| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| 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 determine efficacy of CNTO 148 measured by pulmonary function and number of severe asthma exacerbations in subjects with severe persistent asthma |
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| E.2.2 | Secondary objectives of the trial |
*To assess the effect of CNTO 148 on asthma symptoms, rescue medication use, mild asthma exacerbations, and quality of life (QoL) in subjects with severe persistent asthma.
*To evaluate the maintenance of treatment effect of CNTO 148 during a steroid taper phase measured by the number of asthma exacerbations, pulmonary function parameters, asthma symptoms, rescue medication use, and QoL in subjects with severe persistent asthma.
*To assess the pharmacokinetics (PK) and pharmacodynamcis (PD) of CNTO 148 treatment in subjects with severe persistent asthma.
*To obtain safety information on CNTO148 in subjects with severe persistent asthma.
*To determine the dose(s) of CNTO 148 to be evaluated in Phase 3 trials. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Male or female ≥ 18 years of age.
2. Physician diagnosis of asthma for ≥ 3 years and a diagnosis of severe persistent asthma for ≥ 1 year prior to screening.
3. Has evidence of at least 1 of the following in the 5 years prior to screening or during screening:·Reversible airway obstruction (≥ 12% change in FEV1 postbronchodilator);·Diurnal variation in PEFR (≥ 30% change);·Airway hyperresponsiveness.
4. Continuous treatment with high dose ICS and LABA for at least 3 months prior to screening.
5. Estimated frequency of symptoms on more than one-third of days for at least 3 months prior to screening (eg, wheezing, breathlessness, chest tightness, cough, nocturnal awakening) despite treatment with high dose ICS and LABA, with or without continuous OCS.
6. At least 2 separate occasions in the previous year when worsening of asthma symptoms required treatment with IV CS or an addition or increase in OCS dose (steroid burst).
7. Score of ≥2 points on the ACQ at screening.
8. Screening clinic prebronchodilator FEV1 ≥ 40% and ≤ 80% of the predicted normal value (measured ³ 10 hours after last use of LABA and ≥ 4 hours after the last use of short-acting bronchodilator).
9. No change in dosing regimen of ICS and LABA, and OCS or other controller medication if applicable, for at least 2 weeks prior to the screening visit.
10. Non-smoker for at least 1 year, and have less than a 10 pack year history of smoking (1 pack year = 20 cigarettes smoked per day for 1 year or equivalent).
11. Women of childbearing potential and men must be using adequate birth control measures (abstinence, hormonal contraceptives, intrauterine device, barrier method with spermicide, or surgical sterilization) and must agree to continue such precautions for 6 months after receiving their last treatment with study agent. Women of childbearing potential must test negative on a serum pregnancy test at screening.
12. Eligible according to the tuberculosis (TB) eligibility assessment.
13. Capable of understanding subject assessment forms.
14. Have provided signed, written, informed consent before receiving any protocol specific procedures.
15. Willing to adhere to the study visit schedule and other protocol requirements, such as the electronic diary (eDiary) usage, and able to use the peak flow meter for home monitoring of pulmonary function.
At the end of the run-in phase (at baseline visit, week 0), in addition to the preceding criteria, all of the following criteria must be met in order to be eligible for randomization:
16. Has received a stable dose of fluticasone propionate 500 mg/salmeterol 50 mg (Advair®/Seretide®) (1 puff twice daily [BID]) during the run-in phase.
17. Subjects entering the run-in phase on fluticasone inhaler must have received a stable dose of fluticasone inhaler during the run-in phase.
18. Subjects on continuous OCS must have received the stable, prescreening dose of OCS during the run-in phase.
19. Subjects on other concomitant asthma controller medication(s) must have received stable doses of these asthma controller medication(s) during the run-in phase.
20. ACQ symptom score ≥ 2 and value must not have increased or decreased by ≥ 2 points from value at screening.
21. FEV1 ≥ 40% and ≤ 80% of the predicted normal value (measured ≥ 10 hours after last use of LABA and ≥ 4 hours after the last use of short-acting bronchodilator) and the measured value of clinic prebronchodilator FEV1 must not have increased or decreased by ≥ 20% between the screening visit and the baseline visit.
22. No worsening of asthma symptoms that required treatment with an addition or increase in OCS dose (steroid burst) between screening and randomization.
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| E.4 | Principal exclusion criteria |
1. Diagnosis of COPD, cystic fibrosis, or other significant respiratory disorder.
2. Worsening of asthma symptoms that required treatment with an addition or increase in OCS dose (steroid burst) in the 4-week period prior to the screening visit
3. Life-threatening asthma attack requiring cardiopulmonary support (eg, intubation) in the 6-month period prior to screening.
4. Pregnant, nursing, or planning pregnancy (both men and women) during the study or within the 6-month period after treatment with study agent.
5. Ever used alkylating agents (eg, chlorambucil or cyclophosphamide).
6. Previous treatment with any agent targeted at inhibiting TNF activity (eg, infliximab, etanercept, adalimumab, pentoxifylline, thalidomide, or CDP870) anakinra or cytotoxic agents within 3 months, or 5 half lives of the agent, whichever is longer, prior to the screening visit.
7. Previous treatment with omalizumab within 5 half lives of the agent (approximately 4.3 months) prior to the screening visit.
8. Known hypersensitivity to human immunoglobulin proteins or other components of CNTO 148.
9. Previous treatment with an investigational drug within 1 month, or within 5 half lives of the investigational agent, whichever is longer, prior to screening or are participating in another investigative study.
10. Concomitant diagnosis or any history of CHF, including medically controlled CHF.
11. Current signs or symptoms of severe, progressive or uncontrolled renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, cerebral disease, or any laboratory abnormality which would pose/suggest a risk to the subject during participation in the study.
12. History of known demyelinating diseases, such as multiple sclerosis or optic neuritis.
13. Documented human immunodeficiency virus (HIV) infection.
14. Documented current active hepatitis B or a history of documented hepatitis C infection.
15. Within 3 months prior to screening, has had a clinically important, serious infection (eg, hepatitis, pneumonia, or pyelonephritis), has been hospitalized for an infection, or have been treated with IV antibiotics for an infection. Less serious infections (eg, acute upper respiratory tract infection or simple urinary tract infection) need not be considered exclusions at the discretion of the investigator.
16. Chronic or recurrent infectious disease, including, but not limited to: renal infection (eg, recurrent pyelonephritis); chest infection (eg, bronchiectasis); urinary tract infection (other than simple, recurrent cystitis); or skin wound or ulcer. Subjects with chronic sinusitis are allowed to be enrolled.
17. Opportunistic infection (eg, cytomegalovirus, Pneumocystis carinii, aspergillosis, histoplasmosis, or mycobacteria other than TB) within 6 months prior to screening.
18. Received any live virus or bacterial vaccinations within 3 months prior to screening or are expected to receive any live virus or bacterial vaccinations during the trial or up to 3 months after the last dose of the study agent.
19. A known malignancy or have a history of malignancy within the 5-year period prior to screening (with the exception of basal cell or squamous cell carcinoma of the skin that has been fully excised with no evidence of recurrence).
20. History of lymphoproliferative disease, including lymphoma or signs and symptoms suggestive of possible lymphoproliferative disease.
21. Serious concomitant illness that could interfere with the subject’s participation in the study.
22. History of substance abuse (drugs or alcohol) within the 3 years prior to screening, history of noncompliance to medical regimens, or other condition/circumstance that could interfere with the subject’s adherence to protocol requirements (eg, psychiatric disease, lack of motivation, travel).
23. Major surgery within the 3 months prior to screening.
24. Has a transplanted organ (with the exception of a corneal transplant > 3 months prior to screening). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
*Change from baseline to week 24 in prebronchodilator clinic-measured, percent predicted forced expiratory volume in 1 second (FEV1).
*Number of severe exacerbations from baseline through week 24. |
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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 | Information not present in EudraCT |
| 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 |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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.8.6 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 | Information not present in EudraCT |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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