Immunoglobulin A Nephropathy (IgAN)
Conditions
Keywords
zigakibart, FUB523, anit-APRIL, SHIFT, IgA nephropathy, IgAN, proteinuria, kidney, biopsy, adults
Brief summary
The purpose of the study is to assess the effect of zigakibart on IgA nephropathy (IgAN) disease progression.
Detailed description
This is an open-label multicenter study where participants are randomized into one of two groups, where the only difference between the groups is the on-treatment biopsy time point, end of the first year of treatment (Group A) or at the end of the second year of treatment (Group B). The total study duration for each participant may be up to 125 weeks, including the maximum screening period (8 weeks), the treatment period (104 weeks), and the safety follow up period (13 weeks).
Interventions
BIOLOGICALzigakibart
zigakibart 600 mg sc injections every second week for 104 weeks (2 years)
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants will be randomly assigned in a ratio of 1:1 to undergo the on-treatment biopsy at one of two possible timepoints
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Primary IgAN, confirmed by kidney biopsy, within 5 years prior to Screening * eGFR ≥45 mL/min/1.73 m2, based on the 2021 CKD-EPI equation, at Screening * Persistent proteinuria, defined as either * Total Urine Protein ≥0.5 g/day or UPCR ≥0.5 g/g in a 24-hour urine collection, at Screening, despite maximally tolerated dose or poorly tolerated supportive therapy or * IgAN diagnosis \<6 months prior to Screening with Total Urine Protein \>1.5 g/day or UPCR \>1.5 g/g in a 24-hour urine collection, at the time of clinical presentation or diagnosis * Body weight ≥45 kg and body mass index (BMI) ≤35.0 kg/m2, at Screening
Exclusion criteria
* Secondary forms of IgAN, as determined by the Investigator, diagnosis of IgA vasculitis, or any other nephropathy or chronic urinary tract disorder * Total IgG \<6.0 g/L at screening * Any chronic urinary tract disorder, including but not limited to retention, incontinence, and/or recurrent urinary tract infections * An average systolic blood pressure \>150 mmHg or average diastolic blood pressure \>90 mmHg based on three measurements at Screening * Treatment with complement pathway inhibitors, mycophenolic acids, systemic calcineurin inhibitors or corticosteroids, immunosuppressive or immunomodulatory agents within 12 months prior to screening * Acute kidney injury (AKI), defined by AKI network criteria, within 4 weeks prior to screening * Current treatment with anti-APRIL monoclonal antibodies or dual APRIL/BAFF inhibitors or past treatment of the same at any time for \>3 consecutive months prior to screening * Planned initiation of, or recently (within 24 weeks) initiated, treatment with glucagon-like peptide-1 agonists at screening Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in mesangial IgA deposition | Baseline to Week 53 or 105 | Change in mesangial IgA deposition as assessed by intensity of immunofluorescence staining |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Day 1 to Week 118 | Incidence of AEs and SAEs , including changes in vital signs, injection site reactions, laboratory results and Immunoglobulin responses to vaccination qualifying and reported as AEs |
| Change in MEST-C score | Baseline to Week 53 or 105 | Change in MEST-C, a histologic scoring system used to assess disease prognosis in patients with IgA nephropathy, which includes the components mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T), crescents (C). All five components are scored by categorical values as listed below, where a higher score indicates involvement or a relatively greater degree of involvement (i.e., more severe pathology). 1. Mesangial hypercellularity * M0 (present in ≤50% of glomeruli) * M1 (present in \>50% of glomeruli) 2. Endocapillary hypercellularity * E0 (Absent) * E1 (Present) 3. Segmental glomerulosclerosis (more than four mesangial cells) * S0 (Absent) * S1 (Present) 4. Tubular atrophy/interstitial fibrosis * T0 (0-25% of cortical area) * T1 (26-50% of cortical area) * T2 (\>50% of cortical area) 5. Cellular or fibrocellular crescents * C0 (No crescents) * C1 (\>25% of glomeruli) * C2 (≥25% of glomeruli) |
| Change in CD68+ cells in glomeruli and tubulo-interstitial compartment | Baseline to Week 53 or 105 | Change in CD68+ cells, which are markers of inflammation |
| Change in complement component C3c | Baseline to Week 53 or 105 | Change in C3c, which is a marker of complement (part of the immune system) activation |
| Change in UPCR | Baseline to Week 53 and 105 | Change in the ratio of urine protein to urine creatinine (UPCR), based on 24-hour urine collection |
| Change in eGFR | Baseline to Week 53 and 105 | Change in estimated glomerular filtration rate (eGFR) |
| Change in albuminuria | Baseline to Week 53 and 105 | Change in urine albumin - creatinine ratio (UACR), based on 24-hour urine collection |
| Change in hematuria | Baseline to Week 53 and 105 | Change in presence of red blood cells in urine |
| Change in serum IgA, IgM and IgG | Baseline to Week 13, 29, 53, 79 and 105 | Immunoglobulin (IgA, IgG and IgM) levels will be assessed from blood samples |
| Serum zigakibart concentrations | Baseline, Week 13, 29, 66, 79 and 105 | Serum concentration values will be provided |
| Circulating anti-zigakibart antibodies | Baseline, Week 13, 29, 66, 79 and 105 | Number of participants with circulating binding and neutralizing anti-drug antibodies (ADA/Nab) in blood will be provided |
Countries
Brazil, China, Czechia, Germany, Italy, Japan, Poland, South Korea, Spain, Taiwan, United States
Contacts
CONTACTNovartis Pharmaceuticals
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Outcome results
None listed