Randomized, Double-blind, Placebo-controlled, Crossover Study of Atrasentan in Subjects With IgA Nephropathy

Study Overview
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Brief Summary
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The ASSIST study is a phase 2, double-blind, placebo-controlled crossover study to evaluate the safety and efficacy of atrasentan vs. placebo in subjects with IgA nephropathy (IgAN) while on background standard of care therapy and an SGLT2 inhibitor (SGLT2i).

Detailed Description
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Approximately 52 patients with biopsy-proven IgAN on a background SGLT2i and a maximally tolerated and stable dose of a renin-angiotensin system (RAS) inhibitor [such as angiotensin converting enzyme inhibitor (ACEi) or angiotensin-receptor antagonist (ARB)] as part of standard of care, will be randomized to either sequence AB or sequence BA in which they will receive 0.75 mg atrasentan once daily during one period (period A), complete a 12-week washout period, and then receive matching placebo during the other period (period B) as determined by the randomization schema. Subjects who are not on background SGLT2i therapy must be willing to undergo a run-in period of 8 weeks with an SGLT2i. The primary objective of the study is to evaluate the efficacy of atrasentan vs. placebo while on background therapy with SGLT2i. Subjects will have safety and efficacy assessments for 1 year (52 weeks).

Official Title
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A Randomized, Double-blind, Placebo-controlled, Crossover Study of Atrasentan in Subjects With IgA Nephropathy on Sodium-glucose Cotransporter-2 Inhibitors (SGLT2i)

Conditions
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IgA Nephropathy, Immunoglobulin A Nephropathy

Intervention / Treatment
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* Drug: Atrasentan
* Drug: Atrasentan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects aged 18 and older at the time of signing the informed consent form (ICF) prior to initiation of any study specific activities/procedures. Biopsy-proven IgA nephropathy. Receiving a maximally tolerated and stable dose of RAS inhibitor therapy (ACEi or ARB) for at least 12 weeks prior to screening. Investigator discretion should be used in determining maximally tolerated and stable dose. eGFR of at least 30 mL/min/1.73 m2 at screening based on the CKD-EPI equation. Willing to agree to highly effective forms of contraception, as specified in the protocol, throughout the study and for up to 1 month afterward. In WOCBP, use of hormonal contraceptive agents must have been started at least 1 month prior to baseline. Willing and able to provide informed consent and comply with all study requirements. Inclusion Criteria for SGLT2i stable subjects Receiving a stable dose of an SGLT2i for at least 8 weeks prior to screening Must have a 24-hour urine protein of >0.5 grams/day. Inclusion Criteria for Run-In Subjects Must have a 24-hour total urine protein of >0.85 grams/day at screening Willing to participate in an 8-week run-in period with an SGLT2i (per Investigator choice) Additional Inclusion Criteria for Run-in Subjects at the end of Run-In Must have completed the 8-week run-in period on a stable and well tolerated dose of an SGLT2i Must have a 24-hour total urine protein of >0.5 grams/day confirmed at the Week -1 Visit Must have an eGFR of ≥ 30 mL/min/1.73 m2 based on the CKD-EPI equation at the Week -1 Visit Receiving treatment with SGLT2i at a stable dose for at least 8 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: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence AB<br>Once daily oral administration of 0.75 mg atrasentan for 12 weeks (Period A) followed by once daily oral administration of placebo for 24 weeks (Period B) | Drug: Atrasentan<br>* Period A (12 Weeks) - Film-coated tablet, Washout Period: 12 weeks, Period B (24 Weeks) - Placebo<br>* Other names: ABT-627;Drug: Placebo<br>* Placebo<br>|
| Experimental: Sequence BA<br>Once daily oral administration of placebo for 12 weeks (Period B) followed by once daily oral administration of 0.75 mg atrasentan for 24 weeks (Period A) | Drug: Atrasentan<br>* Period B (12 Weeks) - Placebo, Washout Period: 12 weeks, Period A (24 Weeks) - Film-coated tablet<br>* Other names: ABT-627;Drug: Placebo<br>* Placebo<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 12 | Up to 12 weeks or approximately 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in proteinuria at 24 weeks of treatment | The change in UPCR from baseline to Week 24 | 24 weeks or approximately 6 months | 

 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