| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment for patients with eosinophilic asthma |
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| E.1.1.1 | Medical condition in easily understood language |
| A particular form of asthma characterized by the presence of a high number in the lungs of a certain type of white blood cells, called eosinophils, which lead to airways inflammation and symptoms |
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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 | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068462 |
| E.1.2 | Term | Eosinophilic asthma |
| E.1.2 | System Organ Class | 100000004855 |
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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 |
Demonstrate the efficacy of reslizumab, at a dose of 3 mg/kg administered iv every 4 weeks over 12 months, as assessed by the reduction in frequency of clinical asthma exacerbations (CAEs) during 12 months and by the overall change in forced expiratory volume in 1 second (FEV1) during the first 16 weeks in patients with eosinophilic asthma. The study will be considered positive if either measure meets statistical significance at the respective predefined significance level.
CAE is defined by 1 of the following:
1) hospitalization because of asthma,
2) emergency treatment because of asthma,
3) decrease in FEV1 by 20% or more, or 4) If the PEFR drops below 30% from baseline on 2 consecutive days worsening of asthma will be assessed. If there is a prescribed increase in baseline OCS or ICS or if the symptoms warrant additional asthma treatment (OCS) this would be considered a CAE. For details on how the worsening of asthma is assessed & definition of emergency treatment see protocol |
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| E.2.2 | Secondary objectives of the trial |
• to evaluate the efficacy of reslizumab:
― lung function ([FEV1], [%FEV1], [FVC], [FEF25-75%])
― time to first CAE
― oral corticosteroids prescribed for asthma worsening
― use of short-acting beta-agonists
― blood eosinophil count
― ASUI
― ACQ
― AQLQ
• to evaluate the safety and tolerability of reslizumab:
occurrence of adverse events, clinical laboratory test results, vital signs, ECG, physical examination findings, concomitant medication usage, measurement of anti-drug antibodies
• as exploratory objectives:
― PEFR
― occurrence of nasal polyps in patients subset who are at least 18 years old
― to characterise blood and/or sputum biomarkers of lung tissue remodeling
― to explore differences in efficacy parameters in subsets of patients defined by pharmacogenetic markers related to asthma
― to characterize the PK of reslizumab
― to characterize the relationship between serum concentrations of reslizumab and measures of efficacy and safety
― IgE levels |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Pharmacogenetic analysis (Refer to Study Protocol C38072/3082 section 6.2.12 Pharmacogenetic analysis) |
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| E.3 | Principal inclusion criteria |
Patients are included in the study if all of the following criteria are met:
(a) The patient is male or female, 12 through 75 years of age, with a previous diagnosis of asthma.
(b) Inclusion criterion (b) is replaced by (b1)
(b1) The patient has had at least 1 asthma exacerbation requiring oral, intramuscular or iv corticosteroid use for at least 3 days over the past 12 months before screening.
(c) The patient has a current blood eosinophil level of at least 400/μL.
(d) The patient has airway reversibility of at least 12% to beta-agonist administration.
(e) Inclusion criterium (e) is replaced by (e1)
(e1) The patient has an ACQ score of at least 1.5 at the screening and baseline (before the 1st dose of study drug) visits.
(f) Inclusion criterion (f2) is replaced by (f3).
(f3) The patient is taking inhaled fluticasone at a dosage of at least 440 μg, or equivalent, daily. Chronic oral corticosteroid use (no more than 10 mg/day prednisone or equivalent) is allowed. If a patient is on a stable dose, eg, 2 weeks or more of oral corticosteroid treatment at the time of study enrollment, the patient must remain on this dose throughout the study. The patients’ baseline asthma therapy regimen (including but not limited to inhaled corticosteroids, oral corticosteroids up to a maximum dose of 10 mg prednisone daily or equivalent, leukotriene antagonists, 5 lipooxegnase inhibitors, cromolyn) must be stable for 30 days prior to screening, and continue without dosage changes throughout the study.
(g) All female patients must be surgically sterile, 2 years postmenopausal, or must have a negative pregnancy test ß-HCG at screening (serum) and baseline (urine).
(h) Inclusion criterion (h1) is replaced by (h2)
(h2) Female patients of childbearing potential (not surgically sterile or 2 years postmenopausal), must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for 30 days after participation in the study. Acceptable methods of contraception include barrier method with spermicide, abstinence, intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, implanted, and injected). NOTE: Partner serility alone is not acceptable for inclusion in the study.
(i) Written informed consent is obtained. Patients 12 through 17 years old must provide assent.
(j) Inclusion criterion (j) is replaced by (j1)
(j1) The patient is in reasonable health (except for diagnosis of asthma) as judged by the investigator, and as determined by a medical history, medical examination, ECG evaluation (at screening), serum chemistry, hematology, and urinalysis.
(k) Inclusion criterion (k) is replaced by (k1).
(k1) The patient must be willing and able to understand and comply with study restrictions, requirements and procedures, as specified by the study center, and to remain at the study center for the required duration during the study period, and willing to return to the study center for the follow-up evaluation as specified in this protocol.
(l) Patients who experience an asthma exacerbation during the screening period will be considered to have failed screening and cannot be randomly assigned to study drug. Patients may be rescreened 1 time only. |
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| E.4 | Principal exclusion criteria |
(a) The patient has a clinically meaningful comorbidity that would interfere with the study schedule or procedures, or compromise the patient’s safety.
(b) The patient has known hypereosinophilic syndrome.
(c) Exclusion criterion (c) is replaced by (c1).
(c1) The patient has another confounding underlying lung disorder (eg, chronic obstructive pulmonary disease, pulmonary fibrosis, or lung cancer). Patients with pulmonary conditions with symptoms of asthma and blood eosinophilia (eg, Churg Strauss syndrome, allergic bronchopulmonary aspergillosis) will also be excluded.
(d) The patient is a current smoker (ie. has smoked within the last 6 months prior to screening).
(e) Exclusion criterion (e2) is replaced by (e3).
(e3) The patient is using systemic immunosuppressive, immunomodulating, or otherbiologic agents (including, but not limited to, anti-IgE mAb, methotrexate, cyclosporin, interferon-α, or anti-tumor necrosis factor [anti-TNF] mAb) within 6 months prior to screening.
(f) Exclusion criterion (f1) is replaced by (f2).
(f2) The patient has previously received an anti-hIL-5 monoclonal antibody (eg, reslizumab, mepolizumab, or benralizumab).
(g) Exlusion criterion (g) is replaced by (g1).
(g1) The patient has any aggravating medical factors that are inadequately controlled (eg. rhinitis, gastroesophageal reflux disease, and uncontrolled diabetes).
(h) The patient has participated in any investigative drug or device study within 30 days prior to screening.
(i) Exclusion criterion (i1) is replaced by (i2).
(i2) The patient has participated in any investigative biologics study within 6 months prior to screening.
(j) Exclusion criterion (j1) is replaced by (j2)
(j2) Female patients who are pregnant, nursing, or, if of childbearing potential, and not using a medically accepted, effective method of birth control (eg, barrier method with spermicide, abstinence, IUD, or steroidal contraceptive [oral, transdermal, implanted, and injected]) are excluded from this study. NOTE: Partner sterility alone is not considered an acceptable form of birth control.
(k) The patient has concurrent infection or disease that may preclude assessment of active asthma.
(l) Exclusion criterion (l) is replaced by (l1)
(l1) The patient has a history of concurrent immunodeficiency (human immunodeficiency virus[HIV] or acquired immunodeficiency syndrome or congenital immunodeficiency).
(m) The patient has current suspected drug and alcohol abuse as specified in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM IV TR) criteria.
(n) Exclusion criterion (n) is replaced by (n1)
(n1) The patient has had an active parastic infection within 6 months prior to screening.
(o) The patient may not have received any live attenuated vaccine within the 12 week period prior to screening.
(p) The patient has a history of allergic reactions to or hypersensitivity to any component of the study drug.
(q) The patient has had an infection requiring the following:
- an admission to the hospital for at least 24 hours within 4 weeks prior to screening or during the screening period
- treatment with iv antibiotics within 4 weeks prior to screening or during the screening period
- teratment with oral antibiotics within 4 weeks prior to screening or during the screening period
(r) The patient has a history of exposure to water borne parasites within 6 weeks prior to screening or during the screening period or a history of diarrheal illness of undetermined etiology within 3 months prior to screening or during the screening period.
(s) The patient requires treatment for an asthma exacerbation within 4 weeks of screening or during the screening period. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
This study has 2 coprimary efficacy measures: the frequency of CAEs reported for each patient during the 52 week treatment period, and the overall change in FEV1 in the first 16 weeks of the study drug treatment. The study will be considered positive if either measure meets statistical significance at the respective predefined significance level.
A CAE is defined by 1 of the following:
1) a hospitalization because of asthma,
2) emergency treatment because of asthma,
3) a decrease in FEV1 by 20% or more, or
4) If the PEFR drops below 30% from baseline on 2 consecutive days worsering of asthma will be assessed. If there is a prescribed increase in baseline OCS or ICS or if the sympthoms warrant additional asthma treatment (OCS) this would be considered an exacerbation. For details on how the woresening of asthma is assessed & definition of emergency treatment see protocol. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The number of CAEs reported for each patient will be measured throughout the duration of the study.
The overall change in FEV1 will be measured from baseline to week 16 or the onset of first CAE, whichever occurs first.
A CAE is defined by 1 of the following:
1) a hospitalization because of asthma,
2) emergency treatment because of asthma,
3) a decrease in FEV1 by 20% or more, or
4) a decrease in PEFR of 30% or more in 2 consecutive measurements.
Patients who experience a CAE will be instructed to come to the study center for pulmonary function tests and asthma symptom score assessment. |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy variables and endpoints for this study are as follows:
• change in lung function as measured by FEV1, %FEV1, FVC, FEF25-75% from baseline to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52, and endpoint, or at time of first CAE
• time to first CAE
• change in the number of courses of oral corticosteroids prescribed for asthma worsening (3 or more days of administration or doubling of current dose) from baseline to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52, and endpoint, or at time of first CAE
• change in short-acting beta-agonist use from baseline to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52, and endpoint, or at time of first CAE
• change in blood eosinophil count from baseline to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52, and endpoint, or at time of first CAE
• change in ASUI score from baseline to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52, and endpoint, or at time of first CAE
• change in ACQ score from baseline to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52, and endpoint, or at time of first CAE
• change in AQLQ score from baseline to weeks 16, 32, and 52, and endpoint, or at time of first CAE
The exploratory variables and endpoints for this study are as follows:
• sputum eosinophil levels measured at week 52 or early withdrawal (select patients only)
• PEFR measured at week 52 or early withdrawal
• blood samples for pharmacokinetic analysis at weeks 4, 8, 12, 16, 24, 36, and 48
• blood biomarkers measured at weeks 12, 24, 36, and 48
• the presence or absence of nasal polyps
• blood sample for pharmacogenetic analysis at baseline only, in patients who sign separate consent
• blood sample for IgE level at week 52 or early withdrawal
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 47 |
| 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 |
| Australia |
| Belgium |
| Chile |
| Colombia |
| Czech Republic |
| Denmark |
| Hungary |
| Israel |
| Malaysia |
| New Zealand |
| Philippines |
| Poland |
| Russian Federation |
| South Africa |
| Sweden |
| Thailand |
| 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
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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