E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
symptomatic smoking-related emphysema in ex-smokers |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10014561 |
E.1.2 | Term | Emphysema |
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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 efficacy, safety and tolerability of 5 mg/day RO3300074 (RAR-g agonist) vs. placebo where all subjects are treated with optimal COPD drug therapy. |
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E.2.2 | Secondary objectives of the trial |
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.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria at screening: 1. Ex-smokers with 10 or more pack-year smoking history (subjects must have stopped smoking for 12 months prior to enrollment) 2. Subjects of > 44 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 90 days after discontinuation of treatment. 4. Subjects with moderate to severe COPD defined as follows: Post-bronchodilator FEV1 / FVC < 70% Post-bronchodilator FEV1 value at screening visit greater than or equal to 35% and less than or equal to 60 % of the predicted normal value for gender, age, and height, Dl,co (Tl,co) < 70% of the predicted normal value, MMRC symptom score > 1 (see appendix 8). 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 < 70%. 3. Post-bronchodilator FEV1 value at randomization visit greater than or equal to 35% and less than or equal to 60 % of the predicted normal value for gender, age, and height. 4. Dl,co (Tl,co) < 70% of the predicted normal value 5. Since screening visit no exacerbation of pulmonary symptoms, requiring hospitalization or treatment with oral steroids, or antibiotics. 6. Subjects have been off oral steroids since screening visit (eg. Prednisone, Prednisolone). 7. Subjects must be able to perform the 6-minute walk test. 8. Subjects must not have any changes to medication or treatments for COPD after screening visit. |
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E.4 | Principal 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 300 mg/dl (3.4 mmol/dl) with or without therapy. 11. Unexplained weight loss of 10% of total body weight over the last 6 months or body mass index < 19 kg/m2. 12. History of allergy or sensitivity to retinoids. 13. Concurrent enrollment or participation in any other therapeutic clinical trial within the last 30 days. 14. Medical history or active conditions likely to compromise the safety of the subject, or the absorption, metabolism, or excretion of the study medication. This includes, but is not limited to: Psychiatric disorders, skin disorders, cancer, convulsive disorder, bleeding disorders, current lung cancer or history of lung cancer, renal failure, cirrhosis or chronic liver disease, pancreatic diseases, leukopenia, thrombocytopenia, active infection, myocardial infarction, angina, or coronary artery disease within the last 6 months. 15. History of substance abuse excepting nicotine (i.e. drug, alcohol). 16. Elevated ALT>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)
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E.5 End points |
E.5.1 | 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.
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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 | Yes |
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 | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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) | 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 | 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.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 39 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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Last Patient Last Visit including 4 weeks follow up. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 10 |