers who quit smoking at least 6 months prior to
screening visit, with a smoking history of at least 10 pack years [pack-years =
(number of cigarettes per day x number of years)/20] (If the subjects undergo
smoking cessation therapy, it must be completed 3 months prior to the screening
visit). E-cigarettes and pipe smokers are allowed. E-cigarettes cannot be used
to calculate pack-year history.
5. A post-bronchodilator FEV1 < 60% of the subject predicted normal value and a
post-bronchodilator FEV1/FVC ratio < 0.7 after 400µg (4 puffs x 100µg) of
salbutamol pMDI or equivalent dose of albuterol pMDI in the US. If this
criterion is not met at screening, the test can be repeated once before
randomization.
6. A documented history (e.g. medical record verification) of at least one
moderate or severe COPD exacerbation in previous year.
Documented visits to an emergency department due to COPD exacerbation
associated with prescription of systemic steroids/antibiotics, are considered
acceptable to fulfil this criterion. A stay in emergency room >24h will be
considered a severe event.
7. Symptomatic subject at screening defined as having a CAT score >10
8. Subjects prescribed with maintenance triple therapy (free or fixed
combination of ICS, LABA, LAMA) according to GOLD 2020 recommendations for at
least 12 months prior to screening and receiving regular maintenance triple
therapy for at least 3 months prior to the screening.
9. Subjects are willing and able to be trained to use correctly the DPI
inhalers (NEXThaler®).
10. Subjects are willing and able to be trained to use correctly the electronic
devices with COPD questionnaires, to understand and to perform required outcome
measurements of the protocol (e.g. spirometry manoeuvres etc.) and ability to
understand the risks involved.
Exclusion criteria
1. Subjects with a diagnosis of current asthma. Those with prior history of
asthma in childhood are eligible.
2. Subjects with a moderate or severe COPD exacerbation resulting in the use of
systemic corticosteroids (oral/IV/IM corticosteroids) and/or antibiotics or
need for hospitalisation or a lower respiratory tract infection 4 weeks prior
to study entry and during run-in period.
3. Pregnant and Lactating women.
4. Subjects requiring long term (at least 15 hours daily) oxygen therapy for
chronic hypoxemia.
5. Subjects with known α-1 antitrypsin deficiency as the underlying cause of
COPD
6. Subjects with primary diagnosis of emphysema not related to COPD.
7. Subjects with clinically significant respiratory disorders other than COPD.
This can include but is not limited to active tuberculosis, significant
bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension and
interstitial lung disease.
8. Subjects with lung volume reduction surgery.
9. Subjects having lung cancer or a history of lung cancer fully recovery less
than 1 year after completing cancer therapy.
10. Subjects with active cancer or a history of cancer (other than the lung)
with full recovery less than 1 year after completing cancer therapy or any
untreated localized carcinoma.
11. Subjects with a history of allergy or hypersensitivity to anticholinergics,
β2-agonists, corticosteroids, PDE-4 inhibitors or any of the excipients
contained in any of the formulations used in the trial or a medical condition
such as narrow-angle glaucoma, prostatic hypertrophy or bladder neck
obstruction that in the investigator*s opinion would contra-indicate study
participation.
12. Subjects under Roflumilast treatment within 6 months before study entry
13. Subjects with a diagnosis of depression, generalised anxiety disorder,
suicidal ideation or behaviour that might, according to the investigator
judgement, place the subject at undue risk.
14. Subjects who have clinically significant cardiovascular condition such as,
but not limited to unstable ischemic heart disease, NYHA Class III/IV left
ventricular failure, acute ischemic heart disease within one year prior to
study entry, known history of atrial fibrillation or of sustained and
non-sustained cardiac arrhythmias diagnosed within the last 6 months prior to
study entry, not controlled with a rate and/or rhythm control strategy or with
recurrent episodes in the last 6 months.
15. An abnormal and clinically significant 12-lead ECG finding in relation to
the subject*s medical history that results in active medical problem which may
impact the safety of the subject according to investigator*s judgement. An
abnormal and clinically significant finding that would exclude the subject from
study participation is defined as an ECG tracing that is interpreted as, but
not limited to, any of the following:
• atrial fibrillation with rapid ventricular rate >120bpm
• sustained or non-sustained ventricular tachycardia
• second degree AV block Mobitz type II and third-degree AV block (unless
pacemaker or defibrillator had been inserted)
• QTcF >=480 msec (at screening visit). Criterion not applicable for subjects
with pacemaker and with permanent atrial fibrillation.
16. Subjects with a significant neurological disease including transient
ischemic attack (TIA), stroke, seizure disorder or behavioural disturbances
that in investigator*s opinion, would place the subject at risk by
participating to the study.
17. Subjects who have a history or current evidence of clinically significant
and uncontrolled disease: e.g. hyperthyroidism, diabetes mellitus or other
endocrine disease; significant renal impairment; history of cerebrovascular,
gastrointestinal (e.g. active peptic ulcer); neurological disease; uncontrolled
haematological abnormalities; uncontrolled autoimmune disorders, or other
disease. Significance of renal impairment should be assessed in case of CKD
(Chronic Kidney Disease) presence in medical history. In this case, serum
creatinine level should be checked. Patients will not be allowed to the study
if eGFR value <60 mL/min/1.73 m2* (please see the note for reference to
creatinine level).Uncontrolled is defined as any disease or condition that
might, in the judgement of the investigator, place the subject at undue risk
through participation to the study or might compromise the interpretation of
the results if the disease/condition exacerbated during the study;
18. Subjects with clinically significant laboratory abnormalities indicating a
significant or unstable concomitant disease that might, in the judgement of the
investigator, place the subject at undue risk or potentially compromise the
results or interpretation of the study. In case some parameters are clinically
significant at V1, they can be retested once before randomization
19. Subjects with moderate or severe hepatic impairment (Child-Pugh B or C)
20. Subjects with a known or suspected history of alcohol abuse and/or
substance/drug abuse within 12 months prior to screening visit
21. Subjects having received any other investigational drug within the
preceding 30 days (60 days for biologics), or a longer and more appropriate
time as determined by the investigator (e.g., approximately five half-lives of
the previous investigational drug)
For the subset of subjects undergoing PK assessments
22. Subjects with unsuitable veins for repeated venipuncture.
23. Blood donation (excluding plasma donations) or blood loss equal or more
than 450 mL less than 2 months prior to screening
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 |
|---|---|
| EU-CTR | CTIS2023-510175-60-00 |
| EudraCT | EUCTR2020-003666-40-NL |
| ClinicalTrials.gov | NCT04636801 |
| CCMO | NL77011.028.21 |