Atrasentan in Patients With IgA Nephropathy

Study Overview
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Brief Summary
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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
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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, as well as quality of life. 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 the study may be eligible to enroll in an extension study to receive open-label treatment with atrasentan under a separate protocol.

Official Title
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A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Atrasentan in Patients With IgA Nephropathy at Risk of Progressive Loss of Renal Function

Conditions
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IgA Nephropathy, Immunoglobulin A Nephropathy

Intervention / Treatment
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* Drug: Atrasentan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 m2 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. Exclusion Criteria: Current diagnosis with another chronic kidney disease, including diabetic kidney disease. History of kidney transplantation or other organ transplantation. Use of systemic immunosuppressant medications, such as steroids, for more than 2 weeks in the past 3 months. Blood pressure above 150 mmHg systolic or 95 mmHg diastolic as evaluated by the Investigator. Known history of heart failure or a previous hospital admission for fluid overload. Clinically significant history of liver disease as assessed by the Investigator. Hemoglobin below 9 g/dL as measured by the Investigator or prior history of blood transfusion for anemia within the past 3 months. Malignancy within the past 5 years. Exceptions to this criteria include nonmelanoma skin cancer and curatively treated cervical carcinoma in situ. For women, pregnancy, breast feeding, or intent to become pregnant during the study. and at least 1 month afterward. For men, intent to father a child or donate sperm during the study. Have received any investigational agent or approved treatment for IgAN (other than a RAS inhibitor) including SGLT2i (except for subjects in the SGLT2i stable stratum) within 1 month (or 5 half-lives of the agent, whichever is longer) prior to Screening. If the investigational agent is a cytotoxic or immunosuppressive agent then this washout period is 6 months.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atrasentan<br>Once daily oral administration of 0.75 mg atrasentan for 132 weeks | Drug: Atrasentan<br>* Film-coated tablet<br>* Other names: ABT-627;|
| Placebo Comparator: Placebo<br>Once daily oral administration of placebo for 132 weeks | Drug: Placebo<br>* Film-coated tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in proteinuria | The change in urine protein:creatinine ratio (UPCR) from baseline to Week 24. (non-SGLT2i stratum) | Up to Week 24 or approximately 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in eGFR | Change from baseline to end of study in eGFR. | Up to approximately 2.6 years | 
| Percent of subjects meeting the first composite endpoint | 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/1.73m2, sustained for at least 30 days Chronic dialysis ≥30 days Kidney transplantation All-cause mortality | Up to approximately 2.6 years | 
| Percent of subjects meeting the second composite endpoint | 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/1.73m2, sustained for at least 30 days Chronic dialysis ≥30 days Kidney transplantation All-cause mortality | Up to approximately 2.6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kidney Diseases, Kidney Disease, Chronic, Urologic Diseases, Glomerulonephritis, Glomerular Disease, Glomerulonephritis, IGA, Glomerulopathy, Immunoglobulin Disease