- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01858532
Study Of Diabetic Nephropathy With Atrasentan (SONAR)
A Randomized, Multicountry, Multicenter, Double-Blind, Parallel, Placebo-Controlled Study of the Effects of Atrasentan on Renal Outcomes in Subjects With Type 2 Diabetes and Nephropathy. SONAR: Study Of Diabetic Nephropathy With Atrasentan
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 3
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Participant, or legal representative, had voluntarily signed and dated an Informed Consent Form, approved by an Institutional Review Board (IRB)/Independent Ethics Committee (IEC), after the nature of the study had been explained and the participant had the opportunity to ask questions. The informed consent must have been signed before any study-specific procedures were performed.
- Participant had type 2 diabetes (including participants with latent autoimmune diabetes or insulin-treated participants without a history of diabetic ketoacidosis who also had a negative anti-glutamic acid decarboxylase test AND an elevated post-prandial serum C-peptide level) and had been treated with at least one anti-hyperglycemic medication and an angiotensin-converting enzyme inhibitor (ACEi) or Angiotensin II receptor blocker (ARB; RAS inhibitor) for at least 4 weeks prior to the Screening S2 visit.
For entry into the Run-In Period the participant must have satisfied the following criteria based on the Screening laboratory values:
- Estimated glomerular filtration rate (eGFR) 25 to 75 mL/min/1.73 m^2 [until the eGFR cap on participants (approximately 300) with a baseline of > 60 mL/min/1.73 m^2 was reached] and a urine albumin creatinine ratio (UACR) greater than or equal to 300 and less than 5,000 mg/g (greater than or equal to 34 mg/mmol and less than 565 mg/mmol);
- Serum albumin greater than or equal to 2.5 g/dL (25 g/L);
- Brain natriuretic peptide (BNP) less than or equal to 200 pg/mL (200 ng/L);
- Systolic blood pressure (SBP) greater than or equal to 110 and less than or equal to 180 mmHg;
- Serum potassium greater than or equal to 3.5 mEq/L (3.5 mmol/L) and less than or equal to 6.0 mEq/L (6.0 mmol/L);
- Participants on a maximum tolerated labeled daily dose (MTLDD) of a RAS inhibitor for greater than or equal to 4 weeks and on a diuretic at the time of screening and who satisfied the above criteria may have proceeded to the last visit in the Run-In Period (R6);
- Participants already on a MTLDD of a RAS inhibitor for greater than or equal to 4 weeks and not on a diuretic (unless medically contraindicated) at the time of Screening were to start with a diuretic and participate in Run-In for at least 2 weeks.
For entry into the Enrichment Period the participant must have satisfied the following criteria based on the last visit of the Run-In Period:
- RAS inhibitor at the MTLDD for the previous 4 weeks with no adjustments of the dose;
- Participants that were on a MTLDD RAS inhibitor and not on a diuretic (unless medically contraindicated) at the time of Screening must have been in Run-In for at least 2 weeks.
For entry into the Double-Blind Treatment Period, participants must have satisfied the following criteria based on the last visit of the Enrichment Period:
- RAS inhibitor at the MTLDD for the previous 6 weeks during the Enrichment Period with no adjustments of the dose;
- Diuretic at any dose unless medically contraindicated or clinically intolerable in the investigator's judgement (i.e., hypotension or hypokalemia);
- Participants must not have had a weight change greater than or equal to 3 kg from the beginning of Enrichment to the end of the Enrichment Period and absolute serum BNP greater than or equal to 300 pg/mL (300 ng/L) at the last Enrichment visit;
- Participants must not have had an increase in serum creatinine greater than 0.5 mg/dL and greater than 20% increase from the beginning of Enrichment to the end of the Enrichment Period.
Exclusion Criteria:
A participant was not eligible for entry into the Run-in Period if he/she met any of the following criteria:
- Participant had a history of severe peripheral edema or facial edema requiring diuretics unrelated to trauma or a history of myxedema in the prior 4 weeks to the initial Screening S1 visit.
- Participant had a history of pulmonary hypertension, pulmonary fibrosis or any lung diseases requiring oxygen therapy (e.g., chronic obstructive pulmonary disease, emphysema).
- Participant had a documented diagnosis of heart failure, previous hospitalization for heart failure or current or constellation of symptoms (dyspnea on exertion, pedal edema, orthopnea, paroxysmal nocturnal dyspnea) felt to be compatible with heart failure, that was not explained by other causes, and for which there was a change in medication or other management directed at heart failure.
- Participant had known non-diabetic kidney disease (other than kidney stones).
- Participant had elevated liver enzymes (serum alanine aminotransaminase [ALT] and/or serum aspartate aminotransaminase [AST]) > 3 × the upper limit of normal (ULN).
- Participant had hemoglobin < 9 g/dL (90 g/L).
- Participant had a sensitivity to loop diuretics.
- Participant had a history of an allergic reaction or significant sensitivity to atrasentan (or its excipients) or similar compounds.
- Participant had a history of chronic gastrointestinal disease, which, in the Investigator's opinion, may have caused significant GI malabsorption.
- Participant had a history of secondary hypertension (i.e., hemodynamically significant renal artery stenosis, primary aldosteronism or pheochromocytoma).
- Participant had significant comorbidities (e.g., advanced malignancy, advanced liver disease) with a life expectancy of less than 1 year.
Participant had clinically significant cerebrovascular disease (CVD) or coronary artery disease (CAD) within 3 months prior to the Screening S1 visit, defined as one of the following:
- Hospitalization for MI or unstable angina; or
- New onset angina with positive functional study or coronary angiogram revealing stenosis; or
- Coronary revascularization procedure; or
- Transient Ischemic Attack or Stroke.
- Participant had received any investigational drug including atrasentan within 3 months prior to the Screening S1 visit.
- Participant received dialysis treatments or was expected to receive dialysis or renal transplant within 6 months of screening.
- Participant was currently receiving rosiglitazone, moxonidine, aldosterone blockers, aliskiren or a combination of ACEi and ARB.
- Participant was a premenopausal woman defined as (for study purposes) any female subject with a menses in the past 2 years. For women who were < 50 years old, serum FSH must have been greater than 35 IU/L. Women who were surgically sterile or had a history of hysterectomy may not have necessarily be postmenopausal, and must also have had an FSH > 35 IU/L.
- Participant was at high risk for QT/QTc prolongation such as a family history of Long QT Syndrome, defined as QTc prolongation exceeding 450 ms in men, or 460 ms in women.
- Participant had type 1 diabetes.
- Participant was considered to be clinically unstable regarding general, metabolic or cardiovascular health as determined by the Investigator.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: RANDOMIZED
- Interventional Model: PARALLEL
- Masking: QUADRUPLE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
ACTIVE_COMPARATOR: Atrasentan
0.75 mg atrasentan once daily by mouth for up to 52 months
|
Film-coated tablet
Other Names:
|
PLACEBO_COMPARATOR: Placebo
Placebo once daily by mouth for up to 52 months
|
Film-coated tablet
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Time to the First Occurrence of a Component of the Composite Renal Endpoint in the Intent-to-Treat (ITT) Responder Set (as Randomized)
Time Frame: From randomization to individual end of observation, up to 53 months
|
Time to the first occurrence of a component of the composite renal endpoint was defined as doubling of serum creatinine (confirmed by a 30-day serum creatinine measurement) or the onset of end stage renal disease (estimated glomerular filtration rate [eGFR] less than 15 ml/min/1.73
m^2 confirmed by a 90-day eGFR measurement, receiving chronic dialysis, renal transplantation, or renal death).
Only events adjudicated by the Events Adjudication Committee (EAC) were considered in defining this endpoint.
Data are presented as number of participants with a primary renal composite event (first event per participant).
|
From randomization to individual end of observation, up to 53 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Time to a 50% Estimated Glomerular Filtration Rate Reduction in the Intent-to-Treat (ITT) Responder Set (as Randomized)
Time Frame: From randomization to individual end of observation, up to 53 months
|
The event of interest for this outcome was a 50% reduction in a participant's estimated glomerular filtration rate (eGFR) value as compared to baseline, confirmed by a repeated value at least 20 days apart.
The event time was defined as the first time that a 50% reduction in eGFR was observed.
Data are presented as number of participants with a 50% reduction in eGFR (first event per participant).
|
From randomization to individual end of observation, up to 53 months
|
Time to Cardio-renal Composite Endpoint in the Intent-to-Treat (ITT) Responder Set (as Randomized)
Time Frame: From randomization to individual end of observation, up to 53 months
|
The composite event of interest for this outcome consisted of doubling of serum creatinine, end-stage renal disease (ESRD), cardiovascular (CV) death (including CV death and presumed CV death), nonfatal myocardial infarction (MI; heart attack) and nonfatal stroke.
Presumed sudden cardiac death was included as a subcategory of presumed CV death.
Only events adjudicated by the Events Adjudication Committee (EAC) were considered in defining this endpoint.
Data are presented as number of participants with a cardio-renal composite event (first event per participant).
|
From randomization to individual end of observation, up to 53 months
|
Time to First Occurrence of a Component of Composite Renal Endpoint for All Randomized Participants (Pooled)
Time Frame: From randomization to individual end of observation, up to 53 months
|
Time to the first occurrence of a component of the composite renal endpoint was defined as doubling of serum creatinine (confirmed by a 30-day serum creatinine measurement) or the onset of end stage renal disease (estimated glomerular filtration rate [eGFR] less than 15 ml/min/1.73
m^2 confirmed by a 90-day eGFR measurement, receiving chronic dialysis, renal transplantation, or renal death).
Data for all randomized participants were pooled by treatment and analyzed.
Data are presented as number of participants with a renal composite event (first event per participant).
|
From randomization to individual end of observation, up to 53 months
|
Time to the Cardiovascular Composite Endpoint in the Intent-to-Treat (ITT) Responder Set (as Randomized)
Time Frame: From randomization to individual end of observation, up to 53 months
|
The composite event of interest for this outcome was cardiovascular (CV) death (CV death, presumed CV death), nonfatal myocardial infarction (MI; heart attack), and nonfatal stroke.
Presumed sudden cardiac death was included as a sub-category of presumed CV death.
Only events adjudicated by the Events Adjudication Committee (EAC) were used.
Data are presented as number of participants with a cardiovascular composite event (first event per participant).
|
From randomization to individual end of observation, up to 53 months
|
Collaborators and Investigators
Sponsor
Publications and helpful links
General Publications
- Smeijer JD, Koomen J, Kohan DE, McMurray JJV, Bakris GL, Correa-Rotter R, Hou FF, Januzzi JL, Kitzman DW, Kolansky DM, Makino H, Perkovic V, Tobe S, Parving HH, de Zeeuw D, Heerspink HJL. Increase in BNP in Response to Endothelin-Receptor Antagonist Atrasentan Is Associated With Incident Heart Failure. JACC Heart Fail. 2022 Jul;10(7):498-507. doi: 10.1016/j.jchf.2022.03.004. Epub 2022 May 4.
- Waijer SW, Gansevoort RT, Bakris GL, Correa-Rotter R, Hou FF, Kohan DE, Kitzman DW, Makino H, McMurray JJV, Perkovic V, Tobe S, Parving HH, de Zeeuw D, Heerspink HJL. The Effect of Atrasentan on Kidney and Heart Failure Outcomes by Baseline Albuminuria and Kidney Function: A Post Hoc Analysis of the SONAR Randomized Trial. Clin J Am Soc Nephrol. 2021 Dec 1;16(12):1824-32. doi: 10.2215/CJN.07340521. Online ahead of print.
- Koomen JV, Stevens J, Bakris G, Correa-Rotter R, Hou FF, Kitzman DW, Kohan DE, Makino H, McMurray JJV, Parving HH, Perkovic V, Tobe SW, de Zeeuw D, Heerspink HJL. Individual Atrasentan Exposure is Associated With Long-term Kidney and Heart Failure Outcomes in Patients With Type 2 Diabetes and Chronic Kidney Disease. Clin Pharmacol Ther. 2021 Jun;109(6):1631-1638. doi: 10.1002/cpt.2143. Epub 2021 Jan 5.
- Heerspink HJL, Parving HH, Andress DL, Bakris G, Correa-Rotter R, Hou FF, Kitzman DW, Kohan D, Makino H, McMurray JJV, Melnick JZ, Miller MG, Pergola PE, Perkovic V, Tobe S, Yi T, Wigderson M, de Zeeuw D; SONAR Committees and Investigators. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial. Lancet. 2019 May 11;393(10184):1937-1947. doi: 10.1016/S0140-6736(19)30772-X. Epub 2019 Apr 14. Erratum In: Lancet. 2019 May 11;393(10184):1936.
Study record dates
Study Major Dates
Study Start (ACTUAL)
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- M11-352
- 2012-005848-21 (EUDRACT_NUMBER)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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