Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Conditions
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.
Interventions
DRUGNM8074
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.
DRUGPlacebo
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.
Sponsors
NovelMed Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
This is a double-blind study (subjects and on-site medical/nursing staff at the study site are blinded to study drug/dose assignment). The pharmacy staff preparing the investigational products will not be blinded to NM8074 study drug assignment, but all other site staff, including the Investigator, will be blinded. Unblinding should only be considered for the safety of the subject.
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).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Proportion of subjects achieving disease response at Day 85 defined as BVAS percent decrease of at least 50% from baseline. | Up to Study Day 85 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from Baseline or Percent Change from Baseline in C-reactive protein concentration | Up to Study Day 133 | — |
| Percent Change from Baseline in urinary Monocyte Chemoattractant Protein-1 (MCP-1):creatinine ratio | Up to Study Day 133 | — |
| proportion of subject achieving renal response at Day 85 | Up to Study Day 85 | An \>20% increase from baseline to Day 85 in eGFR, A \>30% decrease from baseline to Day 85 in hematuria, A \>30% decrease from baseline to Day 85 in albuminuria |
| 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. | Up to Study Day 133 | The FACIT-fatigue scale is a 13-item patient-reported measure of fatigue with a 7-day recall period. Items are scored on a 0 - 4 response scale ranging from Not at all to Very much so. All items are summed to create a single fatigue score with a range from 0 to 52 with a better quality of life indicated by a higher score. |
| 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 | Up to Study Day 133 | All EORTC QLQ-C30 scales and single-item measures range from 0 to 100. This includes 3 symptom scales (fatigue, pain, nausea and vomiting), 5 functional scales (physical, role, cognitive, emotional, and social), single-item questions addressing symptoms like insomnia, dyspnea, loss of appetite, and others that are commonly reported by cancer patients, and the perceived financial impact of the disease. A higher score is associated with a greater quality of life for global health status. |
| Change from Baseline or Percent Change from Baseline in Quality of Life (QoL) assessed via EQ-5D-5L | Up to Study Day 133 | The EuroQol 5 Dimension 5 Level (EQ-5D-5L) is a self-assessed, health related QoL which measures QoL in a 5-component scale including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The digits for 5 dimensions can be combined in a 5-digit number describing the respondent's health state. |
| Change from Baseline or Percent Change from Baseline in Quality of Life (QoL) assessed via SF-36v2 | Up to Study Day 133 | The Short Form Health Survey version-2.0 (SF-36v2) questionnaire is a short-form health survey that measures each of the following eight health domains: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. Scales are standardized with a scoring algorithm from 0 to 100. |
| Number of patients with ANCA positivity (anti-PR3 and anti-MPO) | Up to Study Day 133 | — |
| Change from Baseline or Percent Change from Baseline in BVAS (Birmingham Vasculitis Activity Score) | Up to Study Day 133 | — |
| Change from Baseline or Percent Change from Baseline in Vasculitis Damage Index (VDI) | Up to Study Day 133 | — |
| Proportion of patients requiring rescue glucocorticoid treatment | Up to Study Day 133 | — |
| Proportion of patients achieving disease remission on Day 85 defined as BVAS of 0. | Up to Study Day 85 | — |
Other
| Measure | Time frame |
|---|---|
| Change from Baseline or Percent Change from Baseline in plasma concentration of NM8074 | Up to Study Day 133 |
| Maximum plasma concentration (Cmax) | Up to Study Day 133 |
| Time corresponding to Cmax (tmax) | Up to Study Day 133 |
| Area under the drug concentration-time curves (AUC0-t) | Up to Study Day 133 |
| Change from Baseline or Percent Change from Baseline in Factor B levels | Up to Study Day 133 |
| Change from Baseline or Percent Change from Baseline in Classical Pathway (CP) modulation | Up to Study Day 133 |
Contacts
Primary ContactRekha Bansal, PhD
Outcome results
None listed