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    Summary
    EudraCT Number:2011-003117-41
    Sponsor's Protocol Code Number:CAIN457D2204
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2011-09-28
    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 ConcernedUK - MHRA
    A.2EudraCT number2011-003117-41
    A.3Full title of the trial
    A randomized, double-blind, placebo controlled, multiple dose study to evaluate the safety, tolerability, and efficacy of intravenous administration of secukinumab (AIN457) in patients with asthma not adequately controlled with inhaled corticosteroids and long acting beta-agonists
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A controlled clinical study to investigate safety, tolerability and efficacy of secukinumab (AIN457) in patients with asthma which is not controlled by standard treatment
    A.4.1Sponsor's protocol code numberCAIN457D2204
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNovartis Pharma Services AG
    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 supportNovartis Pharma Services AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Pharmaceuticals UK Ltd
    B.5.2Functional name of contact pointMedical Information Services
    B.5.3 Address:
    B.5.3.1Street AddressFrimley Business Park, Frimley
    B.5.3.2Town/ cityCamberley, Surrey
    B.5.3.3Post codeGU16 7SR
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+4401276698370
    B.5.5Fax number+4401276698449
    B.5.6E-mailmedinfo.uk@novartis.com
    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 nameSecukinumab
    D.3.2Product code AIN457
    D.3.4Pharmaceutical form Powder for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeAIN457
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 Yes
    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 placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Asthma not adequately controlled with inhaled corticosteroids and long acting beta-agonists
    E.1.1.1Medical condition in easily understood language
    Asthma which cannot be controlled by standard treatment
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level PT
    E.1.2Classification code 10003553
    E.1.2Term Asthma
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess whether treatment with 10 mg/kg secukinumab versus placebo over 8 weeks, in individuals with asthma who are symptomatic despite treatment with high doses of ICS, leads to significant improvement in the severity of asthma as measured by change in the asthma control questionnaire (ACQ) score at Day 85.
    E.2.2Secondary objectives of the trial
    To assess whether treatment with 10 mg/kg secukinumab versus placebo over 8 weeks, in individuals with asthma who are symptomatic despite treatment with high doses of ICS, leads to improvement in the forced expiratory volume in one second (FEV1) at Day 85.
    • To assess whether treatment with 10 mg/kg secukinumab versus placebo over 8 weeks, in individuals with asthma who are symptomatic despite treatment with high doses of ICS, leads to improvement in:
    - Symptoms of asthma and lung function monitored using an electronic device
    - Asthma Quality of Life Questionnaire (AQLQ)
    Indirect measures of airway inflammation, as measured by:
    - Reduction in exhaled nitric oxide
    - Reduction in sputum neutrophils
    • To assess the safety and tolerability of secukinumab in patients with bronchial asthma
    • To assess the pharmacokinetics of secukinumab in patients with bronchial asthma
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects eligible for inclusion in this study have to fulfill all of the
    following criteria:
    1. Written informed consent must be obtained before any assessment is
    performed.
    2. Male and female adult patients aged ≥ 18 - 75 years with asthma >1
    year duration diagnosed according to the GINA guidelines (GINA 2010).
    3. Subjects must weigh at least 50 kg to participate in the study, and
    must have a body mass index (BMI) within the range of 18 - 39 kg/m2.
    See Appendix 3 of this protocol for BMI ranges.
    4. Daily treatment with > 1000μg beclomethasone dipropionate (BDP),
    or equivalent, plus a LABA (GINA step 4/5 therapy) for ≥ 3 months prior
    to Day 1, that has been stable for at least 4 weeks prior to screening.
    (Subjects may be enrolled on > 1000μg beclomethasone dipropionate
    (BDP) in the absence of a LABA if they have had an adverse reaction or
    worsening of asthma attributed to LABA therapy or if, in the opinion of
    the investigator, they are at high risk of adverse events to LABA therapy,
    or if the patient avoids LABA therapy due to concerns about such
    events).
    5. Asthma which is not adequately controlled on current treatment, as
    demonstrated by an Asthma Control Questionnaire (ACQ) score of ≥ 1.5
    at screening and baseline (see Appendix 4).
    6. Peripheral blood eosinophil count < 400/ul at screening.
    7. Serum IgE <500 IU/mL at screening.
    8. FEV1 of ≥ 40% and ≤ 90% of the predicted normal value for the
    patient, after withholding bronchodilators at screening and baseline.
    9. Compliance with eDiary device during the run-in period.
    10. Able to communicate well with the investigator, to understand and
    comply with the requirements of the study.
    E.4Principal exclusion criteria
    1. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, who are unwilling to use effective contraception during the study and for 16 weeks after stopping treatment.
    2. Use of other investigational drugs at the time of screening, or within 30 days or 5 half-lives of screening, whichever is longer; or longer if required by local regulations, and for any other limitation of participation in an investigational trial based on local regulations.
    3. Treatment with the following medications is not permitted: Betablockers within 5 half lives prior to Run-in visit; Omalizumab or other monoclonal antibody treatment within 4 months prior to Run-in ; Methotrexate, gold salts, cyclosporin, troleandomycin within 3 months prior to Run-in; and other general immune suppressants within 4 months prior to Run-in. Oral steroids up to 20 mg prednisolone daily or equivalent are permitted if stable for at least 4 weeks prior to randomization (Day 1).
    4. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes.
    5. The presence of any clinically relevant ECG abnormalities.
    6. Diagnosed with COPD as defined by the GOLD guidelines (Global Initiative for Chronic Obstructive Lung Disease 2008).
    7. A history of allergic bronchopulmonary aspergillosis.
    8. Patients who have had an asthma attack/exacerbation requiring a change in maintenance ICS or OCS treatment, or a short burst of systemic corticosteroids, within 4 weeks prior to screening.
    9. Patients who have had a respiratory tract infection within 4 weeks prior to screening.
    10. History of certain malignancies within the past 5 years
    11. Pregnant or nursing women.
    12. Smokers or those who have a smoking history of greater than 10 pack years
    13. Donation or loss of 400 ml or more of blood within eight weeks prior to first dose
    14. Significant illness within two (2) weeks prior to first dose.
    15. Recent and/or recurrent history of autonomic dysfunction
    16. History of clinically significant liver disease or liver injury as indicated by abnormal liver function tests
    17. History of recurrent staphylococcal of fungal infections
    18. Any live vaccines before screening, during the study, and after the last dose of secukinumab starting from 6 weeks before
    screening, during the study, and after the last dose
    19. Maintenance Immunotherapy for allergies allowed if maintenance dose has been administered for at least 3 months prior to Run-in visit, and is expected to remain unchanged throughout the course of the study.
    20. History of immunodeficiency diseases, including a positive HIV test result.
    21. A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result.
    22. drug or alcohol abuse within the 12 months prior to dosing
    23. History of ongoing, chronic or recurrent infectious disease or evidence of tuberculosis.
    24. No person directly associated with the administration of the study is
    allowed to participate as a study subject. No family member of the
    investigational study staff is allowed to participate in this study.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is the change in ACQ score (ΔACQ) from baseline to Day 85.
    The ACQ score ranges from 0 to 6 with lower scores reflecting better asthma control. Without loss of generality, ΔACQ is defined as baseline minus Day 85 so that improvements in asthma control translate to positive change scores.

    The primary analysis will consist of an unstructured mean and variance mixed effects regression model for the repeated measures on ΔACQ. The outcome will be the change in ACQ from baseline to each of Days 29, 57 and 85 and include covariates for the baseline ACQ, treatment, time (class variable), a time by treatment interaction, and a time by baseline interaction. The unstructured covariance model places no constraints on the residual variance of ΔACQ at each time-point or on the residual covariance between any two change scores measured on the same subject.
    The posterior distribution of the difference in the change in ACQ from baseline to Day 85 between the treatment and placebo groups (ΔACQ85treatment - ΔACQ85placebo) will be derived from this model and used to ascertain the level of proof of statistical significance (P(ΔACQ85treatment - ΔACQ85placebo) < 0) and clinical significance (P(ΔACQ85treatment - ΔACQ85placebo) < -0.5). Posterior inference on other quantities, such as the changes from baseline to remaining follow-up times and summary measures of change over time, are readily available from this model. The posterior distributions of all statistics of interest will be derived through Bayesian estimation with non-informative priors for the regression and variance parameters.
    Summary statistics and graphical representations of ACQ and ΔACQ over time will also be
    presented.

    The repeated measures regression model can accommodate subjects with missing follow-up
    ACQ scores and will produce valid estimates of mean and covariance parameters if the data
    are missing at random.

    Supportive analyses

    The statistical and clinical significances of the difference in the change in ACQ score between treatment and placebo will be assessed at Days 29 and 57. Statistical and clinical significance are defined in Section 9.4.2, and all relevant posterior distributions will be derived from the primary repeated measures model. As a sensitivity analysis to the primary model, the primary
    E.5.1.1Timepoint(s) of evaluation of this end point
    baseline to day 85, may be extended to include measurements obtained on Days 113, 141, and 197
    E.5.2Secondary end point(s)
    Efficacy / Pharmacodynamics
    - Forced expiratory volume in one second (FEV1) prior to bronchodilation
    - FEV1 following bronchodilation
    - MMEF before and after bronchodilation
    - FeNO
    - AQLQ
    - Sputum neutrophils at Day 85
    - Graphical summaries of daily symptoms of asthma and lung function measured at home will be displayed, and additional exploratory analyses on these endpoints will be performed as appropriate.

    Safety
    - Vital signs
    - ECG evaluations
    - Standard clinical laboratory evaluations
    - Special clinical laboratory evaluations
    - Adverse events
    - concomitant medications/significant non-drug-therapies

    Health related quality of life

    Pharmacokinetics

    Pharmacogenetics

    RNA expression profiling

    Other biomarkers

    PK/PD
    E.5.2.1Timepoint(s) of evaluation of this end point
    day 0 through day 197 (end of study)
    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 No
    E.6.13Others No
    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 No
    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.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA21
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    Bulgaria
    Germany
    Romania
    United Kingdom
    United States
    E.8.7Trial 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
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months2
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 75
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 9
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 72
    F.4.2.2In the whole clinical trial 84
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-11-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-02-03
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2015-01-30
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