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    Summary
    EudraCT Number:2006-002525-23
    Sponsor's Protocol Code Number:NB19751A
    National Competent Authority:Iceland - IMCA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2006-10-31
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedIceland - IMCA
    A.2EudraCT number2006-002525-23
    A.3Full title of the trial
    A double-blind, placebo-controlled efficacy (as assessed by post-bronchodilator FEV1) and safety study of 5 mg RO3300074 once-daily for 2 years in subjects with smoking-related, moderate-to-severe COPD with emphysema receiving concurrent optimal COPD drug therapy.
    A.4.1Sponsor's protocol code numberNB19751A
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorF. Hoffmann-La Roche Ltd
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNot applicable
    D.3.2Product code RO3300074
    D.3.4Pharmaceutical form Capsule, soft
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, soft
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    symptomatic smoking-related emphysema in ex-smokers
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 8.1
    E.1.2Level LLT
    E.1.2Classification code 10014561
    E.1.2Term Emphysema
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.
    E.2.2Secondary 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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    E.4Principal 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)
    E.5 End points
    E.5.1Primary 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.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Biomarkers
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA39
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial 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
    Last Patient Last Visit including 4 weeks follow up.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months10
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state80
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 280
    F.4.2.2In the whole clinical trial 480
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2006-11-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2006-07-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2010-05-24
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