Study of mepolizumab versus placebo in addition to standard of care for the treatment of Eosinophilic Granulomatosis with Polyangiitis.

• Register: EUCTR
• Last refreshed on: 30 April 2018
• Main ID: EUCTR2012-004385-17-BE
• Date of registration: 04/10/2013
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline Research & Development Ltd
• Public title: Study of mepolizumab versus placebo in addition to standard of care for the treatment of Eosinophilic Granulomatosis with Polyangiitis.
• Scientific title: A Double-blind, Randomised, Placebo-controlled Study to Investigate the Efficacy and Safety of Mepolizumab in the Treatment of Eosinophilic Granulomatosis with Polyangiitis in Subjects Receiving Standard of Care Therapy.
• Date of first enrolment: 22/11/2013
• Target sample size: 130
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-004385-17
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Canada, France, Germany, Italy, Japan, Spain, United Kingdom, United States

Contacts

• Name: Clinical Trials HelpDesk
• Affiliation: GlaxoSmithKline Reseacrh & Development Ltd

• Name: Clinical Trials HelpDesk
• Affiliation: GlaxoSmithKline Reseacrh & Development Ltd

Key inclusion & exclusion criteria

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.
? Japan only definition of Relapsing disease:
Subject must have a past history of at least one confirmed EGPA relapse (i.e., requiring increase in OCS dose, initiation of IV prednisolone (or equivalent), initiation/increased dose of immunosuppressive therapy, initiation/increased dose of intravenous immunoglobulin (IVIG) 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/d
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 (Vis

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Treatment of Eosinophilic Granulomatosis with Polyangiitis in Subjects Receiving Standard of Care Therapy.
MedDRA version: 17.1 Level: LLT Classification code 10018701 Term: Granulomatous disease System Organ Class: 100000004867
MedDRA version: 17.1 Level: LLT Classification code 10014956 Term: Eosinophilic granuloma System Organ Class: 100000004864
MedDRA version: 17.1 Level: LLT Classification code 10072580 Term: Granulomatous polyangiitis System Organ Class: 100000004866
MedDRA version: 17.1 Level: LLT Classification code 10014957 Term: Eosinophilic granulomatous vasculitis System Organ Class: 100000004870
MedDRA version: 17.1 Level: LLT Classification code 10056218 Term: Necrotising granulomatous vasculitis System Organ Class: 100000004866
MedDRA version: 17.1 Level: LLT Classification code 10068462 Term: Eosinophilic asthma System Organ Class: 100000004855
MedDRA version: 17.1 Level: LLT Classification code 10036023 Term: Polyangiitis System Organ Class: 100000004866

Intervention(s)

Product Name: Mepolizumab
Product Code: SB-240563
Pharmaceutical Form: Injection
INN or Proposed INN: Mepolizumab
CAS Number: 196078-29-2
Current Sponsor code: SB-240563
Other descriptive name: Recombinant humanized monoclonal antibody specific for human IL-5
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Main Objective: ? 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.

Secondary Objective: ? 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.

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.

Timepoint(s) of evaluation of this end point: Over the 52 week treatment period

Secondary Outcome(s)

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.

Timepoint(s) of evaluation of this end point: As specified in the endpoint.

Secondary ID(s)

MEA115921

Source(s) of Monetary Support

GlaxoSmithKline