Clinical trial NCT06226662: 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)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Lead sponsor: NovelMed Therapeutics
Sponsor class: INDUSTRY
First posted: 2024-01-26
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Eligible subjects will be enrolled and stratified in three strata: (1) granulomatosis with polyangiitis (GPA) (2) microscopic polyangiitis (MPA), and (3) renal-limited vasculitis, and then randomized in a 1:1 ratio of NM8074+SOC to Placebo+SOC (6 subjects in each cohort).
Primary purpose: TREATMENT

Brief summary: 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.

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.

Primary outcomes:
measure: Proportion of subjects achieving disease response at Day 85 defined as BVAS percent decrease of at least 50% from baseline.
timeFrame: Up to Study Day 85
Secondary outcomes:
measure: Number of patients with ANCA positivity (anti-PR3 and anti-MPO)
timeFrame: Up to Study Day 133
measure: Change from Baseline or Percent Change from Baseline in BVAS (Birmingham Vasculitis Activity Score)
timeFrame: Up to Study Day 133
measure: Change from Baseline or Percent Change from Baseline in Vasculitis Damage Index (VDI)
timeFrame: Up to Study Day 133
measure: Change from Baseline or Percent Change from Baseline in C-reactive protein concentration
timeFrame: Up to Study Day 133
measure: Proportion of patients requiring rescue glucocorticoid treatment
timeFrame: Up to Study Day 133
measure: Proportion of patients achieving disease remission on Day 85 defined as BVAS of 0.
timeFrame: Up to Study Day 85
measure: Percent Change from Baseline in urinary Monocyte Chemoattractant Protein-1 (MCP-1):creatinine ratio
timeFrame: Up to Study Day 133
measure: proportion of subject achieving renal response at Day 85
timeFrame: Up to Study Day 85
measure: 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.
timeFrame: Up to Study Day 133
measure: 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
timeFrame: Up to Study Day 133
measure: Change from Baseline or Percent Change from Baseline in Quality of Life (QoL) assessed via EQ-5D-5L
timeFrame: Up to Study Day 133
measure: Change from Baseline or Percent Change from Baseline in Quality of Life (QoL) assessed via SF-36v2
timeFrame: Up to Study Day 133
Other outcomes:
measure: Change from Baseline or Percent Change from Baseline in Classical Pathway (CP) modulation
timeFrame: Up to Study Day 133
measure: Change from Baseline or Percent Change from Baseline in Factor B levels
timeFrame: Up to Study Day 133
measure: Change from Baseline or Percent Change from Baseline in plasma concentration of NM8074
timeFrame: Up to Study Day 133
measure: Maximum plasma concentration (Cmax)
timeFrame: Up to Study Day 133
measure: Time corresponding to Cmax (tmax)
timeFrame: Up to Study Day 133
measure: Area under the drug concentration-time curves (AUC0-t)
timeFrame: Up to Study Day 133
Locations:
Study officials:
References:
citation: 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.
citation: 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.
citation: 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 Guideline for the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Rheumatol. 2021 Aug;73(8):1366-1383. doi: 10.1002/art.41773. Epub 2021 Jul 8.
citation: 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.
citation: 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 update. Ann Rheum Dis. 2024 Jan 2;83(1):30-47. doi: 10.1136/ard-2022-223764.