Study Of Diabetic Nephropathy With Atrasentan

The study objective is to evaluate the effect of atrasentan compared with placebo on time to
doubling of serum creatinine or the onset of end stage renal disease (ESRD) in subjects with
type 2 diabetes and nephropathy who are treated with the maximum tolerated labeled daily dose
(MTLDD) of a Renin Angiotensin System (RAS) inhibitor. In addition, the study will assess the
effects of atrasentan compared with placebo on cardiovascular morbidity and mortality, urine
albumin excretion, changes in estimated glomerular filtration rate (eGFR), as well as on the
impact on quality of life in subjects with type 2 diabetes and nephropathy.

Inclusion Criteria:

- 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-glutamic 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.

- For entry into the Run-In Period the subject must satisfy the following criteria based
on the Screening laboratory values:

- Estimated glomerular filtration rate (eGFR) 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 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);

- Subjects 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 satisfy the above criteria may proceed to the last visit in Run-In Period
(R6);

- Subjects 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 will start with a diuretic and proceed to 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:

- RAS inhibitor at the MTLDD for the previous 4 weeks with no adjustments of the
dose;

- Subjects 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, the subject must satisfy 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);

- Subject must not have 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;

- Subject must not have 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:

- 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.

- Subject has a history of pulmonary hypertension, pulmonary fibrosis or any lung
diseases requiring oxygen therapy (e.g., chronic obstructive pulmonary disease,
emphysema).

- Subject has 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.

- Subject has known non-diabetic kidney disease (other than kidney stones).