A 52-week, randomized, double-blind, double-dummy, parallel-group, multi-centre, non-inferiority study to investigate the efficacy and safety of depemokimab compared with mepolizumab in adults with relapsing or refractory Eosinophilic Granulomatosis with Polyangiitis (EGPA) receiving standard of care (SoC) therapy (OCEAN)
Efficacy and safety of depemokimab compared with mepolizumab in adults with relapsing or refractory Eosinophilic Granulomatosis with Polyangiitis (EGPA) (OCEAN)
Fujii Katsuya
Syneos Health Japan K.K.
12F JP Tower, 2-7-2 Marunouchi, Chiyoda-ku, Tokyo
+81-90-9133-2809
Katsuya.fujii@syneoshealth.com
Fujii Katsuya
Syneos Health Japan K.K.
12F JP Tower, 2-7-2 Marunouchi, Chiyoda-ku, Tokyo
+81-90-9133-2809
Katsuya.fujii@syneoshealth.com
Recruiting
July. 01, 2022
July. 29, 2022
9
Interventional
randomized controlled trial
double blind
active control
parallel assignment
treatment purpose
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant (male or female) must be 18 years or older at the time of signing the informed consent.
Weight
2. Participants who are >=40 kg at Screening Visit 1.
Type of Participant and Disease Characteristics
3. EGPA diagnosis: Participants with a documented diagnosis of EGPA for at least 6 months based on the history or presence of: asthma plus eosinophilia defined in this study as >1.0x10x9/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 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:
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
NOTE:
- Participants who have received a cyclophosphamide (CYC) induction regimen may be included a minimum of 4 weeks after the last dose of daily oral CYC or pulsed IV CYC prior to Baseline (Visit 2), if their total white blood cells (WBC) is >=4x10x9/L (tested at the local laboratory, if necessary) prior to randomization.
- Participants 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).
- Participants 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
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. NOTE: Recurrent symptoms of EGPA do not necessarily need to meet the protocol definition of relapse.
EGPA standard of care therapy
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) or equivalent 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.
NOTE: dose reductions for safety reasons will be permitted.
Sex and Contraceptive/Barrier Requirements
Male or eligible female participants:
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)
OR
- 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):
30 weeks after the last potential administration of depemokimab at Week 1 or Week 26,
16 weeks after the last potential administration of mepolizumab (remaining administrations).
- A WOCBP must have a negative highly sensitive serum pregnancy test at Screening Visit 1 and a negative highly sensitive urine pregnancy test within 24 hours before the first dose of study intervention.
If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
- Additional requirements for pregnancy testing during and after study intervention
- Contraceptive use by WOCBP should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
- The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention).
- The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
Informed Consent
8. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the 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.
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. GPA or MPA: Diagnosed with granulomatosis with polyangiitis (GPA; previously known as Wegeners 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 mg/dL (>513 micro mol/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).
- 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-hour period due to alveolar haemorrhage
- Rapidly progressive glomerulonephritis (RPGN) with creatinine >2.5 mg/dL (>221 micro mol/L) or rise in creatinine >2 mg/dL (>177 micro mol/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. Malignancy: A current malignancy or previous history of cancer in remission for less than 12 months prior to screening. Participants that had localised carcinoma (i.e., basal or squamous cell) 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.
NOTE: Stable non-cirrhotic chronic liver disease (including Gilberts syndrome, asymptomatic gallstones, and chronic stable hepatitis B or C), are acceptable if participant otherwise meets entry criteria.
6. Cardiovascular: 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. Other Concurrent Medical Conditions: 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. Laboratory abnormality: 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. Parasitic infection: Participants with a known, pre-existing parasitic infestation within 6 months prior to Screening Visit 1.
11. Immunodeficiency: A known immunodeficiency (e.g. human immunodeficiency virus-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.
Prior/Concomitant Therapy
14. Monoclonal antibodies
- Monoclonal antibodies targeting IL-5/5R: Participants who have a previous documented failure with anti-IL-5/5R therapy, (e.g., mepolizumab, reslizumab benralizumab), based on investigators discretion.
- Participants who have received mAb who have not undergone the required washout periods, prior to Visit 1.
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 clinicalstudy.
NOTE: Any COVID-19 vaccine or treatment (including mAbs) approved by local government is permitted.
Experimental COVID-19 vaccines/treatment are not permitted.
16. Other prohibited medications: Participants receiving any of the following:
- Oral corticosteroids: Participant requires an oral corticosteroid dose of >50 mg/day prednisolone/prednisone in the 4-week period prior to Baseline (Visit 2)
- Intravenous, intramuscular 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 4 weeks prior to Baseline (Visit 2) and IV CYC within 3 weeks prior to Baseline (Visit 2), if their total WBC is >=4x10x9/L (measured using the local laboratory if necessary)
- Rituximab within 6 months prior to Screening (Visit 1); in addition, the Participant must have shown recovery of peripheral B-cell count to within the normal range
- Tezepelumab with a washout of 5 half-lives prior to Screening Visit 1
- Dupilumab with a washout of 5 half-lives prior to Screening Visit 1
- IV or SC immunoglobulin within 6 months prior to Screening (Visit 1); For China and Japan only within 12 weeks 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
Prior/Concurrent Clinical Study Experience
17. Previous participation: Previously participated in any study with mepolizumab, reslizumab, or benralizumab and received study intervention (including placebo) within 6 months prior to Screening Visit 1.
Diagnostic Assessments
18. ECG Assessment: QTcF >=450 msec or QTcF >=480 msec for participants with Bundle Branch Block in the 12-lead ECG central over-read from Screening Visit 1.
Other Exclusions
19. Alcohol/Substance Abuse: A history (or suspected history) of alcohol misuse or substance abuse within 2 years prior to Visit 1.
20. Pregnancy: Participants who are pregnant or breastfeeding. Participants should not be enrolled if they plan to become pregnant during the time of study participation.
21. Adherence: Participants who have known evidence of lack of adherence to controller medications and/or ability to follow physicians recommendations.
18age 0month 0week old over
No limit
Both
Eosinophilic granulomatosis with polyangiitis for which Standard of care is insufficient.
depemokimab Arm: 200 mg depemokimab administered as 2x100 mg SC injections every 26 weeks and mepolizumab administered as placebo SC injections every 4 weeks.
mepolizumab Arm: 300 mg mepolizumab administered as 3x100 mg SC injections every 4 weeks and depemokimab administered as placebo SC injections every 26 weeks
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
