Clinical trial NCT06230354: Explore the Efficacy and Mechanism of Action of Tezepelumab in Eosinophilic Granulomatosis With Polyangiitis
Official title: A RAndomised Placebo Controlled Trial - to Explore the Efficacy and Mechanism of Action of Tezepelumab in Eosinophilic Granulomatosis With Polyangiitis
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: PHASE2
Conditions: EGPA - Eosinophilic Granulomatosis With Polyangiitis
Keywords: EGPA
Eosinophilic granulomatosis with polyangiitis
Tezepelumab
Mechanism
Alarmin
Vasculitis
Experimental Medicine
Lead sponsor: Imperial College London
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2024-01-30
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RACEMATE is a phase 2b, multicentre, randomised, double-blinded, placebo-controlled study designed to explore the efficacy and mechanism of action of tezepelumab in adults with eosinophilic granulomatosis with polyangiitis (EGPA).

Detailed description: RACEMATE is a randomised double-blind placebo-controlled experimental medicine study designed to explore both the efficacy and mechanism of action of tezepelumab (210 milligram \[mg\] administered subcutaneously \[SC\] every 4 weeks) compared with placebo over a 24-week study treatment period in subjects with active (non-severe) Eosinophilic Granulomatosis with Polyangiitis (EGPA) receiving standard of care therapy including background corticosteroid therapy with or without immunomodulatory therapy. This study will take place across 16 centres in the United Kingdom. Corticosteroid dose will be tapered during the treatment period in accordance with standard of care.

The key outcome of this study focuses on evaluation of clinical remission, defined as a Birmingham Vasculitis Activity Score (BVAS) version 3 of 0 and receipt of prednisolone ≤ 4mg daily and no receipt of oral corticosteroids above baseline during the treatment period. Secondary outcomes will include reduction in disease flare, improvement in scores for asthma control, sino-nasal disease and spirometry amongst others.

Eligibility criteria: Inclusion Criteria:

1. Capable of providing written informed consent
2. Eosinophilic granulomatosis with polyangiitis is defined as a history of asthma, a blood eosinophil level of 10% or an absolute eosinophil count of more than 1.0 x10\^9/L, and the presence of two or more criteria:

   - Histopathological evidence of eosinophilic vasculitis

   - Perivascular eosinophilic infiltration, or eosinophil-rich granulomatous inflammation

   - Neuropathy

   - Pulmonary infiltrate
   * Sino-nasal abnormality
   * Cardiomyopathy
   * Glomerulonephritis
   * Alveolar haemorrhage
   * Palpable purpura
   * Anti-neutrophil cytoplasmic antibody \[ANCA\] positivity
3. History of one or more flares of EGPA in 24 months prior to screening. EGPA flares will be defined as worsening or persistence of active disease characterised by:

   - Active vasculitis (BVAS \>0); OR

   - An asthma exacerbation/asthma worsening OR

   - Active nasal and/or sinus disease

   Warranting:

   - Rescue use of prednisolone for 3 or more days OR an increase in background prednisolone dose by at least 5 mg daily for at least three days OR

   - An increased dose or addition of immunosuppressive therapy; OR
   * Hospitalisation related to EGPA worsening
4. Blood eosinophil level at screening (visit 1) of ≥ 0.2 x10\^9/L (participants can be re screened once within 2 weeks if the BEC is \< 0.2 x10\^9/L at the initial screening assessment).

   n.b. This criterion is not relevant for participants taking background anti-IL-5/5R biological agents mepolizumab (MEPO) or benralizumab (BRZ) in which any baseline blood eosinophil count (BEC) permitted.
5. Non severe EGPA according to the American College of Rheumatology 2021 definition.

Non-Severe EGPA: Vasculitis without life- or organ-threatening manifestations (e.g., rhinosinusitis, asthma, mild systemic symptoms, uncomplicated cutaneous disease, mild inflammatory arthritis).

6. Stable dose of prednisolone (≥5.0 to ≤30.0 mg per day, with or without additional Immunomodulatory therapy) for at least 4 weeks before the baseline visit.

7. Immunomodulatory therapy:

(i) If receiving non-biologic immunomodulatory therapy, the dosage must be stable for the 4 weeks prior to baseline visit.

(ii) Patients on background anti-IL-5/5R therapy (either MEPO or BRZ) at any licensed dose for the current clinical indications of severe asthma and EGPA in the UK and Europe respectively AND have been on treatment for at least 6 months.

n.b. participants on background anti-IL-5/5R therapy will be capped to no more than 50% of the total sample size.

Exclusion Criteria:

1. Diagnosis of Granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA).
2. Pregnancy or unable to use a highly effective method of birth control (confirmed by the Investigator) from randomisation throughout the study duration and within 8 weeks after last dose of IMP.
3. Active life- or organ-threatening manifestations of EGPA within 6 months prior to screening, defined as:

   * Severe alveolar haemorrhage
   * Rapidly progressive glomerulonephritis
   * Severe gastrointestinal or central nervous system involvement requiring intensification of immunosuppression or surgery
   * Severe cardiac involvement including life threatening arrhythmia, heart failure with an ejection fraction \< 20% or acute myocardial infarction or active myocarditis
4. Current active malignancy.
5. Immunodeficiency including HIV
6. Helminth infection within 6-months of screening that has not been treated or remains refractory to treatment.
7. Unstable liver disease with the exception of Gilberts syndrome or asymptomatic gallstones.
8. Use of a prohibited concurrent medication as listed below:

   * Biologic therapy for severe asthma (except MEPO or BRZ) within 4 months or 5 half-lives (whichever is longer) prior to Visit 1 or receipt of any investigational non-biologic agent within 30 days or 5 half-lives (whichever is longest) prior to Visit 1.
   * Biologic therapies for EGPA including Rituximab and Alemtuzumab within 6 months of visit 1.
   * IV or SC immunoglobulin therapy within 3 months of visit 1.
   * Oral cyclophosphamide within 6 weeks of screening or IV cyclophosphamide within 4 months of visit 1.
   * IM or IV corticosteroids within 6 weeks of visit 1.
9. Known adrenal insufficiency (primary or secondary), that in the opinion of the investigator and clinical care team preclude maintenance oral steroid tapering

Primary outcomes:
measure: Proportion of participants who are in remission at week 24
timeFrame: Week 24
Secondary outcomes:
measure: Time to first EGPA flare
timeFrame: Up to Week 24
measure: Total accrued duration of remission
timeFrame: Up to Week 24
measure: Proportion of participants that demonstrate sustained remission
timeFrame: Up to Week 24
measure: Proportion of participants that tapered mOCS by at least 2.5 mg/day
timeFrame: Up to Week 24
measure: Change in SinoNasal Outcome Test-22 (SNOT-22)
timeFrame: Between Week 0 and/or Week 12 and Week 24
measure: Change in European Quality of Life 5 Dimensions 5 Level (EuroQoL-5D-5L)
timeFrame: Up to Week 24
measure: Change in Juniper 6-item Asthma Control Questionnaire (ACQ-6)
timeFrame: Between Week 0 and/or Week 12 and Week 24
measure: Change in blood eosinophil level
timeFrame: Between Week 0 and/or Week 12 and Week 24
measure: Change in spirometry
timeFrame: Between Week 0 and/or Week 12 and Week 24
measure: Change in FeNO
timeFrame: Between Week 0 and/or Week 12 and Week 24
measure: Change in eGFR
timeFrame: Between Week 0 and/or Week 12 and Week 24
Other outcomes:
measure: Glucocorticoid-induced toxic effects
timeFrame: Up to Week 24
measure: EGPA flare type
timeFrame: Up to Week 24
measure: Change in nEPX
timeFrame: Between Week 0 and/or Week 12 and Week 24
measure: Change in uACR
timeFrame: Between Week 0 and/or Week 12 and Week 24
measure: Change in ANCA
timeFrame: Between Week 0 and/or Week 12 and Week 24
Locations:
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary - NHS Grampian
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
city: Leicester
country: United Kingdom
facility: University Hospitals of Leicester NHS Trust
city: Liverpool
country: United Kingdom
facility: Liverpool University Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: Barts Health NHS Trust
city: London
country: United Kingdom
facility: Royal Free London NHS Trust
city: London
country: United Kingdom
facility: Guy's Hospital - Guy's and St Thomas' NHS Foundation Trust
city: London
country: United Kingdom
facility: Royal Brompton Hospital - Guy's and St Thomas' NHS Foundation Trust
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
city: Manchester
country: United Kingdom
facility: Manchester University NHS Foundation Trust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Foundation Trust
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust
Study officials:
affiliation: Imperial College London
name: Salman Siddiqui, MBBS
role: PRINCIPAL_INVESTIGATOR
References: