Strategic considerations

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.

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).

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.

Intent-to-Treat (ITT) Responders (participants who achieved at least 30% reduction in their albumin to creatinine ratio [UACR] in the Enrichment Period [EP]) and ITT Non-responders (Participants who achieved < 30% reduction in their UACR in the EP)

Treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs) were reported from the time of study drug administration until 45 days after the last dose of study drug (up to 24 weeks for the All Atrasentan Set in the Enrichment Period; up to 54 months for the ITT sets in the Double-Blind Period)

TEAEs and TESAEs are defined as any adverse event (AE) with an onset date that is after the first dose of study drug until 45 days after the last dose of study drug and were collected whether elicited or spontaneously reported by the participant.