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 ASSIST study was 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
Patients with biopsy-proven IgAN who were on a background SGLT2i and a maximally tolerated and stable dose of a renin-angiotensin system inhibitor (RASi) \[such as angiotensin converting enzyme inhibitor (ACEi) or angiotensin-receptor antagonist (ARB)\] as part of standard of care, were randomized to either sequence Atrasentan/Placebo or sequence Placebo/Atrasentan in which they received 0.75 mg atrasentan once daily during one period (period A), complete a 12-week washout period, and then received matching placebo during the other period (period B) as determined by the randomization schema. Subjects who were not on background SGLT2i therapy would first undergo a run-in period of 8 weeks with an SGLT2i with a 24-hour total urine protein of \> 0.85 grams/day at screening prior to the run-in period and have 24-hour total urine protein of \> 0.5 grams/day at the end of the run-in period to be eligible for randomization. Subjects remained on their maximally tolerated and stable dose of RASi and stable dose of SGLT2i therapies for the duration of the study following randomization. The primary objective of the study was to evaluate the efficacy of atrasentan vs. placebo while on background therapy with SGLT2i.
Interventions
DRUGAtrasentan
Period A (12 Weeks) - Film-coated tablet, Washout Period: 12 weeks, Period B (24 Weeks) - Placebo
DRUGPlacebo
Placebo
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Double-blind
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Legal adults (per local and country specifications) ≥ 18 years of age 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 a RASi for at least 12 weeks prior to screening. Investigator discretion should be used in determining maximally tolerated and optimized dose. * eGFR of at least 30 mL/min/1.73 m\^2 at screening based on the 2021 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 Run-in Week 8 visit. * Must have an eGFR of ≥ 30 mL/min/1.73 m\^2 based on the CKD-EPI equation at their Run-in Week 8 visit.
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 prior hospital admissions for conditions relating to fluid overload that in the opinion of the Principal Investigator or Sponsor might confound the results of the study or pose additional risk to the participant by their participation in the study. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Proteinuria (UPCR From a 24-Hour Urine Collection) From Baseline to Week 12 | From Baseline to Week 12 | Change in proteinuria from Baseline to Week 12 across both periods between atrasentan versus placebo. Proteinuria was assessed using the urine protein to creatinine ratio (UPCR) measured from a 24-hour urine collection. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Proteinuria (UPCR From a 24-Hour Urine Collection) From Baseline to Week 24 in Treatment Period 2. | From Baseline to Week 24 of Treatment Period 2 | Change in proteinuria from Baseline to Week 24 in Treatment Period 2 between atrasentan versus placebo. Proteinuria was assessed using the urine protein to creatinine ratio (UPCR) measured from a 24-hour urine collection. |
| Number of Subjects With TEAE and TEAESI | From first dose of study treatment until end of study, up to 60 weeks | Number of Subjects With Treatment-Emergent Adverse Events (TEAE) and Treatment-Emergent Adverse Events of Special Interest (TEAESI). Severity assessment of AEs was based on CTCAE (Common Terminology Criteria for Adverse Events). |
| Plasma Concentration of Atrasentan | Treatment Period 1: Pre-dose on Weeks 2, 6 and 12; Treatment Period 2: Pre-dose on Weeks 2, 6, 12 and 24 | Blood samples were collected for the measurement of plasma concentrations of atrasentan. |
Countries
Australia, Brazil, Malaysia, South Korea, Spain, United States
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Participant flow
Pre-assignment details
The screening period was up to 6 weeks, during which participants had to meet all eligibility criteria to continue in the study. If a participant who was not on a stable dose of SGLT2i met all screening eligibility criteria, they entered the 8-week Run-In Period.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 49 Participants |
| Age, Continuous | 52.2 years STANDARD_DEVIATION 11.43 |
| Race/Ethnicity, Customized Asian | 10 Participants |
| Race/Ethnicity, Customized Multiple | 2 Participants |
| Race/Ethnicity, Customized Not reported | 0 Participants |
| Race/Ethnicity, Customized White | 35 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 54 | 0 / 27 | 0 / 27 | 0 / 54 | 0 / 27 | 0 / 27 | 0 / 54 | 0 / 27 | 0 / 27 | 0 / 54 | 0 / 27 | 0 / 27 | 0 / 54 |
| other Total, other adverse events | 1 / 54 | 11 / 27 | 8 / 27 | 19 / 54 | 7 / 27 | 3 / 27 | 10 / 54 | 13 / 27 | 5 / 27 | 18 / 54 | 0 / 27 | 0 / 27 | 0 / 54 |
| serious Total, serious adverse events | 0 / 54 | 0 / 27 | 0 / 27 | 0 / 54 | 0 / 27 | 0 / 27 | 0 / 54 | 0 / 27 | 1 / 27 | 1 / 54 | 0 / 27 | 0 / 27 | 0 / 54 |
Outcome results
None listed