| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsing or refractory Eosinophilic Granulomatosis with Polyangiitis (EGPA) receiving standard of care (SoC) therapy |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsing or refractory Eosinophilic Granulomatosis with Polyangiitis (EGPA) |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10078117 |
| E.1.2 | Term | Eosinophilic granulomatosis with polyangiitis |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of depemokimab SC every 26 weeks compared with mepolizumab SC every 4 weeks in participants with relapsing or refractory EGPA receiving SoC therapy |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the efficacy of depemokimab SC every 26 weeks compared with mepolizumab SC every 4 weeks on additional efficacy assessments in participants with relapsing or refractory EGPA receiving SoC therapy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participant (male or female) must be 18 years or older at the time of signing the informed consent.
2. Participants who are ≥ 40 kg at Screening Visit 1.
3. Participants who have been diagnosed with EGPA for at least 6 months based on the history or presence of: asthma plus eosinophilia defined in this study as >1.0x109/L and/or >10% of leucocytes plus at least 2 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 magnetic resonance imaging [MRI])
• glomerulonephritis (haematuria, red cell casts, proteinuria)
• alveolar haemorrhage (by bronchoalveolar lavage)
• palpable purpura
• ANCA positive Myeloperoxidase (MPO) or Proteinase 3 (PR3).
4. History of relapsing OR refractory disease defined as:
• Relapsing disease: Participants must have a history of at least one confirmed EGPA relapse (i.e., requiring increase in oral corticosteroid (OCS) dose, initiation/increased dose of immunosuppressive therapy or inpatient hospitalisation due to EGPA) within the past 2 years. EGPA relapse should have occurred at least 12 weeks or more prior to Screening (Visit 1) whilst receiving a dose of prednisolone (or equivalent of) ≥7.5 mg/day.
• China and Japan only definition of Relapsing disease: Participant must have a 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: Defined as either:
o Failure to attain remission (BVAS=0 and OCS dose ≤7.5 mg/day prednisolone or equivalent) within the last 6 months prior to Screening Visit 1 and following induction treatment with a standard OCS regimen, administered for at least 3 months
OR
o Participants with recurrence of EGPA symptoms within 6 months prior to Screening (Visit 1) whilst tapering OCS and occurring at any dose level ≥7.5 mg/day prednisolone or equivalent.
5. Corticosteroid therapy: Participants 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.
7. A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:
• Is a woman of nonchildbearing potential (WONCBP)
• Is a woman of childbearing potential (WOCBP) and using a contraceptive method that is highly effective, with a failure rate of <1%, from at least 14 days prior to the first dose of study intervention until the following durations (whichever is greater):
o 30 weeks after the last potential administration of depemokimab at Week 1 or Week 26,
o 16 weeks after the last potential administration of mepolizumab (remaining administrations).
8. Capable of giving signed informed consent as described in Section 10.1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
French participants: In France, a participant will be eligible for inclusion in this study only if he/she is either affiliated to or a beneficiary of a social security category. |
|
| E.4 | Principal exclusion criteria |
1. Diagnosed with granulomatosis with polyangiitis (GPA; previously known as Wegener’s granulomatosis) or microscopic polyangiitis (MPA).
2. EULAR defined 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. Imminently life-threatening EGPA disease defined as any of the following within 3 months prior to Screening (Visit 1):
• Intensive care required
• Severe alveolar haemorrhage or haemoptysis requiring transfusion or ventilation or haemoglobin <8 g/dL (<80 g/L) or drop in haemoglobin >2 g/dL (>20 g/L) over a 48 hours period due to alveolar haemorrhage
• Rapidly progressive glomerulonephritis (RPGN) with creatinine >2.5 mg/dL (>221 μmol/L) or rise in creatinine >2 mg/dL (>177 μmol/L) over a 48 hour period
• Severe gastrointestinal (GI) involvement, e.g., gangrene, bleeding requiring surgery
• Severe central nervous system (CNS) involvement
• Severe cardiac involvement, e.g., life-threatening arrhythmia, cardiac failure: ejection fraction <20%, New York Heart Association Class III/IV, acute myocardial infarction.
4. A current malignancy or previous history of cancer in remission for less than 12 months prior to screening. Participants that had localised carcinoma of the skin which was resected for cure will not be excluded.
5. Liver Disease:
• Alanine aminotransferase (ALT) >2x upper limit of normal (ULN) or if participant is on background methotrexate or azathioprine >3x ULN
• AST >2x ULN or if participant is on background methotrexate or azathioprine >3x ULN
• Alkaline Phosphatase ≥2.0x ULN
• Total bilirubin >1.5x ULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
• Cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice.
6. Participants who have severe or clinically significant cardiovascular disease uncontrolled with standard treatment including but not limited to:
• Known ejection fraction of <20%, OR
• Severe heart failure that meets New York Heart Association Class IV, OR
• Hospitalised in the 12 months prior to Visit 1 for severe heart failure meeting New York Heart Association Class III OR
• Myocardial infarction or angina diagnosed less than 3 months prior to or at Screening Visit 1 OR
• Uncontrolled life threatening arrythmia within 3 months prior to or at Screening Visit 1).
7. Participants who have known, pre-existing, clinically significant cardiac, 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. Evidence of clinically significant abnormality in the haematological, biochemical or urinalysis screen at Visit 1, as judged by the investigator.
9. Infectious disease: Chronic or ongoing active infectious disease requiring systemic treatment.
10. Participants with a known, pre-existing parasitic infestation within 6 months prior to Screening Visit 1.
11. A known immunodeficiency (e.g. HIV), other than that explained by the use of OCS or other immunosuppressants taken as therapy for EGPA.
12. COVID-19: Participants that, according to the investigator's medical judgment, are likely to have active COVID-19 infection. Participants with known COVID-19 positive contacts within the past 14 days must be excluded for at least 14 days following the exposure during which the participant must remain symptom-free.
13. Hypersensitivity: Participants with a known allergy or intolerance to a monoclonal antibody or biologic therapy or any of the excipients of the investigational products listed in Section 6.1.
14. Monoclonal antibodies targeting IL-5/5R: Participants who have a previous documented failure with anti-IL-5/5R therapy.
15. Investigational Medications/clinical study:
• Participants who have received treatment with investigational drug within the past 30 days or 5 terminal phase half-lives of the drug whichever is longer, prior to Visit 1 (this also includes investigational formulations of marketed products).
• Participants who are currently participating in any other interventional clinical study.
16. Participants receiving other prohibited medications
17. Previous participation in any study with mepolizumab, reslizumab, or benralizumab and received study intervention (including placebo) within 6 months prior to Screening Visit 1.
18. ECG Assessment: QTcF ≥450 msec or QTcF ≥480 msec for participants with Bundle Branch Block at Screening Visit 1.
19. Alcohol/Substance Abuse
20. Pregnancy
21. Participants who have known evidence of lack of adherence to controller medications and/or ability to follow physician’s recommendations. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Remission (i.e., a Birmingham Vasculitis Activity Score (BVAS)=0 and a dose of oral corticosteroids (OCS) ≤4mg/day) at both Week 36 and Week 52 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Defined within the primary endpoint description |
|
| E.5.2 | Secondary end point(s) |
• Total accrued duration of remission, i.e., the accrued number of weeks where BVAS=0 plus OCS dose ≤4 mg /day over the 52-week intervention period categorised as zero weeks; >0 to <12 weeks; 12 to <24 weeks; 24 to <36 weeks or ≥36 weeks
• Total accrued duration of remission, i.e., the accrued number of weeks where BVAS=0 plus OCS dose ≤4 mg /day over the 52-week intervention period
• Time to first EGPA relapse
• Mean OCS dose during the last 4 weeks of the study treatment period (Weeks 49 to 52) categorised as 0, >0 to ≤4, >4 to ≤7.5 or >7.5 mg/day
• Remission (BVAS=0 and OCS ≤4mg/day) within the first 24 weeks with continued remission until Week 52
• Remission using the European League against Rheumatism (EULAR) definition; BVAS=0 and OCS ≤7.5 mg/day at both Week 36 and Week 52
• Total accrued duration of remission according to the EULAR definition of remission, i.e., the accrued number of weeks where BVAS=0 plus OCS≤7.5 mg/day over the 52-week intervention period categorised as zero weeks; >0 to <12 weeks; 12 to <24 weeks; 24 to <36 weeks or ≥36 weeks
• Total accrued duration of remission according to the EULAR definition of remission, i.e., the accrued number of weeks where BVAS=0 plus OCS ≤7.5 mg/day over the 52-week intervention period
• Remission (BVAS=0 and OCS ≤7.5 mg/day) within the first 24 weeks with continued remission until Week 52 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Defined within the secondary endpoints description |
|
| 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Double-dummy and non-inferiority study |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| 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 |
| Australia |
| Brazil |
| Canada |
| China |
| Israel |
| Japan |
| Korea, Republic of |
| United States |
| Austria |
| Finland |
| France |
| Poland |
| Sweden |
| Netherlands |
| Spain |
| Czechia |
| Germany |
| Italy |
| Belgium |
| Russian Federation |
| United Kingdom |
|
| 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
|
|
| 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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