Study Of Diabetic Nephropathy With Atrasentan

NCT01858532 | Terminated Phase 3 Results DMC FDA Drug

• 2 other identifiers: M11-3522012-005848-21
• Study Type: interventional
• Target: 5,107
• Locations: 0 countries
• Sites: N/A

Brief Summary

The study objective was to evaluate the effect of atrasentan compared with placebo on time to doubling of serum creatinine (DBSC) or the onset of end-stage renal disease (ESRD) in participants with type 2 diabetes and nephropathy who were treated with the maximum tolerated labeled daily dose (MTLDD) of a renin-angiotensin system (RAS) inhibitor. In addition, the study assessed the effects of atrasentan compared with placebo on cardiovascular (CV) morbidity and mortality, urine albumin excretion, changes in estimated glomerular filtration rate (eGFR), as well as the impact on quality of life in participants with type 2 diabetes and nephropathy.

Conditions

Diabetic Nephropathy

Keywords

Diabetes; Nephropathy

Outcome Measures

Primary Outcomes (1)

• Time to the First Occurrence of a Component of the Composite Renal Endpoint in the Intent-to-Treat (ITT) Responder Set (as Randomized)

  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 Outcomes (4)

• Time to a 50% Estimated Glomerular Filtration Rate Reduction in the Intent-to-Treat (ITT) Responder Set (as Randomized)

  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)

  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)

  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)

  From randomization to individual end of observation, up to 53 months

Study Arms (2)

Atrasentan

ACTIVE COMPARATOR

0.75 mg atrasentan once daily by mouth for up to 52 months

Drug: Atrasentan

Placebo

PLACEBO COMPARATOR

Placebo once daily by mouth for up to 52 months

Drug: Placebo

Interventions

Atrasentan DRUG

Film-coated tablet

Also known as: ABT-627

Atrasentan

Placebo DRUG

Film-coated tablet

Placebo

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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;

You may not qualify if:

• 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

Sponsors & Collaborators

• AbbVie: lead

Related Publications (9)

• Jongs N, Gasparyan SB, Frison L, Schloemer P, Brinker M, Little DJ, Heerspink HJL. Use of eGFR Slope Thresholds as End Point Components in a Kidney Disease Progression Hierarchical Composite End Point. J Am Soc Nephrol. 2025 Dec 1;36(12):2421-2430. doi: 10.1681/ASN.0000000766. Epub 2025 Jun 17.

  PMID: 40526444 DERIVED

• Smeijer JD, de Vries ST, Kohan DE, Hou FF, Heerspink HJL. Sex differences in response to the endothelin receptor antagonist atrasentan in individuals with type 2 diabetes and chronic kidney disease: a post hoc analysis of the SONAR trial. Diabetologia. 2025 Mar;68(3):516-525. doi: 10.1007/s00125-024-06326-x. Epub 2024 Dec 11.

  PMID: 39661119 DERIVED

• Heerspink HJL, Jongs N, Schloemer P, Little DJ, Brinker M, Tasto C, Karpefors M, Wheeler DC, Bakris G, Perkovic V, Nkulikiyinka R, Rossert J, Gasparyan SB. Development and Validation of a New Hierarchical Composite End Point for Clinical Trials of Kidney Disease Progression. J Am Soc Nephrol. 2023 Dec 1;34(12):2025-2038. doi: 10.1681/ASN.0000000000000243. Epub 2023 Oct 24.

  PMID: 37872654 DERIVED

• Smeijer JD, Kohan DE, Rossing P, Correa-Rotter R, Liew A, Tang SCW, de Zeeuw D, Gansevoort RT, Ju W, Lambers Heerspink HJ. Insulin resistance, kidney outcomes and effects of the endothelin receptor antagonist atrasentan in patients with type 2 diabetes and chronic kidney disease. Cardiovasc Diabetol. 2023 Sep 16;22(1):251. doi: 10.1186/s12933-023-01964-8.

  PMID: 37716952 DERIVED

• Chan KW, Smeijer JD, Schechter M, Jongs N, Vart P, Kohan DE, Gansevoort RT, Liew A, Tang SCW, Wanner C, de Zeeuw D, Heerspink HJL. Post hoc analysis of the SONAR trial indicates that the endothelin receptor antagonist atrasentan is associated with less pain in patients with type 2 diabetes and chronic kidney disease. Kidney Int. 2023 Dec;104(6):1219-1226. doi: 10.1016/j.kint.2023.08.014. Epub 2023 Aug 31.

  PMID: 37657768 DERIVED

• 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.

  PMID: 35772861 DERIVED

• 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;16(12):1824-1832. doi: 10.2215/CJN.07340521. Epub 2021 Dec 1.

  PMID: 34853062 DERIVED

• 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.

  PMID: 33338269 DERIVED

• 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.

  PMID: 30995972 DERIVED

MeSH Terms

Conditions

Diabetic Nephropathies; Diabetes Mellitus; Kidney Diseases

Interventions

Atrasentan

Condition Hierarchy (Ancestors)

Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Diabetes Complications; Endocrine System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Benzodioxoles; Dioxoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrrolidines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Global Medical Services
• Organization: AbbVie

abbvieclinicaltrials@abbvie.com

800-633-9110

Study Officials

• AbbVie Inc.

  AbbVie

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 17, 2013
• First Posted: May 21, 2013
• Study Start: May 17, 2013
• Primary Completion: March 29, 2018
• Study Completion: March 29, 2018
• Last Updated: April 24, 2019
• Results First Posted: April 24, 2019

Record last verified: 2019-03