E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects with severe asthma |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 18.1 |
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 determine whether there is an improvement in asthma control when directly switched to mepolizumab, in subjects with a severe eosinophilic asthma phenotype not optimally controlled on omalizumab. |
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E.2.2 | Secondary objectives of the trial |
• To determine whether there is an improvement in Health related Quality of Life (HR-QoL) when directly switched to mepolizumab, in subjects with a severe eosinophilic asthma phenotype not optimally controlled on omalizumab
• To determine the frequency of asthma exacerbations, when directly switched to mepolizumab, in subjects with a severe eosinophilic asthma phenotype not optimally controlled on omalizumab.
• To evaluate the pharmacodynamic effects when directly switched to mepolizumab, in subjects with a severe eosinophilic asthma phenotype not optimally controlled on omalizumab.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
AGE
1. At least 12 years of age at the time of signing the informed consent. [For those countries where local regulations permit enrolment of adults only, subject recruitment will be restricted to those who are ≥ 18 years of age]
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Asthma: A physician diagnosis of asthma for ≥2 years that meets the National Heart and Lung Institute guidelines or GINA guidelines
3. FEV1: Persistent airflow obstruction as indicated by:
For subjects ≥18 years of age at Visit 1, a pre-bronchodilator FEV1 <80% predicted recorded at Visit 1
For subjects 12-17 years of age at Visit 1, a pre-bronchodilator FEV1 <90% predicted recorded at Visit 1
OR
FEV1/FVC ratio <0.8 recorded at Visit 1
4. Eosinophilic asthma: Airway inflammation characterized as eosinophilic in nature as indicated by one of the following:
a. A peripheral blood eosinophil count of ≥300 cells/μL that is related to asthma demonstrated in the past 12 months prior to Visit 1
OR
b. A peripheral blood eosinophil count of ≥150 cells/μL at Visit 1 that is related to asthma.
5. Inhaled Corticosteroid: A well-documented requirement for regular treatment with high-dose inhaled corticosteroid (ICS) in the 12 months prior to Visit 1 with or without maintenance oral corticosteroids (OCS).
For 18 years of age and older:
ICS dose must be ≥880 mcg/day fluticasone propionate (FP) (ex-actuator) or equivalent daily
For ICS/LABA combination preparations, the highest approved maintenance dose in the local country will meet this ICS criterion.
For subjects 12-17 years of age at Visit 1:
ICS dose must be ≥440 mcg/day fluticasone propionate (FP) (ex-actuator) or equivalent daily
For ICS/LABA combination preparations, the highest approved maintenance dose in the local country will meet this ICS criterion.
6. Controller Medication: Current treatment with an additional controller medication, besides ICS, for at least 3 months or a documented failure in the past 12 months of an additional controller medication for at least 3 successive months. [e.g., long-acting beta-2-agonist (LABA), leukotriene receptor antagonist (LTRA), or theophylline.]
7. Asthma symptoms not optimally controlled: An ACQ-5 score of ≥1.5 recorded at Visit 1.
8. Omalizumab Treatment: Receiving omalizumab, based on weight and IgE levels, for at least the 4 months prior to Visit 1.
9. Exacerbation history: Previously confirmed history of two or more exacerbations requiring treatment with systemic corticosteroids (intramuscular, intravenous, or oral) in the 12 months prior to Visit 1 despite the use of high-dose ICS. For subjects receiving omalizumab for ≥8 months, at least one exacerbation must have occurred while on omalizumab treatment. For subjects receiving maintenance oral corticosteroids, the corticosteroid treatment for the exacerbations must have been a two-fold dose increase or greater.
SEX
10. Male or eligible Female
Females:
a. Non-reproductive potential defined as:
•Pre-menopausal females with one of the following:
•Documented tubal ligation
•Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion
•Hysterectomy
•Documented Bilateral Oophorectomy
•Postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels)]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.
b. Reproductive potential and agrees to follow one of the options listed in the Modified
List of Highly Effective Methods for Avoiding Pregnancy in Females of
Reproductive Potential (FRP) (see Appendix 3 of study protocol 204471) from 30 days prior to the first dose of study medication and until at least five terminal half-lives OR until any continuing pharmacologic effect has ended, whichever is longer, after the last dose of study medication and completion of the Exit visit/Early Withdrawal visit.
The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
INFORMED CONSENT
11. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol. |
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E.4 | Principal exclusion criteria |
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER
FUNCTION AND QTc INTERVAL)
1. Concurrent Respiratory Disease: Presence of a known pre-existing, clinically important lung condition other than asthma. This includes current infection, bronchiectasis, pulmonary fibrosis, bronchopulmonary aspergillosis, or diagnoses of emphysema or chronic bronchitis (chronic obstructive pulmonary disease other than asthma) or a history of lung cancer.
2. Malignancy: A current malignancy or previous history of cancer in remission for less than 12 months prior to screening (subjects that had localized carcinoma of the skin which was resected for cure will not be excluded).
3. Liver disease: Subjects must not be enrolled in the study if:
At screening (Visit 1) ALT >2xULN; and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
Current active liver or biliary disease (with the exception of Gilbert’s syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment).
4. Hepatitis status: Diagnosis of chronic hepatitis B, as evidenced by positive Hepatitis B surface antigen (HBsAg) at Visit 1. Chronic stable hepatitis C (e.g.,positive hepatitis C antibody test result at screening (Visit 1) or within 3 months prior to first dose of study treatment) are acceptable if subject otherwise meets entry
5. Cardiovascular: Subjects who have severe or clinically significant cardiovascular disease uncontrolled with standard treatment. Including but not limited to:
a. known ejection fraction of <30% OR
b. severe heart failure meeting New York Heart Association Class IV classification OR
c. hospitalised in the 12 months prior to Visit 1 for severe heart failure meeting New York Heart Association Class III OR
d. angina diagnosed less than 3 months prior to Visit 1 or at Visit 1
6. Subjects with QTc > 450 msec or QTc > 480 msec in subjects with Bundle Branch Block at screening Visit 1
7. Other Concurrent Medical Conditions: Subjects who have known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological or any other system abnormalities that are uncontrolled with standard treatment.
8. Eosinophilic Diseases: Subjects with other conditions that could lead to elevated eosinophils such as Hypereosinophilic Syndromes, including Churg-Strauss Syndrome (Eosinophilic Granulomatosis with Polyangiitis; EGPA), or Eosinophilic Esophagitis.
Subjects with a known, pre-existing parasitic infestation within 6 months prior to Visit 1 are also to be excluded.
9. Immunodeficiency: A known immunodeficiency (e.g., human immunodeficiency virus – HIV), other than that explained by the use of corticosteroids taken as therapy for asthma.
CONCOMITANT MEDICATIONS
10. Other Monoclonal Antibodies: Subjects who have received any monoclonal antibody (other than omalizumab) to treat inflammatory disease within 5 half-lives of Visit 1.
RELEVANT HABITS
11. Smoking history: Current smokers or former smokers with a smoking history of
≥10 pack years (number of pack years = (number of cigarettes per day / 20) x number of years smoked). A former smoker is defined as a subject who quit smoking at least 6 months prior to Screening Visit 1.
12. Alcohol/Substance Abuse: A history (or suspected history) of alcohol misuse or substance abuse within 2 years prior to Visit 1.
13. Adherence: Subjects who have known evidence of lack of adherence to controller medications and/or ability to follow physician’s recommendations.
CONTRAINDICATIONS
14. Hypersensitivity: Subjects with allergy/intolerance to a monoclonal antibody or biologic.
History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical
Monitor, contraindicates their participation.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
15. Investigator opinion: Omalizumab treatment has provided significant clinical benefit despite experiencing 2 exacerbations in the past 12 months, and potential benefit from a switch to mepolizumab would not outweigh the potential harm after omalizumab withdrawal for the subject.
16. Previous participation: Previously participated in any study with mepolizumab and received investigational product (including placebo).
17. Investigational Medications: Subjects who have received treatment with an investigational drug within the past 30 days or five terminal phase half-lives of the drug whichever is longer, prior to Screening (V1) (this also includes investigational formulations of marketed products).
18. Pregnancy: Subjects who are pregnant or breastfeeding. Patients should not be enrolled if they plan to become pregnant during the time of study participation.
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E.5 End points |
E.5.1 | Primary end point(s) |
Mean change from baseline in ACQ- 5 score at Week 32 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
•Mean change from baseline in SGRQ score at Week 32
•Frequency of clinically significant asthma exacerbations over 32 week treatment
•Ratio to baseline in blood eosinophils at Week 32 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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 | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 27 |
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 |
Argentina |
Belgium |
Canada |
France |
Germany |
Netherlands |
Spain |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 20 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 20 |
E.8.9.2 | In all countries concerned by the trial days | 0 |