E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Asthma not adequately controlled with inhaled corticosteroids and long acting beta-agonists |
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E.1.1.1 | Medical condition in easily understood language |
Asthma which cannot be controlled by standard treatment |
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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 | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10003553 |
E.1.2 | Term | Asthma |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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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 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. |
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E.2.2 | Secondary 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 the safety and tolerability of secukinumab in patients with bronchial asthma
• To assess the pharmacokinetics of secukinumab in patients with bronchial asthma |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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.
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E.4 | Principal 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 halflives 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. |
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E.5 End points |
E.5.1 | Primary 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
baseline to day 85, may be extended to include measurements obtained on Days 113, 141, and 197 |
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E.5.2 | Secondary 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
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
day 0 through day 197 (end of study) |
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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 | No |
E.6.13 | Others | No |
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 | No |
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 | 21 |
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 | No |
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 |
Belgium |
Bulgaria |
Germany |
Romania |
United Kingdom |
United States |
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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
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
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 |