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Diabetic NephropathyPhase 3SONARNCT01858532

Study Of Diabetic Nephropathy With Atrasentan

A Phase 3 study testing Atrasentan in people with Diabetic Nephropathy, run by AbbVie.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 to 85 years
Conditions the study is for
Diabetic Nephropathy
What is being tested?
Atrasentan
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
5,107 participants
Where
No sites listed yet
Study dates
17 May 2013to 29 Mar 2018
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 85 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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);
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  • 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.

Who cannot join

  • 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).
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  • 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.

About this study

Official title: 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

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.

Read the detailed description

This was a Phase 3, prospective, randomized, double-blind, enriched-population, placebo controlled, multicenter study in adult participants with type 2 diabetes and nephropathy. Participants who met the inclusion criteria for initial study entry and none of the exclusion criteria were eligible to proceed to the Run-In Period to optimize RAS inhibitor and diuretic doses. Following the Run-In Period, eligible participants entered the 6-week Enrichment Period in which all received atrasentan to determine their urinary albumin to creatinine ratio (UACR) response and to assess tolerability of atrasentan. Responders and nonresponders were then randomly assigned to receive atrasentan or placebo in the Double-Blind Treatment Period. The study was performed in 5 to 6 periods in the following sequence: Pre-Screening Period (optional); Screening Period (Visits S1 and S2); Run-In Period (up to 12 weeks; Visits R1 to R6); Enrichment Period (6 weeks; Visits E1 to E5); Double-Blind Treatment Period (randomization to final treatment visit); and Follow-Up Period (Final Treatment to F1 visit [45 days post treatment] and other post-treatment visits). The study was prematurely discontinued because of a lower than expected event rate for the renal composite endpoint, which was adjudicated by a blinded independent events adjudication committee (EAC).

Being tested
Atrasentan, Placebo
Keywords
Diabetes, Nephropathy
Medical subject headings
Diabetic Nephropathies, Diabetes Mellitus, Kidney Diseases

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AtrasentanDrug

    Also called ABT-627

    Film-coated tablet

  • PlaceboDrug

    Film-coated tablet

Study groups in NCT01858532
Study groupRoleWhat they receive
AtrasentanActive comparator0.75 mg atrasentan once daily by mouth for up to 52 months
Receives: Drug: Atrasentan
PlaceboPlacebo comparatorPlacebo once daily by mouth for up to 52 months
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  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).

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

Secondary outcomes (4)

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

    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).

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

  2. Time to Cardio-renal Composite Endpoint in the Intent-to-Treat (ITT) Responder Set (as Randomized)

    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).

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

  3. Time to First Occurrence of a Component of Composite Renal Endpoint for All Randomized Participants (Pooled)

    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).

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

  4. Time to the Cardiovascular Composite Endpoint in the Intent-to-Treat (ITT) Responder Set (as Randomized)

    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).

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 May 2013 (estimated)
  2. Study start17 May 2013
  3. Primary completion29 Mar 2018
  4. Study completion29 Mar 2018

Why it stopped: Strategic considerations

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
5,107 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01858532
Sponsor's protocol ID
M11-352
Other IDs
2012-005848-21
Acronym
SONAR
Status last verified
Mar 2019
First submitted
17 May 2013
Last updated
24 Apr 2019
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Undecided

Publications

  • 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.

    PubMed 40526444

  • 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.

    PubMed 39661119

  • 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.

    PubMed 37872654

  • 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.

    PubMed 37716952

  • 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.

    PubMed 37657768

  • 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.

    PubMed 35772861

  • 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.

    PubMed 34853062

  • 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.

    PubMed 33338269

  • 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.

    PubMed 30995972

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Atrasentan in people with Diabetic Nephropathy, run by AbbVie.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 18 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 24 Apr 2019. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 24 Apr 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01858532, which also lists 9 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Apr 2019.

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