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Study Of Diabetic Nephropathy With Atrasentan (SONAR)

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ClinicalTrials.gov Identifier: NCT01858532
Recruitment Status : Terminated (Strategic considerations)
First Posted : May 21, 2013
Results First Posted : April 24, 2019
Last Update Posted : April 24, 2019
Sponsor:
Information provided by (Responsible Party):
AbbVie

Tracking Information
First Submitted Date  ICMJE May 17, 2013
First Posted Date  ICMJE May 21, 2013
Results First Submitted Date  ICMJE March 29, 2019
Results First Posted Date  ICMJE April 24, 2019
Last Update Posted Date April 24, 2019
Actual Study Start Date  ICMJE May 17, 2013
Actual Primary Completion Date March 29, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 29, 2019)
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).
Original Primary Outcome Measures  ICMJE
 (submitted: May 17, 2013)
Time to the first occurrence of a component of the composite renal endpoint. [ Time Frame: Approximately 48 months. ]
Time to the first occurrence of a component of the composite renal endpoint: doubling of serum creatinine (confirmed by a 30-day serum creatinine) or the onset of end stage renal disease (needing chronic dialysis or renal transplantation or renal death).
Change History Complete list of historical versions of study NCT01858532 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 29, 2019)
  • 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).
  • 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).
  • 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).
  • 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).
Original Secondary Outcome Measures  ICMJE
 (submitted: May 17, 2013)
  • Change from baseline to Month 24 post-randomization visit on urine albumin creatinine ratio. [ Time Frame: From Day 0 to 24 months. ]
  • Time to a 30% estimated glomerular filtration rate reduction after 3 months post-randomization treatment. [ Time Frame: Approximately 24 months. ]
  • Time to cardio-renal composite endpoint: doubling of serum creatinine, end stage renal disease, cardiovascular death, nonfatal myocardial infarction, nonfatal stroke. [ Time Frame: Approximately 48 months. ]
  • Time to the cardiovascular composite endpoint: cardiovascular death, nonfatal myocardial infarction and nonfatal stroke. [ Time Frame: Approximately 48 months. ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study Of Diabetic Nephropathy With Atrasentan
Official Title  ICMJE 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
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.
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).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Diabetic Nephropathy
Intervention  ICMJE
  • Drug: Atrasentan
    Film-coated tablet
    Other Name: ABT-627
  • Drug: Placebo
    Film-coated tablet
Study Arms  ICMJE
  • Active Comparator: Atrasentan
    0.75 mg atrasentan once daily by mouth for up to 52 months
    Intervention: Drug: Atrasentan
  • Placebo Comparator: Placebo
    Placebo once daily by mouth for up to 52 months
    Intervention: Drug: Placebo
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: March 29, 2019)
5107
Original Estimated Enrollment  ICMJE
 (submitted: May 17, 2013)
4148
Actual Study Completion Date  ICMJE March 29, 2018
Actual Primary Completion Date March 29, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries Argentina,   Australia,   Austria,   Belgium,   Brazil,   Bulgaria,   Canada,   Chile,   China,   Czech Republic,   Czechia,   Denmark,   Finland,   France,   Germany,   Greece,   Hong Kong,   Ireland,   Israel,   Italy,   Japan,   Korea, Republic of,   Malaysia,   Mexico,   Netherlands,   New Zealand,   Peru,   Poland,   Portugal,   Puerto Rico,   Romania,   Russian Federation,   Singapore,   Slovakia,   South Africa,   Spain,   Sweden,   Switzerland,   Taiwan,   Turkey,   Ukraine,   United Kingdom,   United States
 
Administrative Information
NCT Number  ICMJE NCT01858532
Other Study ID Numbers  ICMJE M11-352
2012-005848-21 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party AbbVie
Study Sponsor  ICMJE AbbVie
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: AbbVie Inc. AbbVie
PRS Account AbbVie
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP