symptomatic smoking-related emphysema in ex-smokers MedDRA version: 8.1 Level: LLT Classification code 10014561 Term: Emphysema
Conditions
Interventions
Product Name: Not applicable
Product Code: RO3300074
Pharmaceutical Form: Capsule, soft
INN or Proposed INN: Not assigned
Current Sponso
Sponsors
F. Hoffmann-La Roche Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion criteria at screening: 1. Ex-smokers with 10 or more pack-year smoking history (subjects must have stopped smoking for greater than or equal to 12 months prior to enrollment) 2. Subjects of greater than or equal to 45 years of age. Women must be more than 2 years post-menopausal or have had a hysterectomy or bilateral oophorectomy. 3. Men with partners of child-bearing potential must agree to use barrier contraception during the study and for 30 days after discontinuation of treatment. 4. Subjects with moderate to severe COPD defined as follows: Post-bronchodilator FEV1 / FVC 1 (see appendix 7). 5. Subjects must be able to participate in the study, willing to give written informed consent, and comply with the study restrictions. 6. Subjects must be able to swallow gelatine capsules within 30 minutes after eating breakfast on a daily basis. 7. Subjects must agree to be switched to optimal COPD drug therapy at screening. Optimal COPD drug therapy consists of short-acting bronchodilators as needed and Tiotropium (DPI) and either Salmeterol/Fluticasone (DPI) or Formoterol/Budesonide (DPI) at the highest doses approved by regulatory authorities. Note: Subjects who must be switched to optimal COPD drug therapy must be treated for 6 weeks before attending the randomization visit. The other subjects may be randomized earlier. 8. Subjects have been off oral steroids > 28 days prior to screening visit (eg. Prednisone, Prednisolone). Inclusion criteria at randomisation: 1. Emphysema confirmed by qualitative low-dose, spiral CT performed and officially interpreted within 28 days of expected randomization. 2. Post-bronchodilator FEV1 / FVC =65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Within 12 months prior to screening: more than 2 exacerbations of pulmonary symptoms requiring out patient treatment with oral steroids or antibiotics, or more than 1 exacerbation if the latter required hospitalization. 2. Observation of a solitary nodule (> 8 mm) in the lung (see appendix 9 in the protocol for guidelines of lung nodules). 3. Subjects with giant bullous disease of > 1/3 of a hemithorax. 4. Any predominant diagnosis of bronchiectasis, tuberculosis, interstitial fibrosis, asbestosis, cystic fibrosis. 5. Subjects on lung transplant waiting list. 6. Subjects who have undergone lung volume reduction surgery. 7. Significant other medical conditions, which in the opinion of the investigator, will interfere with the subject’s ability to perform the study tests. 8. Currently using vitamin A or beta carotene, multivitamins containing vitamin A or beta carotene, or herbal preparations (see protocol section 4.4). 9. Exposure to synthetic oral retinoids in the past 12 months. 10. Hypertriglyceridemia greater than or equal to 300 mg/dl (3.4 mmol/dl) with or without therapy. 11. Unexplained weight loss of greater than or equal to 10% of total body weight over the last 6 months or body mass index 2.5x the upper normal limit. 17. Elevated Amylase >1.5 above the upper normal limit. 18. Elevated Lipase >1.5 above the upper normal limit. 19. Concomitant medications which are inhibitors or inducers of CYP 450 3A4 activity as defined in the protocol (see section 4.4). (Assuming subjects cannot or will not elect to stop these medications)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To investigate the efficacy, safety and tolerability of 5 mg/day RO3300074 (RAR-g agonist) vs. placebo where all subjects are treated with optimal COPD drug therapy.; Secondary Objective: 1. The population pharmacokinetic objective is to estimate the PK exposure and to explore concentration-effects relationships 2. The biomarker objective is to explore the effects of RO3300074 over time on candidate plasma biomarkers, to explore correlations between changes from baseline in plasma biomarkers and clinical efficacy, and to assess effects of treatment on systemic markers of cellular inflammation relative to pre- and post treatment profiles. 3. The clinical genotyping objective is to evaluate whether genetic variants of SLC6AS9 affect pharmacokinetic/pharmacodynamic/tolerability/safety parameters of BP20281. In addition, depending on the safety, tolerability and patient retention during the study, consideration will be given to an extension protocol to assess the benefit of RO3300074 beyond 2 years. ; Primary end point(s): Post-bronchodilator clinic FEV1 (mL). This variable has been selected for the purpose of powering the study. Spirometry measurements will be performed at baseline, 3, 6, 9, 12, 15, 18, 21 and 24 months using a standardized spirometer and analyzed by a central laboratory. The treatment group of 5.0 mg of RO3300074 once daily will be statistically compared with placebo. The hypothesis to be tested for the primary assessment of efficacy is: H0: The mean change from baseline in FEV1 (mL) at the end of the treatment period in the active treatment group is equal to that in the placebo group, versus H1: The mean change from baseline in FEV1 (mL) at the end of the treatment period in the active treatment group is different than that in the placebo group. | — |
Countries
Czech Republic, Hungary, Iceland, Italy, Latvia, United Kingdom
Outcome results
None listed