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

To be eligible for initial entry into the study, subjects must meet any of the following criteria:
1. Subject is 18 * 85 years of age at the initial screening S1 visit.
2. Subject, or legal representative, has 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 has been explained and the subject has had the opportunity to ask questions. The informed consent must be signed before any study-specific procedures are performed.
3. Subject has type 2 diabetes (including patients with latent autoimmune diabetes or insulin-treated patients without a history of diabetic ketoacidosis who also have a negative anti-glumatic acid decarboxylase test AND an elevated post-prandial serum C-peptide level) and has been treated with at least one anti-hyperglycemic medication and ACEi/or ARB (RAS inhibitor) for at least 4 weeks prior to the Screening S2 visit.
4. ( intentionally left blank;criterion deleted);For entry into the Run-In Period the subject must satisfy the following criteria:;5. Screening laboratory values:
* Estimated GFR 25 to 75 mL/min/1.73 m2 [until the eGFR cap on subjects (approximately 300) with a baseline of > 60 mL/min/1.73 m2 is reached] and a UACR *
300 and < 5,000 mg/g (* 34 mg/mmol and < 565 mg/mmol);
* Serum albumin * 2.5 g/dL (25 g/L);
* BNP * 200 pg/mL (200 ng/L);
* Serum Potassium * 3.5 mEq/L(3.5 mmol/L) * 6.0 mEq/L (6.0 mmol/L); and
* SBP*110 and * 180 mm Hg at any time during the screening period.
Subjects on a MTLDD of a RAS inhibitor for * 4 weeks and on a diuretic at the time of screening and who satisfy the above criteria may proceed directly to the last visit in Run-In Period (R6);
Subjects already on a MTLDD of a RAS inhibitor for * 4 weeks and not on a diuretic (unless medically contraindicated) at the time of Screening will start with a diuretic and participate in Run-In for at least 2 weeks.;For entry into the Enrichment Period the subject must satisfy the following criteria based on the last visit of the Run-In Period:;6. Based on the last visit of the run-in period:
* Subject received a RAS inhibitor at the MTLDD for the previous 4 weeks with no adjustments of the dose;
* Subject was on a MTLDD RAS inhibitor and not on a diuretic (unless medically contraindicated) at the time of Screening and has been in Run-In for at least 2 weeks.;For entry into the Double-Blind Treatment Period, the subject must satisfy the following criteria:;7. based on his/her last visit of the Enrichment Period:
* Subject has taken a RAS inhibitor at the MTLDD for the previous 6 weeks during the Enrichment Period with no adjustments of the dose;
* Subject has taken a diuretic at any dose unless medically contraindicated or clinically intolerable in the investigator's judgement (i.e., hypotension or hypokalemia);
* Subject must not have a weight change * 3 kg from the beginning of Enrichment (E1) to the end of the Enrichment period AND absolute serum BNP* 300pg/mL (300ng/L) at the last Enrichment visit;
* Subject must not have an increase in serum creatinine > 0.5 mg/dL AND > 20% increase from the beginning of enrichment (E1) to the end of the Enrichment period.
8. If male, subject must be surgically sterile or practicing at least two of the following methods of contraception, from initial study drug administration through 90 days after last dose of study drug unless subject's partner(s) is post-menopausal or has been surgically sterilized:
* Partner(s) using an IUD;
* Partner(s) using hormonal contraceptives (oral, vaginal, parenteral or transdermal);
* Subject and/or partner(s) using barrier method (condoms, contraceptive sponge, diaphragm, or vaginal ring with spermicidal jellies or creams);
* Total abstinence from sexual intercourse as the preferred life style of the subject; periodic abstinence is not acceptable;
9. If male, subject must agree not to donate sperm from initial study drug administration through 90 days after the last dose of study drug.

Subjects meeting the following criteria will be excluded from the study:
1. Subject has 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.
2. Subject has a history of pulmonary hypertension, pulmonary fibrosis or any lung diseases requiring oxygen therapy (e.g., chronic obstructive pulmonary disease, emphysema).
3. Subject has a documented diagnosis of heart failure, previous hospitalization for heart failure or current 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.
4. Subject has known non-diabetic kidney disease (other than kidney stones).
5. (intentionally left blank;criterion deleted)
6. (intentionally left blank;criterion deleted)
7. Subject has elevated liver enzymes (serum alanine aminotransaminase [ALT] and/or serum aspartate aminotransaminase [AST]) > 3 × the upper limit of normal (ULN).
8. Subject has a hemoglobin < 9 g/dL (90 g/L).
9. Subject has a sensitivity to loop diuretics.
10. Subject has a history of an allergic reaction or significant sensitivity to atrasentan (or its excipients)
or similar compounds.
11. Subject has a history of chronic gastrointestinal disease, which in the Investigator's opinion may cause significant GI malabsorption.
12. Subject has a history of secondary hypertension (i.e., hemodynamically significant renal artery stenosis, primary aldosteronism or pheochromocytoma).
13. Subject has significant comorbidities (e.g., advanced malignancy, advanced liver disease) with a life expectancy of less than 1 year.
14. Subject has 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 (TIA) or Stroke
15. Subject has received any investigational drug including Atrasentan within 3 months prior to Screening S1 visit.
16. Subject receives dialysis treatments or is expected to receive dialysis or renal transplant within
6 months of screening.
17. Subject is currently receiving rosiglitazone, moxonidine, aldosterone blockers, aliskiren or a combination of ACEi and ARB.
18. (intentionally left blank;criterion deleted)
19. Subject is a premenopausal woman defined as (for study purposes) any female subject with a menses in the past two years. For women who are < 50 years old, serum FSH must be greater than 35 IU/L. Women who are surgically sterile or have a history of hysterectomy may not necessarily be postmenopausal, and must also have an FSH > 35 IU/L.
20. Subject is 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.
21. Subject has Type I diabetes.
22. Subject is considered to be clinically unstable regarding general, metabolic or cardiovascular health as determined by the investigator.