| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Patients with Chronic Obstructive Pulmonary Disease (COPD)
Patients with Asthma |
|
| E.1.1.1 | Medical condition in easily understood language |
COPD (a smoking related diesase of the airways resulting in difficulty breathing)
Asthma (reversible irritation of the lungs causing wheezing, spasm and difficulty breathing) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010952 |
| E.1.2 | Term | COPD |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | Asthma |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the safety and tolerability of single ascending doses of CHF 6366 in healthy male volunteers, of repeated ascending doses in male and female asthmatic patients and of a single dose in male COPD patients |
|
| E.2.2 | Secondary objectives of the trial |
- To investigate the pharmacokinetic (PK) profile of CHF 6366 and its metabolites CHF 6387 and CHF 6361 in healthy volunteers, asthmatic and COPD patients.
- To investigate the metabolite profiling and identification in plasma, urine and faeces.
- To evaluate the pharmacodynamics of CHF 6366 in COPD patients |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Part 1
- Healthy male subjects, 18-55yrs
- BMI between 18.5 and 32.0kg/m2
- Non-or ex-smokers who smoked <5 pack years and stopped smoking >1 year
- Vital signs within normal limits at screen and prior to randomisation: Diastolic BP 50-90, Systolic BP 90-140 (2 measures after at least 5 minutes resting. For eligibility purposes, the 2 single measurements will be considered). Body temperature 36-37.2ºC
- 12-lead ECG considered as normal (45≤ Heart rate ≤85bpm, 110ms≤ PR ≤200 ms, QRS ≤120 ms, QTcF ≤450 ms) at screen visit and prior to randomisation
- Lung function measurements within normal limits at screen and prior to randomisation: FEV1 equal to or more than 80% of predicted for the subject’s normal value according to GLI, ERS Task Force Lung Function Reference Values and FEV1/FVC ratio >0.70
Part 2
- Male and female subjects, 18-75yrs
- Clinical diagnosis of mild persistent asthma (according to GINA guidelines) for at least 6 months prior to screen
- Non-or ex-smokers who smoked <5 pack years and stopped smoking >1 year
- Vital signs within normal limits at screen and prior to randomisation: Diastolic BP 50-90, Systolic BP 90-150. Body temperature 36-37.2ºC
- Normal resting ECG (after 5 minutes resting) (heart rate 45 to 100 bpm, PR 120 to 200 msec, QRS ≤120 msec, QTcF ≤450 msec (male) and QTcF ≤470 (female),
- Screen FEV1 value of ≥70% of the predicted normal value after a washout of at least 8h for short-acting beta2-agonists and 14 days for long-acting beta2-agonists or long acting antimuscarinic
- FEV1 reversibility of ≥ 12% or 200ml over the baseline value within 20-30min after inhalation of 400 µg of salbutamol
- Using intermittent salbutamol and/or subjects on a stable dose or regimen of low dose ICS at least 4 weeks prior to screen and between screening and first dose
- Otherwise healthy as determined by medical history, physical examination, 12-lead ECG findings
Part 3
- Male and female adults, aged 40-75yrs
- Vital signs at screen and prior to randomisation: Diastolic BP 50-90, Systolic BP 90-160. Body temperature 36-37.2ºC
- Normal resting ECG (after 5 minutes resting) (HR 50 to 100 bpm, PR interval 120 to 200 msec, QRS duration <120 msec, QTcF <450 msec (male) and <470 msec (female))
- Outpatients with diagnosis of COPD (according to current GOLD guidelines)
- A smoking history of at least 10 pack years, current smokers and ex-smokers are eligible
- A post-bronchodilator 40%≤ FEV1 <80% of the predicted normal value, post-bronchodilator FEV1/FVC <0.7 with salbutamol
- Treated with a stable therapy for at least 1 month prior to screen with any of the below:
- Short acting β2-agonist and/or short acting anticholinergic prn,
- inhaled long acting β2-agonist and/or long-acting muscarinic antagonist,
- fixed combination of inhaled long acting β2-agonist and long-acting muscarinic antagonist
- fixed combination of LABA/LAMA/ICS
- ICS
- Response to ipratropium bromide, an increase in FEV1 of ≥7 % starting 30-45min after inhalation of 80µg ipratropium bromide at screen visit
- Response to salbutamol, an increase in FEV1 of ≥7 % starting 20-30min following inhalation of 400µg salbutamol MDI at screen visit
Applicable to Parts 2 & 3
- Female subject of non-childbearing potential (WONCBP) defined as physiologically incapable of becoming pregnant (i.e. post-menopausal or permanently sterile). Tubal ligation or partial surgical interventions are not acceptable. If indicated, as per investigator’s request, post-menopausal status may be confirmed by follicle-stimulating hormone levels.
- Female subjects of childbearing potential fulfil one of the following criteria:
a. WOCBP with fertile male partners: must be willing to use a double barrier contraceptive method including one highly effective birth control method and one acceptable birth control method (male or female condom with or without spermicide and/or cap, diaphragm or sponge with spermicide), from consent until 3 months after follow-up visit;
b. WOCBP with non-fertile male partners: contraception is not required in this case.
Applicable to all Parts
- Written informed consent obtained prior to any study-related procedure;
- Ability to understand the study procedures and the risks involved
- Males fulfilling one of the following criteria:
a. Males with non-pregnant WOCBP partners: they and/or their partner of childbearing potential must be willing to use a highly effective birth control method in addition to the male condom from consent and until 90 days after the last dose. Subjects must not donate sperm during the study and for 90 days after the last dose
b. Males with pregnant WOCBP partner: they must be willing to use male contraception from consent and until 90 days after the last dose. Subjects must not donate sperm during the study and for 90 days after
c. Non-fertile male subjects (contraception is required even in this case)
d. Males with partner of NCBP must use condom |
|
| E.4 | Principal exclusion criteria |
Part 1:
- Female Subjects
- History of sustained and non-sustained cardiac arrhythmias and subjects with a family history of sudden cardiac death
- Blood donation or blood loss (≥450 ml) less than 12 weeks prior to screen or randomisation
- Clinically relevant and uncontrolled hepatic, gastrointestinal, endocrine, metabolic, neurologic, or psychiatric disorder
- Serum K value <3.8 mmol/L
- Taken non-permitted concomitant medications, including vitamins and herbal remedies such as St John’s Wort, in the predefined period
- Heavy caffeine drinker (>5 cups a day)
- Positive urine test for cotinine
- Treated within 2 months before screen and before the first dose with enzyme-inducing or inhibiting drugs
- Treated within 4 weeks before screen with antibiotics
Part 2:
- Pregnant and/or breastfeeding women
- Uncontrolled asthmatic patients according to GINA criteria
- Medical history or current diagnosis of COPD or any other pulmonary disease other than asthma
- History of near fatal asthma or of a past hospitalisation for asthma in intensive care unit or of frequent exacerbations in the last year
- Therapy for gastroesophageal reflux disease or patients with a medical history of GERD that leads to asthma symptoms
- Change in dose, schedule, of ICS in the 4 weeks prior to screen or between screen and first dose
- Hospitalization, emergency room admission or use of systemic corticosteroids for an asthma exacerbation in the 6 weeks prior to screen or between screen and first dose
- Seasonal worsening of asthma and cannot complete the study outside the relevant allergen season
- Systolic Blood pressure <90 or >140 (as mean of 2 measures after at least 5 minute of resting)
- Unstable and uncontrolled blood pressure <60 or >90 mmHg (as mean of 2 measures)
- Abnormal resting ECG (heart rate <40 bpm or >10 bpm, PR interval <120 or >200 msec, QRS duration >120 msec, QTcF >450 msec, any variation from normal waves and tracts morphology
- Treated within 2 months before screen with enzyme-inducing or inhibiting drugs
Part 3:
- Pregnant and/or breastfeeding women
- Current diagnosis of asthma
- Hospital admission for COPD exacerbation within 12 months prior to screen or before first dose
- Hospitalization pneumonia within 3 months prior to screen or before first dose
- Recent COPD exacerbations requiring oral/systemic steroids and/or antibiotics and/or oral or nebulized beta2-agonists or need for increased treatments for COPD
- Use of antibiotics for a lower respiratory tract infection in the 4 weeks prior to screen or before first dose
- Use of beta-blockers with the exception of cardioselective β1-blockers, if taken for at least 2 months prior to screen and maintained constant during the study
- Unstable concurrent disease: e.g. uncontrolled hyperthyroidism, uncontrolled diabetes mellitus or other endocrine disease significant hepatic impairment significant renal impairment significant non-COPD pulmonary disease (e.g. TB, lung cancer) uncontrolled gastrointestinal disease, neurological disease uncontrolled hematological disease uncontrolled autoimmune disorders
- Abnormal resting ECG
- Serum potassium levels below the lower limit of laboratories normal range
- Diagnosis or a history of narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that would prevent use of anticholinergic
- Treated with quinidine, quinidine-like anti arrhythmic and any medication with a potential for QT prolongation 24h prior to screen
- Changes in dose, schedule, formulation or product of xanthine derivatives in the 3 months before screen
Applicable to all Parts
- Clinically significant abnormal Holter ECG, at least 18h recording, at screen
- Unsuitable veins for repeated venepuncture
- History of alcohol, substance or drug abuse within 12 months or with positive urine drug screen evaluated at screen and prior randomization, unless explained by medication
- Positive HIV or Hepatitis serology
- Participation to another clinical trial where investigational drug was received less than 6 (Part 1) or 3 (Parts 2 and 3) months prior to screen
- Treatment within the previous 3 months with any drug known to have a well-defined potential for hepatotoxicity (e.g. nimesulide, ketoconazole)
- Any clinically relevant abnormal laboratory value at screen suggesting an unknown disease and requiring further clinical investigation or which may impact the safety of the subject or the evaluation of the result
- History of hypersensitivity to M3 Antagonist and β2-agonist contained in the formulation used in the trial
- Cardiovascular condition such as, unstable ischemic heart disease, NYHA Class II/IV left ventricular failure, acute ischemic heart disease in the year before screen
- Current infection, or previous respiratory tract infection that resolved less than 4- 6 weeks, any other previous infection that resolved less than 14 days, prior to screen or to randomisation |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Safety variables (AEs, ADRs, ECG, vital signs, spirometry, laboratory data) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| each period of the study and across the study for AEs/ADRs |
|
| E.5.2 | Secondary end point(s) |
Pharmacokinetic variables of CHF 6366 and metabolite profile
Evaluation of pharmacodynamics (PD) of CHF 6366 in COPD patients
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Collection of blood samples, urine and faeces during each period of the study |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The End of Trial is defined as the completion of the study Part 1, Part 2, and Part 3, meaning the last follow-up visit of the last patient in either Part 2 or Part 3. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
Print
