Study of NM8074 in Patients with Anti-Neutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (AAV)

Official title

A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of NM8074 in Patients with Anti-Neutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (AAV)

Overview

This is a Randomized, Double-Blind, Placebo-Controlled Study designed to assess safety, tolerability, and efficacy of NM8074 in AAV patients when used in combination with Standard of Care (SOC) cyclophosphamide/azathioprine or rituximab plus corticosteroids.

Detailed description

The proposed study, NM8074-AAV-501, will initially assign six (6) patients per cohort in a 2-cohort trial. In the first cohort, we will evaluate a biweekly dosing regimen with NM8074 and SOC whereas in the second cohort, we will evaluate placebo with SOC. These studies will assess safety, tolerability, and efficacy of NM8074 in AAV patients when used in combination with SOC cyclophosphamide/azathioprine or rituximab plus corticosteroids.

Interventions

• Drug NM8074
  NM8074 will be administered as an intravenous infusion. In Cohort 1, all subjects will be administered 20 mg/kg of NM8074 intravenously every two weeks for a total of 7 doses from Day 1 to Day 85 of the Treatment Period.
• Drug Placebo
  Saline Placebo will be administered as an intravenous infusion. In Cohort 2, all subjects will be administered saline placebo intravenously every two weeks for a total of 7 doses from Day 1 to Day 85 of the Treatment Period.

Primary outcome measures

• Proportion of subjects achieving disease response at Day 85 defined as BVAS percent decrease of at least 50% from baseline. [Time frame: Up to Study Day 85]

Secondary outcome measures (12)

• Number of patients with ANCA positivity (anti-PR3 and anti-MPO) [Time frame: Up to Study Day 133]
• Change from Baseline or Percent Change from Baseline in BVAS (Birmingham Vasculitis Activity Score) [Time frame: Up to Study Day 133]
• Change from Baseline or Percent Change from Baseline in Vasculitis Damage Index (VDI) [Time frame: Up to Study Day 133]
• Change from Baseline or Percent Change from Baseline in C-reactive protein concentration [Time frame: Up to Study Day 133]
• Proportion of patients requiring rescue glucocorticoid treatment [Time frame: Up to Study Day 133]
• Proportion of patients achieving disease remission on Day 85 defined as BVAS of 0. [Time frame: Up to Study Day 85]
• Percent Change from Baseline in urinary Monocyte Chemoattractant Protein-1 (MCP-1):creatinine ratio [Time frame: Up to Study Day 133]
• proportion of subject achieving renal response at Day 85 [Time frame: Up to Study Day 85]
• Change from Baseline or Percent Change from Baseline in quality of life (QoL) Assessed via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale, Version 4. [Time frame: Up to Study Day 133]
• Change from Baseline or Percent Change from Baseline in Quality of Life (QoL) Assessed via the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 Scale (QLQ- C30), Version 3.0 [Time frame: Up to Study Day 133]
• Change from Baseline or Percent Change from Baseline in Quality of Life (QoL) assessed via EQ-5D-5L [Time frame: Up to Study Day 133]
• Change from Baseline or Percent Change from Baseline in Quality of Life (QoL) assessed via SF-36v2 [Time frame: Up to Study Day 133]

Eligibility criteria

Inclusion criteria

• Clinical diagnosis of granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), or renal limited vasculitis.
• Male and female subjects aged at least 18 years, with newly diagnosed or relapsed Associated Vasculitis (AAV) where treatment with cyclophosphamide or rituximab is needed.
• At least 1 major item, or at least 3 non-major items, or at least the 2 renal items of proteinuria and hematuria on Birmingham Vasculitis Activity Score (BVAS).
• Estimated glomerular filtration rate (eGFR) ≥ 20 mL/ minute.
• Positive ANCA Test: indirect immunofluorescence (IIF) test for P-ANCA or C-ANCA, or positive ELISA test for anti-proteinase-3 (PR3) or anti-myeloperoxidase (MPO) at Screening.
• All patients must be vaccinated prior to dosing with MenACWY Menactra® polysaccharide diphtheria toxoid conjugate vaccination against Neisseria meningitidis serogroups A, C, Y, and W-135. Meningitis B (MenB) meningococcal serogroup B vaccine (Bexsero®) will be administered per local guidelines. If the window of vaccination is short, then patients will be prophylactically treated with appropriate antibiotics. Patients will also be required to have confirmation or administration of vaccination against S. pneumoniae and H. influenzae.
• Willing and able to understand and complete informed consent procedures, including signing and dating the informed consent form (ICF), and complying with the study visit schedule.
• Female partners of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, must have a negative pregnancy test at screening and must agree to use highly effective methods of contraception during dosing and for at least 8 weeks after stopping the investigational drug, and for at least 6 months after the last cyclophosphamide dose (if receiving cyclophosphamide) and at least 12 months after the last rituximab dose (if receiving rituximab).
• Male patients and partners of child-bearing potential must agree to use contraceptives and male patients must agree to refrain from donating sperm for the duration of the study.

Exclusion criteria

• Severe disease as determined by alveolar hemorrhage, hemoptysis, rapid onset mononeuritis multiplex or central nervous system involvement.
• Patients with rapidly progressive glomerulonephritis
• Any other known multi-system autoimmune disease including eosinophilic granulomatosis with polyangiitis (EGPA, Churg Strauss), systemic lupus erythematosus, Immunoglobulin A (lgA) vasculitis (HenochSchönlein purpura), rheumatoid vasculitis, Sjogren's disease, anti
• glomerular basement membrane disease, or cryoglobulinemia.
• Required dialysis or plasma exchange within 12 weeks prior to screening.
• Have a kidney transplant or disease.
• Received cyclophosphamide within 12 weeks prior to screening; if on azathioprine, mycophenolate mofetil or methotrexate at the time of screening, these drugs must be withdrawn prior to receiving the cyclophosphamide or rituximab dose on Day 1.
• Received intravenous glucocorticoids, >3000 mg methylprednisolone equivalent, within 4 weeks prior to screening.
• Have been taking an oral daily dose of a glucocorticoid of more than 10 mg prednisone-equivalent for more than 6 weeks continuously prior to screening.
• Received rituximab or other B-cell antibody within 52 weeks of screening or 26 weeks provided B cell reconstitution has occurred (i.e., Cluster of Differentiation 19 (CD19) count > 0.01x10\^9/L); received anti-tumor necrosis factor (TNF) treatment or other complement inhibitor treatment within 12 weeks prior to screening.
• Currently or previously under other complement inhibitor treatments less than 3 months prior to study Day 1.
• Patients who need the initiation of renal replacement therapy within 7 days
• Have any other clinically significant abnormal laboratory value in the opinion of the investigator.
• History of bone marrow, hematopoietic stem cell, or solid organ transplantation.
• History of currently active primary or secondary immunodeficiency.
• Currently active systemic infection or suspicion of active bacterial, viral, or fungal infection within 2 weeks prior to first dose, or history of unexplained, recurrent bacterial infections.
• Pregnant, planning to become pregnant, or nursing female subjects.
• Females who have a positive pregnancy test result at Screening or on Day 1.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Double blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Tesar V, Hruskova Z. Complement Inhibition in ANCA-Associated Vasculitis. Front Immunol. 2022 Jul 8;13:888816. doi: 10.3389/fimmu.2022.888816. eCollection 2022. PMID 35880179
• Xiao H, Hu P, Falk RJ, Jennette JC. Overview of the Pathogenesis of ANCA-Associated Vasculitis. Kidney Dis (Basel). 2016 Mar;1(4):205-15. doi: 10.1159/000442323. Epub 2015 Dec 3. PMID 27536680
• Chung SA, Langford CA, Maz M, Abril A, Gorelik M, Guyatt G, Archer AM, Conn DL, Full KA, Grayson PC, Ibarra MF, Imundo LF, Kim S, Merkel PA, Rhee RL, Seo P, Stone JH, Sule S, Sundel RP, Vitobaldi OI, Warner A, Byram K, Dua AB, Husainat N, James KE, Kalot MA, Lin YC, Springer JM, Turgunbaev M, Villa-Forte A, Turner AS, Mustafa RA. 2021 American College of Rheumatology/Vasculitis Foundation Guidelin PMID 34235894
• Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021 Oct;100(4S):S1-S276. doi: 10.1016/j.kint.2021.05.021. No abstract available. PMID 34556256
• Hellmich B, Sanchez-Alamo B, Schirmer JH, Berti A, Blockmans D, Cid MC, Holle JU, Hollinger N, Karadag O, Kronbichler A, Little MA, Luqmani RA, Mahr A, Merkel PA, Mohammad AJ, Monti S, Mukhtyar CB, Musial J, Price-Kuehne F, Segelmark M, Teng YKO, Terrier B, Tomasson G, Vaglio A, Vassilopoulos D, Verhoeven P, Jayne D. EULAR recommendations for the management of ANCA-associated vasculitis: 2022 upda PMID 36927642

Identifiers

NCT: NCT06226662 · NM8074-AAV-501

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗