IgA Nephropathy, Immunoglobulin A Nephropathy
Conditions
Keywords
Kidney Diseases, Kidney Disease, Chronic, Urologic Diseases, Glomerulonephritis, Glomerular Disease, Glomerulonephritis, IGA, Glomerulopathy, Immunoglobulin Disease
Brief summary
The ALIGN Study is a phase 3, double-blind, placebo-controlled study to compare the efficacy and safety of atrasentan to placebo in patients with IgA nephropathy (IgAN) at risk of progressive loss of renal function.
Detailed description
Approximately 320 patients with biopsy-proven IgAN will be randomized to receive 0.75 mg atrasentan or placebo daily for 132 weeks. Subjects receive a maximally tolerated and stable dose of a RAS (renin-angiotensin system) inhibitor \[such as angiotensin converting enzyme inhibitor (ACEi) or angiotensin-receptor antagonist (ARB)\] as part of standard of care. An exception will be made for subjects who are unable to tolerate RAS inhibitor therapy. Additional subjects receiving a stable dose of SGLT2i will be enrolled to the study. Enrollment in this SGLT2i stable stratum will be in accordance with local regulations in regions that prescribe SGLT2i and will be independent of the 320 subjects enrolled for the primary and secondary analyses. The primary objective of the study is to evaluate the effect of atrasentan versus placebo on proteinuria as measured by UPCR. Secondary and tertiary objectives include evaluating the change in kidney function over time as measured by eGFR, safety and tolerability. Subjects will have assessments of safety and efficacy over 2 ½ years. To facilitate study participation over this time period, where allowed by local regulations, options for remote study visits using telemedicine and home health may be offered. Subjects who complete treatment through Week 132 and complete the double-blinded portion of the study may be eligible to enroll in the open label (OL) extension of the study to receive atrasentan 0.75 mg daily for up to 48 weeks. Subjects who complete the 48 weeks of atrasentan treatment in OL extension or who are treated with atrasentan long enough to sufficiently determine its efficacy as per clinical judgement of the Principal Investigator may be optionally re-evaluated for eligibility to participate in the substudy if available at their clinical site. Eligible subjects following re-evaluation may enter the co-administration treatment phase, receiving atrasentan 0.75 mg orally once daily plus zigakibart for 48 weeks.
Interventions
DRUGAtrasentan
Film-coated tablet
DRUGPlacebo
Film-coated tablet
DRUGZigakibart
pre-filled syringes with needle safety device
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Double-blind
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Double-Blind period: * Biopsy-proven IgA nephropathy. * Receiving a maximally tolerated dose of RAS inhibitor therapy (ACEi or ARB) that has been stable for at least 12 weeks. Exceptions from this requirement will be made for subjects who are unable to tolerate RAS inhibitor therapy. * Total urine protein ≥1 g/day as measured via 24-hour urine collection by central laboratory at Screening. * eGFR of at least 30 mL/min/1.73 m\^2 at Screening based on the CKD-EPI equation. * Willing and able to provide informed consent and comply with all study requirements. * SGLT2i Stable Stratum Only - Receiving a stable dose of an SGLT2i (per Investigator choice) in addition to a maximally tolerated and optimized dose of a RAS inhibitor that has been stable for at least 12 weeks prior to Screening. * All fertile men and WOCBP who engage in heterosexual intercourse must be willing to abide with highly effective forms of contraception, as specified in the protocol, throughout the study and for 1 month afterward. In WOCBP, use of contraceptive agents must have been started at least 1 month prior to Baseline. Open-Label Period: * Willing and able to provide informed consent and comply with all OL extension study visits and study procedures. * Completed treatment through Week 132 and completed the Week 136 visit. * All fertile men and WOCBP who engage in heterosexual intercourse must be willing to abide with highly effective forms of contraception, as specified in the protocol, throughout the study and for 1 month afterward. In WOCBP, use of contraceptive agents must have been continued after completing the double-blind portion of the study. Substudy: Subjects must meet ALL inclusion criteria to be enrolled. * Subjects who provided written informed consent prior to initiation of any substudy-specific activities/procedures and are willing to comply with all substudy visits and substudy procedures. * Completion of OL extension treatment through Week 48 visit or treated with atrasentan long enough to sufficiently determine its efficacy as per clinical judgement of the Principal Investigator. * Stable on a maximally tolerated dose of ACEi and/or ARB for at least 12 weeks prior to substudy screening visit. * All fertile men and WOCBP who engage in heterosexual intercourse must be willing to abide with highly effective forms of contraception, as specified in the protocol
Exclusion criteria
Double-blind period: * Concurrent diagnosis of another cause of chronic kidney disease including diabetic kidney disease or another primary glomerulopathy. * Clinical diagnosis of nephrotic syndrome. * BNP value of \> 200 pg/mL at Screening. * Platelet count \<80,000 per μL at Screening. * History of organ transplantation (subjects with history of corneal transplant are not excluded). * Use of systemic immunosuppressant medications. * Hemoglobin below 9 g/dL at Screening or prior history of blood transfusion for anemia within 3 months of Screening. Open-label period: * eGFR \< 25 mL/min/1.73m\^2 or evidence of rapidly decreasing eGFR, including unrecovered acute kidney injury or expected to require renal replacement therapy within 3 months * BNP value of \> 200 pg/mL at OL Screening. * Platelet count \< 80,000 per μL at OL Screening. * Hemoglobin below 9 g/dL at OL screening or prior history of blood transfusion for anemia within 3 months of OL Screening. Substudy: Subjects must meet NONE of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Double-blind period: Change in proteinuria | Up to Week 36 or approximately 9 months | The change in urine protein:creatinine ratio (UPCR) from baseline to Week 36. (non-SGLT2i stratum) |
| Open-label period: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) | From open-label baseline up to end of treatment visit, up to 48 weeks | Type, incidence, severity, seriousness, and relatedness of TEAEs. |
| Open-label period: Number of Subjects With Adverse Events of Special Interest (AESI) Including Events of Fluid Overload | From open-label baseline up to end of treatment visit, up to 48 weeks | Incidence, severity, seriousness, and relatedness AESIs. |
| Substudy period: Number of subjects with TEAEs | From substudy baseline to end of treatment, up to 48 weeks | Type, incidence, severity, seriousness, and relatedness of TEAEs |
| Substudy period: Number of subjects with AESI | From substudy baseline to end of treatment, up to 48 weeks | Incidence, severity, seriousness, and relatedness AESIs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Double-blind period: Change in eGFR | Up to Week 136, 4 weeks post end of treatment | Change from Baseline to final study visit (Week 136, 4 weeks post end of treatment) using the chronic kidney disease-epidemiology collaboration (CKD-EPI) creatinine equation (non-SGLT2i stratum) |
| Double-blind period: Percent of subjects meeting the first composite endpoint | Up to approximately 2.6 years | Percent of subjects in the non-SGLT2i stratum meeting the composite endpoint of experiencing at least one of the following during the study: * At least a 30% reduction in eGFR sustained for at least 30 days * eGFR \<15 mL/min/1.73m\^2, sustained for at least 30 days * Chronic dialysis ≥30 days * Kidney transplantation * All-cause mortality |
| Double-blind period: Percent of subjects meeting the second composite endpoint | Up to approximately 2.6 years | Percent of subjects in the non-SGLT2i stratum meeting the composite endpoint of experiencing at least one of the following during the study: * At least a 40% reduction in eGFR sustained for at least 30 days * eGFR \<15 mL/min/1.73m\^2, sustained for at least 30 days * Chronic dialysis ≥30 days * Kidney transplantation * All-cause mortality |
| Double-blind period: Percent of subjects achieving reduction of proteinuria to < 1 g/day at Week 36 | Baseline to Week 36 | Percentage of subjects with reduction of proteinuria to \< 1 g/day and a 25% decrease in total urine protein from Baseline (non-SGLT2i stratum). |
| Double-blind period: Number of Subjects With TEAEs | From first dose of study drug up to 4 weeks post end of treatment in double-blind period, 136 weeks | Type, incidence, severity, seriousness, and relatedness of TEAEs. |
| Double-blind period: Number of Subjects With AESI Including Events of Fluid Overload | From first dose of study drug up to 4 weeks post end of treatment in double-blind period, 136 weeks | Incidence, severity, seriousness, and relatedness AESIs. |
| Open-label period: Change in proteinuria | Open-label Baseline to open-label Week 36 | Change in UPCR based on 24-hour urine collection. |
| Open-label period: Change in eGFR | Open-label Baseline to open-label Week 52 | Change from open-label Baseline to open-label Week 52 using the CKD-EPI creatinine equation. |
Countries
Argentina, Australia, Brazil, Canada, China, Colombia, France, Germany, Hong Kong, India, Italy, Japan, New Zealand, Poland, Portugal, South Korea, Spain, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Outcome results
None listed