E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
severe chronic obstructive pulmonary disease (COPD) |
|
E.1.1.1 | Medical condition in easily understood language |
In all patient information material COPD is used. There is no term in
trivial language available. |
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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 | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010952 |
E.1.2 | Term | COPD |
E.1.2 | System Organ Class | 100000004855 |
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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 investigate the effect of Roflumilast 500 μg tablets once daily versus placebo on inflammation parameters in bronchial biopsy tissue specimen. |
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E.2.2 | Secondary objectives of the trial |
To investigate inflammation parameters in sputum and blood serum.
Safety status will be assessed by vital signs, physical examination (including electrocardiogram [ECG]), clinical laboratory tests, and monitoring of adverse events. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The interaction between changes in the lung microbiota,
airway inflammation and mucin production resulting from
roflumilast therapy
Date of Sub-Study Protocol: 30 May2012
Version no.: FINAL 1.1
Objectives:
This substudy hypothesizes that roflumilast exerts a beneficial effect by altering the inflammatory response to the lung microbiota and decreasing mucin.
This will be tested in three specific aims:
a) We will examine the longitudinal change in microbiota in
roflumilast- and placebo-treated patients over 16 weeks of therapy.
Sub aim – We will examine the interaction of mucosal
inflammatory response with changes in microbiota.
b) We will examine the longitudinal change in epithelial MUC5AC
gene expression in roflumilast- and placebo-treated patients over 16 weeks of therapy.
Sub aim – We will examine the interaction of mucosal
inflammatory response with changes in mucin gene expression.
c) We will examine the interaction of roflumilast- versus placebotherapy on the changes in microbiota, mucosal inflammation and mucin production.
The HULL sub study of the Roflumilast ‘biopsy study’ RO-2455-402-RD
Date of Sub-Study Protocol: 12 June 2012
Version no.: FINAL 1
Objective:
This is an exploratory research approach to study the changes of the degree of airway reflux.
This sub study will only be valid for the site of Professor Alyn H Morice.
It is becoming apparent that a number of exacerbations of COPD are due to episodes of microaspiration into the airways. To investigate if Roflumilast has an effect on this microaspiration in the airways the site is measuring the pH and the symptoms with the Hull Airways Reflux Questionnaire (HARQ) to determine their degree of airway reflux and ascertain whether roflumilast therapy has any beneficial effect on the frequency of these episodes. |
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E.3 | Principal inclusion criteria |
Subjects meeting the following criteria will be considered for inclusion in the run-in period:
1) Written informed consent obtained according to local regulations before any trial-related activities. A trial-related activity is any procedure that would not have been performed during the routine management of the Subject.
2) History of COPD (according to GOLD 2009) for at least 12 months prior to baseline visit V0 associated with chronic productive cough for at least three months in each of the two years prior to baseline visit V0 (with other causes of productive cough ex-cluded)
3) Outpatients 40-80 years of age
4) Post-bronchodilator 30% ≤FEV1 ≤80% predicted
5) Post-bronchodilator FEV1/FVC ratio ≤70%
6) Current or former smokers with smoking history ≥20 pack years |
|
E.4 | Principal exclusion criteria |
1) Clinical instability, defined as experiencing a COPD exacerbation six months prior to V0, as indicated by treatment with a systemically administered glucocorticosteroid and/or antibiotics and/or hospitalization
2) An upper/lower respiratory tract infection e.g. common cold, sinus symptoms, pneu-monia, which has not resolved four weeks prior to V0
3) Diagnosis of asthma and/or other relevant lung disease (e.g. history of primary or clinically significant bronchiectases, cystic fibrosis, bronchiolitis, lung resection, lung cancer, interstitial lung disease [e.g. fibrosis, silicosis, sarcoidosis], active tuberculo-sis) or previous episodes of pneumothorax
4) Known alpha-1-antitrypsin deficiency
Criteria within ethical considerations in terms of general health:
5) Duration of oxygen therapy ≥12 h/day
6) History of intubation for COPD or a respiratory failure of any cause in the past year
7) Hypoxemia defined as oxyhemoglobin concentration <88% when breathing room air measured by pulse oximetry
8) Formal contraindications to sputum collection or impossibility to obtain a sample of sputum valid for analysis
9) Clinically relevant abnormal laboratory values suggesting an undiagnosed disease requiring further clinical evaluation (as assessed by the Investigator)
10) Suspicion or diagnosis of a bleeding disorders irrespective of its pathophysiological mechanism: Thrombocytopenia (platelets <50000/mL) and platelet dysfunction (e.g. uraemia), thrombotic or coagulation disorders and bleeding due to abnormal blood vessels (e.g. purpura simplex)
11) Severe psychiatric or neurological disorders
12)History of depression associated with suicidal ideation or behaviour
13) Hemodynamic instability (e.g. bradycardia with resting heart rate <60 beats per min, tachycardia with resting heart rate ≥120 beats per min and/or a systolic blood pres-sure <100 or >180 mmHg)
14)History of increased intracranial pressure, superior vena cava obstruction, pulmonary hypertension, aneurysms and arteriovenous malformations within the lungs
15)Congestive heart failure severity grade IV according to New York Heart Association Functional Classification (NYHA)
16)Haemodynamically significant cardiac arrhythmias or heart valve deformations
17)History of angina pectoris (Class ≥II Canadian Cardiovascular Society Functional Classification of Angina Pectoris Scale) or a myocardial infarction within last 12 months, unless corrected with Percutaneous Transluminal Coronary Angioplasty (PTCA) or Coronary Artery Bypass Surgery (CABG) ≥3 months prior to V0 and as-ymptomatic since then
18) X-ray Computed Tomography (CT) or X-ray findings indicating a pulmonary disease other than COPD (e.g. tuberculosis, clinically significant bronchiectases, tumours). CT or X-ray results within 12 months prior to visit V0 are required.
19) Immunological diseases or known infection with Human Immunodeficiency Virus (HIV)
20) Liver impairment Child-Pugh B/C and/or active viral hepatitis
21) Severe acute infectious diseases
22) Any diagnosis of a malignant disease (other than basal or squamous cell carcinoma) within five years before enrolment into the trial
23) Excessive alcohol intake or drug/substance abuse within the past year
24) Any history of allergies, suspected hypersensitivity and/or contraindication to local anaesthetics (e.g. xylocaine, lignocaine) and/or sedative agents (e.g. benzodiazepi-nes, propofol, opioids) that would not allow adequate anaesthesia and/or bronchoscopy sedation. Suspected hypersensitivity to the trial treatment (Roflumilast) or in-gredients thereof, or any other contraindication for the use thereof.
25) Female Subjects of childbearing potential, not using or not willing to continue using a medically reliable method of contraception for the entire trial duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, unless they are surgically sterilized/hysterectomized or post-menopausal >1 year or who are not using any other method of contraception considered sufficiently reliable by the Investigator in individual cases.
26) Pregnancy, breast feeding, planned oocyte donation or oocyte implantation
27) Planned donation of germ cells, blood, organs or bone marrow during the course of the trial
28) Participation in another clinical trial (use of investigational product or device) within 30 days preceding the baseline visit V0 or re-entry of Subjects previously enrolled in this trial (for exemption see Section 6.5)
29) Suspected inability to comply with trial procedures (e.g. repeated bronchoscopies, bronchial biopsy and sputum induction procedures, language problems, psychologi-cal disorders)
30) Suffering from any concomitant disease that might interfere with trial procedures or evaluations according to the Investigator’s judgement
31)Use of disallowed drugs (see below)
32) Employee at the investigational site, relative or spouse of the Investigator |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint will be the number of inflammatory cells CD8+ in bronchial biopsy tissue specimen (sub-mucosa) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluated from randomization visit V2 (Week 0) to the end of the intervention period in Week 16 (V6). |
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E.5.2 | Secondary end point(s) |
Secondary endpoints will be the following parameters:
Biopsy Material
• Cell count in biopsied material (sub-mucosa) [cells/mm2]:
1) CD68+
2) Neutrophils
3) CD4+
4) CD45+
• Cell count in biopsied material (bronchial epithelium) [cells/mm2]:
1) CD8+
2) CD68+
Induced Sputum
• Total and differential cell counts in induced sputum (absolute [cells/mL] and percent-age [%]):
1) Neutrophils
2) Macrophages
3) Eosinophils
4) Lymphocytes
• Concentration of inflammatory biomarkers in sputum:
1) Inflammatory mediators (Human InflammationMAP® v.1; Rules-Based Medicine, Inc. (RBM))
Blood Serum
• Concentration of inflammatory biomarkers in blood serum:
1) Inflammatory mediators (Human InflammationMAP® v.1; Rules-Based Medicine, Inc. (RBM))
Pulmonary Function Changes in the Course of the Trial
• Change from randomization (V2) over 16 weeks of treatment for:
1) Forced expiratory volume in the first 1 second (FEV1 [L])
2) Forced vital capacity (FVC [L])
3) FEV1/FVC [%] |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Evaluated from visit V1 (Week -2) or V2 (Week 0) (depending on parameter) to the end of the intervention period in Week 16 (V6)
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|
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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
While Roflumilast is an established drug for the reduction of COPD exacerbations, its mechanism in the lungs, particularly its anti-inflammatory activities, are not well understood. Better understanding of its effects on inflammatory cells and the inflammatory cascade may result in a better understanding which patients would benefit most from a treatment with Roflumilast and which measurable parameters might serve as surrogate predictors for the clinical efficaciousness of Roflumilast. |
|
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
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 database hard lock. The database will be hard-locked after the Blinded Data Review Meeting (BDRM) when it is declared complete and accurate. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 5 |