Study Of Diabetic Nephropathy With Atrasentan
Condition: Diabetic Nephropathy
MeSH terms: Kidney Diseases; Diabetic Nephropathies
Intervention: Atrasentan; Placebo
Intervention description: Film-coated tablet; Film-coated tablet
Intervention MeSH terms: Atrasentan
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 5107.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: Diabetes; Nephropathy

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.
    

Eligibility criteria:

        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.