E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of Eosinophilic Granulomatosis with Polyangiitis in
Subjects Receiving Standard of Care Therapy. |
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E.1.1.1 | Medical condition in easily understood language |
Eosinophilic Granulomatosis with Polyangiitis also known as Churg-Strauss Syndrome |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10018701 |
E.1.2 | Term | Granulomatous disease |
E.1.2 | System Organ Class | 100000004867 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10072580 |
E.1.2 | Term | Granulomatous polyangiitis |
E.1.2 | System Organ Class | 100000004866 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10014956 |
E.1.2 | Term | Eosinophilic granuloma |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10014957 |
E.1.2 | Term | Eosinophilic granulomatous vasculitis |
E.1.2 | System Organ Class | 100000004870 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10056218 |
E.1.2 | Term | Necrotising granulomatous vasculitis |
E.1.2 | System Organ Class | 100000004866 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10036023 |
E.1.2 | Term | Polyangiitis |
E.1.2 | System Organ Class | 100000004866 |
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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 investigate the efficacy of mepolizumab plus standard of care compared with placebo plus standard of care on duration of clinical remission, defined as accrued duration in weeks where a subject achieves a BVAS=0 and corticosteroid dose ≤4 mg/day prednisolone/prednisone, in subjects with relapsing or refractory
eosinophilic granulomatosis with polyangiitis (EGPA) receiving standard of care therapy including corticosteroid therapy reduction/withdrawal.
To investigate the durability of response to treatment with mepolizumab plus standard of care compared with placebo plus standard of care, assessed by the proportion of subjects in remission at both Weeks 36 and 48. |
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E.2.2 | Secondary objectives of the trial |
To investigate the efficacy of mepolizumab compared with placebo on time to relapse in subjects with EGPA on background standard of care treatment including corticosteroid therapy reduction/withdrawal.
To compare the average daily dose of corticosteroid required during the last 4 weeks of the study treatment period.
To evaluate the proportion of subjects who achieve remission within the first 24 weeks of the study and remain in remission for the remainder of the study treatment period.
To investigate the safety of mepolizumab compared with placebo in subjects with EGPA on background standard of care treatment.
View protocol page 28 for further information. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Informed Consent: Able to give written informed consent prior to participation in the study, which will include the ability to comply with the requirements and restrictions listed in the consent form. Subjects must be able to read, comprehend,
and write at a level sufficient to complete study related materials.
2. Age and gender: Male or female subjects age 18 years or older.
3. EGPA diagnosis: subjects who have been diagnosed with EGPA for at least 6 months based on the history or presence of: asthma plus eosinophilia (>1.0x109/L and/or >10% of leucocytes) plus at least two of the following additional features of EGPA.
a biopsy showing histopathological evidence of eosinophilic vasculitis, or perivascular eosinophilic infiltration, or eosinophil-rich granulomatous inflammation;
neuropathy, mono or poly (motor deficit or nerve conduction abnormality);
pulmonary infiltrates, non-fixed;
sino-nasal abnormality;
cardiomyopathy (established by echocardiography or MRI);
glomerulonephritis (haematuria, red cell casts, proteinuria);
alveolar haemorrhage (by bronchoalveolar lavage);
palpable purpura;
ANCA positive (MPO or PR3).
4. History of relapsing OR refractory disease defined as:
Relapsing disease:
Subject must have a past history of at least one confirmed EGPA relapse (i.e., requiring increase in OCS dose, initiation/increased dose of immunosuppressive therapy or hospitalisation) within the past 2 years which occurred at least 12 weeks prior to Screening (Visit 1) whilst receiving a dose of prednisolone (or equivalent) of ≥7.5 mg/day.
Refractory disease:
Either: Failure to attain remission (BVAS=0 and OCS dose ≤7.5 mg/day prednisolone or equivalent) within the last 6 months following induction treatment with a standard regimen, administered for at least 3 months.
Note: a. Subjects who have received a cyclophosphamide (CYC) induction regimen may be included a minimum of 2 weeks after the last dose of daily oral CYC, or 3 weeks after the last dose of pulsed IV CYC prior to Baseline (Visit 2), if their total WBC is ≥4x109/L (tested at the local laboratory, if necessary) prior to randomisation.
b. Subjects who have received a methotrexate, azathioprine, or
mycophenolate mofetil induction regimen may be included if on a stable dose for at least 4 weeks prior to Baseline (Visit 2).
c. Subjects who have received an induction regimen comprising
corticosteroids alone may be included only if they have failed to attain remission after 3 months of treatment AND the corticosteroid dose is ≥15 mg/day prednisolone or equivalent for the 4 weeks prior to Baseline (Visit 2).
Or: Within 6 months prior to Screening (Visit 1), recurrence of symptoms of EGPA (not necessarily meeting the protocol definition of relapse) whilst tapering OCS, occurring at any dose level ≥7.5 mg/day prednisolone or equivalent.
5. Corticosteroid therapy: Subject must be on a stable dose of oral prednisolone or prednisone of ≥7.5 mg/day (but not >50 mg/day) for at least 4 weeks prior to Baseline (Visit 2).
6. Immunosuppressive therapy: If receiving immunosuppressive therapy (excluding cyclophosphamide) the dosage must be stable for the 4 weeks prior to Baseline (Visit 2) and during the study (dose reductions for safety reasons will be permitted).
7. ECG measurements: QTc(F)<450 msec or QTc(F)<480 msec for patients with bundle branch block.
The QTc is the QT interval corrected for heart rate according to either Bazett’s formula (QTcB), Fridericia’s formula (QTcF), or another method, machine or manual overread.
For subject eligibility and withdrawal decisions, QTcF will be used.
For purposes of data analysis, QTcF will be used as primary though data using both correction formulas will be collected and analysed. The QTc should be based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period.
8. Female subjects: To be eligible for entry into the study, females of childbearing potential (FCBP) must commit to consistent and correct use of an acceptable method
of birth control (Appendix 4; see Section 11.4) beginning with consent, for the duration of the trial and for 4 months after the last study drug administration.
French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
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E.4 | Principal exclusion criteria |
1. GPA or MPA: Diagnosed with granulomatosis with polyangiitis (GPA; previously known as Wegener’s granulomatosis) or microscopic polyangiitis (MPA).
2. Organ-threatening EGPA: Organ-threatening EGPA as per EULAR criteria, i.e., organ failure due to active vasculitis, creatinine >5.8 g/dL (>513 μmol/L) within 3 months prior to Screening (Visit 1).
3. Life-threatening EGPA: Imminently life-threatening EGPA disease defined as any of the following within 3 months prior to Screening (Visit 1). Please view protocol page 37 for further information.
4. Malignancy: A current malignancy or previous history of cancer in remission for less than 12 months prior screening (Subjects that had localized carcinoma (i.e., basal or squamous cell) of the skin which was resected for cure will not be excluded).
5. Liver disease: Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices or persistent jaundice), cirrhosis, and known biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones).
6. Cardiovascular: Subjects who have severe or clinically significant cardiovascular disease uncontrolled with standard treatment including but not limited to:
Known ejection fraction of <30%, OR
Severe heart failure that meets New York Heart Association Class IV (Appendix 5; see Section 11.5), OR
Hospitalised in the 12 months prior to Visit 1 for severe heart failure meeting New York Heart Association Class III (Appendix 5; see Section 11.5), OR
Angina diagnosed less than 3 months prior to or at Visit 1 (Screening).
7. Other concurrent medical conditions: Subjects who have known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological, respiratory or any other system abnormalities that are not associated with EGPA and are uncontrolled with standard treatment.
8. Infectious disease: Chronic or ongoing active infectious disease requiring systemic treatment.
9. Parasitic infection: Subjects with a parasitic infestation within 6 months prior to Screening (Visit 1).
10. Hepatitis status: Diagnosis of chronic hepatitis B, as evidenced by positive Hepatitis B surface antigen (HBsAg) at Screening (Visit 1).
11. HIV: Subjects with a known human immunodeficiency virus infection.
12. Hypersensitivity: Subjects with a known allergy or intolerance to a monoclonal antibody or biologic therapy.
13. Previous mepolizumab: Subjects who have previously received mepolizumab within a 1 year period prior to Screening (Visit 1).
14. Prohibited medications: Subjects receiving any of the following:
OCS: Subject requires an oral corticosteroid dose of >50 mg/day prednisolone/prednisone in the 4-week period prior to Baseline (Visit 2).
Intravenous or SC corticosteroids in the 4-week period prior to Baseline (Visit 2).
Omalizumab within 130 days prior to Screening (Visit 1).
Cyclophosphamide: oral CYC within 2 weeks prior to Baseline (Visit 2) and IV CYC within 3 weeks prior to Baseline (Visit 2), if their total WBC is ≥4x109/L (measured using the local laboratory if necessary).
Rituximab within 12 months prior to Screening (Visit 1); in addition, the subject must have shown recovery of peripheral B-cell count to within the normal range.
IV or SC immunoglobulin within 6 months prior to Screening (Visit 1).
Interferon_alpha within 6 months prior to Screening (Visit 1).
Anti-TNF therapy within 12 weeks prior to Screening (Visit 1).
Anti-CD52 (alemtuzumab) within 6 months prior to Screening (Visit 1).
15. Other laboratory parameter exclusions:
Creatinine > 2.5 mg/dL (221 μmol/L)
WBC < 4 x109/L
Platelet count <120,000/mm3
Haemoglobin <8 g/dL (<80 g/L)
16. Pregnancy: Subjects who are pregnant or breastfeeding. Subjects should not be enrolled if they plan to become pregnant during the time of study participation.
17. Alcohol/substance abuse: A history (or suspected history) of alcohol misuse or substance abuse within 2 years prior to Screening (Visit 1).
18. Other investigational product: Subjects who have received treatment with an investigational drug within the past 30 days or 5 terminal phase half-lives of the drug whichever is longer, prior to Screening (Visit 1) (this also includes investigational formulations of marketed products).
19. Other clinical study: Subject is currently participating in any other interventional clinical study.
20. Adherence: Subjects who have known evidence of lack of adherence to controller medications and/or ability to follow physician’s recommendations.
French subjects: the French subject has participated in any study using an investigational drug during the previous 30 days or 5 half-lives (whichever is longer). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Total accrued duration of remission, i.e., the accrued number of weeks where BVAS=0 plus prednisolone/prednisone dose ≤4 mg/day over the 52 week study treatment period reported as proportion of subjects achieving remission in the following categories:- Zero; >0 to <12 weeks;
- 12 to <24 weeks;
- 24 to <36 weeks
- ≥36 weeks.
• The proportion of subjects who are in remission at both Weeks 36 and 48 of the study treatment period. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Over the 52 week treatment period |
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E.5.2 | Secondary end point(s) |
• Time to first confirmed EGPA relapse.
•The proportion of subjects with an average daily prednisolone/prednisone dose during the last 4 weeks of the study treatment period (48 through 52) in each of the following categories:
Zero
>0 to ≤4.0 mg
>4.0 to ≤7.5 mg
>7.5 mg
The proportion of subjects in each treatment group who achieve remission (BVAS=0 and prednisolone/prednisone dose ≤4 mg/day) within the first 24 weeks of the study and then remain in remission for the remainder of the study treatment period. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
As specified in the endpoint. |
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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) | 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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
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 |
Canada |
France |
Germany |
Italy |
Japan |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |