Efficacy and Safety of Atrasentan in Patients with IgA Nephropathy Receiving Sodium-Glucose Cotransporter-2 Inhibitors: A Randomized, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2023-503828-13-00
- Protocol
- CEXV811A12201
- Sponsor
- Novartis Pharma AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of atrasentan compared to placebo in subjects with IgA nephropathy who are on background therapy with sodium-glucose cotransporter-2 inhibitors (SGLT2i). This is clinically relevant as it aims to determine the potential benefits of atrasentan in improving renal outcomes in patients with IgA nephropathy, a condition characterized by progressive kidney damage. Understanding the efficacy of atrasentan could lead to improved therapeutic strategies for managing this chronic kidney disease.
Secondary objectives include evaluating the efficacy of atrasentan versus placebo while on background therapy with SGLT2i at 24 weeks of treatment. This will provide additional insights into the short-term benefits and potential therapeutic impact of atrasentan in the context of existing treatment regimens.
Participants
The clinical trial involves a total of **36 participants** who are being evaluated for the efficacy of atrasentan versus placebo in the context of nephrology, specifically focusing on patients with biopsy-proven IgA nephropathy (IgAN). The study population includes both **male and female subjects** aged 18 and older. Participants are required to be on a stable and maximally tolerated dose of a renin-angiotensin system inhibitor (RASi) for at least 12 weeks prior to screening and must also be receiving treatment with an SGLT2 inhibitor at a stable dose for at least 8 weeks prior to screening. The trial includes individuals who have a 24-hour total urine protein of greater than 0.5 grams per day and an estimated glomerular filtration rate (eGFR) of at least 30 mL/min/1.73 m², based on the CKD-EPI equation. Participants are expected to comply with highly effective forms of contraception throughout the study and for up to one month afterward. The selection process for the trial population involved specific inclusion criteria, such as the willingness to participate in an 8-week run-in period with an SGLT2 inhibitor and the ability to provide written informed consent. The trial also considers vulnerable populations, ensuring that all participants are willing and able to comply with study visits and procedures.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled, crossover study** to evaluate the efficacy of **atrasentan** in subjects with **IgA nephropathy** who are concurrently receiving sodium-glucose cotransporter-2 inhibitors (SGLT2i). The trial is structured to include a series of study visits, beginning with an inclusion (screening) visit, followed by a run-in period, treatment periods, and concluding with an end-of-study visit. The trial is expected to span from October 2023 to May 2026, with participant involvement lasting up to 64 weeks, depending on individual response and adherence to the protocol.
Participants will initially undergo a screening visit to confirm eligibility based on criteria such as age, renal function, and current treatment regimen. Eligible subjects will enter an 8-week run-in period with SGLT2i to ensure stability and tolerance. Following successful completion of the run-in phase, participants will be randomized to receive either atrasentan or a matching placebo in a crossover design, with each treatment period lasting 12 weeks. The primary endpoint is the change in proteinuria from baseline to Week 12, with a secondary endpoint assessing changes from baseline to Week 24 during the second treatment period.
Study visits are scheduled at regular intervals to monitor safety, efficacy, and adherence to the treatment regimen. These visits will include assessments such as urine protein measurements, renal function tests, and other relevant clinical evaluations. The end-of-study visit will occur after the final treatment period, where comprehensive assessments will be conducted to evaluate the overall impact of the intervention.
Participants are expected to comply with all study visits and procedures, and any deviation from the protocol, such as non-compliance or adverse events, may lead to early termination from the study. The trial aims to provide valuable insights into the therapeutic potential of atrasentan in managing IgA nephropathy, contributing to the broader understanding of treatment options for this condition.
Treatment
The clinical trial involves the administration of **dapagliflozin**, an oral medication classified under the ATC code A10BK01. Dapagliflozin is provided in a pharmaceutical form identified as PHF00082MIG. The maximum daily dose is 10 mg, and the treatment period extends up to 64 weeks. The medication is administered orally, and participant compliance is monitored throughout the study duration to ensure adherence to the dosing schedule.
A **matching placebo** is used as a comparator in this study. The placebo is formulated as film-coated round tablets, designed to mimic the appearance of the active medication. The placebo is administered orally, following the same dosing schedule as the active treatment, to maintain the double-blind nature of the trial.
The experimental medication **atrasentan** is also included in the trial. Atrasentan is provided as a film-coated tablet and is administered orally. The active substance, atrasentan hydrochloride, is dosed at a maximum of 0.75 mg per day, with a treatment period of up to 36 weeks. This medication is classified as an orphan drug, with the designation number EU/3/21/2542, and is developed by Chinook Therapeutics. Participant compliance with the dosing regimen is closely monitored to ensure the integrity of the trial data.
Efficacy
The efficacy of atrasentan in the treatment of **IgA Nephropathy** will be assessed through a randomized, double-blind, placebo-controlled, crossover study. The primary endpoint for evaluating efficacy is the change in proteinuria, specifically the urine protein-to-creatinine ratio (UPCR) from a 24-hour urine collection, measured from Baseline to Week 12. A secondary endpoint involves assessing the change in proteinuria from Baseline to Week 24 during Treatment Period 2. These measurements will be collected and analyzed at specified timepoints to determine the efficacy of atrasentan compared to placebo while subjects are on background therapy with sodium-glucose cotransporter-2 inhibitors (SGLT2i). The study will utilize validated laboratory tests to ensure accurate and reliable data collection for these endpoints.
Inclusion and Exclusion Criteria
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 IgAN that, in the opinion of the investigator, is not due to secondary causes. a. Biopsy could have occurred at any point in time prior to study. b. A diagnostic report must be available for review by the Sponsor or designee.
- Receiving a maximally tolerated and stable dose of a renin-angiotensin system inhibitor (RASi) for at least 12 weeks prior to screening. Investigator discretion should be used in determining maximally tolerated and optimized dose.
- eGFR ≥ 30 mL/min/1.73 m2 at screening based on the CKD-EPI equation (https://www.kidney.org/professionals/kdoqi/gfr_calculator).
- Willing to abide with 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 written informed consent and comply with all study visits and study procedures.
- Inclusion Criteria for SGLT2i Stable Subjects. Receiving treatment with SGLT2i at a stable dose for at least 8 weeks prior to screening.
- Inclusion Criteria for SGLT2i Stable Subjects. Must have a 24-hour total 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.
- Inclusion Criteria for Run-In Subjects. Willing to participate in an 8-week run-in period with an SGLT2i.
- 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.
- Additional Inclusion Criteria for Run-in Subjects at the end of Run-In. Must have a 24-hour total urine protein of > 0.5 grams/day confirmed at the Week -1 visit
- Additional Inclusion Criteria for Run-in Subjects at the end of Run-In. Must have an eGFR of ≥ 30 mL/min/1.73 m2 based on the CKD-EPI equation at their Week -1 Visit*. * Please keep in mind for subjects that go through the run-in period with SGLT2i, there is the potential for an acute eGFR reduction of about 10%, but can be up to 30% in rare cases (Meraz-Muñoz, 2021; Heerspink, 2021a).
- Subjects who are unable to fulfill the last 3 criteria during the run-in period will be considered run-in failures.
Exclusion Criteria
- Concurrent diagnosis of another cause of chronic kidney disease including diabetic kidney disease or another primary glomerulopathy.
- Clinical suspicion of rapidly progressive glomerulonephritis (RPGN) based on KDIGO guidelines or clinical suspicion of Henoch-Schonlein Purpura (IgA vasculitis).
- Clinical diagnosis of nephrotic syndrome.
- Diagnosis of Type 1 diabetes.
- Brain natriuretic peptide (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 including systemic corticosteroids (e.g., prednisone, prednisolone, budesonide, etc.) mycophenolate, azathioprine, cyclosporine, tacrolimus, etc.; use of herbs such as Tripterygium Wilfordii Hook F, Caulis sinomenii and Sinomenium acutum; for >2 weeks in the past 3 months. Use of rituximab within the past 6 months.
- Confirmed blood pressure >150 mmHg systolic or >95 mmHg diastolic based on a blood pressure measurement obtained at screening.
- Known history of heart failure or prior hospital admissions for conditions relating to fluid overload such as pulmonary edema, uncontrolled peripheral edema, pleural effusion, or ascites.
- Known history of clinically significant liver disease or transaminase or bilirubin values more than twice the upper limit of normal. Subjects with treated hepatitis C can be considered for inclusion into the study upon consultation with the Sponsor’s Medical Lead (or designee).
- Hemoglobin below 9 g/dL at screening or prior history of blood transfusion for anemia within 3 months of screening.
- History of malignancy unless cancer free for at least 5 years or nonmelanoma skin cancer that was completely resected. A subject with curatively treated cervical carcinoma in situ is eligible for this study.
- Pregnancy, breast feeding, or intent to become pregnant during the study period and at least 1 month afterward for females.
- Intent to father a child or donate sperm during the study period and at least 1 month afterward for males.
- Have received any investigational agent or approved treatment for IgAN (other than a RAS inhibitor and SGT2i) 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.
- Concurrent clinically significant, unstable, or uncontrolled cardiovascular, pulmonary, hepatic, renal, gastrointestinal, genitourinary, hematological, coagulation, immunological, endocrine/metabolic, or other medical disorder that, in the opinion of the Investigator or Sponsor’s Medical Lead (or designee), might confound the results of the study or pose additional risk to the subject by their participation in the study
- History of an alcohol or illicit drug-related disorder within the past 1 year.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 20 Oct 2023 | 10 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Matching placebo film-coated round tablets | Placebo | N/A | — | — | — | N/A |
atrasentan | Test | FILM COATED TABLET | ORAL | 0.75 | 36 | PRD8668432 |
DAPAGLIFLOZIN | Other | PHF00082MIG | ORAL | 10 | 64 | SCP153586 |