Clinical trial NCT01858532
Conditions: Diabetic Nephropathy
Keywords: Diabetes Nephropathy
Sponsor: AbbVie
Start date: 2013-05-17; Completion date: 2018-03-29
Enrollment: 5107 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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).

Arms: arm 1: 0.75 mg atrasentan once daily by mouth for up to 52 months arm 2: Placebo once daily by mouth for up to 52 months
Interventions: intervention 1: Atrasentan intervention 2: Placebo
Intervention descriptions: intervention 1: Film-coated tablet intervention 2: Film-coated tablet

Protocol documents:
Prot_000.pdf: 
Atrasentan
M11-352 Protocol Amendment 7
EudraCT 2012-005848-21
1
1.0
Title Page
Clinical Study Protocol M11-352
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
Incorporating Amendments 1 and 2, Administrative 
Change 1, Amendment 3, Administrative Change 2, 
Amendment 4, Administrative Changes 3 and 4, and 
Amendments 5, 6 and 7
AbbVie Investigational
  Product:
Atrasentan (ABT-627)
Date:
19 May 2017
Development Phase:
3
Study Design:
Phase 3, randomized, double-blind, parallel design, 
placebo-controlled, enriched-population, multicenter study.
EudraCT Number:
2012-005848-21
Investigators:
Multicenter (Investigator information is on file at AbbVie)
Sponsor:
AbbVie Inc.*
NCT01858532


Atrasentan
M11-352 Protocol Amendment 7
EudraCT 2012-005848-21
2
Sponsor/Emergency 
  Contact:
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
*The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are 
provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial 
Application with the Competent Authority.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.


Atrasentan
M11-352 Protocol Amendment 7
EudraCT 2012-005848-21
3
1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
01 April 2013
Amendment 1
17 July 2013
Amendment 2
13 August 2013
Administrative Change 1
29 August 2013
Amendment 3*
08 October 2014
Administrative Change 2
09 December 2014
Amendment 4
11 February 2015
Administrative Change 3
20 March 2015
Administrative Change 4
13 July 2016
Amendment 5*
17 November 2016
Amendment 6*
10 February 2017
*
Amendment was not released to study sites for implementation.
The purpose of this amendment is to:
Substantial Changes (from Amendment 4 through Amendment 7 and includes 
Administrative Changes 3 and 4)
Statistical Design Parameters 
●
Update figures throughout protocol:
○
Revise number of subjects to be enrolled from 4,148 to 3,500.
○
Revise responders (UACR reduction ≥ 30% from baseline) figures in the 
Overall Study Diagram and Figure 1, Study Schematic from 1574 to 1250.  
Also specify study visits extend past the Follow-Up Visit (F1) visit for 
subjects that prematurely discontinued study drug administration.
○
Revise number of responders from 3,148 to 2,500.
○
Clarify treatment visits continue past T48.


Atrasentan
M11-352 Protocol Amendment 7
EudraCT 2012-005848-21
4
Rationale:  The reduction in the responder population and total study 
enrollment is resulted from the change of study duration of Double-Blind 
Period from 48 months to approximately 6 years.
●
Update Statistical Methods, Sample Size Determination:
○
Revise accrual period from 24 to 42 months.
○
Update duration of the Double-Blind Period from 48 months to 
approximately 6 years.
○
Add an annualized lost-to-follow-up rate of 2%.
○
Revised the plan for interim analysis of efficacy to be conducted when the 
number of accrued primary events in the responder population is in the 
range of 50% to 75% of the targeted 425 events for the study.
○
Specify "approximately" 1,000 non-responders will be randomized into the 
study to align throughout protocol.
Rationale:  Reflects current enrollment accrual rate and lost-to-follow-up 
rate.  Interim analysis revised to include the assessment of efficacy.
●
Update Statistical Methods, Definition of Baseline
Rationale:  Clarification.
●
Update Statistical Methods, Primary Efficacy Analysis
Rationale:  Clarification.
●
Update Statistical Methods, Derivation of Safety Endpoints
Rationale:  Clarification.
●
Update Statistical Methods, Interim Analysis
Rationale:  Interim analysis revised to include the assessment of efficacy.
●
Update text in Section 8.1, Statistical and Analytical Plans
Rationale:  To align language throughout protocol.
●
Update text in Section 8.1.2, Demographic, Other Baseline Characteristics, 
Subject Disposition and Concomitant Medication.
Rationale:  Align definition of baseline for consistency throughout protocol.
●
Revise title and text in Section 8.1.3.1, Primary Efficacy Analyses
Rationale:  Clarification.


Atrasentan
M11-352 Protocol Amendment 7
EudraCT 2012-005848-21
5
●
Update text in second paragraph of Section 8.1.3.5, Multiplicity
Rationale:  To align with protocol text.
●
Update text in Section 8.1.4, Safety Analyses
Rationale:  Clarification.
●
Revise text in Section 8.1.4.1, Adverse Events (AEs) Analyses
Rationale:  Clarification.
●
Add sentence to Section 8.1.4.4, ECG Analyses
Rationale:  To more accurately describe planned analysis of ECG data.
●
Revise text in Section 8.1.5, Interim Analysis
Rationale:  Interim analysis revised to include the assessment of efficacy.
●
Modify text in Section 8.1.6, Independent Data Monitoring Committee 
(IDMC) and Independent External Statistician.
Rationale:  Change incorporated to specify which events trigger the IDMC 
meetings and clarify committee recommendations are provided to the sponsor.
●
Update text in Section 8.2, Determination of Sample Size
Rationale:  Align text throughout protocol.
●
Update bullet point three in Section 8.3, Randomization Methods
Rationale:  Clarification.
Increase in Study Duration
●
Update duration of the Double-Blind Period from 48 months to approximately 
6 years.
Rationale:  Sentence clarifies approximate duration of the double-blind 
treatment period.
●
Revise Section 1.2, Synopsis, Duration of Treatment
Rationale:  Clarification
Study Procedures
●
Define visit completion sequence at study completion and align open-label 
extension study text.


Atrasentan
M11-352 Protocol Amendment 7
EudraCT 2012-005848-21
6
Rationale:  Clarification.
●
Add text to Inclusion Criterion 5, bullet point one, to highlight eGFR range of 
25 to 75 mL/min/1.73 m2 is valid until the eGFR cap is met.
Rationale:  Clarification.
●
Add End Stage Renal Disease text.
Rationale:  Clarify laboratory sample collection is not required at the 
discretion of the Investigator after the Premature Discontinuation visit for 
subjects that receive chronic dialysis or renal transplantation.
●
Revise study assessment text.
Rationale:  Clarify on-site visits are preferred and telephone assessments 
should only be utilized when necessary to complete study assessments.
●
Add Home Visits text.
Rationale:  Presents optional visit plan to reduce number of discontinued 
subjects.
●
Add lead in sentence before Inclusion Criterion 8 to specify male subjects 
must meet both Inclusion Criterion 8 and 9 from initial study drug 
administration through 90 days after last dose of study drug.
Rationale:  Clarification.
●
Modify lead in sentence before Exclusion Criterion 1 to specify subjects will 
not be eligible for entry into the Run-In Period of the study if any exclusion 
criteria are met.
Rationale:  Clarification.
●
Modify Exclusion Criterion 19 to re-define premenopausal women are not 
eligible for study participation.
Rationale:  Clarification.
●
Update Table 1, Study Activities footnotes
○
Delete footnote "j." for Complete Chemistry
○
Revise footnote "d." to extend yearly visits past T48
○
Specify footnote "i." procedures to be conducted during Medical History.
○
Clarify footnote "k." sentence.


Atrasentan
M11-352 Protocol Amendment 7
EudraCT 2012-005848-21
7
○
Revise footnote "w." description of IVRS/IWRS transaction at Final 
Treatment/PD visit. 
Rationale:  Administrative error and clarification.
●
Update Table 2, Reminder Phone Calls
○
Extend Yearly Visits past T48
○
Administrative Change 3 update of naming convention of Final 
Treatment/Premature Discontinuation Visit to align with terminology used 
in rest of protocol.
○
Delete reference to 24-hour urine collection at Final Treatment/Premature 
Discontinuation Visit as sample is not collected at either visit.
○
Add statement to F1 visit for subjects that consented to initiate their 
24-hour urine collection.
Rationale:  Clarification.
●
Added Clinical Laboratory Tests text
Rationale:  Provides option to utilize local laboratory test results.
●
Update Section 5.3.1.1.1, 24-Hour Urine Collection Sub-Study (Additional 
Consent Needed)
○
Reference Table 4, Study Activities for Optional 24-hour Urine Sub-Study, 
schedule for urine sample collection frequency.
○
Administrative Change 3 raised the number of subjects participating in the 
sub-study to 800 to increase the sample size and mitigate potential 
response variation.
○
Define yearly visits in Table 4, Study Activities for Optional 24-hour Urine 
Sub-Study.
Rationale:  Clarification.
●
Delete number of planned PK samples in Section 5.3.2.1, Collection of 
Samples for Pharmacokinetic Analysis
Rationale:  Clarification.
●
Update Section 5.3.3.3, Additional Endpoints
Rationale:  Clarification.
●
Update text in Section 5.4.2, Discontinuation of Entire Study


Atrasentan
M11-352 Protocol Amendment 7
EudraCT 2012-005848-21
8
Rationale:  Clarification.
●
Update text in Section 5.4.3, Study Completion
Rationale:  Clarification.
●
Revise Figure 2, Adverse Event Collection table to clarify collection period for 
Potential Endpoints and SAEs.
Rationale:  Clarification.
●
Update Section 6.5.1, Potential Endpoint Reporting title and text to specify 
events to be reported for subjects in the Enrichment Period.
Rationale:  Clarification.
●
Modify urine collection time points in Section 8.1.3.4, Efficacy Analyses for 
the 24-Hour Urine Sub-Study.
Rationale:  Clarification.
Administrative Changes
●
Administrative Change 4 update Sponsor/Emergency contact
Rationale:  Clarification.
●
Revise Sponsor/Emergency contact 
Rationale:  Clarification.
●
Delete reference in Section 1.2, Synopsis 
Rationale:  Clarification.
●
Added Kaplan-Meier and Hazard ratio abbreviations to List of Abbreviations 
and Definition of Terms
Rationale:  Clarification.
●
Administrative Change 3 inclusion of visit window for Run-In Treatment 
Period.
Rationale:  Clarification.
●
Administrative Change 4 deletion of international system of units in 
Section 5.1, Overall Study Design and Plan:  Description. 
Rationale:  Application of inclusion criteria consistently across all geographic 
regions.


Atrasentan
M11-352 Protocol Amendment 7
EudraCT 2012-005848-21
9
●
Administrative Change 3 removal of the specific ratio for the chronologic 
distribution of non-responders to responders randomized.
Rationale:  Allows for flexibility to alter the ratio if necessary to ensure 
proportional distribution of the two populations.
●
Update Section 5.1, Overall Study Design and Plan:  Description, 
Randomization Visit.
Rationale:  Clarification.
●
Administrative Change 3 inclusion of visit windows during the Double-Blind 
Treatment Period. 
Rationale:  Clarification.
●
Modify End Stage Renal Disease text.
Rationale:  Clarify acceptance of confirmatory values within intended visit 
window, and correct typographical error. 
●
Add Subject Withdrawal header and revise text.
Rationale:  Clarification.
●
Modify Open-Label Extension Study text
Rationale:  To clarify participation will be based on subject eligibility and site
agreement to participate in the open-label study.
●
Administrative Change 4 delete international system of units for Inclusion 
Criterion 7, bullet point four.
Rationale:  Application of inclusion criteria consistently across all geographic 
regions.
●
Delete extra word in Exclusion Criterion 3
Rationale:  Typographical error.
●
Add country code to Sample Receiving contact numbers
Rationale:  Clarification.
●
Administrative Change 3 update PK samples preparation instructions to 
remove the requirements for an ice bath.
Rationale:  Clarification.
●
Revise title and add parenthesis brackets in Section 5.3.3.1, Primary Variables


Atrasentan
M11-352 Protocol Amendment 7
EudraCT 2012-005848-21
10
Rationale:  Clarification.
●
Reference Table 1, Study Activities, in Section 5.3.5, Pharmacokinetic 
Variables for PK collection time points. 
Rationale:  Clarification.
●
Revise text in Section 5.5.5, Blinding
Rationale:  Clarification.
●
Revise text in Section 5.5.5.1, Blinding of Data for Independent Data 
Monitoring Committee (IDMC)
Rationale:  Clarification.
●
Revise Renal Safety Management Team contact information in Section 6.5, 
Adverse Event Reporting.
Rationale:  Clarification.
●
Administrative Change 4 update primary study designated physician in 
Section 6.5, Adverse Event Reporting.
Rationale:  Clarification.
●
Update Section 7.0, Protocol Deviations.
○
Administrative Change 3 update of primary contact.
○
Administrative Change 4 update of alternate contact.
Rationale:  Clarification.
●
Update country code for primary contact office number in Section 7.0, 
Protocol Deviations
Rationale:  Clarification.
●
Administrative Change 4 addition of missing parentheses bracket in 
Section 8.1.3.5, Multiplicity.
Rationale:  Clarification.
●
Administrative Change 3 removed the specific ratio for the chronologic 
distribution of non-responders to responders randomized, to allow for 
flexibility to alter the ratio if necessary to ensure proportional distribution of 
the two populations.
Rationale:  Clarification.


Atrasentan
M11-352 Protocol Amendment 7
EudraCT 2012-005848-21
11
●
Update Appendix B, List of Protocol Signatories
Rationale:  Clarification.
An itemized list of all changes made to the protocol under this amendment can be found 
in Appendix C.


Atrasentan
M11-352 Protocol Amendment 7
EudraCT 2012-005848-21
12
1.2
Synopsis
AbbVie Inc.
Protocol Number:  M11-352
Name of Study Drug:  Atrasentan (ABT-627)
Phase of Development:  3
Name of Active Ingredient:  (2R,3R,4S)-4-
(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-
oxoethyl])-2-(4-methoxyphenyl) pyrrolidine-3-
carboxylic acid, monohydrochloride
Date of Protocol Synopsis:  19 May 2017
Protocol Title:  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
Objectives:  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.
Investigators:  Multicenter study
Study Sites:  800 – 900 sites globally.
Study Population:  Subjects that have type 2 diabetes with nephropathy (eGFR of 
25 – 75 ml/min/1.73 m2 and a urinary albumin to creatinine ratio (UACR) ≥300 mg/g creatinine and 
< 5,000 mg/g).
Number of Subjects to be Enrolled:  Approximately 3,500 subjects will be randomized to the 
Double-Blind Treatment Period.


Atrasentan
M11-352 Protocol Amendment 7
EudraCT 2012-005848-21
13
Overall Study Design:
Methodology:
This is a prospective, randomized, double-blind, enriched-population, placebo-controlled, multicenter 
study.  Eligible subjects will proceed to a run-in period to optimize RAS inhibitor and diuretic doses.
Following the Run-in period, eligible subjects will enter the Enrichment Period in which all will receive 
Atrasentan 0.75 mg once daily (QD) to determine their UACR response and to assess tolerability of 
Atrasentan.  Approximately 2,500 responders (UACR reduction ≥ 30% from baseline) and 
approximately 1,000 non-responders (UACR reduction < 30% from baseline) will then be randomized 
1:1 into the double-blind treatment period.


Atrasentan
M11-352 Protocol Amendment 7
EudraCT 2012-005848-21
14
Methodology (Continued):
The duration of the Double-Blind Period is estimated to be approximately 6 years.  Subjects' doses of 
RAS inhibitors and diuretic should be stable during the treatment period and remain unchanged through 
the end of the study.  If at any time during the study there is an interruption or decrease of RAS inhibitor 
dose, resumption of the previous dose should be attempted within 1 month, according to the 
Investigator's medical judgment.  If there is significant worsening of peripheral edema or other 
symptoms of fluid overload, such as dyspnea with walking or lying down, during any of the treatment 
visits, the Investigator may adjust the diuretic dose as needed.  The study will continue until 425 distinct 
primary renal composite events (doubling of serum creatinine or the onset of ESRD) occurring in the 
responder population have been adjudicated by an independent Events Adjudication Committee (EAC).  
Subjects who reach the endpoint of doubling of serum creatinine or eGFR < 15 ml/min/1.73 m2 will 
remain on study drug until they reach chronic dialysis, renal transplantation or renal death or the 
completion of the trial.  If a subject stops taking study drug, every attempt will be made to keep him/her 
in the study by continuing scheduled study visits and restarting study drug if medically appropriate at the 
discretion of the Investigator.  After 425 events have occurred in the responder population, all subjects 
who have not permanently discontinued study drug will return for a Final Treatment visit and 45-day 
follow-up visit.  Subjects who were permanently discontinued from study drug will complete the next 
scheduled visit.  Upon study completion, eligible subjects will be invited to participate in an open-label 
study if their site is participating in the extension study to determine the long-term safety of Atrasentan.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
To be eligible for initial entry into the study, subjects must meet all of the following criteria:
!
Subject is 18 – 85 years of age at the initial Screening visit (S1).
!
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.
!
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.


Atrasentan
M11-352 Protocol Amendment 7
EudraCT 2012-005848-21
15
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
For entry into the Run-In Period, the subject must satisfy the following criteria:  
!
Screening laboratory values:
o
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);
o
Serum albumin ≥ 2.5 g/dL (25 g/L);
o
BNP ≤ 200 pg/mL (200 ng/L);
o
Serum Potassium ≥ 3.5 mEq/L (3.5 mmol/L) ≤ 6.0 mEq/L (6.0 mmol/L); and
o
SBP ≥ 110 and ≤ 180 mmHg 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 the Run-In 
Period (R6 visit).
!
Subjects on a MTLDD RAS inhibitor for ≥ 4 weeks and not on a diuretic (unless medically 
contra-indicated) at the time of Screening will start with a diuretic and participate in Run-In for 
at least 2 weeks.
Main Exclusion:
Subjects meeting any of the following criteria will be excluded from the study:
!
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 disease 
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).
!
Subject has elevated liver enzymes (serum alanine aminotransaminase [ALT] and/or serum 
aspartate aminotransaminase [AST]) > 3 × the upper limit of normal (ULN).
!
Subject is currently receiving rosiglitazone, moxonidine, aldosterone blockers, aliskiren, or a 
combination of ACEi and ARB.
Investigational Product:
Atrasentan
Dose:
0.75 mg once daily (QD)
Mode of Administration:
Oral
Reference Therapy:
Placebo
Dose:
Not Applicable
Mode of Administration:
Oral


Atrasentan
M11-352 Protocol Amendment 7
EudraCT 2012-005848-21
16
Duration of Treatment:  Subjects will continue on randomized study treatment until discontinued from 
study drug.
Criteria for Evaluation:
Efficacy:
Primary Efficacy Endpoint:
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 ESRD (eGFR < 15 ml/min/1.73 m2
confirmed by a 90-day eGFR, receiving chronic dialysis, renal transplantation or renal death).
Secondary Efficacy Endpoints:
!
Time to a 50% eGFR reduction.
!
Time to cardio-renal composite endpoint:  confirmed doubling of serum creatinine, ESRD, CV 
death, nonfatal myocardial infarction, nonfatal stroke.
!
Time to first occurrence of a component of composite renal end-point: confirmed doubling of 
serum creatinine, or the onset of ESRD for all randomized subjects (pooled).
!
Time to the CV composite endpoint:  CV death, nonfatal myocardial infarction and nonfatal 
stroke.
Pharmacokinetic:
Atrasentan clearance (CL/F) and volume of distribution (Vss/f) will be determined using population 
pharmacokinetic techniques.
Pharmacodynamic:
The relationship between Atrasentan exposure and clinical efficacy and/or safety response(s) may be 
explored.
Statistical Methods:
Analysis Datasets:
The following datasets will be used for the analysis of all efficacy and other non-safety endpoints.  For 
these analyses, subjects will be analyzed in the treatment group to which they were randomized.
!
The Intention-to-treat (ITT) Responder Set will serve as the primary dataset for the analysis 
of efficacy in this study.  It will consist of all randomized subjects who achieve at least 30% 
reduction in UACR in the Enrichment Period (responders).
!
The ITT Non-responder Set will consist of all randomized subjects who achieve less than 30% 
reduction in UACR in the Enrichment Period (non-responders).
!
The ITT Pooled Set will consist of all randomized subjects (both responders and 
non-responders) and will be used for a pooled analysis of efficacy.
The following datasets will be used for the analysis of safety endpoints.  For these analyses, subjects will 
be analyzed according to the treatment they actually receive during the double-blind phase.
!
The All Treated Responder Set includes all randomized subjects who achieve at least 30% 
reduction in UACR in the Enrichment Period and receive at least one dose of study drug during 
double-blind phase.
!
The All Treated Non-responder Set includes all randomized subjects who achieve less than 
30% reduction in UACR in the Enrichment Period and receive at least one dose of study drug 
during double-blind phase.


Atrasentan
M11-352 Protocol Amendment 7
EudraCT 2012-005848-21
17
Statistical Methods (Continued):
Analysis Datasets (Continued):
!
The All Treated Set includes all randomized subjects who receive at least one dose of study 
drug during double-blind phase.
Additionally, an All Atrasentan Set comprising all subjects who receive at least one dose of Atrasentan, 
including both Enrichment and Double-Blind Treatment Periods, is defined for the purposes of data 
analysis.
Sample Size Determination:
The sample size for the Double-Blind Treatment Period is based on the primary efficacy endpoint of 
time to the renal composite event comparing Atrasentan to placebo. A total of 425 events in the ITT set 
is required to detect a 27% hazard reduction (HR of 0.73) with approximately 90% power using a log-
rank test at a two sided significance level of 0.05.  Based on the annual event rate in RENAAL study 
(~13%) and ALTITUDE (~3%), the estimate of the annual placebo event rate in the SONAR study is 
6%.  With the assumption of annual event rate of 6% in placebo group, 42-month accrual period, 
approximate 6 year duration of the Double-Blind Period and an annualized lost to follow-up rate of 2%, 
a total of about approximately 2,500 subjects who achieve at least 30% UACR reduction (responders) in 
the Enrichment Period (1,250 subjects per group) would be needed to be randomized.
In addition, approximately 1,000 subjects who achieve less than 30% UACR reduction in the 
Enrichment Period will also be randomized in a 1:1 ratio to Atrasentan or placebo.
Definition of Baseline:
For treatment comparisons and summaries based on the Double-Blind Treatment Period, baseline values 
refer to the last non-missing value observed prior to or at the time of randomization.  This includes 
treatment comparisons performed for the ITT analysis sets (ITT responder set, ITT non-responder set 
and the ITT pooled set).
For purposes of summarizing safety and efficacy for the Enrichment Period and the entire study 
treatment period (Enrichment and Double-Blind Treatment Period combined), baseline values refer to 
the last non-missing value observed prior to or pre-dose on the first day of Atrasentan therapy 
(Treatment Day 1) at the beginning of the Enrichment Period. 
For specific purposes, e.g., determination of doubling of serum creatinine, baseline values refer to the 
last non-missing value observed prior to or pre-dose on the first day of Atrasentan therapy at the 
beginning of the Enrichment Period.
Primary Efficacy Analysis:
A Cox proportional-hazard regression model will be performed on the ITT responder set to estimate the 
hazard ratio of Atrasentan to placebo and its 95% confidence interval.  The primary efficacy analysis for 
treatment comparison will also be conducted using a stratified log-rank test, adjusting for the following 
stratification factors:
!
UACR level at the beginning of the Enrichment Period (≤ 1,000 mg/g [113 mg/mmol] or 
> 1,000 mg/g [113 mg/mmol]), and 
!
UACR reduction during Enrichment Period (30% – < 45%, 45% – < 60%, and ≥ 60%).  
Kaplan-Meier (KM) estimates for cumulative event rates will be plotted.  


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Statistical Methods (Continued):
Primary Efficacy Analysis (Continued):
In addition, the individual components of the primary efficacy endpoint, i.e., the time to the 
first occurrence of doubling of serum creatinine (confirmed by a 30-day serum creatinine) and the time 
to the first occurrence of the onset of ESRD will be analyzed separately using the same methods as 
specified above.  In analyzing the individual components, first occurrence of only that specific endpoint 
will be considered as events.
Subgroup analyses for subgroups based on age, gender, race, geographical region and important baseline 
characteristics will also be performed.
Secondary Efficacy Analysis:
These pre-specified secondary efficacy endpoints are listed according to their clinical importance and 
will be analyzed in a hierarchical (step-down) fashion.  The analyses of these time-to-event endpoints of 
a 50% eGFR reduction (ITT responder set), a cardio-renal composite endpoint (ITT responder set), the 
composite renal endpoint (ITT pooled set), and the CV composite endpoint (ITT responder set), will 
follow the same methods as specified for the primary efficacy analysis.
Pharmacokinetics:
Population modeling techniques will be used to estimate population central values for Atrasentan 
clearance (CL/F) and volume of distribution (Vss/f), and post hoc values of these parameters for the 
individual subjects will also be estimated.  Additional parameters may be estimated if useful in the 
interpretation of the data.
Safety:
All safety analyses will be conducted on the all treated analysis sets (i.e., all treated responder set, all
treated non-responder set and all treated set, respectively) and the all Atrasentan analysis set (where 
indicated).  No formal statistical tests of treatment difference are planned.
Derivation of Safety Endpoints:
Safety data collected from the first dose up to 45-days post last dose in the double blind period will be 
included in the relevant analyses for the all treated analysis sets, unless otherwise specified in the 
Statistical Analysis Plan (SAP) document.  Safety data collected during the Enrichment Period will be 
summarized for exploratory purposes for the all Atrasentan analysis set.
Study Drug Exposure and Compliance:
The number of days on study drug will be summarized by treatment group and overall.  The number and 
percentage of subjects with at least 70% compliance with study drug at each visit will be summarized by 
treatment group and overall.
Adverse Events (AEs) Analyses:
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Treatment-emergent AEs (i.e., AEs that begin or worsen in severity after initiation of study drug) 
throughout the follow-up period of the study will be summarized by the treatment group in descending 
order of overall frequency by MedDRA preferred term, as well as by system organ class (SOC) and 
MedDRA preferred term.  The incidence rates of treatment-emergent AEs for each treatment group will 
be summarized.  Additionally, the treatment-emergent AEs and serious adverse events (SAEs) will also 
be summarized by the relationship to study drug and their maximum severity.


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Statistical Methods (Continued):
Laboratory Data:
For each laboratory test, the mean change from baseline to the minimum, maximum, and to each visit 
will be summarized by treatment groups.  For selected laboratory tests of interests, the number and 
percentage of subjects whose laboratory value has shifted from normal at baseline to abnormally high or 
low at final will be tabulated by treatment group.
Interim Analysis:
An interim analysis of efficacy will be performed when the number of accrued primary events in the 
responder population is in the range of 50% to 75% of the targeted 425 events for the study.  An alpha-
spending function approach will be used to ensure that the overall one-sided type I error rate will be 
controlled at 0.025 or less.  In addition, an interim analysis of efficacy data for futility only may be 
performed at an earlier time point.  No adjustment to the type I error rate will be made for the futility 
assessment.
To preserve the integrity and the validity of trial data, an external Statistical Analysis Center will 
perform the requisite interim analyses and present the results to IDMC.  Further details of the interim 
analysis plan will be provided in the Statistical Analysis Plan (SAP) and IDMC Charter.  In making any 
decision to recommend discontinuation of the study, either for superior efficacy of Atrasentan or for 
futility, the IDMC shall be guided by a formal stopping rule described in the SAP.
Independent Data Monitoring Committee:
This study will have an IDMC composed of at least two external clinicians and one external statistician 
to review and make recommendations based on the results of the unblinded interim analysis and periodic 
reviews of the safety of Atrasentan. 
Adjudication of Potential Outcome Events:
An independent events adjudication committee (EAC), blinded to study treatment assignment, will 
adjudicate all events that have the potential to be considered endpoints that will be specified in the EAC 
charter.
Steering Committee:
A steering committee will be involved in the design and implementation of the study.  Its membership 
will be representative of the global nature of the study sites and regular meetings will be conducted to 
evaluate the conduct of the trial, including evaluations from the IDMC and EAC.
References:
Westfall PH, Krishen A.  Optimally weighted, fixed sequence and gatekeeper multiple testing 
procedures.  J Stat Plan Inference.  2001;99:25-40.


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
ABP
Ambulatory blood pressure
ACEi
Angiotensin-converting enzyme
AE
Adverse event
AKI
Acute kidney injury
ALT
Serum alanine aminotransaminase
ANOVA
Analysis of variance
AQOL-4D
Assessment of Quality of Life – 4 Dimensions
ARB
Angiotensin II receptor blocker
AST
Serum aspartate aminotransaminase
BMI
Body mass index
BNP
Brain natriuretic peptide
BP
Blood pressure
BUN
Blood urea nitrogen
CAD
Coronary artery disease
CCB
Calcium channel blocker
CFR
Code of federal regulations
CHF
Congestive heart failure
CKD
Chronic kidney disease
CL/F
Oral clearance
Cr
Creatinine
CRF
Case report form
CV
Cardiovascular
CVD
Cerebrovascular Disease
CYP3A
Cytochrome P450, family 3, subfamily A
DBP
Diastolic blood pressure
DNA
Deoxyribonucleic acid
EAC
Events adjudication committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EDTA
Edetic acid (ethylenediaminetetraacetic acid)


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eGFR
Estimated glomerular filtration rate
EMEA
European agency for the evaluation of medicinal products
EPI
Epidemiology collaboration
EQ-5D
EuroQol 5 Dimensions
ESRD
End stage renal disease
ET
Endothelins
ETA
Endothelin-A
ETB
Endothelin-B
FMV
First morning void
FSH
Follicle stimulating hormone
GCP
Good clinical practice
GI
Gastrointestinal
HR
Hazard ratio
Hb
Hemoglobin
HBA1c
Glucosylated hemoglobin A1c
HDL
High density lipoprotein
HOMA-IR
Homeostatic model assessment
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
IND
Investigational new drug
IRB
Institutional Review Board
ITT
Intention to treat
IUD
Intrauterine device
IVR
Interactive voice response
IVRS
Interactive voice response system
IWRS
Interactive Web response system
K
Potassium
KDQOL
Kidney disease quality of life
KM
Kaplan-Meier
LDL
Low density lipoprotein
LDH
Lactic dehydrogenase
MI
Myocardial infarction


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MMRM
Mixed model of repeated measures
MTLDD
Maximum tolerated labeled daily dose
Na
Sodium
NSAIDS
Non-steroidal anti-inflammatory drugs
PD
Premature discontinuation
PG
Pharmacogenetic
P-gp
P-glycoprotein
PI
Principal Investigator
PK
Pharmacokinetic
POC
Point of care
QD
Once daily
QOL
Quality of life
QT
QT interval
QTc
QT interval corrected for heart rate
MedDRA
Medical dictionary for regulatory activities
RAS
Renin angiotensin system
RAAS
Renin-angiotensin-aldosterone system
RBC
Red blood cell
SAE
Serious adverse event
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SDT
Study drug termination
SGPT
Serum glutamic pyruvic transaminase
SGOT
Serum glutamic oxaloacetic transaminase
SI
Standard International Units
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reactions
TGF-β
Transforming growth factor beta
TIA
Transient Ischemic Attack
UACR
Urinary albumin to creatinine ratio
ULN
Upper limit of normal
V/F
Volume of distribution
VLDL
Very low density lipoprotein
WBC
White blood cell


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WHO
World Health Organization
Definition of Terms
First morning void urine
The first void of the morning collected after 5:00 a.m. or upon rising for 
the day.
CKD-EPI (epidemiology 
collaboration) calculation for 
SCr based eGFR
GFR = 141 × min(SCr/κ,1)α × max(SCr/κ,1)–1 209 × 0.993Age
× 1.018 [if female] × 1.159 [if black]
Where SCr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for 
males, α is –0.329 for females and –0.411 for males, min indicates the 
minimum of SCr/κ or 1, and max indicates the maximum of SCr/κ or 1.
HOMA-IR calculation for 
Insulin resistance
Homeostatic model assessment:  (fasting plasma insulin [FPI] × fasting 
plasma glucose [FPG])/22.5.
Stable Dose
Same type and regimen of medication.
Maximum Tolerated Labeled 
Daily Dose (MTLDD) 
The subject's daily dose of ACEi or ARB, at or below the maximum 
dose on the label, that does not exhibit any intolerable adverse effects 
(i.e., hypotension or hyperkalemia), based on the Investigator's 
assessment.
Baseline UACR
Baseline UACR will be the average of the UACR values collected at 
the last week of Run-In (Visit R6) and the first day of Enrichment 
(Visit E1).
Responders 
Subjects who achieve at least a ≥ 30% UACR reduction at the end of 
the Enrichment Period compared to baseline.
Non-Responders
Subjects who achieve < 30% UACR reduction at the end of the 
Enrichment Period compared to baseline.
End-Stage Renal Disease 
(ESRD)
eGFR < 15 ml/min/1.73 m2 (confirmed by a 90-day eGFR), receiving 
chronic dialysis, renal transplant, or renal death.
Study Completion
Study Completion is defined as the occurrence of 425 distinct primary 
renal events in the responder population.  


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2.0
Table of Contents
1.0
Title Page ...............................................................................1
1.1
Protocol Amendment:  Summary of Changes ......................................... 3
1.2
Synopsis............................................................................................... 12
1.3
List of Abbreviations and Definition of Terms...................................... 20
2.0
Table of Contents ................................................................24
3.0
Introduction......................................................................... 29
3.1
Differences Statement .......................................................................... 32
3.2
Benefits and Risks................................................................................ 32
4.0
Study Objectives..................................................................32
5.0
Investigational Plan.............................................................33
5.1
Overall Study Design and Plan:  Description ........................................ 33
5.2
Selection of Study Population............................................................... 48
5.2.1
Inclusion Criteria.................................................................................. 48
5.2.2
Exclusion Criteria................................................................................. 50
5.2.3
Prior and Concomitant Therapy............................................................ 53
5.2.3.1
Guidance for Blood Pressure Management ........................................... 53
5.2.3.2
Guidance for Using RASi and Other Blood Pressure Lowering 
Drugs During the Study........................................................................ 54
5.2.3.3
Guidance for Managing Elevated Serum Creatinine During 
Enrichment Period................................................................................ 55
5.2.3.4
Guidance for Hyperkalemia Management (Serum Potassium 
> 5.5 mmol/L) ...................................................................................... 56
5.2.3.5
Guidance for Stopping RAS Inhibitors During the Double-Blind 
Treatment Period.................................................................................. 57
5.2.3.6
Guidance for Managing Edema or Weight Gain.................................... 57
5.2.3.7
Guidance for Glucose Control .............................................................. 59
5.2.3.8
Guidance for the Diagnosis of Acute Kidney Injury (AKI) ................... 59
5.3
Efficacy and Safety Assessments/Variables.......................................... 60
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ............... 60
5.3.1.1
Study Procedures.................................................................................. 66


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5.3.1.1.1
24-Hour Urine Collection Sub-Study (Additional Consent 
Needed)................................................................................................ 77
5.3.1.2
Blood Samples for Pharmacogenetic Analysis ...................................... 80
5.3.2
Drug Concentration Measurements....................................................... 82
5.3.2.1
Collection of Samples for Pharmacokinetic Analysis............................ 82
5.3.2.2
Handling/Processing of Samples........................................................... 82
5.3.2.3
Disposition of Samples......................................................................... 82
5.3.2.4
Measurement Methods ......................................................................... 83
5.3.3
Efficacy Variables................................................................................ 83
5.3.3.1
Primary Endpoint (Adjudicated)........................................................... 83
5.3.3.2
Secondary Efficacy Endpoints.............................................................. 83
5.3.3.3
Additional Endpoints............................................................................ 83
5.3.4
Safety Variables ................................................................................... 84
5.3.5
Pharmacokinetic Variables ................................................................... 85
5.3.6
Pharmacogenetic Variables................................................................... 85
5.4
Removal of Subjects from Therapy or Assessment ............................... 85
5.4.1
Discontinuation of Individual Subjects ................................................. 85
5.4.2
Discontinuation of Entire Study............................................................ 87
5.4.3
Study Completion................................................................................. 87
5.5
Treatments ........................................................................................... 88
5.5.1
Treatments Administered...................................................................... 88
5.5.2
Identity of Investigational Products ...................................................... 88
5.5.2.1
Packaging and Labeling........................................................................ 89
5.5.2.2
Storage and Disposition of Study Drugs ............................................... 89
5.5.3
Method of Assigning Subjects to Treatment Groups............................. 90
5.5.4
Selection and Timing of Dose for Each Subject.................................... 91
5.5.5
Blinding ............................................................................................... 91
5.5.5.1
Blinding of Data for Independent Data Monitoring Committee 
(IDMC) ................................................................................................ 91
5.5.5.2
Blinding of Data for Events Adjudication Committee (EAC)................ 92
5.5.5.3
Steering Committee.............................................................................. 92
5.5.6
Treatment Compliance ......................................................................... 92
5.5.7
Drug Accountability............................................................................. 93


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5.6
Discussion and Justification of Study Design........................................ 94
5.6.1
Discussion of Study Design and Choice of Control Groups .................. 94
5.6.1.1
Use of an Independent Data Monitoring Committee (IDMC)................ 94
5.6.2
Appropriateness of Measurements........................................................ 94
5.6.3
Suitability of Subject Population .......................................................... 94
5.6.4
Selection of Doses in the Study ............................................................ 95
6.0
Adverse Events .................................................................... 95
6.1
Definitions ........................................................................................... 96
6.1.1
Adverse Event...................................................................................... 96
6.1.2
Serious Adverse Events........................................................................ 97
6.2
Adverse Event Severity ........................................................................ 98
6.3
Relationship to Study Drug................................................................... 98
6.4
Adverse Event Collection Period.......................................................... 99
6.5
Adverse Event Reporting.....................................................................100
6.5.1
Potential Endpoint Reporting for Adjudication ....................................102
6.6
Pregnancy............................................................................................103
7.0
Protocol Deviations ........................................................... 103
8.0
Statistical Methods and Determination of Sample 
Size ..................................................................................... 104
8.1
Statistical and Analytical Plans............................................................104
8.1.1
Analysis Datasets ................................................................................105
8.1.2
Demographic, Other Baseline Characteristics, Subject Disposition 
and Concomitant Medication...............................................................106
8.1.3
Efficacy Analyses................................................................................108
8.1.3.1
Primary Efficacy Analyses (Responders).............................................109
8.1.3.2
Secondary Efficacy Analysis ...............................................................110
8.1.3.3
Additional Efficacy Analysis...............................................................110
8.1.3.4
Efficacy Analyses for the 24-Hour Urine Sub-Study............................111
8.1.3.5
Multiplicity .........................................................................................112
8.1.4
Safety Analyses...................................................................................112
8.1.4.1
Adverse Events (AEs) Analyses ..........................................................113
8.1.4.2
Clinical Laboratory Data .....................................................................114
8.1.4.3
Vital Signs Data ..................................................................................114


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8.1.4.4
ECG Analyses.....................................................................................114
8.1.4.5
Safety Data in the Enrichment Period ..................................................114
8.1.5
Interim Analysis..................................................................................115
8.1.6
Independent Data Monitoring Committee (IDMC) and 
Independent External Statistician.........................................................115
8.2
Determination of Sample Size .............................................................116
8.3
Randomization Methods......................................................................117
9.0
Ethics.................................................................................. 117
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ........................................................................................117
9.2
Ethical Conduct of the Study...............................................................118
9.3
Subject Information and Consent.........................................................118
9.3.1
Informed Consent Form and Explanatory Material ..............................120
9.3.2
Revision of the Consent Form and Explanatory Material .....................120
10.0
Source Documents and Case Report Form 
Completion ........................................................................ 120
10.1
Source Documents...............................................................................120
10.2
Case Report Forms..............................................................................121
11.0
Data Quality Assurance .................................................... 122
12.0
Use of Information ............................................................ 123
13.0
Completion of the Study ................................................... 124
14.0
Investigator's Agreement.................................................. 125
15.0
Reference List.................................................................... 126
List of Tables
Table 1.
Study Activities.................................................................................... 61
Table 2.
Reminder Phone Calls .......................................................................... 71
Table 3.
Clinical Laboratory Tests ..................................................................... 75
Table 4.
Study Activities for Optional 24-hour Urine Sub-Study........................ 79
Table 5.
Identity of Investigational Products ...................................................... 88


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List of Figures
Figure 1.
Study Schematic................................................................................... 34
Figure 2.
Adverse Event Collection....................................................................100
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator.........................................128
Appendix B.
List of Protocol Signatories .................................................................130
Appendix C.
Protocol Amendment:  List of Changes ...............................................131


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3.0
Introduction
The endothelins (ET), first identified in 1988, are a family of three paracrine/autocrine 
peptide factors (ET-1, ET-2 and ET-3) produced in a variety of tissues.1  ET-1, the main 
isoform in mammalian tissues and fluids, is produced primarily in endothelial cells, but 
also in vascular smooth muscle cells.  ET-2 is produced predominantly in the kidney and 
intestine, and ET-3 has been found in high concentrations in the brain.2,3  Endothelins act 
as modulators of vasomotor tone, nociception, cell proliferation, and hormone 
production.2-4  Two types of endothelin receptors have thus far been identified, ETA and 
ETB.  ETA receptors have a high affinity for ET-1 and ET-2, whereas ETB receptors have 
equal affinity for all ET-related peptides.4,5  ETA receptors are primarily responsible for 
ET-1 mediated vasoconstriction, cell proliferation, and promotion of vascular 
remodeling.6  ETB receptors are thought to provide a mechanism for the removal of 
excessive endothelins; they may also modulate arterial tone, however, when ET-1 
concentrations are elevated.7
The roles for ETA and ETB receptor subtypes in renal and cardiovascular (CV) disease are 
under investigation.  Animal and human data suggest that ETB receptor blockade could be 
harmful to the kidney, whereas ETA receptor blockade may improve glomerular function 
by attenuating the vasoconstrictive action of ET-1.8,9  Endothelins may play a significant 
role in the pathophysiologic changes that occur at the vascular level in diabetes mellitus 
and lead to complications of retinopathy, neuropathy, and renal failure.10  Glucose is a 
strong stimulator of endothelin receptor expression in cultured endothelial and vascular 
smooth muscle cells11 and recent evidence suggests a relationship between the duration of 
type I diabetes mellitus and the elevation of plasma ET-1.  ET-1 levels are higher in 
subjects with both diabetes and hypertension12 and they correlate with long-term control 
of the disease in type I diabetes.  Additionally, endothelins may play a role in volume 
homeostasis by inducing renal vasoconstriction and sodium retention, as has been 
demonstrated in humans.13


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The drug substance ABT-627 (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-
2-oxoethyl]-2-(4-methoxyphenyl) pyrrolidine-3-carboxylic acid, monohydrochloride is an 
orally bioavailable, potent endothelin receptor antagonist with a high selectivity for the 
ETA receptor.14  Preclinical studies have demonstrated that ABT-627 (Atrasentan) inhibits 
mitogen and vascular biological responses induced by ET-1 challenge.15
ET-1 has also been shown to play a role in the pathogenesis of proteinuria and glomerular 
injury in a rat model of proliferative nephritis.16  Administration of a selective ETA
receptor antagonist to rats with experimental glomerulonephritis showed reduction in 
mesangial cell proliferation, supporting the hypothesis that ET-1 is a potent mitogen for 
mesangial cells.17  In a rat model of diabetic nephropathy, Atrasentan treatment attenuated 
albuminuria and glomerulosclerosis in association with reductions in glomerular 
permeability (and urine TGFβ).17,18  In a double-blind, placebo-controlled, Phase 2 
crossover study in 11 subjects with type 1 diabetes and proteinuria who were not 
receiving renin-angiotensin system (RAS) inhibitors, 
 Atrasentan 5 mg 
per day for 42 days resulted in a 65% reduction in urinary albumin excretion.  Mean 
arterial blood pressure (BP) was also reduced, however there was only a weak correlation 
between change in BP and albuminuria reduction.  
 
 
  
In subsequent Study M10-815, a double-blind, randomized, placebo-controlled study of 
89 subjects with type 2 diabetes and albuminuria who were on stable doses of RAS 
inhibitors, treatment with Atrasentan 0.75 or 1.75 mg per day for 8 weeks resulted in 
significant reductions in the mean urinary albumin to creatinine ratio (UACR) from 
baseline for subjects taking 0.75 mg per day (42% reduction, one-sided P = 0.023) and 
1.75 mg per day (35% reduction, one-sided P = 0.073) compared to placebo 
(11% reduction), whereas subjects receiving 0.25 mg per day had a non-significant mean 
UACR reduction of 21% (P = 0.291).  The most commonly experienced 
treatment-emergent adverse events were peripheral edema in 9% of placebo, 14% in 


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0.25 mg Atrasentan, 18% in 0.75 mg Atrasentan and 46% in the 1.75 mg Atrasentan dose 
groups, most of which were mild to moderate in severity and did not result in 
discontinuation from the study.  There was no statistical significant difference in serum 
concentration of ET-1 of those subjects receiving Atrasentan as compared to placebo.
In a series of Phase 2b, dose-ranging studies involving 255 subjects who were taking the 
maximum tolerated labeled daily dose (MTLDD) of RAS inhibitors (Studies M11-350, 
M12-812 and M12-830), the UACR lowering effect of Atrasentan was confirmed. In 
Study M11-350 (RADAR), 153 subjects from the US, Canada and Taiwan, were 
randomized to placebo, 0.75 mg or 1.25 mg daily of Atrasentan for 12 weeks.  UACR 
reductions of 37.7% and 40.6% were observed with the respective doses (0.75 and 
1.25 mg per day), compared to placebo (P < 0.01).  In the M12-812 study of 54 Japanese 
subjects, doses of 0.75 and 1.25 mg daily resulted in 31.4% and 53.7% UACR reduction, 
respectively, compared to placebo.  In the M12-830 study of 48 subjects, doses of 0.5 and 
1.25 mg daily resulted in 27.6% and 37.4% UACR reduction, respectively.  The most 
common adverse event was peripheral edema, which was not different among the 
treatment groups in all three studies.  There were three serious adverse events of 
congestive heart failure (1 [1.5%] in placebo, 1 [1.2%] in 0.75 mg and 1 [1.0%] in 
1.25 mg groups).
A detailed discussion of the preclinical toxicology, metabolism, clinical safety and 
pharmacology can be found in the Investigator's Brochure.19
The purpose of this Phase 3 study is to characterize the efficacy and safety of Atrasentan 
in subjects with type 2 diabetes and nephropathy who have residual albuminuria while 
receiving MTLDD of RAS inhibitors (Section 4.0), in delaying renal disease progression.  
The primary endpoint will be the time to doubling of serum creatinine or end stage renal 
disease (ESRD).


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3.1
Differences Statement
This is the first Phase 3 study in subjects with type 2 diabetes and nephropathy to utilize 
the Atrasentan tablet formulation.  This study differs from the previous Phase 2 studies in 
that it is an event driven trial, with time to doubling of serum creatinine or ESRD as the 
primary composite endpoint, and including cardiovascular events as secondary endpoints.
3.2
Benefits and Risks
Atrasentan is a highly potent and selective endothelin-A (ETA) receptor antagonist being 
developed for the treatment of patients with diabetic nephropathy.
Atrasentan has been evaluated in 5 studies in subjects with diabetic nephropathy:  
one Phase 2a study in subjects with type 1 diabetic nephropathy who were not receiving 
renin-angiotensin-aldosterone system (RAS) inhibitors 
 one Phase 2a 
study in subjects with type 2 diabetic nephropathy who were receiving stable doses of 
RAS inhibitors (Study M10-815) and three Phase 2b studies (Studies M11-350, M12-830, 
and M12-812) in subjects with type 2 diabetes and nephropathy who were receiving 
MTLDD of RAS inhibitors.
All studies showed that Atrasentan effectively reduced urinary albumin excretion with 
minimal fluid retention for up to 12 weeks of treatment.  This study will provide definitive 
long-term efficacy and safety information of Atrasentan for slowing the progression of 
chronic kidney disease (CKD).  There is a potential for fluid retention as CKD progresses 
over time.
The hypothesis of this Phase 3 study is that Atrasentan 0.75 mg QD is superior to placebo 
in delaying renal disease progression in subjects with type 2 diabetes and nephropathy.
4.0
Study Objectives
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 


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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.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a prospective, randomized, double-blind, enriched-population, placebo-controlled, 
multicenter study.
The study was designed to randomize approximately 3,500 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations. Therefore, if the target number of subjects has been randomized, 
there is a possibility that additional subjects in screening will not be enrolled.
Subjects who meet the inclusion for initial study entry and none of the exclusion criteria 
will be eligible to proceed to the Run-In Period to optimize RAS inhibitor prior to 
receiving study drug (Atrasentan) in an Enrichment Period.
The study will be performed in five to six periods in the following sequence:
●
Pre-Screening Period (optional)
●
Screening Period
●
Run-In Period
●
Enrichment Period
●
Double-Blind Treatment Period
●
Follow-Up Period
A schematic of the study design is shown below in Figure 1.


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Figure 1.
Study Schematic
A description of the study periods is noted below.  Study procedures for each visit are 
outlined in Table 1.
Pre-Screening Period (Optional)
The Pre-Screening Period is for subjects who do not have recent documented eGFR 
and/or UACR values.  Subjects will sign a pre-screening informed consent and will need 
to complete the Pre-Screening Visit activities.  The activities include collection of a blood 
and urine sample to measure eGFR and UACR with the point of care (POC) devices.
Data collected during the pre-screening will not be recorded on an electronic case report 
form (eCRF) and included in the study database.


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Screening Period (Visits S1 and S2)
The Screening Period will consist of 2 visits.  The procedures to be performed at the 
initial Screening visit (S1) are outlined in the Study Activities Table (Table 1).  The site 
will also call into the Interactive Voice Response System/Interactive Web Response 
System (IVRS/IWRS) to register the subject and obtain the subject number.  All subjects 
will be given supplies and instructions for obtaining 2 consecutive first morning void 
(FMV) urine collections that need to be collected within 2 days of the second visit in the 
Screening Period.
The second Screening visit (S2) will be scheduled within 2 weeks after the initial 
Screening visit.  The procedures to be performed at the second Screening visit (S2) are 
outlined in Table 1.  At this visit, the subject will bring in their 2 consecutive FMV urine 
collections that will be used to determine the UACR for assessing the subject's eligibility.
While subject is in screening, tests for eligibility may be repeated within the screening 
window.  Subjects who screen fail will be allowed to rescreen per investigator's judgment.
During Screening, the Investigator should document in the source if the subject is or is not 
on a MTLDD of a RAS inhibitor and which Run-In visit the subject should proceed to (as 
described below in the Run-In Period).  If the subject is currently on the MTLDD of a 
RAS inhibitor and a diuretic, he/she will be given supplies and instructions for obtaining 
3 consecutive FMV urine collections that need to be collected within the 3 days of his/her 
next visit (Run-In R6 visit).
Run-In Period (Up to 12 Weeks) (Visits R1 – R6)
If the subject meets inclusion criteria for run-in, the subject will be allowed to proceed to 
the Run-In Period within 1 – 2 weeks of confirmed eligibility.  IVRS/IWRS will be called 
to confirm eGFR cap has not been met in order for the subject to continue.  The Run-In 
Period will consist of up to 6 visits.


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The purpose of the Run-In Period is to optimize RAS inhibitor doses to a MTLDD for 
optimal blood pressure (BP) control according to local guidelines and to add a diuretic (if 
possible) for blood pressure control as well as to enhance RAS inhibitor effects on UACR 
reduction.23  The procedures to be performed at each Run-In visit are outlined in Table 1.  
Subjects will be given supplies and instructions for collecting 3 consecutive FMV urine 
samples that need to be collected within the 3 days of the last visit in the Run-In Period 
(R6).
The subject will enter into the Run-In Period as follows:
●
If the subject is already receiving a MTLDD of a RAS inhibitor, such as 
angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor 
blocker (ARB), and a diuretic at Screening, he/she may proceed to the last visit 
in the Run-In Period (R6) and then proceed to the Enrichment Period 
approximately 2 weeks later.
●
If the subject is already receiving a MTLDD of a RAS inhibitor but not on a 
diuretic (unless medically contraindicated), he/she will proceed to the first visit 
of the Run-In Period (R1) to be placed on a diuretic for a minimum of 
2 weeks, then proceed to the R6 visit.
●
If the subject is currently not receiving a MTLDD of a RAS inhibitor, the dose 
will be titrated up to the MTLDD over the course of up to 12 weeks.
●
If subject is currently receiving a RAS inhibitor and has hyperkalemia the dose 
of RAS inhibitor may be down titrated according to the Investigator's 
judgment.  The new lower dose would be the MTLDD and the subject would 
proceed to Run-In (R1) for 4 weeks of stable MTLDD of RAS inhibitor, then 
proceed to the R6 visit.
During the Run-In Period, BP control and tolerance to the new therapeutic doses will be 
assessed approximately every other week (± 2 days).  The RAS inhibitor dose should 
remain stable during the 4 weeks immediately prior to the Enrichment Period; however, 
dose adjustments of non-RASi may be necessary based on the clinical discretion of the 
Investigator for BP control and worsening or new onset of edema.  Diuretic 
discontinuation or decrease in dose will be allowed for clinical signs and symptoms of 


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volume depletion (e.g., orthostatic hypotension, unexplained dizziness).  If a subject is on 
the MTLDD of a RAS inhibitor and a diuretic and experiences symptomatic hypotension, 
dose reductions of non-RAS antihypertensive medications should be performed first.  If 
the subject continues to have hypotension after an additional week, the diuretic dose 
should be reduced or withdrawn at the discretion of the Investigator.  If the subject 
continues to have symptomatic hypotension after an additional week, the subject should 
be discontinued from the RAS inhibitor and discontinued from the study as a screen failed 
subject.
Non-RAS blood pressure medications (calcium channel blockers, beta blockers, central 
acting agents) may be adjusted during the Run-In Period, if needed, to achieve optimal 
blood pressure control according to local guidelines.  Refer to Section 5.2.3 guidance for 
managing concomitant medications.
Subjects who fail to meet eligibility criteria for the Enrichment Period may be 
re-screened.  If at Run-In R5 visit, the dose of the RAS inhibitor is not tolerated in the 
opinion of the Investigator, the Run-In R5 visit can be repeated 2 weeks (±10 days) after 
the RAS inhibitor adjustments.
If at the Run-In R6 visit, the dose of the RAS inhibitor is not tolerated in the opinion of 
the Investigator, the Run-In R6 visit can be repeated 4 weeks (±10 days) after the RAS 
inhibitor adjustments.  The Run-In R6 visit may not be repeated if the Run-In R5 visit was 
repeated.
If the subject meets the inclusion criteria for the Enrichment Period at the last Run-In visit 
(R6), the subject will be allowed to proceed to the Enrichment Period 2 weeks (±10 days) 
after his/her last Run-In visit.  Subjects will be given supplies and instructions for 
collection of 3 consecutive FMV urine samples within 3 days of the first visit of the 
Enrichment Period (E1).  


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Enrichment Period (6 Weeks) (Visits E1 – E5)
The Enrichment Day 1 (E1) visit will occur 2 weeks (±10 days) after the Run-In R6 visit.  
The procedures to be performed at the first Enrichment Period E1 visit are outlined in 
Table 1, including administration of open-label study drug (Atrasentan).  At this visit, the 
subject will bring in his/her 3 consecutive FMV urine collections.  The site will call into 
the IVRS/IWRS and dispense open-label study drug (Atrasentan) to the subject.  Subjects 
will remain on open-label Atrasentan until Randomization into the Double-Blind 
Treatment Period.
All Enrichment visits should take place the same day of the week, if possible (i.e., if 
Enrichment visit E1 occurred on a Wednesday then Enrichment visit E2 should take place 
the following Wednesday).  Subject compliance to study drug administration will be 
assessed by the Investigator or designee at each visit during the Enrichment Period 
(Section 5.5.6).
The Enrichment E2 visit will take place 1 week (±2 days) after the E1 visit.  The 
Enrichment E3 visit will take place 1 week (±2 days) after the E2 visit.  The procedures to 
be performed at Enrichment E2 and E3 visits are outlined in Table 1.  At the Enrichment 
E3 visit, subjects will be given supplies and instructions for collection of 3 consecutive 
FMV urine samples that need to be collected within 3 days of the Enrichment E4 visit.
The Enrichment E4 visit will take place 2 weeks (±2 days) after the E3 visit.  The 
procedures to be performed at the Enrichment E4 visit are outlined in Table 1.  Supplies 
and instructions for collection of 3 consecutive FMV urine samples that need to be 
collected within the 3 days prior to the last visit (E5) in the Enrichment Period will be 
given to the subject.  The site will also call into the IVRS/IWRS at this visit and provide 
the subject with study drug (Atrasentan).
The Enrichment E5 visit will take place 2 weeks (±2 days) after the E4 visit.  The 
procedures to be performed at the E5 visit are listed in Table 1.


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The geometric mean of the FMV urine samples collected at Enrichment E4 and E5 visits 
will be used to determine the response group for each subject as compared to the baseline 
UACR.  Initial UACR for the Enrichment Period is defined as the geometric mean of the 
3 UACR values at the last Run-In visit (R6) and the 3 UACR values at the 
first Enrichment visit (E1).  Every subject should have 6 FMV samples analyzed from R6 
and E1 visits to calculate the initial UACR; however, the subject will be allowed to enter 
the Enrichment period if a minimum of three FMVs have been collected between the 
two visits.  In addition, every subject should have 6 FMV samples analyzed (from E4 and 
E5 visits); however, the subject may be allowed to enter the Double-Blind Treatment 
period if a minimum of three FMVs have been collected between the two visits.
If the subject meets the inclusion criteria for randomization at the last Enrichment Period 
visit, the subject will be allowed to proceed to the Double-Blind Treatment Period; 
however, if the subject meets one of the primary or secondary endpoints, as defined for 
the Double-Blind Treatment Period (refer to Section 6.5.1), during Enrichment or if the 
subject has a significant increase in serum creatinine (defined below), he/she will be 
discontinued from the study and will not be allowed to proceed to the Double-Blind 
Treatment Period.
Serum Creatinine Elevation During Enrichment
Subjects must not have an increase in serum creatinine > 0.5 mg/dL AND > 20% from 
E1 to the E5 visit.  Subjects that experience an increase in serum creatinine 
> 0.5 mg/dL and 20% from baseline (E1) should be permanently discontinued from 
study drug, return for the Premature Discontinuation visit within 9 days, and be 
followed weekly, up to 4 weeks, to test for serum creatinine until serum creatinine 
returns to baseline ±10%.  In addition, the 45-day Follow-Up (F1) visit should be 
completed.
The number of subjects with eGFR 60 – 75 ml/min/1.73 m2 at the E1 visit who are 
randomized in the responder population will be capped at approximately 300 subjects.  
After the cap has been reached, subjects with an eGFR of > 60 ml/min/1.73 m2 at 


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Screening (S1) will not be allowed to enter into the study.  Such subjects will be 
considered screen failures.  Even after the cap has been reached, subjects who have 
entered the Run-In Period or are already receiving Atrasentan in the Enrichment Period 
who have an eGFR 60 – 75 ml/min/1.73 m2 at the E1 visit will be allowed to move into 
the Double-Blind Treatment Period.
A responder/non-responder ratio design was set up to ensure proportional distribution to 
the expected enrollment.  The implementation of this ratio will be through the IRT 
system.  The ability to randomize non-responders will "turn on and off" based on the 
responder/non-responder ratio of randomization.  The non-responder arm will re-open to 
enrollment at any given time without notice, as the randomization scheme is applied, until 
enrollment of approximately 1,000 subjects in the non-responder arm of the protocol is 
complete.
Subjects discontinued in the Enrichment Period may be re-screened and re-enrolled at the 
S1 visit after 3 months have passed from last dose of study drug at the discretion of the 
Investigator.
Randomization Visit
The Randomization visit will occur 1 – 2 weeks after the subject's last Enrichment Period 
visit.  The site will call into the IVRS/IWRS to obtain the blinded treatment.  If the 
non-responder cap is met and a subject has achieved < 30% UACR reduction at the end of 
the Enrichment Period compared to baseline, the IVRS/IWRS will inform the site that the 
subject cannot continue into the Double-Blind Treatment Period.  Procedures to be 
performed at this visit are outlined in Table 1. Subjects that have consented to the 
separate pharmacogenetic (PG) analysis will have a sample collected at this visit.  
Subjects who have met the entry criteria will be randomized in a 1:1 ratio to receive 
Atrasentan or placebo; the subject will receive a drug supply adequate until the 
first Treatment Period visit (T1).  Subjects should be administered the first dose of study 
drug at the Randomization visit.  Subjects will be given supplies and instructions for the 
collection of 1 FMV urine sample that needs to be collected within 1 day of the T1 visit.


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Subjects will be randomized in the Treatment Period if the subject did not experience a 
serious adverse event(s) or reaction(s) possibly related to the study drug during the 
Enrichment Period.  Randomization will be based on UACR response to Atrasentan from 
the Enrichment Period (Please refer to Section 8.3 for details of the stratification factors).  
Approximately 1,000 subjects in the non-responder population will be randomized.  For 
subjects who present for the Randomization visit that are determined to be ineligible for 
the Double-Blind Treatment Period or if the non-responder cap has been reached, a 
Premature Discontinuation visit can be conducted instead.  Collection of the FMV urine 
sample for the Premature Discontinuation visit will not be required for these subjects.
Double-Blind Treatment Period (Randomization – Final Treatment Visit)
Subjects will be contacted by telephone at 1 and 2 weeks after the subject's 
Randomization visit to inquire about symptoms of hypotension (dizziness, dizziness with 
standing, falling, excess thirst).  If necessary, unscheduled visits should be made during 
this time for a limited physical exam and to measure blood pressure.  Dosages of diuretics 
or other blood pressure medications may be adjusted during these unscheduled visits.
The first Treatment Period visit (T1) will occur 1 month (±7 days) after the 
Randomization visit.  Procedures to be performed at the Treatment T1 visit are outlined in 
Table 1.  The subject will bring in his/her 1 FMV urine sample that was collected within 
1 day of the T1 visit.  The site will call into the IVRS/IWRS at this visit and provide the 
subject with study drug and perform drug accountability (Section 5.5.6).
T3 will occur 3 months (± 2 weeks) after randomization (2 months after T1).
The procedures conducted at the 3-month visits during the Treatment Period are listed in 
Table 1.  The visit window for all Treatment Visits after T1 is ± 2 weeks.  The site will 
call into the IVRS/IWRS at each of these visits, collect unused study drug dispensed at the 
previous visit, perform drug accountability (Section 5.5.6), and provide the subject with 
adequate supply of study drug.  Subjects will also be given supplies and instructions when 


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required for the collection of 1 FMV urine sample that needs to be collected within 1 day 
of the yearly treatment visit (T12, T36, T48, etc).
For the T24 visit, 3 FMV urine samples are needed.  At the T21 visit, subjects will be 
given supplies and instructions for the collection of 3 FMV urine samples that need to be 
collected within the 3 days of the T24 visit.
At the Final Treatment/PD visit, IVRS/IWRS will be called.  Subjects will return study 
drug and site staff will perform and document drug accountability.
Subjects' doses of RAS inhibitor and diuretic should remain stable during the 
Double-Blind Treatment Period and remain unchanged through the end of the study, 
unless there is a medical need to alter the doses.  Subjects will be provided diaries to 
collect information regarding weight between visits, with instructions on actions to be 
taken if significant weight gain occurs.
If at any time during the study there is an interruption or decrease of the RAS inhibitor 
dose, the subject should be returned to the previous dose within 1 month, if possible, 
according to the Investigator's medical judgment.  If there is significant worsening of 
peripheral edema during any of the treatment visits, the Investigator may increase the 
diuretic dose as needed.
If at any time during the study there is an interruption of the study drug administration, 
the reason for interruption should be captured on the eCRF and the subject should be 
re-started as soon as possible according to the Investigator's judgment.  The study drug 
should only be restarted if it is medically appropriate.  There is no time limit for a subject 
to be off the study drug that would prevent re-starting it.  The subject would not be 
considered a premature discontinuation unless the subject permanently discontinues study 
drug administration.


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Primary Efficacy Endpoints
Doubling of Serum Creatinine
Once a doubling of serum creatinine has been recorded, the Investigator will be informed 
by the central laboratory; subsequently, the site personnel will contact the subject to 
schedule a return visit sometime between 30 and 40 days from the last visit to have blood 
sampling for serum creatinine to confirm doubling of serum creatinine.  If the subject 
misses the return visit during the 30 – 40 day window, the subject will continue to be 
followed until a return visit can be conducted.  The Investigator will make all reasonable 
attempts to exclude reversible causes of elevation of serum creatinine such as volume 
depletion or nephrotoxic medication.  Once doubling of serum creatinine is confirmed, the 
site will report the event in eClinical©, as described in Section 6.5.1, to begin the process 
of collecting the information required to have the event properly adjudicated by the 
independent Event Adjudication Committee (EAC).  Subjects who reach the endpoint of 
doubling of serum creatinine will remain on study drug until they receive chronic dialysis 
or experience renal transplantation or the occurrence of renal death or until completion of 
the trial.
End Stage Renal Disease
ESRD will be defined as eGFR < 15 ml/min/1.73 m2 receiving chronic dialysis, renal 
transplantation or the occurrence of renal death.  Once an eGFR < 15 ml/min/1.73 m2 is 
reported the Investigator will be informed by the central laboratory.  The lab should be 
confirmed at the next 3 month scheduled visit or at an unscheduled visit at approximately 
90 days (confirmatory values within the intended study visit window will be acceptable).  
If the subject misses the return visit, the visit should be rescheduled as soon as possible.  
The Investigator will make all reasonable attempts to exclude reversible causes of 
elevation of serum creatinine such as volume depletion or nephrotoxic medication.  Once 
an eGFR < 15 ml/min/1.73m2 is confirmed, the site will report the event in eClinical©, as 
described in Section 6.5.1, to begin the process of collecting the information required to 
have the event properly adjudicated by the independent EAC.  Subjects who reach the 
endpoint of an eGFR < 15 ml/min/1.73 m2 will remain on study drug until they receive 


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chronic dialysis or experience renal transplantation or the occurrence of renal death or 
until completion of the trial.
Renal death as an event is defined as death that occurs when:  1) the patient refuses renal 
replacement therapy (RRT) because they believe their current quality of life, with their 
expected lifespan, outweighs the quality and quantity of life following RRT, or 2) when 
both the clinician and the subject consider RRT futile and believe that the patient's current 
quality of life, with their expected lifespan, outweighs the quality and quantity of life 
following RRT.  Such events will be classified as renal death when the subject dies 
following refusal of dialysis AND no other cause of death is adjudicated.  The diagnosis 
of renal death is not intended for subjects in whom dialysis is not offered or withdrawn 
because of advanced cancer, severe sepsis, advanced heart failure, or terminal organ 
failure.  In such instances, the primary diagnosis that led to withholding RRT will be 
designated the cause of death.  Renal death is intended for those events in which dialysis 
is deliberately withheld due to advanced age of the subject, lack of availability of dialysis, 
or the wishes of the subject not to be dialyzed.  When a more specific cause of death is 
adjudicated, such as sepsis, pneumonia, or trauma, such more specific causes will be 
designated as the primary cause of death.
Subjects who reach the endpoint of confirmed doubling of serum creatinine or confirmed 
eGFR < 15 ml/min will remain on study drug until they experience chronic dialysis, or 
renal transplantation.  If the subject receives chronic dialysis or renal transplantation, 
he/she will permanently discontinue study drug administration and complete the 
Premature Discontinuation visit procedures and Follow-Up (F1) visit.  For subjects 
receiving chronic dialysis or renal transplantation, laboratory samples will be collected at 
the Follow-Up (F1) visit or any remaining study visits at the discretion of the Investigator.  
In addition, they will be encouraged to continue the study visit assessments or be followed 
by quarterly phone calls or allow medical record review until the completion of the trial 
(refer to Premature Discontinuation and Retention section below).


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Premature Discontinuation and Retention
Subjects who have received at least one dose of study drug (i.e., enrolled in the 
Enrichment Period) will be considered a Premature Discontinuation if he/she has 
permanently discontinued study drug administration before study completion.  Subjects 
permanently discontinued during the Enrichment Period should have a Final 
Treatment/Premature Discontinuation visit within 9 days and a Follow-Up (F1) visit 
45 days (±14 days) of the last dose of study drug.  These subjects should not continue 
further in the study.  Subjects permanently discontinued during the Double-Blind 
Treatment Period should have a Final Treatment/Premature Discontinuation visit within 
9 days and a Follow-Up (F1) visit 45 days (±14 days) of the last dose of study drug.  
These subjects should continue with all scheduled study visits if possible as specified in 
Section 5.3.1.1.
It is recommended that subjects not be permanently discontinued from the study drug 
administration or from the study until the Investigator discusses the reason for permanent 
discontinuation with the Sponsor.  The Investigator may have a subject pause study drug 
at any time for any reason.
As noted above, if a subject permanently discontinues study drug, the Final 
Treatment/Premature Discontinuation visit should occur within 9 days of the last dose of 
study drug.  Procedures to be performed at the Final Treatment/Premature Discontinuation 
visit are outlined in Table 1.  The reason for discontinuation will be documented in the 
subject's source documents at the site and the electronic case report forms (eCRF).
If the study drug administration is temporarily stopped for an individual subject, the 
Investigator should make every attempt to re-start study drug, if medically appropriate, 
regardless of the time passed from discontinuation.  A premature discontinuation visit and 
F1 visit will not be performed on the subjects that temporarily stop study drug 
administration.  Whenever possible, Investigators should encourage subjects to continue 
with on-site study assessments even after they discontinue taking study drug during the 
Double-Blind Treatment Period.  Study assessments and visits would occur following the 


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schedule of activities (Table 1).  IVRS/IWRS, dispense study drug, drug accountability, 
and PK sampling would not occur at these visits unless study drug administration has 
resumed.  If the subject is unable or unwilling to undergo on-site assessments for an 
upcoming quarterly visit, study staff should make telephone contact and encourage 
subjects to allow further assessments.  Telephone assessments should only be utilized 
when necessary.  As part of the telephone assessment, the site will elicit or collect 
information regarding, but not limited to, concurrent medications, occurrence of renal and 
cardiovascular events including chronic dialysis, and local laboratory reports (if 
available).  If the subject is unwilling to receive phone calls, he/she should be encouraged 
to allow collection of data about renal and cardiovascular events and recent laboratory 
values from medical records or through contacts with the treating physician.  An 
authorization to release information from the subject should be obtained.
Home Visits
In exceptional cases, visiting nurse services may be available for use, as needed.  Sponsor 
approval will be required prior to implementation of the nursing service.  Study activities 
such as local or central laboratory sample collection and processing may be conducted in 
the home or non-hospital/clinic environment by qualified individuals.  
Subject Withdrawal
Withdrawal refers to the complete withdrawal from the study for any reason before the 
end of the study, including death.  A subject who withdraws consent will discontinue 
taking study drug and will be encouraged to return for the Final Treatment/Premature 
Discontinuation visit within 9 days and the Follow-Up F1 visit 45 days (±14 days) of the 
last dose of study drug. Withdrawal of consent for follow-up should be accompanied by 
documentation of the reason for withdrawal.  Withdrawal of consent for study drug should 
be distinguished from withdrawal of consent for follow-up visits and from withdrawal of 
consent for non-subject contact follow-up (e.g., medical records checks).  Subjects 
requesting withdrawal should be informed that withdrawal of consent for follow-up will 
jeopardize the public health value of the study.  Subjects who withdraw should be 


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explicitly asked about the contribution of possible adverse events to their decision to 
withdraw consent and any adverse event information elicited should be documented.  
Subjects who withdraw should do so in writing and failure to do that should be 
documented by the site and include the reason for the subject's failure to provide written 
withdrawal of consent.  It is expected that subjects who permanently discontinue study 
drug will agree to remain for follow-up status evaluations.  For subjects who are lost to 
follow-up without withdrawing consent, attempts will be made by the Investigator (or 
designee) to obtain further information.
Follow-Up Period (45 Days) (Visit F1)
Upon permanent discontinuation of study drug administration or study completion 
(425 distinct primary renal events have occurred in the responder population), all subjects 
will have one scheduled Follow-Up (F1) visit occurring 45 days (±14 days) after the last 
dose of study drug.  Procedures to be performed at the F1 visit are outlined in Table 1.  If 
the subject indicates that he/she will not be able to return for the F1 visit, a telephone 
contact should be made to assess for the occurrence of adverse events (AEs), serious 
adverse events (SAEs), and potential endpoints.
Unscheduled Visits
Unscheduled visits may occur for various reasons, including the following:  management 
of an AE or SAE, performing additional investigation(s) for clinically abnormal 
laboratory test values (e.g., confirming an elevated transaminase value) or other signs and 
symptoms, any time the investigator feels that it is appropriate for subject safety, 
dispensing of study drug, etc.  If a scheduled visit was missed, all procedures and tests for 
the missed visit should be performed at an unscheduled visit.
Open-Label Extension Study
Upon study completion, eligible subjects will be invited to participate in an open-label 
study if their site is participating in the extension study to determine the long-term safety 
of Atrasentan.


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5.2
Selection of Study Population
5.2.1
Inclusion Criteria
A subject will be eligible for initial entry into the study if he/she meets 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-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.
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 mmHg at any time during the Screening Period.


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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 the Run-In Period (R6 visit).
Subjects on a MTLDD RAS inhibitor for ≥ 4 weeks and not on a diuretic (unless 
medically contra-indicated) 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:
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 contra-indicated) 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 judgment (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 ≥ 300 pg/mL (300 ng/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.


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Male subjects must satisfy the following criteria from initial study drug administration 
through 90 days after last dose of study drug:
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.
Rationale for the Inclusion Criteria:
(1)  For the safety of the study subjects.
(2)  In accordance with harmonized GCP.
(3 – 7)  To select the adequate subject population with appropriate disease severity for the 
evaluation.
(8 – 9)  The impact of Atrasentan on pregnancies is unknown.
5.2.2
Exclusion Criteria
A subject will not be eligible for entry into the Run-in Period if he/she meets any of the 
following criteria:


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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.


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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 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 2 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 1 diabetes.
22.
Subject is considered to be clinically unstable regarding general, metabolic or 
cardiovascular health as determined by the Investigator.


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The Rationale for the Exclusion Criteria
(1 – 22)  The rationale for the exclusion criteria is to ensure the safety of subjects 
throughout the study.
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject is receiving at the time of the initial 
Screening S1 visit and receives during the study, must be recorded along with the reason 
for use, date(s) of administration including start and end dates, and dosage information 
including dose, route and frequency.
If medically necessary, interruption of ACEi or ARB doses during the Double-Blind 
Treatment or Follow-Up Periods of the study will be allowed.  When returning to 
treatment, the subject should return to the previous regimen of ACEi or ARB therapy that 
was prescribed prior to the interruption, although it will not be a requirement.  
Conversions from one product to another (e.g., ACEi to ARB) must be at equivalent 
doses.  Combinations of ACEi/ARB medications and/or concomitant use of aldosterone 
blockers or aliskiren are not allowed.
Plasma levels of Atrasentan may be affected by concomitant use of CYP3A or OATP 
inhibitors (e.g., protease inhibitors, clarithromycin, ketoconazole, gemfibrozil, 
ciclosporin).  In addition, plasma levels of sensitive P-gp substrates (e.g., dabigatran) may 
be affected by concomitant use of Atrasentan. Caution should be used in subjects taking 
any of these medications during the study.
The AbbVie Study Designated Physician (listed in Section 6.5) should be contacted if 
there are any questions.
5.2.3.1
Guidance for Blood Pressure Management
Recommendations for treatment of hypertension throughout the study will be based on 
accepted published guidelines for diabetic patients with CKD (e.g., KDIGO, JNC 8)  that 


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utilize various combinations of anti-hypertensive medications which are applied in a 
step-wise manner to achieve the blood pressure target as recommended by clinical 
guidelines (standard of care).  Diuretics and MTLDDs of RAS inhibitors are essential 
treatments for blood pressure management in patients with type 2 diabetes and 
nephropathy.20
Step-wise addition of maximum tolerated labeled doses of anti-hypertensive drugs, such 
as CCBs (e.g., amlodipine, verapamil or diltiazem) or beta 1-selective agents 
(e.g., atenolol, metoprolol) have shown benefit in diabetic patients.  Alpha-1 blockers 
(e.g., doxasocin), central alpha-2 agonists or other centrally acting drugs (e.g., clonidine, 
methyldopa, reserpine) and direct vasodilators (e.g., hydralazine, minoxidil) should only 
be considered for the most resistant forms of hypertension, recognizing that orthostatic 
hypotension and edema are commonly observed side-effects.
In cases of orthostatic hypotension, CCBs or beta blocker agents should be first modified 
or withdrawn at the discretion of the Investigator.  The Investigator may be contacted by 
the Sponsor regarding decreases in blood pressure.
5.2.3.2
Guidance for Using RASi and Other Blood Pressure 
Lowering Drugs During the Study
●
Investigators should attempt to maintain the blood pressure within the range 
recommended by local guidelines (e.g., KDIGO).
●
Per protocol, the MTLDD is defined as the subject's dose of ACEi or ARB, at 
or below the labeled dose, that does not exhibit any intolerable adverse effects 
(e.g., hypotension, hyperkalemia), based on the Investigator's assessment.
●
If the subject is currently receiving one drug (ACEi or ARB) below the 
maximum labeled dose, the drug should be titrated to the MTLDD during the 
Run-In period.  Subject's dose of ACEi or ARB will be titrated based on the 
assessment of tolerability by the Investigator and according to local practice 
guidelines.
●
Subjects should be encouraged to limit their dietary salt intake (< 5 grams per 
day of sodium chloride) as recommended by the WHO.


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●
The ACEi or ARB must be stable the 4 weeks before Enrichment.  The diuretic 
should be administered at stable doses during 2 weeks before Enrichment.
●
Diuretics may be titrated to help maintain BP target levels.
●
If a subject is on the maximum tolerated labeled dose of RAS inhibitor and a 
diuretic at the lowest possible dose and experiences an adverse medical 
condition, such as hypotension:
○
The non-RASi blood pressure medications should be down titrated 
(calcium channel blockers, beta blockers, etc.) before altering the diuretic 
dose.
○
Subjects under these circumstances are eligible to proceed to the 
Enrichment period.
●
Any changes in RAS inhibitor use or diuretic therapy should be preceded by 
consideration of any relevant contraindications as per the local product 
information.
5.2.3.3
Guidance for Managing Elevated Serum Creatinine During 
Enrichment Period
Reductions in blood pressure may be associated with elevated serum creatinine in patients 
with CKD.  In addition, medications which improve renovascular resistance and 
glomerular filtration fraction (e.g., RAS inhibitors and ETA receptor blockers like
Atrasentan) may cause temporary increases in serum creatinine independent of any blood 
pressure lowering effect.  Subjects who receive Atrasentan during the Enrichment Period 
may experience elevations of serum creatinine that reflect its effect on renal 
hemodynamics.  For those subjects that demonstrate elevated serum creatinine during 
enrichment, it is recommended to implement the following activities and re-measure 
blood for serum creatinine as needed:
1.
If the decrease in SBP is > 20 mm Hg from the E1 visit or the absolute value is 
< 110 mmHg and weight gain from E1 visit is:
a.
< 2 kg:  stop or reduce the dose of diuretic before reducing the dose of 
non-RAS blood pressure lowering drugs 


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b. ≥ 2 kg:  reduce the dose of non-RAS blood pressure lowering drugs 
2.
If the decrease in systolic BP is < 20 mm Hg from E1 and the absolute value is 
> 110 mmHg evaluate for other causes of elevated serum creatinine:
a.
Use of nonsteroidal anti-inflammatory drugs (NSAIDs)
b. Use of cimetidine
c.
Volume depletion assessed by presence of orthostatic hypotension
d. Urinary tract obstruction
5.2.3.4
Guidance for Hyperkalemia Management (Serum Potassium 
> 5.5 mmol/L)
When serum potassium is > 5.5 mmol/L at any period of the study (including run-in, 
enrichment and double-blind treatment period), it is recommended to implement the 
following activities:
1.
If serum potassium is ≥ 6.5 mmol/L, emergency management is recommended.
2.
If serum potassium is > 5.5 and < 6.5 mmol/L, rule out measurement errors or 
obvious reasons for the increase (i.e., hemolysis of the sample, subject stopped 
taking diuretics/lack of compliance, diet transgression, e.g., salt substitutes, 
bananas, dried fruits, potatoes).
3.
If all obvious reasons are ruled out and the subject is receiving a diuretic, increase 
the dose of the diuretic by 50%.  Reassess the subject's tolerability within 1 week 
as well as their blood pressure, eGFR, Na and K.
4.
If all obvious reasons are ruled out and the subject is not receiving a diuretic, it is 
recommended to start a diuretic.  The choice of a thiazide or loop diuretic is at the 
discretion of the Investigator.  Reassess the subject's tolerability within 1 week as 
well as their blood pressure, eGFR, Na and K.
5.
In both of the above noted scenarios (numbers 3 and 4), adjust the dose of diuretic 
accordingly after 1 week.  If the subject's serum potassium is still > 5.5 mmol/L, 


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reinforce diet counseling/restrictions and consider increasing the dose of the 
diuretic.  If, after another additional week the serum potassium is still 
> 5.5 mmol/L, reduce the dose of RAS inhibitors by 50%.  If hyperkalemia persists 
or recurs, the RAS inhibitor may be discontinued and the subject may continue in 
the trial if they are in the Double-Blind Treatment Period.
6.
Chronic hyperkalemia should be managed according to the standard of care.
7.
Kayexalate treatment may be used for chronic hyperkalemia at the discretion of the 
Investigator.  Because kayexalate can result in sodium loading, susceptible subjects 
may be at increased risk for fluid retention.
5.2.3.5
Guidance for Stopping RAS Inhibitors During the Double-
Blind Treatment Period
1.
Hyperkalemia (serum potassium > 5.5 mmol/L) not responding to other 
interventions (such as diet and diuretics or down-titration of RAS inhibitor).
2.
Hypotension where RASi is the only anti-hypertensive medication.
3.
Discontinuing RASi is discouraged as a method to delay ESRD.
5.2.3.6
Guidance for Managing Edema or Weight Gain
Weight will be measured at each visit during the study, preferably using the same device 
and under the same circumstances (i.e., same time of the day, no shoes or coats during 
measurement).  Results will be compared with the previous visit and the site may be 
contacted by the Sponsor.  If there is an increase of ≥ 2 kg during the Enrichment Period 
or in the Double-Blind Treatment Period, it is recommended to implement the following 
activities:
1.
Rule out measurement errors or obvious reasons for the increase (i.e., diet 
transgression, different clothing than previously).


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2.
Evaluate for the presence of edema.  This may be indicative of fluid retention as 
the cause for weight gain.
3.
Ascertain whether the subject has exceeded the recommended daily dietary salt 
intake (≤ 5 grams of sodium chloride).
4.
If the subject is receiving a diuretic and has edema, increase the dose of the diuretic 
as necessary.  Re-assess the subject's tolerability within 1 week as well their blood 
pressure, edema, weight, eGFR, hemoglobin, sodium and potassium.
5.
If the asymptomatic subject is not receiving a diuretic, it is suggested to start a 
diuretic according to eGFR stratum and titrate the dose according to the response to 
the initial dose (see below).
eGFR < 45 mL/min
eGFR 45 – 60 mL/min
eGFR > 60
Recommended 
Diuretic and Dose
Loop diuretic 20 – 40 mg 
per day of furosemide or 
equivalent 
OR
Chlorthalidone 25 mg per 
day or equivalent
Loop diuretic 20 mg per 
day of furosemide or 
equivalent 
OR
Chlorthalidone 
12.5 – 25 mg per day or 
equivalent
Chlorthalidone 12.5 mg 
per day or equivalent
Re-check for BP, 
weight, edema, 
eGFR and Hb
1 week SBP target 110 – 140
6.
In both of the above noted scenarios (numbers 4 and 5), adjust the dose of diuretic 
accordingly after 1 week or sooner if the subject is short of breath.  Changes in the 
type of diuretic can be made at the discretion of the Investigator.  There is no upper
diuretic dose limit during the Treatment Period.
7.
If weight continues to increase (i.e., > 3 kg in 6 weeks or the previous visit during 
the Double-Blind Treatment Period), despite the modification in the doses of 
diuretics, contact the Study Designated Physician for the study.
8.
Discontinuation of a diuretic may be allowed under the following conditions:


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●
Orthostatic Hypotension:  by the presence of a supine-to-standing BP decrease 
≥ 20 mmHg systolic or ≥ 10 mmHg diastolic within 3 minutes of standing.
●
SBP equal to or below 110 mmHg at any visit.
●
Hypokalemia (< 3.5 mEq/L) unresponsive to replacement therapy.
9.
An unscheduled visit may be utilized at any time to assess and/or intervene per the 
Investigator's clinical judgment.
10.
The AbbVie Study Designated Physician should be contacted if there are any 
questions.
5.2.3.7
Guidance for Glucose Control
1.
Adjust anti-diabetic medications to A1C target levels that are recommended by 
local guidelines.
2.
Rosiglitazone should not be used throughout the study.
3.
Any changes in anti-diabetic therapy should be preceded by consideration of any 
relevant contraindications as per the local product information.
5.2.3.8
Guidance for the Diagnosis of Acute Kidney Injury (AKI)
1.
It is suggested that the KDOQI Commentary of the 2012 KDIGO Clinical Practice 
Guideline for Acute Kidney Injury be used for the assessment and treatment of 
AKI (Am J Kidney Dis 2013).20
2.
The cause of AKI should be determined whenever possible.
3.
Evaluate subject with AKI promptly to determine the cause, with special attention 
to reversible causes, such as use of NSAIDs, hypotension, volume depletion or 
urinary tract obstruction.
4.
Diuretics should not be used to prevent or treat AKI except in the management of 
volume overload.


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In the presence of AKI, study drug can be stopped or discontinued temporarily based on 
the Investigator judgment.
5.3
Efficacy and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures described in this protocol are summarized in Table 1.


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Table 1.
Study Activities
Screening 
(2 Weeks)
Run-In Perioda
(1 to 12 Weeks)
Enrichment Period
Double-Blind Treatment Period
F/U 
Period
Visit Duration in 
Weeks until 
Randomization
Wk
–14
Wk 
–13
Wk 
–12
Week
–10, –8, 
–6, –4
Wk 
–2
Day 
1
Wk 
1
Wk 
2
Wk 
4
Wk 
6
Wk 
7
Activities
S1
S2
R1
R2, R3, 
R4, R5
R6
E1
E2
E3
E4
E5b
Randomi-
zationc
Wk 
1 
Call
Wk 
2 
Call
T1
Every 
3 Mths* Yearlyd
Final 
Treatment/ 
PDe
F1f
Informed Consentg
X
Medical History
X
Xi
Xi
Xi
Xi
Xi
Concurrent 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete Physical 
Examt
X
X
Vital Signsh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess Peripheral 
Edema
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
Limited Chemistry
X
X
X
X
X
X
X
Complete Chemistry
X
X
X
X
X
X
X
Liver Function
X
X
X
X
X
X
X
Lipid Profile 
(fasting)j
X
X
X
X


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62
Table 1.
Study Activities (Continued)
Screening 
(2 Weeks)
Run-In Perioda
(1 to 12 Weeks)
Enrichment Period
Double-Blind Treatment Period
F/U 
Period
Visit Duration in 
Weeks until 
Randomization
Wk
–14
Wk 
–13
Wk 
–12
Week
–10, –8, 
–6, –4
Wk 
–2
Day 
1
Wk 
1
Wk 
2
Wk 
4
Wk 
6
Wk 
7
Activities
S1
S2
R1
R2, R3, 
R4, R5
R6
E1
E2
E3
E4
E5b
Randomi-
zationc
Wk 
1 
Call
Wk 
2 
Call
T1
Every 
3 Mths* Yearlyd
Final 
Treatment/ 
PDe
F1f
BNP
X
X
X
X
X
X
X
HbA1c
X
X
X
X
Urinalysis
X
X
X
X
FMV Urine 
Collection for 
UACRk
X
X
X
X
X
X
X
X
X
RAS Dose 
Adjustment
Xl
Xl
Xl
Xl
Call into IVRSw
X
X
X
X
X
X
X
X
X
Dispense Study 
Drugm
X
X
X
X
X
X
Monitor AEs and 
SAEsn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient (QOL) 
Questionnaireso
X
X
T3, T6 
and T9 
only
X
X
Serum and Urine 
Biomarkers
X
X
T3 only
X
X
X


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63
Table 1.
Study Activities (Continued)
Screening 
(2 Weeks)
Run-In Perioda
(1 to 12 Weeks)
Enrichment Period
Double-Blind Treatment Period
F/U 
Period
Visit Duration in 
Weeks until 
Randomization
Wk
–14
Wk 
–13
Wk 
–12
Week
–10, –8, 
–6, –4
Wk 
–2
Day 
1
Wk 
1
Wk 
2
Wk 
4
Wk 
6
Wk 
7
Activities
S1
S2
R1
R2, R3, 
R4, R5
R6
E1
E2
E3
E4
E5b
Randomi-
zationc
Wk 
1 
Call
Wk 
2 
Call
T1
Every 
3 Mths* Yearlyd
Final 
Treatment/ 
PDe
F1f
PG Sample
Xv
PK Analysisq,y
X
X
X
X
Xy
Xy
X
Drug Accountability/ 
Compliance 
Assessmentp
X
X
X
X
X
X
X
X
X
Serum FSHr
X
Review Subject 
Diarys
X
X
X
X
Telephone Contactu
X
X
*
From the randomization visit.
a.
If the subject is already receiving a maximum tolerated labeled daily dose of RAS inhibitor and a diuretic then they will proceed to the Run-In Period R6 visit.  The 
first Run-In visit may start immediately after the subject has met all of the inclusion and none of the exclusion criteria.  If the subject is currently not receiving a maximum 
tolerated labeled daily dose of RAS inhibitor, then the subject will be in the Run-In Period for a minimum of 4 weeks and a maximum of 12 weeks.
b.
If the subject has a change in serum creatinine > 0.5 mg/dL and > 20% from the beginning of Enrichment to the last visit of the Enrichment Period, a PD visit should be 
completed within 9 days, and be followed weekly until serum creatinine returns to baseline ±10%, up to 4 weeks.  Subject should also have an F1 visit. 
c.
The number of subjects with eGFR 60 – 75 ml/min/1.73 m2 at the Enrichment Period E1 visit who are randomized in the responder population will be capped at 
approximately 300 subjects.


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64
Table 1.
Study Activities (Continued)
d.
T12, T24, T36, T48, etc.
e.
Premature Discontinuation visit should be performed within 9 days after the last dose of study drug for subjects that permanently discontinue study drug prior to study 
completion.
f.
Upon permanent discontinuation of study drug administration or study completion (425 distinct primary renal events have occurred in the responder population), all subjects 
will have one scheduled Follow-Up (F1) visit occurring 45 days (±14 days) after the last dose of study drug.
g.
Informed consent can be collected up to 30 days prior to the initial Screening (S1) visit.  Informed consent should be obtained prior to the performance of any study 
procedures.
h.
Vital signs including BP, weight and pulse rate will be collected at every visit.  Height will be collected at initial Screening visit only.  Temperature will be collected at 
Randomization visit only.  Weight gain will be assessed at each visit.  Subject will be queried on an intervening occurrence of laser photocoagulation for diabetic retinopathy.
i.
Complete medical history, including history of tobacco and alcohol use and colonoscopy history, will be obtained during initial Screening visit and updated through the 
Enrichment Period E1.
j.
Lipid profile tests should be done under fasting conditions.
k.
For Screening, the first morning void (FMV) urine collection will consist of two consecutive FMV samples collected within 2 days of the second Screening visit.  For Run-In 
and Enrichment, the FMV urine collection will consist of three consecutive FMV samples collected within 3 days of the Run-In R6 Visit, E1 visit, E4 visit and the E5 visit.  
For Treatment and the F1 visit, the FMV urine collection will consist of one FMV sample collected within 1 day of the required Treatment Period Visit (with the exception of 
3 FMVs to be collected at the T24 visit).  FMV is not required for subjects who present for the Randomization visit and are not randomized and a Final Treatment visit is 
conducted instead of a Randomization visit.
l.
Only adjust the RAS dose in the Screening or Run-In Period if required to reach the MTLDD.
m.
Doses of the study drug for scheduled visit days should be administered to the subject by site personnel at the clinical site.
n.
Serious adverse events will be recorded after informed consent.  Adverse events (serious and non-serious) will be captured beginning at the E1 visit through 45 days after last 
dose of study drug.  Serious adverse event monitoring will continue to be captured 45 days after last dose of study drug and through study completion.
o.
The KDQoL-SF™Version 1.3, AQOL-4D (for Australia only) and EQ-5D-5L questionnaires should be administered and completed prior to any study procedures being 
performed.
p.
Calculation instructions are provided in Section 5.5.6.
q.
Blood samples only to be collected for Atrasentan PK analysis and possible metabolites of Atrasentan.
r.
For women under 50 years of age.


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Table 1.
Study Activities (Continued)
s.
Subjects will be provided a diary at the Randomization visit and will be instructed to record their weekly weights on the diary under the same circumstances (i.e., same time of 
day, no shoes or coat during measurement) using the same scale.
t.
Symptom directed physical exam should be performed at all other subsequent visits.
u.
The Investigator or designee will contact each subject 1 and 2 weeks post-randomization to assess for signs and symptoms of hypotension.
v.
For subjects who provide consent and are moving forward into the Double-Blind Treatment Period, if the PG sample is not collected at this visit, it may be collected at any 
subsequent visit.  
w.
IVRS/IWRS will be called at the S1 visit to obtain the subject's screening number and at the first Run-In visit for that subject to confirm the eGFR cap has not been met in 
order for the subject to continue.  The IVRS/IWRS call at the Final Treatment/PD visit is only for the discontinuation of study drug.  An IVRS/IWRS call will not be 
completed at visits for subjects who will not be dispensed study drug.
y.
Samples to be collected at T3, T6, T9, T12 and every 6 months thereafter.


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5.3.1.1
Study Procedures
The study procedures outlined in Table 1 are discussed in detail in this section with the 
exception of the collection of adverse event information (discussed in Section 6.0) and 
Pre-screening activities (discussed in Section 5.1).  All study data will be recorded on the 
appropriate eCRF.
Informed Consent
A signed informed consent will be obtained from the subject before any study procedures 
are undertaken.  Informed consent can be collected up to 30 days prior to the initial 
Screening (S1) visit.  Details about how informed consent will be obtained and 
documented are provided in Section 9.3.
Medical History
A complete medical history, including history of tobacco and alcohol use and 
colonoscopy history, will be obtained from each subject during the initial Screening visit 
and updated through the Enrichment Period E1 visit.  Alcohol and tobacco use definitions 
are as follows:
Tobacco:
Cigarettes, pipes, cigars, chewing tobacco
Alcohol Use:
Non-drinker:
consumes less than 3 drinks per year
Drinker:
consumes at least 3 drinks per year
Light:
less than 2 drinks per day
Moderate:
2 to 4 drinks per day
Heavy:
more than 4 drinks per day
Physical Examination
A complete physical examination will be performed at the Enrichment E1 visit (baseline 
physical), and the Final Treatment/Premature Discontinuation visit.
Symptom directed physical exam should be performed at all other visits.


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Any clinically significant changes occurring after the baseline physical will be 
documented as adverse events.
Vital Signs
Vital sign determination of sitting BP, weight and pulse rate will be obtained at all visits.  
Vital signs performed at the Randomization visit will serve as the baseline.  Weight gain 
will be assessed at every visit.  Careful consideration should be used to ensure that the 
appropriate cuff size is used for all sitting BP determinations.  BP will be measured twice 
according to local standards.  One such method includes obtaining BP (using the 
appropriate cuff size) in the non-dominant arm two times at 2-minute intervals after 
5 minutes of rest in the seated position.  All BP readings should be collected by 
experienced site personnel using appropriate technique and equipment.  BP should be 
measured consistently by the same method for all visits.  Temperature will be obtained at 
the Randomization visit only.  Height will be collected at the initial Screening visit only.  
Subjects will be queried for an intervening occurrence of laser photocoagulation for 
diabetic retinopathy at each visit.
12-Lead Electrocardiogram (ECG)
A 12-lead resting ECG will be obtained at the E1 visit, the yearly Double-Blind Treatment 
Period visits, and Final Treatment/PD visit.  The ECG measurements at the E1 visit will 
serve as the baseline measurements for clinical assessment.
Patient Reported Quality of Life (QOL) Questionnaires:  EQ-5D-5L, AQOL-4D 
(Australia only) and Kidney Disease Quality of Life (KDQOL-SF™ v1.3)
Subjects will be asked to complete standard quality of life (QOL) questionnaires, 
EQ-5D-5L, AQOL-4D (for Australia only) and Kidney Disease Quality of Life 
(KDQOL-SF∀v1.3) as noted in Table 1.  The questionnaires should be administered and 
completed prior to any other study procedures being performed at these visits.  
Questionnaires will be completed by subjects directly onto paper case report forms (CRF).  


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When possible, subjects should complete the questionnaires on their own.  Subjects with 
applicable limitations may have the questionnaires completed for them based on their 
verbal responses by study personnel and/or a legally authorized representative, following 
questionnaire administration instructions.  The site will document in the source Document 
whether the QOL questionnaires were completed by subject on their own or if their verbal 
responses were captured by study personnel and/or a legally authorized representative.
Subject questionnaires such as health related QOL or functional status will be captured via 
subject self-administration to assess treatment efficacy, as outlined elsewhere in the 
protocol.  The subject questionnaires included in this trial are measures of treatment 
efficacy, data collected in this manner will not be analyzed in any way that would impact 
the blinded nature of the study, and therefore will only be analyzed at pre-specified time 
periods where other measures of efficacy are assessed.  As part of their guidance on 
subject reported outcomes, the FDA recommends that adverse effects of treatment be 
captured separately from measures of treatment effectiveness (i.e., collected within 
separate instruments).  Therefore, given the focus of subject questionnaire data on 
measuring treatment efficacy, and the fact that these data are not analyzed until database 
lock (and therefore will not be available to assess safety during the study), these data 
would not be expected to be reconciled with the safety database nor would they be 
reported to the Independent Data Monitoring Committee.
Assessment of Edema
Assessment of edema will be performed at every visit.  The assessment of edema should 
be performed by qualified site personnel at approximately the same time (if possible) at 
each visit and the time of assessment will be recorded.  The severities of edema for each 
subject will be defined by the following categories:
●
None:  edema is not present on examination;
●
Mild:  edema is present on examination, but asymptomatic and the subject is 
willing to continue study medication;


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●
Moderate:  edema is present on examination, but symptomatic and the subject 
is willing to continue study medication;
●
Severe:  edema is present on examination, but symptomatic and the subject is 
unwilling to continue study medication, or subject has an adverse event of 
pulmonary edema or congestive heart failure (CHF).
New onset or worsening edema, as deemed by the Investigator, will be captured as 
adverse events.  The date of edema resolution will also be captured.
Subject Diaries
Subjects will be given a diary at the Randomization visit to record their weight on a 
weekly basis during the double-blind treatment period.  Subjects will bring their diary to 
each visit and site personnel will review the weight changes recorded.
Subjects will be instructed to record their weight every week under the same 
circumstances (i.e., same time of day, no shoes or coats during measurement) using the 
same scale.  Subjects will be instructed to notify the Investigator if they notice a weight 
change greater than 2 kilograms over a 2 week period.
Post-Discontinuation Visits/Phone Calls
Subjects who have permanently discontinued study drug administration during the 
Double-Blind Treatment Period will continue with study assessments and visits following 
the schedule of activities (Table 1).  IVRS/IWRS, dispense study drug, drug 
accountability, and PK sampling would not occur at these visits.  
If the subject is unable or unwilling to undergo on-site planned assessments, study staff 
should make telephone contact and encourage subjects to allow further assessments.  
Telephone assessments should only be utilized when necessary.  The telephone 
assessments will consist of a phone call to the subject every 3 months until the study end.  
Procedures to be performed during the telephone contact include, but not limited to, 
eliciting and collecting information regarding concurrent medications, occurrence of renal 


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and cardiovascular events, SAEs, local laboratory reports (if available), and inquire as to 
whether the subject has started receiving chronic dialysis.  If the subject is unwilling to 
receive phone calls, he/she should be encouraged to allow collection of data about renal 
and cardiovascular events and recent laboratory values from medical records or through 
contacts with the treating physician.  An authorization to release information from the 
subject should be obtained.
Reminder Phone Calls
Subjects will be required to perform several study procedures at home.  Therefore, it is 
recommended that reminder phone calls be performed by Study Site Personnel at 
specified intervals.  Table 2 is an outline for the description and timing of the reminder 
calls.
Contact
One and two weeks after Randomization, the Investigator or designee will contact the 
subject to query about occurrence of signs and symptoms of hypotension.


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Table 2.
Reminder Phone Calls
Study Period
Study Day
Call Description
Screening Period
Approximately 
3 days prior to the 
S2 visit.
Call the subject to remind them to initiate their 
two consecutive first morning void urine sample 
collections the 2 days prior to the S2 visit.
Run-In Period
Approximately 
4 days prior to the 
R6 visit.
Call the subject to remind them to initiate their 
three consecutive first morning void urine samples the 
3 days prior to their R6 visit.
Run-In Period
Approximately 
4 days prior to the 
E1 visit (for those
subjects that have 
passed the Run-In 
Period).
Call the subject to remind them to initiate their 
three consecutive first morning void urine samples the 
3 days prior to their E1 visit and that they must fast for 
8 hours prior to the visit and hold their morning dose of 
antihyperglycemic agents prior to the E1 visit.  Also 
remind them to initiate their 24-hour urine collection (if 
the subject consented) immediately after their 
third first morning void urine has been collected.
Enrichment Period
Approximately
4 days prior to the 
E4 visit (for those 
subjects that have 
entered the 
Enrichment Period).
Call the subject to remind them to initiate their 
three consecutive first morning void urine samples the 
3 days prior to their E4 visit.
Enrichment Period
Approximately 
4 days prior to the 
E5 visit (for those 
subjects that have 
entered the 
Enrichment Period).
Call the subject to remind them to initiate their 
three consecutive first morning void urine samples the 
3 days prior to their E5 visit.  Also remind them to 
initiate their 24-hour urine collection (if the subject 
consented) immediately after their third first morning 
void urine has been collected.
Randomization
Approximately 1 day 
prior to the visit.
Call the subject to remind them of their Randomization 
visit.


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Table 2.
Reminder Phone Calls (Continued)
Study Period
Study Day
Call Description
Treatment T1 Visit
Approximately 
2 days prior to the 
visit.
Call the subject to remind them to initiate their 
first morning void urine sample the day prior to their 
T1 visit.  At this time, also remind the subject that they 
must fast for 8 hours prior to the visit and hold their 
morning dose of antihyperglycemic agents prior to their 
T1 visit.  Subjects should be reminded to bring their 
diary to the visit. 
Treatment Visits 
Every 3 Months
Approximately 
2 days prior to the 
visit.
Call to remind the subject to bring their diary to the visit.  
Yearly Visits 
(i.e., T12, T36, T48, 
etc).
Approximately 
2 – 3 days prior to the 
visit.
Call the subject to remind them to initiate their 
first morning void urine sample the day prior to their 
yearly Treatment visit.  Also remind them to initiate 
their 24-hour urine collection (if the subject consented) 
immediately after the first morning void urine has been
collected.  At this time, also remind the subject that they 
must fast for 8 hours prior to the visit and hold their 
morning dose of antihyperglycemic agents prior to their 
yearly Treatment visit.  Remind the subject to bring their 
diary to the visit.
Yearly Visit T24
Approximately 
4 days prior to the 
visit.
Call the subject to remind them to initiate their 
three consecutive first morning void urine samples the 
3 days prior to their yearly Treatment visit.  Also remind 
them to initiate their 24-hour urine collection (if the 
subject consented) immediately after their 
third first morning void urine has been collected.  At this 
time, also remind the subject that they must fast for 
8 hours prior to the visit and hold their morning dose of 
antihyperglycemic agents prior to their yearly Treatment 
visit.  Remind the subject to bring their diary to the visit.


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Table 2.
Reminder Phone Calls (Continued)
Study Period
Study Day
Call Description
Final Treatment/ 
Premature 
Discontinuation 
Visit
Approximately 
2-3 days prior to the 
Final Treatment/ 
Premature 
Discontinuation visit.
Call the subject to remind them to initiate their 
first morning void urine sample the day prior to their 
Final Treatment/Premature Discontinuation visit.  
Remind the subject to bring their diary to the visit.
F1 Visit
Approximately 
2 days prior to the 
F1 visit.
Call the subject to remind them to initiate their first 
morning void urine sample the 2 days prior to their F1 
visit.  Also remind them to initiate their 24-hour urine 
collection (if the subject consented) immediately after 
the first morning void urine has been collected.  At this 
time, also remind the subject that they must fast for 
8 hours prior to the visit and hold their morning dose of 
antihyperglycemic agents prior to their F1 visit.
Clinical Laboratory Tests
Blood draws should be performed before the dose of study drug and after vital sign 
determinations have been completed at each visit.
A certified central laboratory will be utilized to process and provide results for all clinical 
laboratory tests throughout the study.  In exceptional cases, test results from a local 
laboratory may be acceptable.  Samples will be obtained for the laboratory tests listed in 
Table 3 according to the schedule of activities in Table 1.  The subject should fast 
(nothing by mouth except water) for 8 hours prior to lipid profile assessments collected at 
the study visits identified in Table 1.  If a subject is not able to fast due to unforeseen 
circumstances, the non-fasting status will be recorded in the study source documentation.  
The central laboratory will provide instructions regarding the collection, processing and 
shipping of these samples.
The Investigator will review all laboratory test results.  All laboratory test results that are 
considered clinically significant by the Investigator will be followed to satisfactory 
resolution.  Laboratory abnormalities are considered to be adverse events only if they 
result in discontinuation from the study, necessitate therapeutic medical intervention, 


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and/or if the Investigator considers them to be an adverse event.  The Investigator and 
AbbVie will be blinded to the UACR laboratory results during the Double-Blind 
Treatment Period.
Instructions regarding the collection, processing and shipping of these samples will be 
provided by the central laboratory chosen for this study.
Covance CLS
8211 SciCor Drive
Indianapolis, IN  46214-2985 USA
Tel:
(+1) 317-271-1200
Fax: (+1) 317-273-4030
Laboratory samples will be sent to the following Covance CLS locations depending on 
the geographic location of the site:
●
Indianapolis, IN, USA
●
Geneva, Switzerland
●
Singapore
●
Shanghai, China
●
Saitama, Japan


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Table 3.
Clinical Laboratory Tests
Hematology
Complete Chemistry
Urinalysis
Hematocrit
Hemoglobin
Red Blood Cells (RBC)
White Blood Cells (WBC)
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count 
(estimate not acceptable)
Albumin
Alkaline phosphatase*
ALT (SGPT)*
AST (SGOT)*
Bicarbonate
Blood Urea Nitrogen (BUN)
Calcium
Cystatin C
Potassium
Chloride
Cholesterol**
Creatinine
Direct Bilirubin*
Glucose**
HDL**
Insulin (HOMA-IR)**
LDH
Lipoprotein A**
LDL**
Phosphorus
Sodium
Total bilirubin*
Total protein
Triglycerides**
Uric acid
VLDL**
Blood
Glucose
Ketones
pH
Protein
Specific gravity
Urine Tests
First morning void urine:
UACR
24-hour urine:
Albumin
Creatinine
Sodium
Potassium
Chloride
Additional Tests
BNP
Pharmacokinetic 
measurement
HbA1c
Serum and Urine samples for 
biological markers
Serum FSH
Limited Chemistry
Sodium
Albumin
Potassium
Bicarbonate
Creatinine
Chloride
BUN
*
Liver enzymes.
**
Lipid and metabolic profile tests (obtained under fasting conditions).
Estimated Glomerular Filtration Rate (eGFR)
The CKD-EPI formula will be used to calculate eGFR at the Screening S1 visit to 
determine eligibility for the Run-In Period.  The central laboratory will also calculate the 
GFR on the laboratory profile report at each visit during the treatment period.


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First Morning Void (FMV) Urine Sample Collections
The first morning void is defined as the subject's first void after 5:00 AM or upon rising 
for the day.  The central laboratory will provide specific instructions for collection and 
storage of specimens.  
Three first morning void urine sample collections will be obtained prior to the 
Run-In R6 visit, Enrichment E1 visit, Enrichment E4 visit, Enrichment E5 visit, and the 
Treatment T24 visit.  One first morning void sample collection will be obtained prior to 
the Treatment visit T1, the yearly visits (T12, T36, T48, etc.), the Final 
Treatment/Premature Discontinuation visit, and the Follow-Up Visit F1.  
Two first morning void urine sample collections will be obtained prior to the 
second screening visit.
If a subject did not collect the required samples at any of these visits, re-dispense supplies 
and instructions for collection of the FMV samples.  Once the FMV samples are collected 
by the subject, he/she will return the samples to the site.
If the FMV sample collection needs to be recollected for a Treatment Period visit, the site 
should make every effort to maintain the original visit schedule for that subject.
During the Screening and Run-In Periods, the UACR values will be reported to the 
Investigator by the central laboratory on the laboratory reports.
Subjects who are in the Enrichment Period and present for the randomization visit and 
who are determined to be ineligible for participation in the Double-Blind Treatment 
Period or if the non-responder cap has been reached, a premature discontinuation visit can 
be conducted instead.  An FMV for the premature discontinuation visit will not be 
required for these subjects. 


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5.3.1.1.1
24-Hour Urine Collection Sub-Study (Additional Consent 
Needed)
The 24-hour urine collection will be collected as outlined in Table 4 during the study for 
each subject that consents to participate in this optional sub-study up to a limit of 
800 subjects.  The subject will be provided with urine collection containers prior to each 
visit where 24-hour urine is required as outlined in Table 4.  The central laboratory will 
provide specific instructions for collection and storage of the specimens.  Subjects will 
initiate the 24-hour collection within 1 day prior to the respective visit (where 24-hour 
urine collections are required) and after the third FMV is collected during Enrichment and 
after the one FMV is collected during Treatment.  The 24-hour urine collection will end 
on the morning of the subject's scheduled study visit.  The specimen will be brought to the 
study visit.  All 24-hour urine collections should be initiated on an empty bladder.  Each 
24-hour urine sample will be analyzed at the central laboratory for the following:  
albumin, chloride, creatinine, potassium and sodium.
For the Enrichment E1 visit, Enrichment E5 visit and the F1 visit, where subjects must 
collect their FMVs and a 24-hour urine collection, the procedure is as follows:
●
The FMV urine samples will be collected the 3 days prior to (for Enrichment) 
and the 1 day prior to (for Treatment) the scheduled study visit in the morning.  
The third (for Enrichment and the T24 visit) or only (for Treatment, with the 
exception of the T24 visit) FMV is collected the day prior to the scheduled 
study visit.  Immediately after the final FMV is collected (the day before the 
subject's visit), the subject will then start collecting their 24-hour urine 
collection.  The subject will complete the 24-hour urine collection on the 
morning of their scheduled study visit.
If a subject did not complete the 24-hour urine collection at the E1 (baseline) visit, the 
subject should not continue in the 24-hour sub-study.  If a subject did not complete the 
24-hour urine collection at a subsequent visit, re-dispense supplies and repeat the 
instructions for the 24-hour urine collection.  


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If the 24-hour urine collection needs to be recollected for a Treatment Period visit and the 
subject has consented, the site should make every effort to maintain the original visit 
schedule.
Table 4 is an outline of the schedule for the 24-hour urine collection sub-study.


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Table 4.
Study Activities for Optional 24-hour Urine Sub-Study
Screening
Run-In Period
Enrichment Period
Double-Blind Treatment Period
F/U 
Period
Activities
S1
S2
R1
R2, R3, 
R4, R5
R6
E1
E2
E3
E4
E5
Randomization
T1
Yearly*
Final 
Treatment/ 
PD
F1
24-hour urine 
collection
X
X
X
X
*
T12, T24, T36, T48, etc.


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Serum and Urine Samples for Biological Markers
Additional samples of serum and urine will be collected according to the schedule 
outlined in Table 1.  These samples will be sent to the central laboratory (stored at –70°C 
at the central laboratory) for exploratory analyses of additional biomarkers.  The results of 
serum and urine biomarkers may not be reported in the study summary.
Randomization and Assignment of Subject Numbers
A unique 6-digit Subject Number will be assigned by the IVR to all subjects that complete 
their first Screening visit.  This number will be used to identify the subject throughout the 
study.
All Screening and Run-In R6 laboratory results must be reviewed by the Investigator prior 
to the Enrichment Period.  Subjects who meet the eligibility criteria will proceed to the 
Enrichment Period for treatment with Atrasentan 0.75 mg QD.  All E5 visit laboratory 
results must be reviewed by the Investigator and subject eligibility assessed prior to the 
subject proceeding to randomization.
Eligible subjects will be randomized to receive either placebo or Atrasentan 0.75 mg once 
daily at the Randomization visit.  Unique 8-digit randomization numbers will be assigned 
as subjects are enrolled in the study and will be captured in the eCRF.
5.3.1.2
Blood Samples for Pharmacogenetic Analysis
One 4 mL whole blood sample for DNA isolation will be collected from each subject who 
enters the Double-Blind Treatment Period and consents to provide samples for 
pharmacogenetic analysis.  If the sample is not collected at the required visit, it may be 
collected at any subsequent visit.  The procedure for obtaining and documenting informed 
consent is discussed in Section 9.3.
Whole blood will be collected by standard phlebotomy techniques as described below:


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●
Collect approximately 4 mL of blood into an appropriately labeled EDTA 
tube.
●
Immediately invert the collection tube 8 to 10 times to reduce the likelihood of 
clot formation.
●
Store samples at –20°C or colder within 30 minutes of the blood draw until 
shipped/transported to the central laboratory on dry ice sufficient to last during 
shipment/transport.
Samples will be shipped frozen to AbbVie for DNA extraction and long-term storage.  
Samples should not be allowed to thaw prior to arrival at AbbVie.  Arrangements will be 
made with the central laboratory for the shipment of samples to AbbVie:
AbbVie Sample Receiving
For China, arrangements will be made with the central laboratory for shipment of samples 
to the reference laboratories following separately provided instructions.
The sample collection tubes will minimally be labeled with "Pharmacogenetic Sample," 
the drug number, protocol number, subject number and the study day.  AbbVie will store 
the DNA samples in a secure storage space with adequate measures to protect 
confidentiality.  The samples will be retained while research on Atrasentan (or drugs of 
this class) continues but no longer than 20 years from the end of the study.


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5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Pharmacokinetic Analysis
For all subjects, blood samples for assay of Atrasentan and possible metabolites of 
Atrasentan will be collected by venipuncture into a 4 mL evacuated K2 EDTA containing 
collection tube at timepoints outlined in Table 1.  A sufficient amount of blood will be 
collected to provide approximately 2 mL plasma from each sample.  Immediately after 
collection, the blood samples will be inverted several times to ensure good mixing of the 
blood and anticoagulant.
The date and time that each blood sample will be noted, and the date and time of the 
two previous doses of study drug will be recorded to the nearest minute on the appropriate 
eCRF.
Arrangements will be made with the central laboratory for shipment of samples to the 
reference laboratories following separately provided instructions.
5.3.2.2
Handling/Processing of Samples
The blood samples for pharmacokinetic analysis will be centrifuged (1100 – 1600 # G for 
approximately 10 minutes) within 1 hour of collection using a centrifuge to separate the 
plasma.  The plasma samples will be transferred using plastic pipettes into screw-capped 
polypropylene tubes labeled with the drug name, type of sample (plasma), the protocol 
number, the subject number and study visit.  The plasma samples will be frozen at –20°C 
or colder within 2 hours after collection and will remain frozen until shipped to the central 
laboratory.
5.3.2.3
Disposition of Samples
The frozen plasma samples for pharmacokinetic analysis will be packed in dry ice 
sufficient to last during transport (3 days) and shipped from the study site to the central 
laboratory.  An inventory of the samples included in the shipment will accompany the 


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package.  The central laboratory will provide instructions regarding the collection, 
processing and shipping of these samples.
5.3.2.4
Measurement Methods
Plasma concentrations of Atrasentan and possible metabolites will be measured under the 
supervision of the Drug Analysis Department at AbbVie.
5.3.3
Efficacy Variables
5.3.3.1
Primary Endpoint (Adjudicated)
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 ESRD (eGFR 
< 15 ml/min/1.73m2 (confirmed by a 90-day eGFR), receiving chronic dialysis, renal 
transplantation or renal death).
5.3.3.2
Secondary Efficacy Endpoints
●
Time to a 50% eGFR reduction.
●
Time to cardio-renal composite endpoint: confirmed doubling of serum 
creatinine, ESRD, CV death, nonfatal myocardial infarction, nonfatal stroke.
●
Time to first occurrence of a component of composite renal endpoint:  
confirmed doubling of serum creatinine or the onset of ESRD for all 
randomized subjects (pooled).
●
Time to the CV composite endpoint:  CV death, nonfatal myocardial infarction 
and nonfatal stroke.
5.3.3.3
Additional Endpoints
●
Time to 40% reduction in eGFR.
●
Change in eGFR slope.
●
Change in eGFR after 3 months post randomization treatment.
●
Change in eGFR to 45 days after end of treatment (or final observation on 
treatment).


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●
Change from baseline to Month 24 post-randomization visit on UACR.
●
Time to major vascular event:  CV death, nonfatal myocardial infarction, 
nonfatal stroke, hospitalized unstable angina.
●
Time to any vascular event:  CV death, nonfatal myocardial infarction, 
nonfatal stroke, hospitalized unstable angina, or arterial revascularization 
(coronary, carotid or peripheral).
●
Time to congestive heart failure (hospitalized and non-hospitalized).
●
Time to major coronary disease events:  fatal coronary event, non-fatal 
myocardial infarction, hospitalized unstable angina.
●
Time to Total Stroke:  fatal and non-fatal stroke.
●
Number of new onset atrial fibrillation/flutter events. 
●
Cumulative number of acute kidney injury (AKI) events after randomization 
that are associated with temporary dialysis (< 30 days duration of dialysis).
●
Change from baseline to each post-baseline assessment in EQ-5D-5L Index 
Score and AQOL-4D (Australia only) and KDQOL SF™ version 1.3 
parameters.
●
Time to all-cause mortality.
●
Time to first laser photocoagulation for diabetic retinopathy.
●
Cumulative number of laser photocoagulations for diabetic retinopathy (where 
a laser treatment is considered new if it occurs more than 10 weeks after the 
last treatment).
5.3.4
Safety Variables
Safety data will be analyzed for the data collected throughout Treatment Period and up to 
45 days post-treatment.  The following safety endpoints will be collected:
●
The incidence of adverse events and the proportion of subjects who are 
discontinued from the study due to adverse events
●
The change from baseline to each visit in chemistry, hematology, and urine 
measurements
●
The change from baseline to each visit in vital signs


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5.3.5
Pharmacokinetic Variables
Plasma concentrations of Atrasentan and its possible metabolites will be obtained at the 
treatment visits outlined in Table 1.  Population pharmacokinetic modeling techniques 
may be used to estimate population central values for apparent oral clearance (CL/F) and 
volume of distribution (V/F) and conditional estimate values of these parameters for the 
individual subjects may also be determined.  Additional parameters may be calculated if 
useful in the interpretation of the data.  Relationship between Atrasentan exposure and 
clinical efficacy response will be explored using population modeling techniques.
5.3.6
Pharmacogenetic Variables
DNA samples may be analyzed for genetic factors contributing to the subject's response to 
Atrasentan, or other study treatment, in terms of pharmacokinetics, efficacy, tolerability 
and safety.  Such genetic factors may include genes for drug metabolizing enzymes, drug 
transport proteins, genes within the target pathway, or other genes believed to be related 
to drug response.  Some genes currently insufficiently characterized or unknown may be 
understood to be important at the time of analysis.  The samples may be analyzed as part 
of a multi-study assessment of genetic factors involved in the response to Atrasentan or 
drugs of this class.  The samples may also be used for the development of diagnostic tests 
related to Atrasentan (or drugs of this class).  The results of pharmacogenetic analyses 
may not be reported with the study summary.
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Subjects will be discontinued from study drug administration immediately if any of the 
following events occur:
●
Chronic dialysis, or renal transplant.
●
The subject or subject's legally authorized representative requests withdrawal 
from the study.
●
Investigator request (for any reason).


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Subjects who have had study drug discontinuation for any reason other than the above 
should be encouraged to restart study drug as soon as practically and medically 
appropriate at the discretion of the Investigator.
If the subject permanently discontinues from study drug administration, after discussion 
with the Sponsor, the procedures outlined for the Premature Discontinuation/Final 
Treatment visit must be completed within 9 days of the last dose of study drug.  In 
addition, the procedures outlined for the F1 visit must be completed 45 days (±14 days) of 
the last dose of study drug.  Following discontinuation of the study drug during the 
Double-Blind Treatment Period, the subject will continue to be monitored for potential 
primary and cardiovascular outcome events, including CV death and all SAEs.  Events 
requiring adjudication will continue to be adjudicated using the eClinical© system 
(Section 6.5.1).  Subjects who prematurely discontinue from the study will not be 
replaced.  The date and reason for premature discontinuation will be recorded in the 
subject's source documents and on the appropriate eCRF.
A subject may withdraw at any time without prejudice.  If the Investigator, for any reason, 
decides it is in the best interest of the subject to permanently discontinue study drug, 
treatment should be stopped but the subject should be encouraged to continue in the study 
so that important and complete safety information can be obtained.  If a subject withdraws 
or is lost to follow-up, such should be noted, along with the reason for withdrawal on the 
eCRF.  Safety-related reasons for withdrawal are reported to AbbVie as adverse events.
Every effort will be made to retain all randomized subjects in the study.  All subjects that 
are unreachable after at least three documented attempts every 3 months for 9 months, 
including attempts to contact the subject via phone, email, certified letter, and/or to 
attempt to reach the subject's secondary contact that was provided on the informed 
consent, will be considered lost to follow-up.
For subjects who are lost to follow-up during the study, the Sponsor will take reasonable 
actions to ascertain vital status at the end of the study.  The Sponsor will make every 
effort to encourage investigational sites to match subjects lost to follow-up against the 


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National Death Registries, and against national/regional cancer registries and vital 
registries.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause (e.g., early study termination after interim futility or efficacy analyses) 
provided that written notice is submitted to the site(s) in advance of the intended 
termination.  The Investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie or designee will 
immediately notify the Investigator by telephone and subsequently provide written 
instructions for study termination.
Following study termination for any reason, all subjects must be contacted.  At this time, 
subjects who have not permanently discontinued study drug will be scheduled for the 
Final Treatment visit and Follow-Up Visit (F1).  In subjects who were permanently 
discontinued from study drug, the next scheduled on-site visit (preferred) or phone call 
(only if the subject is unable or unwilling to undergo on-site assessments) should be 
completed to solicit and collect information about any potential endpoint events, SAEs, 
and local laboratory reports for values such as serum creatinine and eGFR since the 
previous visit or phone call.
5.4.3
Study Completion
Study Completion is defined as the occurrence of 425 distinct primary renal events in the 
responder population.  Upon reaching Study Completion, the Sponsor (or designee) will 
contact the Investigators to inform them of Study Completion and request all subjects be 
contacted.  Subjects who have not permanently discontinued from study drug will be 
scheduled for the Final Treatment Visit and Follow Up visit (F1).  Subjects who were 
permanently discontinued from study drug should complete the next scheduled visit or 
phone call to solicit information about any potential endpoint events, SAEs, and 


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laboratory values such as serum creatinine and eGFR since the previous visit or phone call 
(refer to Premature Discontinuation and Retention section).
The Sponsor will track the number of positively adjudicated primary renal events and the 
events undergoing adjudication.  Because all potential events occurring on or before each 
subject's last contact will be adjudicated and due to the time it will take to have every 
subject complete a follow-up visit, there is a possibility the EAC will positively adjudicate 
more than 425 primary efficacy events.
5.5
Treatments
5.5.1
Treatments Administered
Before randomization, each subject will receive 0.75 mg of Atrasentan once daily during 
an Enrichment Period.  The subjects will continue to take study drug until the 
Randomization visit and be stratified according to geographic region, baseline 
albuminuria, and percentage of UACR reduction.  Within each stratum, subjects will be 
randomly assigned in a 1:1 ratio to one of the following blinded treatments:
●
Placebo once daily
●
Atrasentan 0.75 mg once daily
5.5.2
Identity of Investigational Products
The individual study drug information is presented in Table 5.
Table 5.
Identity of Investigational Products
Study Drug
Dosage Strength
Formulation
Manufacturer
Atrasentan
0.75 mg
Film-coated tablet
AbbVie
Placebo for Atrasentan
N/A
Film-coated tablet
AbbVie
Note:  All tablets will be identical in appearance.


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5.5.2.1
Packaging and Labeling
Study drug in tablet form will be packaged in bottles containing 32 tablets and a desiccant 
canister.  Each bottle will be labeled as per country requirements.
Each label must remain affixed to the bottle.  All blank spaces on the label will be 
completed by site staff prior to dispensing.
In the Enrichment Period, subjects will receive open-label Atrasentan 0.75 mg.  Subjects 
will be instructed to take 1 tablet daily.
In the Double-Blind Treatment Period, subjects will receive bottles containing either 
Atrasentan 0.75 mg or matching Placebo.  Subjects will be instructed to take 1 tablet 
daily.  To provide blinded subject doses of Placebo or Atrasentan 0.75 mg once daily, 
tablets will be manufactured such that they are identical in appearance, and will be 
packaged and labeled in an identical fashion.
Each bottle will have a unique kit number.  This kit number is assigned to a subject via 
IVRS/IWRS and encodes the appropriate study drug to be dispensed at the subject's 
corresponding study visit.  Each kit number will be captured in the eCRF system.  Study 
drug product is not to be re-dispensed among subjects.
5.5.2.2
Storage and Disposition of Study Drugs
The study drug must be stored between 15° to 25°C (59° to 77°F), protected from 
moisture, in the supplied bottle which contains a desiccant.  Desiccant canister should be 
returned to the bottle directly after each tablet removal.  Each clinical site should have a 
temperature recording device in the drug storage area.  A temperature log is to be 
maintained to document proper storage conditions.  The temperature must be recorded 
every business day.  If the storage temperature falls outside the allowed range, the 
excursion must be reported immediately, either by contacting AbbVie directly, or through 
the ATEMS module of the IVRS/IWRS system.  In the event of a temperature excursion, 


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affected study drug should be quarantined and should not be dispensed until notification 
of the final assessment and disposition is received.
The investigational products are for investigational use only and are to be used only 
within the context of this study.  The study drug supplied for this study must be 
maintained under adequate security and stored under the conditions specified on the label 
until dispensed for subject use, destroyed at the site according to local regulations and 
instructions from AbbVie or returned to AbbVie or a local depot for destruction.  The 
Investigator will keep a current and accurate inventory of clinical supplies provided by 
AbbVie.  All original study medication containers supplied by AbbVie, whether empty or 
containing unused medications, will be kept until instructions are provided from the 
Clinical Monitor, in conjunction with AbbVie.
5.5.3
Method of Assigning Subjects to Treatment Groups
The randomization schedules will be computer generated by the Clinical Statistics 
Department at AbbVie, North Chicago, IL prior to the start of the study.  The original 
randomization schedules will be securely stored at AbbVie, and a hard copy and 
electronic file of the randomization schedules will be supplied to Perceptive Informatics 
in accordance with AbbVie's standard operating procedures (SOP).
At the Screening visit, each subject will be assigned a unique 6-digit subject number by 
the IVRS/IWRS.  
 
Subjects meeting entry criteria into the Double-Blind Treatment Period will be 
randomized via IVRS/IWRS supplied by Perceptive Informatics.  The kit bottle number 
will be 7 digits.
A stratified randomization scheme will be used to ensure desired subject allocation ratio 
among treatment groups within geographic region (North America, Latin America, 
Europe, Asia Pacific and Japan), baseline UACR level ≤ or > 1000 mg/g, and UACR 
reduction achieved during the Enrichment Period (< 0%, 0% – < 15%, 15% – < 30%, 30% 


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– < 45%, 45% – < 60% and ≥ 60%).  The randomization methods are described in 
Section 8.3.
Through the IVRS/IWRS, subjects will be assigned in a 1:1 ratio to one of the 
two treatment groups:  placebo once daily or Atrasentan 0.75 mg once daily.  All clinical 
drug supplies (Atrasentan and matching placebo) will be supplied by AbbVie.
5.5.4
Selection and Timing of Dose for Each Subject
Before randomization, each subject will receive Atrasentan 0.75 mg once daily during an 
Enrichment Period.  The subjects will continue to take study drug until the Randomization 
visit and be randomized to one of the two treatment groups described in Section 5.5.1.  
Subjects should be administered the first dose of blinded study drug during the 
Randomization visit.  Subjects will be instructed to take study drug once daily at 
approximately the same time each day (preferably in the morning).
5.5.5
Blinding
Both the Investigator and the subject will remain blinded to the subject's treatment group 
during the double-blind period of the study.  The IVRS/IWRS will be programmed with 
blind-breaker instructions.  The study blind may be broken if, in the opinion of the 
Investigator, it is in the subject's best interest to know the study drug assignment.  The 
Sponsor (AbbVie) MUST be notified before breaking the blind unless identification of the 
study drug is required for emergency therapeutic measures.  If an emergency therapeutic 
measure is necessary which warrants breaking of the blind, the Sponsor must be notified 
within 24 hours of the blind being broken.  The date and reason for blind breakage must 
be recorded in source documentation and on the appropriate eCRF.
5.5.5.1
Blinding of Data for Independent Data Monitoring 
Committee (IDMC)
An Independent Data Monitoring Committee (IDMC) comprised of external physicians 
and an external statistician will review unblinded safety data periodically throughout the 
study.  The objective of the IDMC is to review key safety information in Study M11-352 


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and make recommendations to the Sponsor and the Steering Committee (described in 
Section 5.5.5.3) regarding continuation, modification, or termination of the study without 
compromising study blind from the perspective of the Sponsor or any other party involved 
in conduct of the study.  The IDMC membership and responsibilities are defined in the 
IDMC Charter.  In addition, the IDMC will review the pre-planned interim analyses and 
make recommendations guided by the formal stopping rules described in the statistical 
analysis results plan (SAP).
5.5.5.2
Blinding of Data for Events Adjudication Committee (EAC)
An independent EAC, blinded to study treatment assignment, will adjudicate all events 
that have the potential to be considered as doubling of serum creatinine, ESRD, 
cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, heart failure 
(hospitalized and non-hospitalized), and possibly other endpoints of interest.  The EAC 
Charter describes the roles and responsibilities of the EAC and defines the events to be 
adjudicated and the manner in which they will be adjudicated.  The EAC will judge 
whether an event meets the predetermined definitions.  The Investigator will notify 
George Clinical of a potential endpoint through a Web portal as outlined in Section 6.5.1.  
George Clinical will give the Investigator instructions for collecting documentation for the 
EAC review.
5.5.5.3
Steering Committee
A steering committee will be involved in the design and implementation of the study.  Its 
membership will be representative of the global nature of the study sites and regular 
meetings will be conducted to evaluate the conduct of the trial, including evaluations from 
the IDMC and EAC.  A separate Steering Committee charter describes the roles and 
responsibilities of the Steering Committee.
5.5.6
Treatment Compliance
In order to document compliance with the treatment regimen, subjects will be instructed 
to return all bottles (even if empty) to the study site personnel at each visit.  The study site 


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personnel will document compliance during the Enrichment Period by recording the total 
number of doses returned (brought back) per bottle during each visit in the source 
document and on the appropriate eCRF page.
The Investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
To calculate compliance at each visit:
[(# of tablets dispensed – # of tablets returned) / # of days from previous visit] * 
100% = % compliance
Note:  The previous visit should be included in the count when calculating number of 
days from previous visit.  The current visit should not be included in the count when 
calculating the number of days from previous visit.
Subjects will be encouraged to take study drug as prescribed.  At each visit, compliance 
will be assessed and the subject will be counseled if there is evidence of non-compliance.  
The Investigator or designee will investigate and document the reason for 
non-compliance.
5.5.7
Drug Accountability
The Investigator or representative will verify that study drug supplies are received intact 
and in the correct amounts.  This will be documented by signing and dating the Proof of 
Receipt or similar document or via direct recording in the IVRS/IWRS.  An accurate 
(running) inventory of study drug will be kept by the site in the IVRS/IWRS, and will 
include the lot number, Proof of Receipt number(s), the number of tablets dispensed, 
subject number, initials of person who dispensed the drug and the date study drug was 
dispensed for each subject.  An overall accountability of the study drug will be performed 
and verified by the Monitor throughout the study and at the site close-out visit.  All study 


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drug unit doses must be inventoried, accounted for, and returned to AbbVie or destroyed 
per instructions from AbbVie and according to local regulations.
The Investigator and/or designated and qualified representatives agree not to supply study 
medication to any persons not enrolled in the study.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
The design of this study provides a placebo control to assess the efficacy and safety of 
Atrasentan.  Double-blind, parallel group designs are generally acknowledged as standard 
for unbiased estimates of treatment group differences.
5.6.1.1
Use of an Independent Data Monitoring Committee (IDMC)
Use of an IDMC, comprised of independent experts, to perform the unbiased and 
consistent evaluation of safety is a well-established component of ethical, well-run 
clinical studies.
5.6.2
Appropriateness of Measurements
All efficacy measurements in this study are standard.  All clinical and laboratory 
procedures in this study are standard and generally accepted.
5.6.3
Suitability of Subject Population
The purpose of this study is to assess the efficacy and safety of Atrasentan on slowing the 
progression of chronic kidney disease (CKD) as adjudicated by assessing time to doubling 
of serum creatinine or time to ERSD (composite primary endpoint) in subjects with type 2 
diabetes and nephropathy that are currently being treated with the MTLDD of a RAS 
inhibitor.
Therefore, subjects who have been treated with a stable dose of ACEi or ARBs, who have 
an estimated GFR ≥ 25 and ≤ 75 mL/min/1.73 m2 by epidemiology collaboration (EPI) 


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formula, who have a UACR ≥300 and ≤ 5000 mg/g, and who are ≥ 18 years of age have 
been selected as the target population for this study.  Subjects who have a history of an 
allergic reaction or significant sensitivity to Atrasentan or to drugs similar to the study 
drug will be excluded to avoid confounding factors related to the active disease process.
5.6.4
Selection of Doses in the Study
The dose of 0.75 mg was selected following analysis of the results of the Phase 2b trials.  
The rationale for selecting a single dose of Atrasentan is based on the narrow therapeutic 
index of this drug and the need to balance the efficacy in reducing albuminuria with the 
safety and blood pressure change parameters.  Subjects that enroll in the study will receive 
0.75 mg QD of ABT-627 for up to 7 weeks during the Enrichment Period.  After 
enrichment, subjects may be randomized to receive a maximum of 0.75 mg QD of 
ABT-627 for up to approximately 6 years.
Dose selection for the Phase 2b studies was based on the exposure-response analyses and 
clinical results from Study M10-815.  Statistically significant exposure-response 
relationships for both the efficacy (UACR reduction) and the incidence of edema were 
then quantified from all Phase 2 studies.  The simulations showed that a proportion of 
subjects achieving a 40% reduction in UACR increase with increasing dose from 0.25 mg 
per day approximately reaching a nadir in the range of 0.75 to 1.25 mg per day dose.  
 
 
 
 
6.0
Adverse Events
The Investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The Investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 


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considered as having "no reasonable possibility" of being associated with study drug, the 
Investigator will provide an Other cause of the event.  For adverse events to be considered 
intermittent, the events must be of similar nature and severity.  Adverse events, whether in 
response to a query, observed by site personnel, or reported spontaneously by the subject 
will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1
Definitions
6.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, and/or if the Investigator considers them to be adverse events.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre-planned prior to study entry.  However, if the 
pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.


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6.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the serious 
adverse event.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the Investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study subject.  
Disability is not intended to include experiences of relatively 
minor medical significance such as headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle).


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Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but based 
on medical judgment may jeopardize the subject and may 
require medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of subject, life-threatening, 
hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity).  
Additionally, any elective or spontaneous abortion or 
stillbirth is considered an important medical event.  Examples 
of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or 
drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.2
Adverse Event Severity
The Investigator will use the following definitions to rate the severity of each adverse 
event:
Mild
The adverse event is transient and easily tolerated by the subject.
Moderate
The adverse event causes the subject discomfort and interrupts the 
subject's usual activities.
Severe
The adverse event causes considerable interference with the subject's 
usual activities and may be incapacitating or life-threatening.
6.3
Relationship to Study Drug
The Investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:


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Reasonable 
Possibility
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.
No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the Investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an Investigator's opinion of no reasonable possibility of being related to study drug is 
given, an Other cause of event must be provided by the Investigator for the serious 
adverse event.
6.4
Adverse Event Collection Period
All adverse events (non-serious and serious) reported from the time of study drug 
administration until 45 days following discontinuation of study drug administration have 
elapsed will be collected, whether solicited or spontaneously reported by the subject. In 
addition, serious adverse events will be collected from the time the subject signed the 
study-specific informed consent.
In the event that study drug is interrupted, adverse events and serious adverse events will 
be collected throughout the interruption.  If treatment with study drug is discontinued for 
any reason the reason will be recorded and the subject should be encouraged to remain in 
the study so important safety information can be obtained.  All adverse events and serious 
adverse events leading to discontinuation of study drug or discontinuation of study will be 
collected.  Once a subject withdraws consent to participate in the study, no further 
information can be collected from the subject.
For subjects who permanently discontinue study drug and continue in the study, 
beginning after the 45-day post study drug discontinuation period, the Investigator will 


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monitor each subject for potential endpoints and SAEs for the duration of the study (refer 
to Section 5.1 and Section 6.5.1).
Adverse event information will be collected as shown in Figure 2.
Figure 2.
Adverse Event Collection
*
Final visit refers to final subject contact as referenced in Section 5.4.2 and Section 5.4.3.
6.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the 
investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the 
electronic data capture (EDC) system.  Serious adverse events that occur prior to the site 
having access to the RAVE system, or if RAVE is not operable, should use the SAE 
non-CRF paper forms and be faxed to the Clinical Pharmacovigilance within 24 hours of 
site being made aware of the serious adverse event:
FAX to:  
Email:  


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For safety concerns, contact the Renal Safety Management Team at:
Renal Safety Management
AbbVie Inc.
1 North Waukegan Road
North Chicago, IL  60064
Office:
Email:
For any subject safety concerns, please contact the physician listed below:
Primary Study Designated Physician:
In case of subject safety concerns or medical emergencies and the Primary Study 
Designated Physician is unavailable, please call the following central back-up number:
Phone:  
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 


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Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure.
In Japan, the Investigator will provide documentation of all protocol-related serious 
adverse events to the Director of the investigative site and the Sponsor.
6.5.1
Potential Endpoint Reporting for Adjudication
The Investigator or designee will report potential endpoints through a Web Portal 
(eClinical©) within 5 days of being aware of potential event.  The vendor (George 
Clinical) will work with the site to obtain pertinent information to complete a case packet.  
Once the packet is confirmed complete by George Clinical, they will assign to the EAC 
committee for review and adjudication.  Details of the endpoint reporting process are 
listed in the Endpoint Reporting site manual.
The following events will be reported by the site in eClinical© for subjects in the 
Enrichment Period: 
●
Death
●
Nonfatal Stroke
●
Nonfatal MI
●
Heart Failure (hospitalized and non-hospitalized) 
The following events will be reported by the site in eClinical© for subjects in the Double-
Blind Treatment Period including subjects who continue follow-up after premature 
discontinuation of study drug during the Double-Blind Treatment Period:
●
Doubling of Serum Creatinine
●
ESRD
●
Death
●
Nonfatal Stroke
●
Nonfatal MI
●
Heart Failure (hospitalized and non-hospitalized)


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The Sponsor may request reporting of additional safety-related events into eClinical©.
6.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site 
becoming aware of the pregnancy.  Subjects who become pregnant during the study must 
be discontinued immediately (Section 5.4.1).
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected.
Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to AbbVie within 24 hours of the 
site becoming aware of the event.  In the event of pregnancy occurring in the partner of an 
enrolled subject, written informed consent for release of medical information from the 
partner must be obtained prior to the collection of any pregnancy-specific information and 
the pregnancy will be followed to outcome.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol.  The 
Investigator is responsible for complying with all protocol requirements, and applicable 
global and local laws regarding protocol deviations.  If a protocol deviation occurs (or is 
identified) after a subject has been enrolled, the Investigator is responsible for notifying 
Independent Ethics Committee (IEC)/Independent Review Board (IRB) regulatory 
authorities (as applicable), and their assigned CRO Clinical Monitor or AbbVie:


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Primary Contact:
Alternate Contact:
Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study.
In Japan, the Investigator will record all protocol deviations in the appropriate medical 
records at site.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
All statistical analyses with between treatment comparisons are conducted for the 
Double-Blind Period.  Testing of treatment group differences for efficacy endpoints 
between the Atrasentan arm and placebo arm will be conducted at a two-sided 
significance level of 0.05 (suitably adjusted for group-sequential testing and multiplicity 
for the primary and secondary endpoints).  Safety data involving the Enrichment Period 
will be presented for exploratory purposes and no statistical comparisons will be made.
The primary efficacy endpoint of the study is the time to first occurrence of an adjudicated 
renal composite event defined as either doubling of serum creatinine (confirmed by a 
30-day serum creatinine) or the onset of ESRD in subjects who achieve at least 30% 
reduction in UACR in the Enrichment Period (responders).  Approximately 3,500 subjects 
(2,500 subjects who achieve at least 30% reduction in UACR in the Enrichment Period 
and approximately 1,000 subjects who achieve less than 30% reduction in UACR in the 


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Enrichment Period) will be randomized in a 1:1 ratio to 2 treatment groups:  placebo or 
Atrasentan 0.75 mg/day.
For summarizing continuous variables (e.g., weight) the mean, standard deviation, 
median, minimum and maximum values will be provided.  For selected variables, 
appropriate percentiles may also be provided.  For categorical variables (e.g., gender), 
frequencies and percentages will be provided.
Unless noted otherwise, all analyses will be performed using SAS version 9.3 (SAS 
Institute Inc., Cary, NC  27513) under the UNIX operating system.
8.1.1
Analysis Datasets
The following datasets will be used for the analysis of all efficacy and other non-safety 
endpoints.  For these analyses, subjects will be classified according to the treatment group 
to which they were randomized.
●
The Intention-to-treat (ITT) Responder Set will serve as the primary dataset 
for the analysis of efficacy in this study.  It will consist of all randomized 
subjects who achieve at least 30% reduction in UACR in the Enrichment 
Period (responders).
●
The ITT Non-responder Set will consist of all randomized subjects who 
achieve less than 30% reduction in UACR in the Enrichment Period 
(non-responders).
●
The ITT Pooled Set will consist of all randomized subjects (both responders 
and non-responders) and will be used for a pooled analysis of efficacy.
The following datasets will be used for the analysis of safety endpoints.  For these 
analyses, subjects will be analyzed according to the treatment they actually receive during 
the double-blind phase.
●
The All Treated Responder Set includes all randomized subjects who achieve 
at least 30% reduction in UACR in the Enrichment Period and receive at least 
one dose of study drug during double-blind phase.


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●
The All Treated Non-responder Set includes all randomized subjects who 
achieve less than 30% reduction in UACR in the Enrichment Period and 
receive at least one dose of study drug during double-blind phase.
●
The All Treated Set includes all randomized subjects who receive at least
one dose of study drug during double-blind phase.
Additionally, an All Atrasentan Set comprising all subjects who receive at least one dose 
of Atrasentan, including both Enrichment and Double-Blind Treatment Periods, is defined 
for the purposes of data analysis.
8.1.2
Demographic, Other Baseline Characteristics, Subject 
Disposition and Concomitant Medication
Definition of Baseline
For treatment comparisons and summaries based on the Double-Blind Period, baseline 
values refer to the last non-missing value observed prior to or at the time of 
randomization.  This includes treatment comparisons performed for the ITT responder set, 
ITT non-responder set and the ITT pooled set (Section 8.1.1).
For determination of doubling of serum creatinine, baseline values refer to the last non-
missing value observed prior to or pre-dose on the first day of Atrasentan therapy at the 
beginning of the Enrichment Period.
For purposes of summarizing safety and efficacy for the Enrichment Period and the entire 
study treatment period (Enrichment and Double-Blind Treatment Periods combined), 
baseline values refer to the last non-missing value observed prior to or pre-dose on the 
first day of Atrasentan therapy (Treatment Day 1) at the beginning of the Enrichment 
Period.  For the Enrichment Period, initial UACR is computed as the geometric mean of 
UACR collected at Visits R6 and E1, and final UACR is computed as the geometric mean 
of the UACR values collected at Visits E4 and E5, provided at least three UACR values 
are available in each case.  UACR will be considered to be missing otherwise.


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Analysis
All demographic and baseline characteristics such as gender, race, age, weight, etc., will 
be summarized by treatment group to assess comparability of treatment groups for the ITT 
analysis sets.
Subject disposition, completion of study, or discontinuation from the study (along with 
the primary reason for discontinuation), will be summarized by treatment group for the 
ITT analysis sets.  The primary reasons for discontinuation of study drug during the 
Double-Blind Treatment Period will be summarized by treatment group.  A summary of 
subject disposition and discontinuation during the Enrichment Period will be provided 
using the all Atrasentan set.
Concomitant medications will be reported by generic name assigned by the World Health 
Organization (WHO) dictionary and their usage will be summarized by treatment group 
for the ITT analysis sets.
In addition, the concomitant use of RAS inhibitors will be summarized for the ITT 
analysis sets as follows:
●
For each medication in the RAS inhibitor class, the average daily dose will be 
calculated across the Double-Blind Treatment Period and summary statistics of 
the average daily dose will be provided by treatment group.
●
The number and percentage of subjects who change their dosage or initiate 
prescriptions of another RAS inhibitor during the Double-Blind Treatment 
Period of the study will be tabulated by treatment group.
The concomitant use of diuretics will be summarized for the ITT analysis sets as follows:
●
For each medication in the diuretics class, the average daily dose will be 
calculated across the days that diuretics are taken during the Double-Blind 
Treatment Period and summary statistics for the average daily dose will be 
provided by treatment group.


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●
The number of days that a subject is on any diuretics during the Double-Blind 
Treatment Period and the percentage of such days over the subject's total 
duration of the Double-Blind Treatment Period will be computed. Summary 
statistics will be provided for the percentage of days on any diuretics by 
treatment group.
●
The number and percentage of subjects who take diuretics, change their 
dosage, or initiate prescriptions of another diuretic medication during the 
Double-Blind Treatment Period will be tabulated by treatment group.
8.1.3
Efficacy Analyses
Efficacy analyses for treatment comparisons will be performed on the ITT responder 
population, ITT analysis sets as follows.
For UACR value for the screening visit, the geometric mean of UACR values from 
two consecutive FMV urine samples collected prior to that visit will be used.  For 
scheduled visits during the Run-In and Enrichment Period, the geometric mean of values 
from all FMV urine samples available for that visit will be used.  The initial UACR value 
(at the beginning of enrichment) is defined as the average (geometric mean) of the UACR 
values collected at the last week of Run-In (Visit R6) and the first day of Enrichment 
(Visit E1) (a minimum of three UACR values are required).  The final UACR in the 
Enrichment period is defined as the average (geometric mean) of the UACR values 
collected from the Enrichment Week 4 (Visit E4) to Enrichment Week 6 (Visit E5) (a 
minimum of three UACR values are required).  The initial (or final) average UACR value 
will be considered to be missing if less than three values are available for its calculation.  
The percent change in UACR that is used to define responders and non-responders at the 
end of the Enrichment Period is calculated with the initial UACR as the reference value.  
For on-treatment visits and the 45-day follow-up, the FMV urine samples will consist of a 
single collection within 1 day of the yearly Treatment visits (with the exception of 
3 FMVs to be collected just prior to the T24 visit).


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8.1.3.1
Primary Efficacy Analyses (Responders)
The primary efficacy endpoint is the 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 ESRD.  Only events adjudicated by the Events Adjudication 
Committee (EAC) will be considered in defining this endpoint.  The time of randomized 
treatment assignment will be considered "time zero" (time origin) for the derivation of the 
primary endpoint.  In defining the composite endpoint, reaching any component of the 
composite will be considered as attaining the endpoint.  For subjects for whom an event is 
not recorded, the time-to-event will be right-censored at the date of the last 
visit/assessment at which there is complete information for all components of the 
composite.
A Cox proportional-hazard regression model will be performed on the ITT responder set 
to estimate the hazard ratio of Atrasentan to placebo and its 95% confidence interval.  The 
primary efficacy analysis for treatment comparison will be conducted using a stratified 
log-rank test, adjusting for the following stratification factors.
●
UACR level at the beginning of the Enrichment Period (≤ 1,000 mg/g 
[113 mg/mmol] or > 1,000 mg/g [113 mg/mmol]) and
●
UACR reduction during Enrichment Period (30% – < 45%, 45% – < 60%, and 
≥60%).
Kaplan-Meier estimates for cumulative event rates will be plotted.  A Cox 
proportional-hazards regression model with treatment group and the relevant factors 
(defined in the Statistical Analysis Plan) as explanatory variables will be performed to 
estimate the hazard ratio of events comparing placebo to Atrasentan and its 95% 
confidence interval.
In addition, the individual components of the primary efficacy endpoint, i.e., the time to 
the first occurrence of doubling of serum creatinine (confirmed by a 30-day serum 
creatinine) or eGFR < 15 ml/min (confirmed by a 90 day eGFR) and the time to the 


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first occurrence of the onset of dialysis, renal transplant or renal death will be analyzed 
separately using the same methods as specified above.  In analyzing the individual 
components, first occurrence of only that specific endpoint will be considered as events.
Subgroup analyses for subgroups based on age, gender, race, geographical regions and 
important baseline characteristics will also be performed.
8.1.3.2
Secondary Efficacy Analysis
These pre-specified secondary efficacy endpoints are listed according to their clinical 
importance (Section 5.3.3.2) and will be analyzed in a hierarchical (step-down) fashion as 
described in Section 8.1.3.5.
The analyses of these time-to-event endpoints will follow the same methods as specified 
for the primary efficacy analysis.
8.1.3.3
Additional Efficacy Analysis
The additional time-to-event endpoints will be analyzed for all ITT analysis sets using the 
same methodology as specified for the primary efficacy endpoint. 
The additional endpoints of change from baseline in eGFR to 45 days after end of 
treatment, change from baseline to Month 24 post-randomization visit on UACR, change 
from baseline to each post-baseline assessment in EQ-5D-5L Index Score and AQOL-4D 
(Australia only) and KDQOL SF™ version 1.3 parameters will be analyzed using a mixed 
model of repeated measures (MMRM).  In this model, the response vector consists of the 
change from baseline values at each post-randomization assessment.  The model will 
include the fixed effects of treatment, time (treated as a categorical variable), 
treatment-by-time interaction, baseline value and baseline-by-visit interaction.  An 
unstructured covariance matrix will be used to model the correlation among longitudinal 
measurements, and Satterthwaites's approximation will be used to estimate the 
denominator degrees of freedom.  The treatment difference between placebo and 
Atrasentan 0.75 mg QD at Month 24 will be estimated from the model using a 


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CONTRAST statement.  P value and associated 95% confidence interval will be 
provided.  The treatment effect at each post-baseline visit will be estimated from the 
model using a CONTRAST statement.  The endpoints of change in eGFR after 3 months 
post-randomization treatment and change in eGFR slope from baseline to 45 days after 
end of treatment will be analyzed using a linear regression model.
The additional efficacy endpoints of  number of new onset atrial fibrillation/flutter events, 
cumulative number of AKI events after randomization that are associated with temporary 
dialysis, and cumulative number of laser photocoagulations for diabetic retinopathy 
(where a laser treatment is considered new if it occurs more than 10 weeks after the last 
treatment), will be analyzed using chi-square tests.
Estimates of treatment effects and associated 95% confidence intervals will be provided.
8.1.3.4
Efficacy Analyses for the 24-Hour Urine Sub-Study
Twenty-four-hour urine will be collected prior to dosing in the Enrichment Period 
(Visit E1), and during enrichment at Visit E5, 12 months after randomization (Visit T12), 
yearly thereafter and at the follow-up visit (Visit F1) for each subject that consents to 
participate in this optional sub-study up to a limit of 800 subjects.
Longitudinal analyses of change from baseline in mean 24-hour urine indices (albumin, 
creatinine, sodium, potassium and chloride) will be performed using an MMRM.  The 
model will include the fixed categorical effects of treatment, country, visit, and 
treatment-by-visit interaction, as well as the continuous fixed covariates of baseline 
measurements and baseline-by-visit interaction.  Within group LS mean change from 
baseline to each post-baseline visit as estimated from the MMRM will be presented 
graphically.
The mean of each 24-hour urine component for each subject is calculated as the average 
of all the valid measurements taken in that 24-hour period.


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8.1.3.5
Multiplicity
There is a single primary efficacy endpoint (time to the first occurrence of a component of 
the composite renal endpoint:  doubling of serum creatinine, eGFR < 15 ml/min or the 
onset of chronic dialysis, renal transplant or renal death), and one primary comparison 
between placebo and Atrasentan 0.75 mg QD for the ITT responder set.  Other than a 
group-sequential adjustment for the interim analysis (Section 8.1.5), no additional 
adjustment for multiplicity is needed for the primary efficacy analysis.
To control the family-wise type I error rate at 0.05, each secondary endpoint will be tested 
at the interim or final analysis only when the primary endpoint is statistically significant at 
the corresponding analysis using the same alpha level as the alpha spent for the primary 
endpoint at the interim or final analysis, respectively, following a hierarchical (step-down) 
multiple testing procedure.  The primary efficacy comparison of the study will serve as 
the gatekeeper for the test of the secondary endpoints.
8.1.4
Safety Analyses
All safety analyses will be conducted on the all treated analysis sets (i.e., all-treat 
responder set, all-treated non-responder set, and all treated set, respectively) and the all 
Atrasentan analysis set (where indicated).  No formal statistical testing of treatment 
difference is planned.
Derivation of Safety Endpoints
Safety data collected from the first dose up to 45 days post last dose in the Double-Blind 
Period will be included in the relevant analyses for the all treated analysis sets, unless 
otherwise specified in the Statistical Analysis Plan (SAP) document.  Safety data collected 
during the Enrichment Period will be summarized for exploratory purposes for the all 
Atrasentan analysis set.


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Study Drug Exposure and Compliance
The number of days on study drug will be summarized by treatment group and overall.  
The number and percentage of subjects with at least 70% compliance with study drug at 
each visit will be summarized by treatment group and overall.
8.1.4.1
Adverse Events (AEs) Analyses
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Treatment-emergent AEs (i.e., AEs that begin or worsen in severity after initiation of 
study drug) throughout the follow-up period of the study will be summarized by the 
treatment group in descending order of overall frequency by MedDRA preferred term, as 
well as by system organ class (SOC) and MedDRA preferred term.  The incidence rates of 
treatment-emergent AEs for each treatment group will be summarized.  Additionally, the 
treatment-emergent AEs will also be summarized by the relationship to study drug and 
their maximum severity.
The adverse events reported as reasons for discontinuation will be summarized by 
treatment group.  Serious adverse events will be evaluated in a similar manner.
Specifically, adverse events will be summarized by treatment group as described below:
1.
An overview of the number and percentage of subjects with treatment-emergent 
adverse events.
2.
A summary of the number and percentage of subjects with treatment-emergent 
adverse events by primary MedDRA system organ class and preferred term.
3.
A summary of the number and percentage of subjects with treatment-emergent 
serious adverse events by primary MedDRA system organ class and preferred term.
4.
A summary of the number and percentage of subjects with treatment-emergent 
adverse events leading to discontinuation by primary MedDRA system organ class 
and preferred term.


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5.
A summary of the number and percentage of subjects with drug-related treatment-
emergent adverse events by primary MedDRA system organ class and preferred 
term.
6.
A summary of the number and percentage of subjects with treatment-emergent 
adverse events by primary MedDRA system organ class, preferred term and 
maximum severity.
7.
A summary of subject numbers associated with treatment-emergent adverse events 
by primary MedDRA system organ class and preferred term.
8.1.4.2
Clinical Laboratory Data
For each laboratory test, the mean change from baseline to the minimum, maximum, and 
to each visit will be summarized by treatment groups.  For selected laboratory tests of 
interests, the number and percentage of subjects whose laboratory value has shifted from 
normal at baseline to abnormally high or low at final will be tabulated by treatment group.
8.1.4.3
Vital Signs Data
The mean change from baseline to each visit in vital signs, including weight, will be 
summarized by treatment group.
8.1.4.4
ECG Analyses
The number and percentage of subjects with shifts from baseline to the final in the 
categories of normal, abnormal as indicated by the study site investigators will be 
summarized.  Shifts from baseline at each visit where ECG data is collected will be 
summarized similarly.
8.1.4.5
Safety Data in the Enrichment Period
Safety data in Enrichment Period and will be summarized.  Descriptive statistics, 
including the number of observations (N), mean, and standard deviation (SD) for 
continuous variables and counts and percentages for discrete variables, will be provided 


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for AE, serious AE, laboratory, vital sign and ECG parameters, for the Enrichment Period.  
In addition, the cumulative incidence of AE and serious AE adjusting for the duration of 
exposure on Atrasentan during the Enrichment Period and the Double-Blind Treatment 
Period will be summarized.  For subjects who discontinue prior to randomization or who 
are randomized to placebo, this duration of exposure on Atrasentan will be their duration 
of exposure in the Enrichment Period.
8.1.5
Interim Analysis
An interim analysis of efficacy will be performed when the number of accrued primary 
events in the responder population is in the range of 50% to 75% of the targeted 
425 events for the study.  An alpha-spending function approach will be used to ensure that 
the overall one-sided type I error rate will be controlled at 0.025 or less.  In addition, an 
interim analysis of efficacy data for futility only may be performed at an earlier time 
point.  No adjustment to the type I error rate will be made for the futility assessment.  
To preserve the integrity and the validity of trial data, an external Statistical Analysis 
Center will perform the requisite interim analyses and present the results to IDMC.  
Further details of the interim analysis plan will be provided in the Statistical Analysis Plan 
(SAP) and IDMC Charter.  In making any decision to recommend discontinuation of the 
study, either for superior efficacy of Atrasentan or for futility, the IDMC shall be guided 
by a formal stopping rule described in the SAP.
8.1.6
Independent Data Monitoring Committee (IDMC) and 
Independent External Statistician
This study will have an IDMC composed of at least two external clinicians and 
one external statistician to review and make recommendations based on the results of the 
unblinded interim analysis and periodic reviews of the safety of Atrasentan.  The IDMC 
membership and responsibilities, and details of the interim analyses and safety reviews, 
will be documented in a charter that will be prepared prior to the first IDMC review 
meeting.


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The AbbVie project statistician will serve as an intermediary between the external 
Statistical Analysis Center and the Sponsor if the IDMC has questions or requests for 
additional data.
Communications from the IDMC to the Sponsor will not contain information that can 
potentially unblind the representatives of the Sponsor directly responsible for the study.
The first IDMC meeting will occur after the first 30 subjects with a UACR < 0% 
(non-responders) are randomized and have completed the T1 visit or after the 
first 100 subjects have completed the enrichment period, whichever occurs first.  The 
second IDMC meeting will occur after the first 100 subjects are randomized.  
Subsequently IDMC meetings will occur after 25%, 50%, and 75% of the primary end-
points have occurred.  In addition, the IDMC will meet at least every 6 months and, if 
necessary, at times other than those scheduled if either the Sponsor or the IDMC 
determines that an unplanned meeting is warranted based on safety concerns.
The IDMC will make recommendation(s) to AbbVie (Sponsor representative) based on 
their review.  The Sponsor representative will accept or reject the IDMC's 
recommendation.
The IDMC will review unblinded efficacy data as specified in Section 8.1.5.
8.2
Determination of Sample Size
The sample size for the Double-Blind Treatment Period is calculated based on the primary 
efficacy endpoint of time to the first occurrence of a renal composite event comparing 
Atrasentan treatment with placebo in the responder population.  A total of 425 events in 
the ITT set are needed to detect a 27% hazard reduction (HR of 0.73) with approximately 
90% power at two-sided alpha level of 0.05.  Based on the annual event rate in RENAAL 
study (~13%) and ALTITUDE (~3%), our estimate of the annual placebo event rate in our 
study is 6%.21,22  With the assumption of annual event rate of 6% in placebo group, 
42-month accrual period, approximate 6 year duration of the Double-Blind Period, and an 
annualized lost to follow-up rate of 2%, a total of approximately 2,500 subjects who 


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achieve at least 30% reduction in UACR (responders) during the Enrichment Period 
(1,250 subjects per group) are needed for randomization.
In addition, approximately 1,000 subjects who achieve less than 30% reduction in UACR 
(non-responders) in Enrichment period will also be randomized in a 1:1 ratio to 
Atrasentan treatment or placebo since it has not been determined whether Atrasentan can
reduce long-term CKD progression in this population.
8.3
Randomization Methods
Subjects will be randomized to Placebo QD (plus stable dose of RAS inhibitor) or 
Atrasentan 0.75 mg QD (plus stable dose of RAS inhibitor) in a 1:1 ratio at the beginning 
of the Double-Blind Treatment Period.  The Randomization will be stratified by the 
following factors:  
●
Geographic region (North America, Latin America, Europe, Asia Pacific, and 
Japan),
●
UACR level at the beginning of the Enrichment Period ≤ or > 1000 mg/g, and
●
UACR reduction during the Enrichment Period:  < 0% (approximately at 250); 
0% to < 15% and 15% to < 30% (approximately at 750); 30% to < 45%, 45% 
to < 60% and ≥ 60%.
A strategy will be utilized to provide gating of subjects into the responder and non-
responder groups in order to allow for temporal similarity in accrual of subjects and 
relatively similar exposure times on study drug.  The implementation of the 
responder/non-responder ratio will be through the IRT system.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 


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subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The Investigator will be required to submit, 
maintain and archive study essential documents according to ICH GCP.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
Investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IEC/IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the Clinical Investigator are specified in Appendix A.
9.3
Subject Information and Consent
The Investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 


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the informed consent form will be given to the subject and the original will be placed in 
the subject's medical record.  An entry must also be made in the subject's dated source 
documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
Pre-screening will only be performed if the subject has voluntarily signed and dated a 
pre-screening informed consent, approved by an IRB/IEC, after the nature of the testing 
has been explained and the subject has had an opportunity to ask questions.  The 
pre-screening informed consent must be signed before the pre-screening testing is 
performed.  If the subject does not consent to the pre-screening testing, it will not impact 
the subject's participation in the study.
Pharmacogenetic sample collection and analysis will only be performed if the subject has 
voluntarily signed and dated a pharmacogenetic informed consent, approved by an 
IRB/IEC, after the nature of the testing has been explained and the subject has had an 
opportunity to ask questions.  The pharmacogenetic informed consent must be signed 
before the pharmacogenetic testing is performed.  If the subject does not consent to the 
pharmacogenetic testing, it will not impact the subject's participation in the study.
Twenty four-hour urine sub-study testing will only be performed if the subject has 
voluntarily signed and dated a 24-hour urine informed consent, approved by an IRB/IEC, 
after the nature of the sub-study testing has been explained and the subject has had an 
opportunity to ask questions.  The 24-hour urine sub-study informed consent must be 
signed before the 24-hour urine collections are taken.  If the subject does not consent to 
the 24-hour urine sub-study testing, it will not impact the subject's participation in the 
study.
If the subject has provided consent, the subject's primary physician will be notified about 
the subject's involvement in the study once the subject has entered the Run-In Period.  
This is not applicable if the Investigator is the subject's primary physician or if the subject 
does not have a primary physician.


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If the subject is willing, he/she will be asked to provide a name and phone number for a 
secondary contact in the event that the Investigator is unable to reach the subject for 
follow-up.
9.3.1
Informed Consent Form and Explanatory Material
In Japan, the Investigator will prepare the consent form and explanatory material required 
to obtain subject's consent to participate in the study with the cooperation of the sponsor 
and will revise these documents as required.  The prepared or revised consent forms and 
explanatory material will be submitted to the sponsor.  Approval of the IRB will be 
obtained prior to use in the study.
9.3.2
Revision of the Consent Form and Explanatory Material
In Japan, when important new information related to the subject's consent becomes 
available, the Investigator will revise the consent form and explanatory material based on 
the information without delay and will obtain the approval of the IRB prior to use in the 
study.  The Investigator will provide the information, without delay, to each subject 
already participating in the study, and will confirm the intention of each subject to 
continue the study or not.  The Investigator shall also provide a further explanation using 
the revised form and explanatory material and shall obtain written consent from each 
subject of their own free will to continue participating in the study.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.


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The Investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an electronic data capture (EDC) system called Rave® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study-specific electronic case report forms (eCRFs) will comply with Title 21 CFR 
Part 11.  The documentation related to the validation of the EDC system is available 
through the vendor, Medidata, while the validation of the study-specific eCRFs will be 
conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.
The Investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation including adjudicated primary and 
secondary endpoints.
The Investigator or an authorized member of the Investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
Principal Investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.


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Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
Investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
Investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the Investigator to make paper printouts from that media.
Subject completed Quality of Life surveys will be recorded directly on the paper 
questionnaire and the site staff will enter data directly into the eCRF.
11.0
Data Quality Assurance
Prior to the initiation of the study, an Investigator's meeting will be held with AbbVie 
personnel, the Investigators and appropriate site personnel, and the clinical research 
associates (CRA) for the study.  This meeting will include a detailed discussion of the 
protocol, performance of study procedures, CRF completion, and specimen collection 
methods.  In addition to the Investigator's meeting, the study personnel at each site will be 
trained on the study procedures by a CRA at a study initiation visit and will be given an 
eCRF completion workbook for reference.
The CRAs will monitor each site throughout the study.  Source document verification will 
be performed against entries on the eCRF and a quality assurance check will be performed 
to ensure that the Investigator is complying with the protocol and regulations.  In addition, 
after eCRFs are retrieved by the CRA, a review of the data will be conducted by a 
physician and a clinical review team at AbbVie.  Computer logic and manual checks will 
be created to identify items such as inconsistent study dates.  Any necessary corrections 
will be made to the eCRF and documented via addenda or audit trail.
Routine hematology, serum chemistry, and urinalysis will be conducted using a central 
laboratory.  The data from these analyses will be electronically transferred from the 
central laboratory to the study database.  A final review of all laboratory results will be 
conducted by a physician and clinical review team at AbbVie.


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12.0
Use of Information
All information concerning Atrasentan and AbbVie operations, such as AbbVie patent 
applications, formulas, manufacturing processes, basic scientific data, or formulation 
information, supplied by AbbVie and not previously published is considered confidential 
information.
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by AbbVie in connection with the development of 
Atrasentan.  This information may be disclosed as deemed necessary by AbbVie to other 
clinical Investigators, other pharmaceutical companies, to the US Food and Drug 
Administration (FDA) and to other governmental agencies.  To allow for the use of the 
information derived from this clinical study and to ensure complete and thorough analysis, 
the Investigator is obligated to provide AbbVie with complete test results and all data 
developed in this study and to provide direct access to source data/documents for 
trial-related monitoring, audits, IRB/IEC review and regulatory inspection.
This confidential information shall remain the sole property of AbbVie, shall not be 
disclosed to others without the written consent of AbbVie and shall not be used except in 
the performance of this study.
The Investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study (by name and subject number).  This list will be maintained at the 
site and will not be retrieved by AbbVie.
Any pharmacogenetic research that may be done using DNA samples from this study will 
be experimental in nature and the results will not be suitable for clinical decision making 
or patient management.  Hence, neither the Investigator, the subject, nor the subject's 
physician (if different from the Investigator) will be informed of individual subject 
pharmacogenetic results, should analyses be performed, nor will anyone not directly 
involved in this research.  Correspondingly, genetic researchers will have no access to 
subject identifiers.  Individual results will not be reported to anyone not directly involved 


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in this research other than for regulatory purposes.  Aggregate pharmacogenetic 
information from this study may be used in scientific publications or presented at medical 
conventions.  Pharmacogenetic information will be published or presented only in a way 
that does not identify any individual subject.
13.0
Completion of the Study
The Investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the Investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the Investigator and AbbVie.  The Investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The Investigator must retain any records related to the study according to local 
requirements.  If the Investigator is not able to retain the records, he/she must notify 
AbbVie to arrange alternative archiving options.
AbbVie will select the signatory Investigator from the Investigators who participate in the 
study.  Selection criteria for this Investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory Investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.
The Last Subject Last Visit date is defined as the last date of an observation or contact 
with a subject.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for Atrasentan and the 
product labeling for Atrasentan.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title:
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
Protocol Date:
19 May 2017
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
1.
Yanagisawa M, Kurihara H, Kimura S, et al.  A novel potent vasoconstrictor 
peptide produced by vascular endothelial cells.  Nature.  1988;332:411-5.
2.
Levin ER.  Endothelins.  New Engl J Med.  1995;333:356-63.
3.
Rubanyi GM, Polokoff MA.  Endothelins:  molecular biology, biochemistry, 
pharmacology, physiology, and pathophysiology.  Pharmacol Rev.  
1994;46(3):325-415.
4.
Raffa RB, Schupsky JJ, Martinez RP, et al.  Endothelin-1-induced nociception.  
Life Sci/Pharmacol Lett.  1991;49:PL61-PL65.
5.
Opgenorth TJ.  Endothelin receptor antagonism.  Adv Pharmacol.  1995;33:1-62.
6.
Haynes WG, Ferro CE, Webb DJ.  Physiologic role of endothelin in maintenance 
of vascular tone in humans.  J Cardiovasc Pharmacol.  1995;26(suppl 3):S183-85.
7.
Bax WA, Saxena PR.  The current endothelin receptor classification:  time for 
reconsideration?  Trends in Pharmacol Sci.  (TIPS) 1994;15:379-86.
8.
Rabelink TJ, Kaasjager KAH, Stroes ESG, et al.  Endothelin in renal 
pathophysiology:  From experimental to therapeutic application.  Kidney Int.  
1996;50:1827-33.
9.
Kaasjager KAH, Shaw S, Koomans HA, et al.  Role of endothelin receptor 
subtypes in the systemic and renal responses to endothelin-1 in humans.  J Am Soc 
Nephrol.  1997;8:32-9.
10.
Kirilov G, Dakovska L, Borisova AM, et al.  Increased plasma endothelin levels in 
patients with insulin-dependent diabetes mellitus and end-stage vascular 
complications.  Horm Metab Res.  1994;26:119-20.
11.
Yamauchi T, Ohnaka K, Takayanagi R, et al.  Enhanced secretion of endothelin-1 
by elevated glucose levels from cultured bovine aortic endothelial cells.  
FEBS Lett.  1990;267:16-18.
12.
Haak T, Jungmann E, Felber A, et al.  Increased plasma levels of endothelin in 
diabetic patients with hypertension.  Am J Hypertens.  1992;5:161-6.


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13.
Rabelink TJ, Kaasjager KAH, Boer P, et al.  Effects of endothelin-1 on renal 
function in humans:  Implications for physiology and Pathophysiology.  
Kidney Int.  1994;46:376-81.
14.
Opgenorth TJ, Adler AL, Calzadilla SV, et al.  Pharmacological characterization of 
A-127722:  an orally active and highly potent ETA-selective receptor antagonist.  
J Pharmacol Exp Ther.  1996;276:473-81.
15.
Data on file at AbbVie.
16.
Gómez-Garre D, Largo R, Liu XH, et al.  An orally active ETA/ETB receptor 
antagonist ameliorates proteinuria and glomerular lesions in rats with proliferative 
nephritis.  Kidney Int.  1996;50:962-72.
17.
Fukuda K, Yanagida T, Okuda S, et al.  Role of endothelin as a mitogen in 
experimental glomerulonephritis in rats.  Kidney Int.  1996;49:1320-9.
18.
Sasser JM, Sullivan JC, Hobbs JL, et al.  Endothelin A receptor blockade reduces 
diabetic renal injury via an anti-inflammatory mechanism.  J Am Soc Nephrol.  
2007;18:143-54.
19.
AbbVie.  Atrasentan (ABT-627) Investigator's Brochure Edition 20.  
25 March 2013.
20.
Palevsky PM, Liu KD, Brophy PD, et al.  KDOQI US commentary on the 
2012 KDIGO clinical practice guideline for acute kidney injury.  Am J Kidney Dis.  
2013;61(5):649-72.
21.
Brenner BM, Cooper ME, de Zeeuw D, et al; RENAAL Study Investigators.  
Effects of losartan on renal and cardiovascular outcomes in patients with type 2 
diabetes and nephropathy.  N Engl J Med.  2001;345(12):861-9.
22.
Parving HH, Brenner BM, McMurray JJ, et al; ALTITUDE Investigators.  
Cardiorenal end points in a trial of aliskiren for type 2 diabetes.  N Engl J Med.  
2012;357(23):2204-13.
23.
Vogt L, Waanders F, Boomsma F, et al.  Effects of dietary sodium and 
hydrochlorothiazide on the antiproteinuric efficacy of losartan.  J Am Soc Nephrol.  
2008;19:999-1007.


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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the Investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees (e.g., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making
those records available for inspection by representatives of AbbVie and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and
approved the initial clinical investigation and all amendments.


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9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating Investigator, institution director) and/or directly to the ethics 
committees and AbbVie.
10.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
General Medicine Therapeutic Area
General Medicine Therapeutic Area
Clinical
Data and Statistical Sciences, Statistics
Bioanalysis
Pharmacokinetics and 
Pharmacodynamics
Clinical Drug Supply Management


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Appendix C.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes:
Section 1.0  Title Page
"Sponsor/Emergency Contact:" previously read:
Sponsor/Emergency 
  Contact:
Has been changed to read
Sponsor/Emergency 
  Contact:


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Section 1.2  Synopsis
Previously read:
AbbVie Inc.
Protocol Number:  M11-352
Name of Study Drug:  Atrasentan (ABT-627)
Phase of Development:  3
Name of Active Ingredient:  (2R,3R,4S)-4-
(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-
oxoethyl])-2-(4-methoxyphenyl) pyrrolidine-3-
carboxylic acid, monohydrochloride
Date of Protocol Synopsis:  11 February 2015
Protocol Title:  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
Objectives:  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.
Investigators:  Multicenter study
Study Sites:  800 – 900 sites globally.
Study Population:  Subjects that have type 2 diabetes with nephropathy (eGFR of 
25 – 75 ml/min/1.73 m2 and a urinary albumin to creatinine ratio (UACR) ≥300 mg/g creatinine and 
< 5,000 mg/g).
Number of Subjects to be Enrolled:  Approximately 4,148 subjects will be randomized to the 
Double-Blind Treatment Period.
Overall Study Design:


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Methodology:
This is a prospective, randomized, double-blind, enriched-population, placebo-controlled, multicenter 
study.  Eligible subjects will proceed to a run-in period to optimize RAS inhibitor and diuretic doses.
Following the Run-in period, eligible subjects will enter the Enrichment Period in which all will receive 
Atrasentan 0.75 mg once daily (QD) to determine their UACR response and to assess tolerability of 
Atrasentan.  Approximately 3,148 responders (UACR reduction ≥ 30% from baseline) and 
approximately 1,000 non-responders (UACR reduction < 30% from baseline) will then be randomized 
1:1 into the double-blind treatment period.
The double-blind treatment period is estimated to continue for approximately 48 months.  Subjects' 
doses of RAS inhibitors and diuretic should be stable during the treatment period and remain unchanged 
through the end of the study.  If at any time during the study there is an interruption or decrease of RAS 
inhibitor dose, resumption of the previous dose should be attempted within 1 month, according to the 
Investigator's medical judgment.  If there is significant worsening of peripheral edema or other 
symptoms of fluid overload, such as dyspnea with walking or lying down, during any of the treatment 
visits, the Investigator may adjust the diuretic dose as needed.  The study will continue until 425 distinct 
primary renal composite events (doubling of serum creatinine or the onset of ESRD) occurring in the 
responder population have been adjudicated by an independent Events Adjudication Committee (EAC).  
Subjects who reach the endpoint of doubling of serum creatinine or eGFR < 15 ml/min/1.73 m2 will 
remain on study drug until they reach chronic dialysis, renal transplantation or renal death or the 
completion of the trial.  If a subject stops taking study drug, every attempt will be made to keep him/her 
in the study by continuing scheduled study visits and restarting study drug if medically appropriate at the 
discretion of the Investigator.  After 425 events have occurred in the responder population, all subjects 
will discontinue study drug and return for a Final Treatment visit and 45-day follow-up visit.  After the 
follow-up visit, all subjects who have not reached the endpoints of dialysis, renal transplantation or renal 
death will be eligible to enroll in a separate open-label extension study where each subject receives 
Atrasentan.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
To be eligible for initial entry into the study, subjects must meet all of the following criteria:
!
Subject is 18 – 85 years of age at the initial Screening visit (S1).
!
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.
!
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.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
For entry into the Run-In Period, the subject must satisfy the following criteria:  
!
Screening laboratory values:
o
Estimated GFR 25 to 75 ml/min/1.73 m2 and a UACR ≥ 300 and < 5,000 mg/g 
(≥34 mg/mmol and < 565 mg/mmol);
o
Serum albumin ≥ 2.5 g/dL (25 g/L);
o
BNP ≤ 200 pg/mL (200 ng/L);
o
Serum Potassium ≥ 3.5 mEq/L (3.5 mmol/L) ≤ 6.0 mEq/L (6.0 mmol/L); and
o
SBP ≥ 110 and ≤ 180 mmHg 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 the Run-In 
Period (R6 visit).
!
Subjects on a MTLDD RAS inhibitor for ≥ 4 weeks and not on a diuretic (unless medically 
contra-indicated) at the time of Screening will start with a diuretic and participate in Run-In for 
at least 2 weeks.
Main Exclusion:
Subjects meeting any of the following criteria will be excluded from the study:
!
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 disease 
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).
!
Subject has elevated liver enzymes (serum alanine aminotransaminase [ALT] and/or serum 
aspartate aminotransaminase [AST]) > 3 × the upper limit of normal (ULN).
!
Subject is currently receiving rosiglitazone, moxonidine, aldosterone blockers, aliskiren, or a 
combination of ACEi and ARB.
Investigational Product:
Atrasentan
Dose:
0.75 mg once daily (QD)
Mode of Administration:
Oral
Reference Therapy:
Placebo
Dose:
Not Applicable
Mode of Administration:
Oral
Duration of Treatment:  Estimated 48-month Double-Blind Treatment Period.


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Criteria for Evaluation:
Efficacy:
Primary Efficacy Endpoint:
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 ESRD (eGFR < 15 ml/min/1.73 m2
confirmed by a 90-day eGFR, receiving chronic dialysis, renal transplantation or renal death).
Secondary Efficacy Endpoints:
!
Time to a 50% eGFR reduction.
!
Time to cardio-renal composite endpoint:  confirmed doubling of serum creatinine, ESRD, CV 
death, nonfatal myocardial infarction, nonfatal stroke.
!
Time to first occurrence of a component of composite renal end-point: confirmed doubling of 
serum creatinine, or the onset of ESRD for all randomized subjects (pooled).
!
Time to the CV composite endpoint:  CV death, nonfatal myocardial infarction and nonfatal 
stroke.
Pharmacokinetic:
Atrasentan clearance (CL/F) and volume of distribution (Vss/f) will be determined using population 
pharmacokinetic techniques.
Pharmacodynamic:
The relationship between Atrasentan exposure and clinical efficacy and/or safety response(s) may be 
explored.
Statistical Methods:
Analysis Datasets:
The following datasets will be used for the analysis of all efficacy and other non-safety endpoints.  For 
these analyses, subjects will be analyzed in the treatment group to which they were randomized.
!
The Intention-to-treat (ITT) Responder Set will serve as the primary dataset for the analysis 
of efficacy in this study.  It will consist of all randomized subjects who achieve at least 30% 
reduction in UACR in the Enrichment Period (responders).
!
The ITT Non-responder Set will consist of all randomized subjects who achieve less than 30% 
reduction in UACR in the Enrichment Period (non-responders).
!
The ITT Pooled Set will consist of all randomized subjects (both responders and 
non-responders) and will be used for a pooled analysis of efficacy.
The following datasets will be used for the analysis of safety endpoints.  For these analyses, subjects will 
be analyzed according to the treatment they actually receive during the double-blind phase.
!
The All Treated Responder Set includes all randomized subjects who achieve at least 30% 
reduction in UACR in the Enrichment Period and receive at least one dose of study drug during
double-blind phase.
!
The All Treated Non-responder Set includes all randomized subjects who achieve less than 
30% reduction in UACR in the Enrichment Period and receive at least one dose of study drug 
during double-blind phase.
!
The All Treated Set includes all randomized subjects who receive at least one dose of study 
drug during double-blind phase.


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Statistical Methods (Continued):
Analysis Datasets (Continued):
Additionally, an All Atrasentan Set comprising all subjects who receive at least one dose of Atrasentan, 
including both Enrichment and Double-Blind Treatment Periods, is defined for the purposes of data 
analysis.
Sample Size Determination:
The sample size for the Double-Blind Treatment Period is based on the primary efficacy endpoint of 
time to the renal composite event comparing Atrasentan to placebo.  A total of 425 events in the ITT set 
is required to detect a 27% hazard reduction (HR of 0.73) with 90% power using a log-rank test at a 
two-sided significance level of 0.05.  Based on the annual event rate in RENAAL study (~13%) and 
ALTITUDE (~3%), the estimate of the annual placebo event rate in the SONAR study is 6%, With the 
assumption of annual event rate of 6% in placebo group, 24-month accrual period, approximate 
48-month double-blind treatment duration and the discontinuation rate of 15%, 3,148 subjects who 
achieve at least 30% UACR reduction (responders) in the Enrichment Period (1,574 subjects per group) 
would be needed to be randomized.
In addition, 1,000 subjects who achieve less than 30% UACR reduction in the Enrichment Period will 
also be randomized in a 1:1 ratio to Atrasentan or placebo.
Definition of Baseline:
For treatment comparisons and summaries based on the Double-Blind Treatment Period, baseline values 
refer to the last non-missing value observed prior to or at the time of randomization.  This includes 
treatment comparisons performed for the ITT analysis sets (ITT responder set, ITT non-responder set 
and the ITT pooled set).
For purposes of summarizing safety and efficacy for the Enrichment Period and the entire study 
treatment period (Enrichment and Double-Blind Treatment Period combined), baseline values refer to 
the last non-missing value observed prior to or pre-dose on the first day of Atrasentan therapy 
(Treatment Day 1) at the beginning of the Enrichment Period. 
For specific purposes, e.g., determination of doubling of serum creatinine, the values prior to Enrichment 
may be used as reference values.
Primary Efficacy Analysis:
The primary efficacy analysis for treatment comparison will be conducted on the ITT responder set for 
the primary efficacy endpoint using a stratified log-rank test, adjusting for the following stratification 
factors:
!
Geographical region (North America, Latin America, Europe, Asia Pacific, and Japan), 
!
UACR level at the beginning of the Enrichment Period (≤ 1,000 mg/g [113 mg/mmol] or 
> 1,000 mg/g [113 mg/mmol]), and 
!
UACR reduction during Enrichment Period (30% – < 45%, 45% – < 60%, and ≥ 60%).  
Kaplan-Meier estimates for cumulative event rates will be plotted.  A Cox proportional-hazards 
regression model with treatment group and the above stratification factors as explanatory variables will 
be performed to estimate the hazard ratio of events comparing placebo to Atrasentan, and its 95% 
confidence interval.


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Statistical Methods (Continued):
Primary Efficacy Analysis (Continued):
In addition, the individual components of the primary efficacy endpoint, i.e., the time to the 
first occurrence of doubling of serum creatinine (confirmed by a 30-day serum creatinine) and the time 
to the first occurrence of the onset will be analyzed separately using the same methods as specified 
above.  In analyzing the individual components, first occurrence of only that specific endpoint will be 
considered as events. 
Subgroup analyses for subgroups based on age, gender, race and important baseline characteristics will 
also be performed.
Secondary Efficacy Analysis:
These pre-specified secondary efficacy endpoints are listed according to their clinical importance and 
will be analyzed in a hierarchical (step-down) fashion.  The analyses of these time-to-event endpoints of 
a 50% eGFR reduction (ITT responder set), a cardio-renal composite endpoint (ITT responder set), the 
composite renal endpoint (ITT pooled set), and the CV composite endpoint (ITT responder set), will 
follow the same methods as specified for the primary efficacy analysis.
Pharmacokinetics:
Population modeling techniques will be used to estimate population central values for Atrasentan 
clearance (CL/F) and volume of distribution (Vss/f), and post hoc values of these parameters for the 
individual subjects will also be estimated.  Additional parameters may be estimated if useful in the 
interpretation of the data.
Safety:
All safety analyses will be conducted on the all treated analysis sets (i.e., all treated responder set, all 
treated non-responder set and all treated set, respectively) and the all Atrasentan analysis set (where 
indicated).  No formal statistical tests of treatment difference are planned.
Derivation of Safety Endpoints:
Safety data collected from randomization up to the 45-day Follow-up visit will be included in the 
relevant analyses for the all treated analysis sets, unless otherwise specified in the Statistical Analysis 
Plan (SAP) document.  Safety data collected during the Enrichment Period will be summarized for 
exploratory purposes for the all Atrasentan analysis set.
Study Drug Exposure and Compliance:
The number of days on study drug will be summarized by treatment group and overall.  The number and 
percentage of subjects with at least 70% compliance with study drug at each visit will be summarized by 
treatment group and overall.
Adverse Events (AEs) Analyses:
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Treatment-emergent AEs (i.e., AEs that begin or worsen in severity after initiation of study drug) 
throughout the follow-up period of the study will be summarized by the treatment group in descending 
order of overall frequency by MedDRA preferred term, as well as by system organ class (SOC) and 
MedDRA preferred term.  The incidence rates of treatment-emergent AEs for each treatment group will 
be summarized.  Additionally, the treatment-emergent AEs and serious adverse events (SAEs) will also 
be summarized by the relationship to study drug and their maximum severity.


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Statistical Methods (Continued):
Laboratory Data:
For each laboratory test, the mean change from baseline to the minimum, maximum, and to each visit 
will be summarized by treatment groups.  For selected laboratory tests of interests, the number and 
percentage of subjects whose laboratory value has shifted from normal at baseline to abnormally high or 
low at final will be tabulated by treatment group.
Interim Analysis:
One interim analysis of the primary efficacy endpoint will be performed when approximately 50% of the 
events (total of adjudicated and unadjudicated) required for completion of the trial are available.  The 
primary analysis will be based on the EAC-adjudicated events.  Supportive analyses will also be based 
upon both the total of adjudicated and unadjudicated events.  A futility stopping boundary is specified 
using Gamma (–6) as the beta-spending function (Hwang et al).
An alpha spending of 0.0009 using a Gamma (–8) function will also be applied to the interim analysis.  
Hence for the final analyses, the primary efficacy endpoint will be tested at an expected nominal alpha 
level of 0.0498.  The final adjustment will be based on the exact number of EAC-adjudicated events 
observed for the interim analysis. 
To preserve the integrity and the validity of trial data, an external Statistical Analysis Center will 
perform the interim analysis.
Independent Data Monitoring Committee:
This study will have an IDMC composed of at least two external clinicians and one external statistician 
to review and make recommendations based on the results of the unblinded interim analysis and periodic 
reviews of the safety of Atrasentan. 
Adjudication of Potential Outcome Events:
An independent events adjudication committee (EAC), blinded to study treatment assignment, will 
adjudicate all events that have the potential to be considered endpoints that will be specified in the EAC 
charter.
Steering Committee:
A steering committee will be involved in the design and implementation of the study.  Its membership 
will be representative of the global nature of the study sites and regular meetings will be conducted to 
evaluate the conduct of the trial, including evaluations from the IDMC and EAC.
References:
Hwang IK, Shih WJ, De Cani JS.  Group sequential designs using a family of type I error probability 
spending functions.  Stat Med.  1990;9(12):1439-45.
Westfall PH, Krishen A.  Optimally weighted, fixed sequence and gatekeeper multiple testing 
procedures.  J Stat Plan Inference.  2001;99:25-40.


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Has been changed to read:
AbbVie Inc.
Protocol Number:  M11-352
Name of Study Drug:  Atrasentan (ABT-627)
Phase of Development:  3
Name of Active Ingredient:  (2R,3R,4S)-4-
(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-
oxoethyl])-2-(4-methoxyphenyl) pyrrolidine-3-
carboxylic acid, monohydrochloride
Date of Protocol Synopsis:  19 May 2017
Protocol Title:  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
Objectives:  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.
Investigators:  Multicenter study
Study Sites:  800 – 900 sites globally.
Study Population:  Subjects that have type 2 diabetes with nephropathy (eGFR of 
25 – 75 ml/min/1.73 m2 and a urinary albumin to creatinine ratio (UACR) ≥300 mg/g creatinine and 
< 5,000 mg/g).
Number of Subjects to be Enrolled:  Approximately 3,500 subjects will be randomized to the 
Double-Blind Treatment Period.


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Overall Study Design:
Methodology:
This is a prospective, randomized, double-blind, enriched-population, placebo-controlled, multicenter 
study.  Eligible subjects will proceed to a run-in period to optimize RAS inhibitor and diuretic doses.
Following the Run-in period, eligible subjects will enter the Enrichment Period in which all will receive 
Atrasentan 0.75 mg once daily (QD) to determine their UACR response and to assess tolerability of 
Atrasentan.  Approximately 2,500 responders (UACR reduction ≥ 30% from baseline) and 
approximately 1,000 non-responders (UACR reduction < 30% from baseline) will then be randomized 
1:1 into the double-blind treatment period.


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Methodology (Continued):
The duration of the Double-Blind Period is estimated to be approximately 6 years.  Subjects' doses of 
RAS inhibitors and diuretic should be stable during the treatment period and remain unchanged through 
the end of the study.  If at any time during the study there is an interruption or decrease of RAS inhibitor 
dose, resumption of the previous dose should be attempted within 1 month, according to the 
Investigator's medical judgment.  If there is significant worsening of peripheral edema or other 
symptoms of fluid overload, such as dyspnea with walking or lying down, during any of the treatment 
visits, the Investigator may adjust the diuretic dose as needed.  The study will continue until 425 distinct 
primary renal composite events (doubling of serum creatinine or the onset of ESRD) occurring in the 
responder population have been adjudicated by an independent Events Adjudication Committee (EAC).  
Subjects who reach the endpoint of doubling of serum creatinine or eGFR < 15 ml/min/1.73 m2 will 
remain on study drug until they reach chronic dialysis, renal transplantation or renal death or the 
completion of the trial.  If a subject stops taking study drug, every attempt will be made to keep him/her 
in the study by continuing scheduled study visits and restarting study drug if medically appropriate at the 
discretion of the Investigator.  After 425 events have occurred in the responder population, all subjects 
who have not permanently discontinued study drug will return for a Final Treatment visit and 45-day 
follow-up visit.  Subjects who were permanently discontinued from study drug will complete the next 
scheduled visit.  Upon study completion, eligible subjects will be invited to participate in an open-label 
study if their site is participating in the extension study to determine the long-term safety of Atrasentan.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
To be eligible for initial entry into the study, subjects must meet all of the following criteria:
!
Subject is 18 – 85 years of age at the initial Screening visit (S1).
!
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.
!
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.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
For entry into the Run-In Period, the subject must satisfy the following criteria:  
!
Screening laboratory values:
o
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);
o
Serum albumin ≥ 2.5 g/dL (25 g/L);
o
BNP ≤ 200 pg/mL (200 ng/L);
o
Serum Potassium ≥ 3.5 mEq/L (3.5 mmol/L) ≤ 6.0 mEq/L (6.0 mmol/L); and
o
SBP ≥ 110 and ≤ 180 mmHg 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 the Run-In 
Period (R6 visit).
!
Subjects on a MTLDD RAS inhibitor for ≥ 4 weeks and not on a diuretic (unless medically 
contra-indicated) at the time of Screening will start with a diuretic and participate in Run-In for 
at least 2 weeks.
Main Exclusion:
Subjects meeting any of the following criteria will be excluded from the study:
!
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 disease 
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).
!
Subject has elevated liver enzymes (serum alanine aminotransaminase [ALT] and/or serum 
aspartate aminotransaminase [AST]) > 3 × the upper limit of normal (ULN).
!
Subject is currently receiving rosiglitazone, moxonidine, aldosterone blockers, aliskiren, or a 
combination of ACEi and ARB.
Investigational Product:
Atrasentan
Dose:
0.75 mg once daily (QD)
Mode of Administration:
Oral
Reference Therapy:
Placebo
Dose:
Not Applicable
Mode of Administration:
Oral


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Duration of Treatment:  Subjects will continue on randomized study treatment until discontinued from 
study drug.
Criteria for Evaluation:
Efficacy:
Primary Efficacy Endpoint:
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 ESRD (eGFR < 15 ml/min/1.73 m2
confirmed by a 90-day eGFR, receiving chronic dialysis, renal transplantation or renal death).
Secondary Efficacy Endpoints:
!
Time to a 50% eGFR reduction.
!
Time to cardio-renal composite endpoint:  confirmed doubling of serum creatinine, ESRD, CV 
death, nonfatal myocardial infarction, nonfatal stroke.
!
Time to first occurrence of a component of composite renal end-point: confirmed doubling of 
serum creatinine, or the onset of ESRD for all randomized subjects (pooled).
!
Time to the CV composite endpoint:  CV death, nonfatal myocardial infarction and nonfatal 
stroke.
Pharmacokinetic:
Atrasentan clearance (CL/F) and volume of distribution (Vss/f) will be determined using population 
pharmacokinetic techniques.
Pharmacodynamic:
The relationship between Atrasentan exposure and clinical efficacy and/or safety response(s) may be 
explored.
Statistical Methods:
Analysis Datasets:
The following datasets will be used for the analysis of all efficacy and other non-safety endpoints.  For 
these analyses, subjects will be analyzed in the treatment group to which they were randomized.
!
The Intention-to-treat (ITT) Responder Set will serve as the primary dataset for the analysis 
of efficacy in this study.  It will consist of all randomized subjects who achieve at least 30% 
reduction in UACR in the Enrichment Period (responders).
!
The ITT Non-responder Set will consist of all randomized subjects who achieve less than 30% 
reduction in UACR in the Enrichment Period (non-responders).
!
The ITT Pooled Set will consist of all randomized subjects (both responders and 
non-responders) and will be used for a pooled analysis of efficacy.
The following datasets will be used for the analysis of safety endpoints.  For these analyses, subjects will 
be analyzed according to the treatment they actually receive during the double-blind phase.
!
The All Treated Responder Set includes all randomized subjects who achieve at least 30% 
reduction in UACR in the Enrichment Period and receive at least one dose of study drug during 
double-blind phase.
!
The All Treated Non-responder Set includes all randomized subjects who achieve less than 
30% reduction in UACR in the Enrichment Period and receive at least one dose of study drug 
during double-blind phase.


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Statistical Methods (Continued):
Analysis Datasets (Continued):
!
The All Treated Set includes all randomized subjects who receive at least one dose of study 
drug during double-blind phase.
Additionally, an All Atrasentan Set comprising all subjects who receive at least one dose of Atrasentan, 
including both Enrichment and Double-Blind Treatment Periods, is defined for the purposes of data 
analysis.
Sample Size Determination:
The sample size for the Double-Blind Treatment Period is based on the primary efficacy endpoint of 
time to the renal composite event comparing Atrasentan to placebo.  A total of 425 events in the ITT set 
is required to detect a 27% hazard reduction (HR of 0.73) with approximately 90% power using a log-
rank test at a two sided significance level of 0.05.  Based on the annual event rate in RENAAL study 
(~13%) and ALTITUDE (~3%), the estimate of the annual placebo event rate in the SONAR study is 
6%.  With the assumption of annual event rate of 6% in placebo group, 42-month accrual period, 
approximate 6 year duration of the Double-Blind Period and an annualized lost to follow-up rate of 2%, 
a total of about approximately 2,500 subjects who achieve at least 30% UACR reduction (responders) in 
the Enrichment Period (1,250 subjects per group) would be needed to be randomized.
In addition, approximately 1,000 subjects who achieve less than 30% UACR reduction in the 
Enrichment Period will also be randomized in a 1:1 ratio to Atrasentan or placebo.
Definition of Baseline:
For treatment comparisons and summaries based on the Double-Blind Treatment Period, baseline values 
refer to the last non-missing value observed prior to or at the time of randomization.  This includes 
treatment comparisons performed for the ITT analysis sets (ITT responder set, ITT non-responder set 
and the ITT pooled set).
For purposes of summarizing safety and efficacy for the Enrichment Period and the entire study 
treatment period (Enrichment and Double-Blind Treatment Period combined), baseline values refer to 
the last non-missing value observed prior to or pre-dose on the first day of Atrasentan therapy 
(Treatment Day 1) at the beginning of the Enrichment Period. 
For specific purposes, e.g., determination of doubling of serum creatinine, baseline values refer to the 
last non-missing value observed prior to or pre-dose on the first day of Atrasentan therapy at the 
beginning of the Enrichment Period.
Primary Efficacy Analysis:
A Cox proportional-hazard regression model will be performed on the ITT responder set to estimate the 
hazard ratio of Atrasentan to placebo and its 95% confidence interval.  The primary efficacy analysis for 
treatment comparison will also be conducted using a stratified log-rank test, adjusting for the following 
stratification factors:
!
UACR level at the beginning of the Enrichment Period (≤ 1,000 mg/g [113 mg/mmol] or 
> 1,000 mg/g [113 mg/mmol]), and 
!
UACR reduction during Enrichment Period (30% – < 45%, 45% – < 60%, and ≥ 60%).  
Kaplan-Meier (KM) estimates for cumulative event rates will be plotted.  


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Statistical Methods (Continued):
Primary Efficacy Analysis (Continued):
In addition, the individual components of the primary efficacy endpoint, i.e., the time to the 
first occurrence of doubling of serum creatinine (confirmed by a 30-day serum creatinine) and the time 
to the first occurrence of the onset of ESRD will be analyzed separately using the same methods as 
specified above.  In analyzing the individual components, first occurrence of only that specific endpoint 
will be considered as events.
Subgroup analyses for subgroups based on age, gender, race, geographical region and important baseline 
characteristics will also be performed.
Secondary Efficacy Analysis:
These pre-specified secondary efficacy endpoints are listed according to their clinical importance and 
will be analyzed in a hierarchical (step-down) fashion.  The analyses of these time-to-event endpoints of 
a 50% eGFR reduction (ITT responder set), a cardio-renal composite endpoint (ITT responder set), the 
composite renal endpoint (ITT pooled set), and the CV composite endpoint (ITT responder set), will 
follow the same methods as specified for the primary efficacy analysis.
Pharmacokinetics:
Population modeling techniques will be used to estimate population central values for Atrasentan 
clearance (CL/F) and volume of distribution (Vss/f), and post hoc values of these parameters for the 
individual subjects will also be estimated.  Additional parameters may be estimated if useful in the 
interpretation of the data.
Safety:
All safety analyses will be conducted on the all treated analysis sets (i.e., all treated responder set, all
treated non-responder set and all treated set, respectively) and the all Atrasentan analysis set (where 
indicated).  No formal statistical tests of treatment difference are planned.
Derivation of Safety Endpoints:
Safety data collected from the first dose up to 45-days post last dose in the double blind period will be 
included in the relevant analyses for the all treated analysis sets, unless otherwise specified in the 
Statistical Analysis Plan (SAP) document.  Safety data collected during the Enrichment Period will be 
summarized for exploratory purposes for the all Atrasentan analysis set.
Study Drug Exposure and Compliance:
The number of days on study drug will be summarized by treatment group and overall.  The number and 
percentage of subjects with at least 70% compliance with study drug at each visit will be summarized by 
treatment group and overall.
Adverse Events (AEs) Analyses:
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Treatment-emergent AEs (i.e., AEs that begin or worsen in severity after initiation of study drug) 
throughout the follow-up period of the study will be summarized by the treatment group in descending 
order of overall frequency by MedDRA preferred term, as well as by system organ class (SOC) and 
MedDRA preferred term.  The incidence rates of treatment-emergent AEs for each treatment group will 
be summarized.  Additionally, the treatment-emergent AEs and serious adverse events (SAEs) will also 
be summarized by the relationship to study drug and their maximum severity.


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Statistical Methods (Continued):
Laboratory Data:
For each laboratory test, the mean change from baseline to the minimum, maximum, and to each visit 
will be summarized by treatment groups.  For selected laboratory tests of interests, the number and 
percentage of subjects whose laboratory value has shifted from normal at baseline to abnormally high or 
low at final will be tabulated by treatment group.
Interim Analysis:
An interim analysis of efficacy will be performed when the number of accrued primary events in the 
responder population is in the range of 50% to 75% of the targeted 425 events for the study.  An alpha-
spending function approach will be used to ensure that the overall one-sided type I error rate will be 
controlled at 0.025 or less.  In addition, an interim analysis of efficacy data for futility only may be 
performed at an earlier time point.  No adjustment to the type I error rate will be made for the futility 
assessment.
To preserve the integrity and the validity of trial data, an external Statistical Analysis Center will 
perform the requisite interim analyses and present the results to IDMC.  Further details of the interim 
analysis plan will be provided in the Statistical Analysis Plan (SAP) and IDMC Charter.  In making any 
decision to recommend discontinuation of the study, either for superior efficacy of Atrasentan or for 
futility, the IDMC shall be guided by a formal stopping rule described in the SAP.
Independent Data Monitoring Committee:
This study will have an IDMC composed of at least two external clinicians and one external statistician 
to review and make recommendations based on the results of the unblinded interim analysis and periodic 
reviews of the safety of Atrasentan. 
Adjudication of Potential Outcome Events:
An independent events adjudication committee (EAC), blinded to study treatment assignment, will 
adjudicate all events that have the potential to be considered endpoints that will be specified in the EAC 
charter.
Steering Committee:
A steering committee will be involved in the design and implementation of the study.  Its membership 
will be representative of the global nature of the study sites and regular meetings will be conducted to 
evaluate the conduct of the trial, including evaluations from the IDMC and EAC.
References:
Westfall PH, Krishen A.  Optimally weighted, fixed sequence and gatekeeper multiple testing 
procedures.  J Stat Plan Inference.  2001;99:25-40.
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Add:  "HR" and "KM"
HR
Hazard ratio
KM
Kaplan-Meier


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Section 5.1  Overall Study Design and Plan:  Description
Second paragraph, first sentence previously read:
The study was designed to randomize approximately 4,148 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.
Has been changed to read:
The study was designed to randomize approximately 3,500 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  
Figure 1.  Study Schematic
Previously read:


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Has been changed to read:
Section 5.1  Overall Study Design and Plan:  Description
Subsection Run-In Period (Up to 12 Weeks) (Visits R1 – R6)
Fourth paragraph, first sentence previously read:
During the Run-In Period, BP control and tolerance to the new therapeutic doses will be 
assessed approximately every other week.
Has been changed to read:
During the Run-In Period, BP control and tolerance to the new therapeutic doses will be 
assessed approximately every other week (± 2 days).


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Section 5.1  Overall Study Design and Plan:  Description
Subsection Enrichment Period (6 Weeks) (Visits E1 – E5)
Heading "Serum Creatinine Elevation During Enrichment"
First paragraph, first sentence previously read:
Subjects must not have an increase in serum creatinine > 0.5 mg/dL (> 48 umol/L) AND 
> 20% from E1 to the E5 visit.
Has been changed to read:
Subjects must not have an increase in serum creatinine > 0.5 mg/dL AND > 20% from E1 
to the E5 visit.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Enrichment Period (6 Weeks) (Visits E1 – E5)
Heading "Serum Creatinine Elevation During Enrichment"
Third paragraph previously read:
A responder/non-responder ratio design was set up to ensure proportional distribution to 
the expected enrollment.  The implementation of this ratio will be through the IRT system 
and will allow the randomization of 50 non-responders for every 150 responders that are 
randomized (1:3 proportion).  The ability to randomize non-responders will "turn on and 
off" based on the responder/non-responder ratio of randomization.  The non-responder 
arm will re-open to enrollment at any given time without notice, as the randomization 
scheme is applied, until enrollment of the 1000 subject non-responder arm of the protocol 
is complete.  
Has been changed to read:
A responder/non-responder ratio design was set up to ensure proportional distribution to 
the expected enrollment.  The implementation of this ratio will be through the IRT 
system.  The ability to randomize non-responders will "turn on and off" based on the 
responder/non-responder ratio of randomization.  The non-responder arm will re-open to 
enrollment at any given time without notice, as the randomization scheme is applied, until 


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enrollment of approximately 1,000 subjects in the non-responder arm of the protocol is 
complete.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Randomization Visit
First paragraph, third sentence previously read:
If the non-responder cap is met, the IVRS/IWRS will inform the site that the subject 
cannot continue into the Double-Blind Treatment Period.  
Has been changed to read:
If the non-responder cap is met and a subject has achieved < 30% UACR reduction at the 
end of the Enrichment Period compared to baseline, the IVRS/IWRS will inform the site 
that the subject cannot continue into the Double-Blind Treatment Period.  
Section 5.1  Overall Study Design and Plan:  Description
Subsection Randomization Visit
Last paragraph, first sentence previously read:
Only 1,000 subjects in the non-responder population will be randomized.
Has been changed to read:
Approximately 1,000 subjects in the non-responder population will be randomized.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Double-Blind Treatment Period (Randomization – Final Treatment Visit)
Third paragraph previously read:
T3 will occur 3 months after randomization (2 months after T1).
Has been changed to read:
T3 will occur 3 months (± 2 weeks) after randomization (2 months after T1).


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Section 5.1  Overall Study Design and Plan:  Description
Subsection Double-Blind Treatment Period (Randomization – Final Treatment Visit)
Fourth paragraph
Add:  new second sentence
The visit window for all Treatment Visits after T1 is ± 2 weeks.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Double-Blind Treatment Period (Randomization – Final Treatment Visit)
Fourth paragraph, last sentence previously read:
Subjects will also be given supplies and instructions when required for the collection of 
1 FMV urine sample that needs to be collected within 1 day of the yearly treatment visit 
(T12, T36, T48).
Has been changed to read:
Subjects will also be given supplies and instructions when required for the collection of 
1 FMV urine sample that needs to be collected within 1 day of the yearly treatment visit 
(T12, T36, T48, etc).
Section 5.1  Overall Study Design and Plan:  Description
Subsection End Stage Renal Disease
First paragraph previously read:
ESRD will be defined as eGFR < 15 ml/min/1.73 m2 (confirmed by a 90-day eGFR), 
receiving chronic dialysis, renal transplantation or the occurrence of renal death.  Once an 
eGFR < 15 ml/min/1.73 m2 is reported the Investigator will be informed by the central 
laboratory.  The lab should be confirmed at the next 3 month scheduled visit or at an 
unscheduled visit at approximately 90 days.  If the subject misses the return visit, the visit 
should be rescheduled as soon as possible.  The Investigator will make all reasonable 
attempts to exclude reversible causes of elevation of serum creatinine such as volume 
depletion or nephrotoxic medication.  Once an eGFR < 15 ml/min/1.73m2 is confirmed 
at , the site will report the event in eClinical©, as described in Section 6.5.1, to begin the 
process of collecting the information required to have the event properly adjudicated by 


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the independent EAC.  Subjects who reach the endpoint of an eGFR < 15 ml/min/1.73 m2
will remain on study drug until they receive chronic dialysis or experience renal 
transplantation or the occurrence of renal death or until completion of the trial.
Has been changed to read:
ESRD will be defined as eGFR < 15 ml/min/1.73 m2 receiving chronic dialysis, renal 
transplantation or the occurrence of renal death.  Once an eGFR < 15 ml/min/1.73 m2 is 
reported the Investigator will be informed by the central laboratory.  The lab should be 
confirmed at the next 3 month scheduled visit or at an unscheduled visit at approximately 
90 days (confirmatory values within the intended study visit window will be acceptable).  
If the subject misses the return visit, the visit should be rescheduled as soon as possible.  
The Investigator will make all reasonable attempts to exclude reversible causes of 
elevation of serum creatinine such as volume depletion or nephrotoxic medication.  Once 
an eGFR < 15 ml/min/1.73m2 is confirmed, the site will report the event in eClinical©, as 
described in Section 6.5.1, to begin the process of collecting the information required to 
have the event properly adjudicated by the independent EAC.  Subjects who reach the 
endpoint of an eGFR < 15 ml/min/1.73 m2 will remain on study drug until they receive 
chronic dialysis or experience renal transplantation or the occurrence of renal death or 
until completion of the trial.
Section 5.1  Overall Study Design and Plan:  Description
Subsection End Stage Renal Disease
Last paragraph
Add:  new third sentence
For subjects receiving chronic dialysis or renal transplantation, laboratory samples will be 
collected at the Follow-Up (F1) visit or any remaining study visits at the discretion of the 
Investigator.  


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Section 5.1  Overall Study Design and Plan:  Description
Subsection Premature Discontinuation and Retention
Last paragraph, third sentence previously read:
Whenever possible, Investigators should encourage subjects to continue with study 
assessments even after they discontinue taking study drug during the Double-Blind 
Treatment Period.  
Has been changed to read:
Whenever possible, Investigators should encourage subjects to continue with on-site study 
assessments even after they discontinue taking study drug during the Double-Blind 
Treatment Period.  
Section 5.1  Overall Study Design and Plan:  Description
Subsection Premature Discontinuation and Retention
Last paragraph, sixth, seventh, and eighth sentence previously read:
If the subject is unable or unwilling to undergo planned assessments, study staff should 
make telephone contact and encourage subjects to allow further assessments.  The 
telephone assessments will consist of a phone call to the subject every 3 months until the 
study end.  Procedures to be performed during the telephone contact include, but not 
limited to, eliciting information regarding concurrent medications, occurrence of renal and 
cardiovascular events, ask about recent laboratory values, and inquire as to whether the 
subject has started receiving chronic dialysis.
Has been changed to read:
If the subject is unable or unwilling to undergo on-site assessments for an upcoming 
quarterly visit, study staff should make telephone contact and encourage subjects to allow 
further assessments.  Telephone assessments should only be utilized when necessary.  As 
part of the telephone assessment, the site will elicit or collect information regarding, but 
not limited to, concurrent medications, occurrence of renal and cardiovascular events 
including chronic dialysis, and local laboratory reports (if available).  


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Section 5.1  Overall Study Design and Plan:  Description
Subsection Premature Discontinuation and Retention
Heading "Home Visits"
Add:  new heading title and text
Home Visits
In exceptional cases, visiting nurse services may be available for use, as needed.  Sponsor 
approval will be required prior to implementation of the nursing service.  Study activities 
such as local or central laboratory sample collection and processing may be conducted in 
the home or non-hospital/clinic environment by qualified individuals.
Subject Withdrawal
Section 5.1  Overall Study Design and Plan:  Description
Subsection Premature Discontinuation and Retention
Last paragraph, eighth sentence previously read:
It is expected that subjects who leave the study and stop taking study drug will agree to 
remain for follow-up status evaluations.
Has been changed to read:
It is expected that subjects who permanently discontinue study drug will agree to remain 
for follow-up status evaluations.  
Section 5.1  Overall Study Design and Plan:  Description
Subsection Open-Label Extension Study
Previously read:
Upon study completion, those subjects who have completed the Final Treatment visit and 
the Follow-Up (F1) visit will be invited to participate in an open-label study to determine 
the long-term safety and efficacy of Atrasentan 0.75 mg QD.


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Has been changed to read:
Upon study completion, eligible subjects will be invited to participate in an open-label 
study if their site is participating in the extension study to determine the long-term safety 
of Atrasentan.
Section 5.2.1  Inclusion Criteria
Criterion 5, first bullet previously read:
Estimated GFR 25 to 75 mL/min/1.73 m2 and a UACR ≥ 300 and < 5,000 mg/g 
(≥34 mg/mmol and < 565 mg/mmol);
Has been changed to read:
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);
Section 5.2.1  Inclusion Criteria
Criterion 7, last bullet previously read:
●
Subject must not have an increase in serum creatinine > 0.5 mg/dL 
(> 48 umol/L) AND > 20% increase from the beginning of Enrichment (E1) 
to the end of the Enrichment Period.
Has been changed to read:
●
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.
Male subjects must satisfy the following criteria from initial study drug administration 
through 90 days after last dose of study drug:


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Section 5.2.2  Exclusion Criteria
First paragraph previously read:
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
Has been changed to read:
A subject will not be eligible for entry into the Run-in Period if he/she meets any of the 
following criteria:
Section 5.2.2  Exclusion Criteria
Criterion 3 previously read:
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.
Has been changed to read:
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.
Section 5.2.2  Exclusion Criteria
Criterion 19, last sentence previously read: 
Women who are surgically sterile or have a history of hysterectomy may not be 
premenopausal.


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Has been changed to read:
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.
Table 1.  Study Activities
Activity "Complete Chemistryj" previously read:
Complete Chemistryj
Has been changed to read:
Complete Chemistry
Table 1.  Study Activities
Table note "d." previously read:
T12, T24, T36, and T48.
Has been changed to read:
T12, T24, T36, T48, etc.
Table 1.  Study Activities
Table note "i." previously read:
Updates.
Has been changed to read:
Complete medical history, including history of tobacco and alcohol use and colonoscopy 
history, will be obtained during initial Screening visit and updated through the 
Enrichment Period E1.


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Table 1.  Study Activities
Table note "k.," last sentence previously read:
FMV is not required for subjects who present for the Randomization visit and are not 
randomized and a Final Treatment visit is conducted instead of a randomization.
Has been changed to read:
FMV is not required for subjects who present for the Randomization visit and are not 
randomized and a Final Treatment visit is conducted instead of a Randomization visit.
Table 1.  Study Activities
Table note "w.," second sentence previously read:
The IVRS/IWRS call at the Final Treatment/PD visit is only for study 
completion/premature discontinuation.
Has been changed to read:
The IVRS/IWRS call at the Final Treatment/PD visit is only for the discontinuation of 
study drug.
Section 5.3.1.1  Study Procedures
Subsection Post-Discontinuation Visits/Phone Calls
Last paragraph, first sentence previously read:
If the subject is unable or unwilling to undergo planned assessments, study staff should 
make telephone contact and encourage subjects to allow further assessments.  
Has been changed to read:
If the subject is unable or unwilling to undergo on-site planned assessments, study staff 
should make telephone contact and encourage subjects to allow further assessments.  
Telephone assessments should only be utilized when necessary.


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Section 5.3.1.1  Study Procedures
Subsection Post-Discontinuation Visits/Phone Calls
Last paragraph, third sentence previously read:
Procedures to be performed during the telephone contact include, but not limited to, 
eliciting information regarding concurrent medications, occurrence of renal and 
cardiovascular events, and SAEs, and ask about recent laboratory values, and inquire as to 
whether the subject has started receiving chronic dialysis.
Has been changed to read:
Procedures to be performed during the telephone contact include, but not limited to, 
eliciting and collecting information regarding concurrent medications, occurrence of renal 
and cardiovascular events, SAEs, local laboratory reports (if available), and inquire as to 
whether the subject has started receiving chronic dialysis.
Table 2.  Reminder Phone Calls
Study Period "Yearly Visits (i.e., T12, T36, T48)" previously read:
Yearly Visits (i.e., T12, T36, T48)
Has been changed to read:
Yearly Visits (i.e., T12, T36, T48, etc).


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Table 2.  Reminder Phone Calls
Study Period "Final Treatment/Premature Discontinuation Visit" and "F1 Visit" 
previously read:
Study Period
Study Day
Call Description
Final Treatment/ 
Premature 
Discontinuation 
Visit
Approximately 
2-3 days prior to the 
Final Treatment/ 
Premature 
Discontinuation visit.
Call the subject to remind them to initiate their 
first morning void urine sample the day prior to their 
T48/Premature Discontinuation visit.  Also remind them 
to initiate their 24-hour urine collection (if the subject 
consented) immediately after their third first morning 
void urine has been collected.  Remind the subject to 
bring their diary to the visit.
F1 Visit
Approximately 
2 days prior to the 
F1 visit.
Call the subject to remind them to initiate their 
first morning void urine sample the 2 days prior to their 
F1 visit.  Also remind the subject that they must fast for 
8 hours prior to the visit and hold their morning dose of 
antihyperglycemic agents prior to their F1 visit.
Has been changed to read:
Study Period
Study Day
Call Description
Final Treatment/ 
Premature 
Discontinuation 
Visit
Approximately 
2-3 days prior to the 
Final Treatment/ 
Premature 
Discontinuation visit.
Call the subject to remind them to initiate their 
first morning void urine sample the day prior to their 
Final Treatment/Premature Discontinuation visit.  
Remind the subject to bring their diary to the visit.
F1 Visit
Approximately 
2 days prior to the 
F1 visit.
Call the subject to remind them to initiate their first 
morning void urine sample the 2 days prior to their F1 
visit.  Also remind them to initiate their 24-hour urine 
collection (if the subject consented) immediately after 
the first morning void urine has been collected.  At this 
time, also remind the subject that they must fast for 
8 hours prior to the visit and hold their morning dose of 
antihyperglycemic agents prior to their F1 visit.
Section 5.3.1.1  Study Procedures
Subsection Clinical Laboratory Tests
Second paragraph
Add:  new second sentence
In exceptional cases, test results from a local laboratory may be acceptable.


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Section 5.3.1.1  Study Procedures
Subsection First Morning Void (FMV) Urine Sample Collections
Second paragraph, second sentence previously read:
One first morning void sample collection will be obtained prior to the Treatment visit T1, 
the yearly visits (T12, T36, and T48), the Final Treatment/Premature Discontinuation 
visit, and the Follow-Up Visit F1.
Has been changed to read:
One first morning void sample collection will be obtained prior to the Treatment visit T1, 
the yearly visits (T12, T36, T48, etc.), the Final Treatment/Premature Discontinuation 
visit, and the Follow-Up Visit F1.
Section 5.3.1.1.1  24-Hour Urine Collection Sub-Study (Additional Consent Needed)
First paragraph, first sentence previously read:
The 24-hour urine collection will be collected six times during the study for each subject 
that consents to participate in this optional sub-study up to a limit of 400 subjects.
Has been changed to read:
The 24-hour urine collection will be collected as outlined in Table 4 during the study for 
each subject that consents to participate in this optional sub-study up to a limit of 
800 subjects.
Table 4.  Study Activities for Optional 24-hour Urine Sub-Study
Header row, column "Yearly" previously read:
Yearly
Has been changed to read:
Yearly*


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Table 4.  Study Activities for Optional 24-hour Urine Sub-Study
Add:  new table note "*"
T12, T24, T36, T48, etc.
Section 5.3.1.2  Blood Samples for Pharmacogenetic Analysis
"AbbVie Sample Receiving," "Phone:" and "Fax:" previously read:
Phone:
Fax:
Has been changed to read:
Phone:
Fax:
Section 5.3.2.1  Collection of Samples for Pharmacokinetic Analysis
First paragraph
Delete:  second sentence
A total of 14 blood samples per subject are planned to be collected for pharmacokinetic 
(PK) analysis.  
Section 5.3.2.1  Collection of Samples for Pharmacokinetic Analysis
First paragraph, last sentence previously read:
Immediately after collection, the blood samples will be inverted several times to ensure 
good mixing of the blood and anticoagulant, and be placed in an ice bath.
Has been changed to read:
Immediately after collection, the blood samples will be inverted several times to ensure 
good mixing of the blood and anticoagulant.
Section 5.3.3.1  Primary Variables
Section title previously read:
Primary Variables


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Has been changed to read:
Primary Endpoint (Adjudicated)
Section 5.3.3.1  Primary Variables
Previously read:
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 ESRD (eGFR 
< 15 ml/min/1.73m2 confirmed by a 90-day eGFR, receiving chronic dialysis, renal 
transplantation or renal death).
Has been changed to read:
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 ESRD (eGFR 
< 15 ml/min/1.73m2 (confirmed by a 90-day eGFR), receiving chronic dialysis, renal 
transplantation or renal death).
Section 5.3.3.3  Additional Endpoints
Third bullet previously read:
●
Change in eGFR to 45 days after end of treatment.
Has been changed to read:
●
Change in eGFR after 3 months post randomization treatment.
●
Change in eGFR to 45 days after end of treatment (or final observation on 
treatment).
Section 5.3.5  Pharmacokinetic Variables
First sentence previously read:
Plasma concentrations of Atrasentan and its possible metabolites will be obtained at all 
treatment visits.


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Has been changed to read:
Plasma concentrations of Atrasentan and its possible metabolites will be obtained at the 
treatment visits outlined in Table 1.
Section 5.4.2  Discontinuation of Entire Study
First paragraph, first sentence previously read:
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.
Has been changed to read:
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause (e.g., early study termination after interim futility or efficacy analyses) 
provided that written notice is submitted to the site(s) in advance of the intended 
termination.  
Section 5.4.2  Discontinuation of Entire Study
Last paragraph previously read:
Following study termination for any reason, all subjects who have not withdrawn or died 
must be contacted.  At this time, subjects who have not permanently discontinued study 
drug will be scheduled for the Final Treatment visit and will be scheduled for the 
Follow-Up Visit (F1).  In subjects who were permanently discontinued from study drug, a 
phone call can be completed to solicit information about any potential endpoint events and 
SAEs since the previous visit.
Has been changed to read:
Following study termination for any reason, all subjects must be contacted.  At this time, 
subjects who have not permanently discontinued study drug will be scheduled for the 
Final Treatment visit and Follow-Up Visit (F1).  In subjects who were permanently 
discontinued from study drug, the next scheduled on-site visit (preferred) or phone call 


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(only if the subject is unable or unwilling to undergo on-site assessments) should be 
completed to solicit and collect information about any potential endpoint events, SAEs, 
and local laboratory reports for values such as serum creatinine and eGFR since the 
previous visit or phone call.
Section 5.4.3  Study Completion
First paragraph, last sentence previously read:
Upon reaching Study Completion, the sponsor (or designee) will contact the Investigators 
to inform them of Study Completion and request all subjects who have not withdrawn or 
died be contacted and scheduled for the Final Treatment Visit and Follow Up visit (F1).  
Has been changed to read:
Upon reaching Study Completion, the Sponsor (or designee) will contact the Investigators 
to inform them of Study Completion and request all subjects be contacted.  Subjects who 
have not permanently discontinued from study drug will be scheduled for the Final 
Treatment Visit and Follow Up visit (F1).  Subjects who were permanently discontinued 
from study drug should complete the next scheduled visit or phone call to solicit 
information about any potential endpoint events, SAEs, and laboratory values such as 
serum creatinine and eGFR since the previous visit or phone call (refer to Premature 
Discontinuation and Retention section).
Section 5.4.3  Study Completion
Last paragraph, first sentence previously read:
The EAC will track the number of positively adjudicated primary renal events and the 
events undergoing adjudication.
Has been changed to read:
The Sponsor will track the number of positively adjudicated primary renal events and the 
events undergoing adjudication.


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Section 5.5.5  Blinding
First sentence previously read:
Both the Investigator and the subject will remain blinded to the subject's treatment group 
during the double-blind treatment period of the study.
Has been changed to read:
Both the Investigator and the subject will remain blinded to the subject's treatment group 
during the double-blind period of the study.
Section 5.5.5.1  Blinding of Data for Independent Data Monitoring Committee 
(IDMC)
Fourth and fifth sentence previously read:
In addition, the IDMC will review the pre-planned interim futility analysis results.  The 
study can be stopped for futility if the criteria defined in Section 8.1.5 are met.
Has been changed to read:
In addition, the IDMC will review the pre-planned interim analyses and make 
recommendations guided by the formal stopping rules described in the statistical analysis 
results plan (SAP).
Section 5.6.4  Selection of Doses in the Study
First paragraph, last sentence previously read:
After enrichment, subjects may be randomized to receive a maximum of 0.75 mg QD of 
ABT-627 for up to 48 months.
Has been changed to read:
After enrichment, subjects may be randomized to receive a maximum of 0.75 mg QD of 
ABT-627 for up to approximately 6 years.


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Figure 2.  Adverse Event Collection
Previously read:
SAEs
SAEs and Non-Serious AEs
Elicited and/or Spontaneously Reported
Potential Endpoints 
and SAEs
∃
∃
∃
∃
Consent 
Signed
Study 
Drug 
Start
Study 
Drug 
Stopped
45 Days after 
Study Drug 
Stopped
Final Visit
Has been changed to read:
*
Final visit refers to final subject contact as referenced in Section 5.4.2 and Section 5.4.3.
Section 6.5  Adverse Event Reporting
"Renal Safety Management:"
Delete:  building number


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Section 6.5  Adverse Event Reporting
"Primary Study Designated Physician:" previously read:
Has been changed to read:
Section 6.5.1  Potential Endpoint Reporting
Section title and text previously read:
6.5.1
Potential Endpoint Reporting
The Investigator or designee will report potential endpoints through a Web Portal 
(eClinical©) within 5 days of being aware of potential event.  The vendor (George 
Clinical) will work with the site to obtain pertinent information to complete a case packet.  


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Once the packet is confirmed complete by George Clinical, they will assign to the EAC 
committee for review and adjudication.  The Investigator will be notified on the outcome 
of the review.  Details of the process are listed in the site manual.  The following events 
will be reported by the site in eClinical© for subjects in the Double-Blind Treatment 
Period:
●
Doubling of Serum Creatinine
●
ESRD
●
Death
●
Nonfatal Stroke
●
Nonfatal MI
●
Heart Failure (hospitalized and non-hospitalized; including those events 
occurring during the Enrichment Period)
Has been changed to read:
6.5.1
Potential Endpoint Reporting for Adjudication
The Investigator or designee will report potential endpoints through a Web Portal 
(eClinical©) within 5 days of being aware of potential event.  The vendor (George 
Clinical) will work with the site to obtain pertinent information to complete a case packet.  
Once the packet is confirmed complete by George Clinical, they will assign to the EAC 
committee for review and adjudication.  Details of the endpoint reporting process are 
listed in the Endpoint Reporting site manual.
The following events will be reported by the site in eClinical© for subjects in the 
Enrichment Period: 
●
Death
●
Nonfatal Stroke
●
Nonfatal MI
●
Heart Failure (hospitalized and non-hospitalized) 


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The following events will be reported by the site in eClinical© for subjects in the Double-
Blind Treatment Period including subjects who continue follow-up after premature 
discontinuation of study drug during the Double-Blind Treatment Period:
●
Doubling of Serum Creatinine
●
ESRD
●
Death
●
Nonfatal Stroke
●
Nonfatal MI
●
Heart Failure (hospitalized and non-hospitalized)
The Sponsor may request reporting of additional safety-related events into eClinical©.
Section 7.0  Protocol Deviations
Contact information previously read:
Primary Contact:
Alternate Contact:


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Has been changed to read:
Primary Contact:
Alternate Contact:
Section 8.1  Statistical and Analytical Plans
First paragraph, first and second sentence previously read:
All statistical analyses with between treatment comparisons are conducted for the 
Double-Blind Treatment Period.  Testing of treatment group differences between the 
Atrasentan arm and placebo arm will be conducted at a two-sided significance level of 
0.05 (suitably adjusted for group-sequential testing and multiplicity for the primary and 
secondary endpoints).  
Has been changed to read:
All statistical analyses with between treatment comparisons are conducted for the 
Double-Blind Period.  Testing of treatment group differences for efficacy endpoints 
between the Atrasentan arm and placebo arm will be conducted at a two-sided 
significance level of 0.05 (suitably adjusted for group-sequential testing and multiplicity 
for the primary and secondary endpoints).  
Section 8.1  Statistical and Analytical Plans
Second paragraph previously read:
The primary efficacy endpoint of the study is the time to first occurrence of a renal 
composite event defined as either doubling of serum creatinine (confirmed by a 30-day 
serum creatinine) or the onset of ESRD.  Approximately 4,148 subjects (3,148 subjects 


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who achieve at least 30% reduction in UACR in the Enrichment Period and 1,000 subjects 
who achieve less than 30% reduction in UACR in the Enrichment Period) will be 
randomized in a 1:1 ratio to 2 treatment groups:  placebo or Atrasentan 0.75 mg/day.
Has been changed to read:
The primary efficacy endpoint of the study is the time to first occurrence of an adjudicated 
renal composite event defined as either doubling of serum creatinine (confirmed by a 
30-day serum creatinine) or the onset of ESRD in subjects who achieve at least 30% 
reduction in UACR in the Enrichment Period (responders).  Approximately 3,500 subjects 
(2,500 subjects who achieve at least 30% reduction in UACR in the Enrichment Period 
and approximately 1,000 subjects who achieve less than 30% reduction in UACR in the 
Enrichment Period) will be randomized in a 1:1 ratio to 2 treatment groups:  placebo or 
Atrasentan 0.75 mg/day.
Section 8.1.2  Demographic, Other Baseline Characteristics, Subject Disposition and 
Concomitant Medication
Subsection Definition of Baseline
First paragraph, first sentence previously read:
For treatment comparisons and summaries based on the Double-Blind Treatment Period, 
baseline values refer to the last non-missing value observed prior to or at the time of 
randomization.
Has been changed to read:
For treatment comparisons and summaries based on the Double-Blind Period, baseline 
values refer to the last non-missing value observed prior to or at the time of 
randomization.


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Section 8.1.2  Demographic, Other Baseline Characteristics, Subject Disposition and 
Concomitant Medication
Subsection Definition of Baseline
Second paragraph previously read:
For determination of doubling of serum creatinine, values obtained prior to Enrichment 
will be used as reference values.
Has been changed to read:
For determination of doubling of serum creatinine, baseline values refer to the last non-
missing value observed prior to or pre-dose on the first day of Atrasentan therapy at the 
beginning of the Enrichment Period.
Section 8.1.2  Demographic, Other Baseline Characteristics, Subject Disposition and 
Concomitant Medication
Subsection Definition of Baseline
Last paragraph 
Add:  new second and third sentence
For the Enrichment Period, initial UACR is computed as the geometric mean of UACR 
collected at Visits R6 and E1, and final UACR is computed as the geometric mean of the 
UACR values collected at Visits E4 and E5, provided at least three UACR values are 
available in each case.  UACR will be considered to be missing otherwise.
Section 8.1.2  Demographic, Other Baseline Characteristics, Subject Disposition and 
Concomitant Medication
Subsection Analysis
Second paragraph 
Delete:  third sentence
P values for the treatment difference in the discontinuation rate and that for each primary 
reason will be provided using Fisher's exact test at the significance level of 0.05.  
Section 8.1.3.1  Primary Efficacy Analyses
Section title previously read:
Primary Efficacy Analyses


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Has been changed to read:
Primary Efficacy Analyses (Responders)
Section 8.1.3.1  Primary Efficacy Analyses
First paragraph
Delete:  second sentence 
For determination of doubling of serum creatinine, values obtained prior to Enrichment 
will be used as reference values.
Section 8.1.3.1  Primary Efficacy Analyses
Second paragraph previously read: 
The primary efficacy analysis for treatment comparison will be conducted on the ITT 
responder set for the primary efficacy endpoint using a stratified log-rank test, adjusting 
for the following stratification factors.
Has been changed to read:
A Cox proportional-hazard regression model will be performed on the ITT responder set 
to estimate the hazard ratio of Atrasentan to placebo and its 95% confidence interval.  The 
primary efficacy analysis for treatment comparison will be conducted using a stratified 
log-rank test, adjusting for the following stratification factors.
Section 8.1.3.1  Primary Efficacy Analyses
Delete:  first bullet
Geographical region (North America, Latin America, Europe, Asia Pacific, and Japan),
Section 8.1.3.1  Primary Efficacy Analyses
Third paragraph, last sentence previously read:
A Cox proportional-hazards regression model with treatment group and the above 
stratification factors as explanatory variables will be performed to estimate the hazard 
ratio of events comparing placebo to Atrasentan and its 95% confidence interval.


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Has been changed to read:
A Cox proportional-hazards regression model with treatment group and the relevant 
factors (defined in the Statistical Analysis Plan) as explanatory variables will be 
performed to estimate the hazard ratio of events comparing placebo to Atrasentan and its 
95% confidence interval.
Section 8.1.3.1  Primary Efficacy Analyses
Last paragraph previously read:
Subgroup analyses for subgroups based on age, gender, race and important baseline
characteristics will also be performed.
Has been changed to read:
Subgroup analyses for subgroups based on age, gender, race, geographical regions and 
important baseline characteristics will also be performed.
Section 8.1.3.4  Efficacy Analyses for the 24-Hour Urine Sub-Study
First paragraph previously read:
Twenty-four-hour urine will be collected at baseline (prior to the Enrichment Period), and 
subsequently at the E5, T12, visits yearly and F1 visit thereafter in a subset of subjects.
Has been changed to read:
Twenty-four-hour urine will be collected prior to dosing in the Enrichment Period 
(Visit E1), and during enrichment at Visit E5, 12 months after randomization (Visit T12), 
yearly thereafter and at the follow-up visit (Visit F1) for each subject that consents to 
participate in this optional sub-study up to a limit of 800 subjects.


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Section 8.1.3.5  Multiplicity
Last paragraph, first sentence previously read:
To control the family-wise type I error rate at 0.05, each secondary endpoint will be tested 
at a 0.05 level (two-sided) following a hierarchical (step-down) multiple testing 
procedure.
Has been changed to read:
To control the family-wise type I error rate at 0.05, each secondary endpoint will be tested 
at the interim or final analysis only when the primary endpoint is statistically significant at 
the corresponding analysis using the same alpha level as the alpha spent for the primary 
endpoint at the interim or final analysis, respectively, following a hierarchical (step-down) 
multiple testing procedure.  
Section 8.1.4  Safety Analyses
Subsection Derivation of Safety Endpoints
First sentence previously read:
Safety data collected from randomization up to the 45-day Follow-Up Visit will be 
included in the relevant analyses for the all treated analysis sets, unless otherwise 
specified in the Statistical Analysis Plan (SAP) document.
Has been changed to read:
Safety data collected from the first dose up to 45 days post last dose in the Double-Blind 
Period will be included in the relevant analyses for the all treated analysis sets, unless 
otherwise specified in the Statistical Analysis Plan (SAP) document.
Section 8.1.4.1  Adverse Events (AEs) Analyses
Item 5 and 6 previously read:
5. A summary of the number and percentage of subjects with possibly or probably drug-
related treatment-emergent adverse events by primary MedDRA system organ class 
and preferred term.


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6. A summary of the number and percentage of subjects with treatment-emergent 
adverse events by primary MedDRA system organ class, preferred term and maximum 
relationship to study drug.
Has been changed to read:
5. A summary of the number and percentage of subjects with drug-related treatment-
emergent adverse events by primary MedDRA system organ class and preferred term.
Section 8.1.4.4  ECG Analyses
Add:  new last sentence
Shifts from baseline at each visit where ECG data is collected will be summarized 
similarly.
Section 8.1.5  Interim Analysis
Previously read:
One futility analysis of the primary efficacy endpoint will be performed when
approximately 50% of the events (total of adjudicated and unadjudicated) required for 
completion of the trial are available.  The primary analysis will be based on the 
EAC-adjudicated events.  Supportive analyses will also be based upon both the total of 
adjudicated and unadjudicated events.  A futility stopping boundary is specified using 
Gamma (–6) as the beta-spending function (Hwang et al).  An alpha spending of 0.0009 
using a Gamma (–8) function will also be applied to the interim analysis.  Hence for the 
final analyses, the primary efficacy endpoint will be tested at an expected nominal alpha 
level of 0.0498.  The final adjustment will be based on the exact number of 
EAC-adjudicated events observed for the interim analysis.
To preserve the integrity and the validity of trial data, an external Statistical Analysis 
Center will perform the interim analysis.


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Has been changed to read:
An interim analysis of efficacy will be performed when the number of accrued primary 
events in the responder population is in the range of 50% to 75% of the targeted 
425 events for the study.  An alpha-spending function approach will be used to ensure that 
the overall one-sided type I error rate will be controlled at 0.025 or less.  In addition, an 
interim analysis of efficacy data for futility only may be performed at an earlier time 
point.  No adjustment to the type I error rate will be made for the futility assessment.  
To preserve the integrity and the validity of trial data, an external Statistical Analysis 
Center will perform the requisite interim analyses and present the results to IDMC.  
Further details of the interim analysis plan will be provided in the Statistical Analysis Plan 
(SAP) and IDMC Charter.  In making any decision to recommend discontinuation of the 
study, either for superior efficacy of Atrasentan or for futility, the IDMC shall be guided 
by a formal stopping rule described in the SAP.
Section 8.1.6  Independent Data Monitoring Committee (IDMC) and Independent 
External Statistician
First paragraph, second sentence previously read:
The IDMC membership and responsibilities, and details of the interim analysis and safety 
reviews, will be documented in a charter that will be prepared prior to the first IDMC 
review meeting.
Has been changed to read:
The IDMC membership and responsibilities, and details of the interim analyses and safety 
reviews, will be documented in a charter that will be prepared prior to the first IDMC 
review meeting.


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Section 8.1.6  Independent Data Monitoring Committee (IDMC) and Independent 
External Statistician
Fourth and fifth paragraph previously read:
The first IDMC meeting will occur after the first 30 subjects with a UACR < 30% 
(non-responders) are randomized and have completed the T1 visit or after the 
first 100 subjects have completed the enrichment period, whichever occurs first.  The 
second IDMC meeting will occur after the first 100 subjects are randomized.  
Subsequently IDMC meetings will occur approximately every 6 months and, if necessary, 
at times other than those scheduled if either the Sponsor or the IDMC determines that an 
unplanned meeting is warranted based on safety concerns.
The IDMC will review unblinded efficacy data at the single interim futility analysis as 
specified in Section 8.1.5.
Has been changed to read:
The first IDMC meeting will occur after the first 30 subjects with a UACR < 0% 
(non-responders) are randomized and have completed the T1 visit or after the 
first 100 subjects have completed the enrichment period, whichever occurs first.  The 
second IDMC meeting will occur after the first 100 subjects are randomized.  
Subsequently IDMC meetings will occur after 25%, 50%, and 75% of the primary end-
points have occurred.  In addition, the IDMC will meet at least every 6 months and, if 
necessary, at times other than those scheduled if either the Sponsor or the IDMC 
determines that an unplanned meeting is warranted based on safety concerns.
The IDMC will make recommendation(s) to AbbVie (Sponsor representative) based on 
their review.  The Sponsor representative will accept or reject the IDMC's 
recommendation.
The IDMC will review unblinded efficacy data as specified in Section 8.1.5.


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Section 8.2  Determination of Sample Size
First paragraph, second previously read:
A total of 425 events in the ITT set are needed to detect a 27% hazard reduction (HR of 
0.73) with 90% power at two-sided alpha level of 0.05.
Has been changed to read:
A total of 425 events in the ITT set are needed to detect a 27% hazard reduction (HR of 
0.73) with approximately 90% power at two-sided alpha level of 0.05.  
Section 8.2  Determination of Sample Size
First paragraph, last sentence previously read:
With the assumption of annual event rate of 6% in placebo group, 24-month accrual 
period, approximate 48-month double-blind treatment duration, and the discontinuation 
rate is 15%, a total of 3,148 subjects who achieve at least 30% reduction in UACR 
(responders) during the Enrichment Period (1,574 subject per group) are needed for 
randomization.
Has been changed to read:
With the assumption of annual event rate of 6% in placebo group, 42-month accrual 
period, approximate 6 year duration of the Double-Blind Period, and an annualized lost to 
follow-up rate of 2%, a total of approximately 2,500 subjects who achieve at least 30% 
reduction in UACR (responders) during the Enrichment Period (1,250 subjects per group) 
are needed for randomization.
Section 8.2  Determination of Sample Size
Second and third paragraph previously read:
In addition, a maximum of 1,000 subjects who achieve less than 30% reduction in UACR 
(non-responders) in Enrichment period will also be randomized in a 1:1 ratio to 
Atrasentan treatment or placebo since it has not been determined whether Atrasentan can 
reduce long-term CKD progression in this population.


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A blinded event rate calculation is planned before the enrollment is completed to confirm 
or potentially revise the event rate assumption and sample size for the study.
Has been changed to read:
In addition, approximately 1,000 subjects who achieve less than 30% reduction in UACR 
(non-responders) in Enrichment period will also be randomized in a 1:1 ratio to 
Atrasentan treatment or placebo since it has not been determined whether Atrasentan can 
reduce long-term CKD progression in this population.
Section 8.3  Randomization Methods
Last bullet previously read:
UACR reduction during the Enrichment Period:  < 0% (capped at 250); 0% to < 15% and 
15% to < 30% (capped at 750); 30% to < 45%, 45% to < 60% and ≥ 60%.
Has been changed to read:
UACR reduction during the Enrichment Period:  < 0% (approximately at 250); 0% to 
< 15% and 15% to < 30% (approximately at 750); 30% to < 45%, 45% to < 60% and 
≥60%.
Section 8.3  Randomization Methods
Last paragraph previously read:
Randomization of non-responders will be distributed chronologically throughout the study 
in a 1:3 proportion to the number of responders randomized in an attempt to maintain 
proportionate balance between the two populations (e.g., in terms of rate of primary 
events and representation of global regions).  The implementation of the 
responder/non-responder ratio will be through the IRT system and will allow the 
randomization of 50 non-responders for every 150 responders that are randomized.
Has been changed to read:
A strategy will be utilized to provide gating of subjects into the responder and non-
responder groups in order to allow for temporal similarity in accrual of subjects and 


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relatively similar exposure times on study drug.  The implementation of the 
responder/non-responder ratio will be through the IRT system.
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Clinical
Clinical
Clinical
Clinical
Statistics
Clinical
Pharmacokinetics
Global Drug Supply Management
Has been changed to read:
Name
Title
Functional Area
General Medicine Therapeutic Area
General Medicine Therapeutic Area
Clinical
Data and Statistical Sciences, Statistics
Bioanalysis
Pharmacokinetics and 
Pharmacodynamics
Clinical Drug Supply Management



SAP_001.pdf: 
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M11-352 – Statistical Analysis Plan
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1.0
Title Page
Statistical Analysis Plan
Study M11-352
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
Date:  20 Mar 2018
Version 3.0
NCT01858532


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2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................5
4.0
Study Background.................................................................6
4.1
Study Objectives .................................................................................... 6
4.2
Study Design.......................................................................................... 6
4.3
Sample Size............................................................................................ 9
4.4
Planned Interim Analysis...................................................................... 12
4.5
Type I Error Adjustment Procedures for Multiple Testing .................... 12
5.0
Definitions, Derivations and Data-Handling 
Conventions .........................................................................13
5.1
Definition of Study Treatment Dates .................................................... 13
5.1.1
Date of First Dose of Atrasentan in EP ................................................. 13
5.1.2
Date of Last Dose of Atrasentan in EP.................................................. 13
5.1.3
Date of First Dose of Study Treatment in DB-Period............................ 14
5.1.4
Date of Last Dose of Study Treatment in DB-Period ............................ 14
5.1.5
Date of Last Dose of Study Treatment .................................................. 14
5.2
Describing Study Time Points .............................................................. 14
5.3
Baseline................................................................................................ 15
5.3.1
Baseline for Summaries in DB-Period .................................................. 15
5.3.2
Baseline for Summaries in EP/Entire Study Period............................... 15
5.4
Urine Albumin to Creatinine Ratio (UACR) and UACR Related 
Randomization Stratification ................................................................ 16
5.5
Randomization Stratifications and Analysis Stratifications ................... 17
5.6
Last Contact Date................................................................................. 17
6.0
Analysis of Data from the DB-Period.................................18
6.1
Visit Windows...................................................................................... 18
6.2
General Statistical Methods.................................................................. 21
6.2.1
Methods of Categorical Endpoints........................................................ 21
6.2.2
Methods of Continuous Endpoints........................................................ 21
6.2.3
Methods of Time-to-Event Endpoints................................................... 21


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6.2.4
Methods of Longitudinal Repeated Measurements................................ 23
6.3
Analysis Sets........................................................................................ 24
6.3.1
Efficacy/Non-Safety Analysis Sets ....................................................... 24
6.3.2
Safety Analysis Sets ............................................................................. 26
6.4
Demographics and Baseline Characteristics.......................................... 26
6.5
Subject Disposition............................................................................... 27
6.6
Study Treatment and Concomitant Medications.................................... 27
6.6.1
Study Treatment and Compliance......................................................... 27
6.6.2
Prior and Concomitant Medications...................................................... 28
6.7
Efficacy Analyses................................................................................. 30
6.7.1
Primary Efficacy Endpoint ................................................................... 30
6.7.2
Secondary Efficacy Endpoints.............................................................. 31
6.7.2.1
Time to 50% eGFR Reduction.............................................................. 32
6.7.2.2
Time to Cardio-Renal Composite Endpoint .......................................... 32
6.7.2.3
Time to Renal Composite Endpoint in the Combined Responder 
and Non-Responder Population ............................................................ 33
6.7.2.4
Time to CV Composite Endpoint.......................................................... 34
6.7.3
Additional Supportive/Sensitivity Analyses.......................................... 35
6.7.4
Subgroup Analyses............................................................................... 36
6.7.5
Additional Endpoints............................................................................ 37
6.8
Safety Analyses.................................................................................... 40
6.8.1
Summaries of AEs and SAEs ............................................................... 41
6.8.2
Listing of TEAEs ................................................................................. 43
6.8.3
TEAEs of Special Interest..................................................................... 43
6.8.4
Laboratory Results ............................................................................... 44
6.8.5
Vital Signs............................................................................................ 47
6.8.6
ECG Parameters................................................................................... 48
6.9
Pharmacokinetic (PK) Parameters ........................................................ 48
7.0
Analysis of Data from the EP ............................................. 48
7.1
Analysis Set ......................................................................................... 48
7.2
Demographics and Baseline Characteristics.......................................... 49
7.3
Subject Disposition............................................................................... 49
7.4
Study Treatment and Concomitant Medications.................................... 49


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7.4.1
Drug Exposure and Compliance ........................................................... 49
7.4.2
Concomitant Medications..................................................................... 50
7.5
Efficacy................................................................................................ 50
7.5.1
UACR .................................................................................................. 50
7.5.2
Other Key Laboratory Data and Vital Sign ........................................... 50
7.6
Safety................................................................................................... 51
7.7
PK........................................................................................................ 51
8.0
Analysis of Data from the Screening Period and RP......... 52
9.0
Analysis of Data for the 24-Hour Urine Sub Study........... 52
10.0
References............................................................................53
List of Tables
Table 1.
Number of Events Required to Achieve 80% or 90% Power Based 
on Different Effect Size Assumptions (2-Sided Alpha = 0.05) .............. 11
Table 2.
Nominal Time and Visit Windows (as Days from First Dose of 
Study Treatment in DB-Period) for eGFR and Other 
Measurements* Performed at Each Scheduled Visit ............................. 19
Table 3.
Nominal Time and Visit Windows (as Days from First Dose of 
Study Treatment in DB-Period) for Laboratory Measurements 
Performed Annually, at T3 and then Annually, or at T1 and then 
Annually .............................................................................................. 19
Table 4.
Interval and Nominal Day (as Days from First Dose of Study 
Treatment in DB-Period) for Quality of Life Questionnaires................. 20
Table 5.
TEAESI Search Criteria ....................................................................... 44
Table 6.
Laboratory Variables and Corresponding Statistical Analyses .............. 45
Table 7.
Criteria for Potentially Clinically Significant (PCS) Vital Sign and 
Weight Values...................................................................................... 48
List of Figures
Figure 1.
Study Schematic..................................................................................... 8


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3.0
Introduction
Study M11-352 (SONAR) is a randomized, multi-country, multicenter, double-blind, 
parallel, placebo-controlled, Phase 3 study of the effects of atrasentan 0.75 mg QD on 
renal outcomes in subjects with type 2 diabetes and nephropathy (DN).  This statistical 
analysis plan (SAP) describes the analysis to be performed by AbbVie clinical 
statisticians and programmers for the SONAR study protocol Amendment 6, under the 
guidance of the Steering Committee.  The SAP may not be updated for a future 
amendment unless such amendment is expected to have a tangible impact on the planned 
statistical analysis of the primary and secondary efficacy endpoints or adverse events of 
special interest.  The first subject was screened on 17 May 2013; the first subject was 
randomized on 28 August 2013. 
The purpose of this document is to pre-specify all statistical analyses and data summaries 
of the primary and secondary efficacy endpoints, and safety outcomes to be included in 
the clinical study report (CSR) of SONAR and/or other scientific reporting.  It further 
elaborates on the statistical methods outlined in the protocol and describes analysis 
conventions to guide the statistical programming work.
Unless noted otherwise, all analyses will be performed using SAS version 9.4 (SAS 
Institute Inc., Cary, NC  27513) under the UNIX operating system.
During the trial, the rate of occurrence of the primary endpoint was observed to be lower 
than expected and, as a result, a much longer duration of follow-up would be required to 
collect the originally planned 425 primary endpoints.  Because of this, a decision was 
made in December 2017 to stop the trial and conduct the final analyses on the number of 
events accrued at the time of study closure.  
The trial power calculations have been updated based on the observed event rate, the 
anticipated number of primary endpoints and new external information about the potential 
treatment benefit of drugs that reduce urinary albumin excretion (see Section 4.3 for more 
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Not all the planned analyses specified in the SAP will be included in the CSR.  The 
detailed scope of the CSR analyses will be specified in the SAP addendum.
4.0
Study Background
4.1
Study Objectives
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.
4.2
Study Design
The design of SONAR follows a predictive enrichment strategy (US FDA, 2012).  The 
study is conducted in the following three main periods or 'study epochs' for each subject, 
data from which will form the basis of the planned analyses:
●
Run-In Period (RP)
●
Enrichment Period (EP)
●
Double-Blind Period (DB-Period)
Here DB-Period is defined as the total duration covering the Double-Blind Treatment 
Period and the total Follow-up Period which may continue beyond Visit F1.  In addition 
there is a subject screening period and, if necessary for specific subjects, a pre-screening 
period.  The purpose of these two additional study epochs is to identify subjects who have 
the right diagnosis and other characteristics to potentially qualify for enrollment into the 
study.  These epochs are not discussed in this document since no analysis is planned for 
the data from the pre-screening and screening periods.


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The purpose of the RP is to titrate the dose of Renin-Angiotensin System (RAS) inhibitor 
that the subject is receiving to its maximum tolerated labeled daily dose (MTLDD), and to 
maintain the subject at the MTLDD prior to atrasentan exposure.  The RP varies in length 
for individual subject from 2 to 12 weeks. 
The purpose of the EP is to expose eligible subjects to atrasentan over a 6-week period to 
assess the subject's tolerability to atrasentan, to optimize the dose and type of diuretic if 
necessary and to assess the albuminuria reduction response of atrasentan over the 
6-weeks. 
All subjects who successfully complete the EP and achieve at least a 30% reduction in 
their urinary albumin to creatinine ratio (UACR) over the 6 weeks, hereafter referred to as 
responders, are allowed to enter the DB-Period and randomized to continue on atrasentan 
or placebo in a 1:1 fashion, further stratified by predefined albuminuria response 
sub-categories, pretreatment albuminuria level and geographic region.  A total of 
2500 responders are planned to be enrolled into the DB-Period (see sample-size section, 
Section 4.3, below for further details, actual number of randomized responders:  2648).  In 
addition, approximately 1000 non-responders (< 30% UACR reduction) will also enter the 
DB-Period and randomized in a similar fashion (actual number of randomized non-
responders:  1020).
A schematic of the study design is shown below in Figure 1.


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Figure 1.
Study Schematic
Randomization of subjects in the DB-Period is stratified by the following factors:  
●
Geographic region (North America, Latin America, Europe, Asia Pacific, and 
Japan),
●
UACR level at the beginning of the EP (≤ 1,000 mg/g [113 mg/mmol] or 
> 1,000 mg/g [113 mg/mmol]), and
●
UACR reduction during the EP:  < 0%; 0% to < 15% and 15% to < 30%; 30% 
to < 45%, 45% to < 60% and ≥ 60%.
The DB-Period is the most important epoch of the study, and data from this period will be 
the basis for assessing the efficacy and safety of atrasentan therapy compared to placebo.  
To address the separate considerations of the three main epochs (RP, EP, DB-Period) of 


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the study, this analysis plan will describe the planned analysis of these three epochs 
separately.
The number of subjects with eGFR 60 – 75 ml/min/1.73 m2 at the E1 visit who are 
randomized in the responder population will be capped at approximately 300 subjects.  
After the cap has been reached, subjects with an eGFR of ≥ 60 ml/min/1.73 m2 at 
Screening (S1) will not be allowed to enter into the study.  Such subjects will be 
considered screen failures.  However, subjects who have an eGFR 60 – 75 ml/min/1.73 m2
at the E1 visit after the cap has been reached but have not been randomized will be 
allowed to move into the Double-Blind Treatment Period.
4.3
Sample Size
In the original design of the study and as stated in the protocol, a total of 425 renal 
composite events among responders during the DB-Period of the study were needed to 
detect a 27% hazard reduction (HR of 0.73) with approximately 90% power at a two-sided 
alpha level of 0.05.  Based on the annual placebo renal event rates observed in the 
RENAAL (~13%) (Brenner et al 2001) and ALTITUDE (~3%) (Parving et al 2012) 
studies, the estimated annual placebo event rate in SONAR during initial planning was 
assumed to be 6%.  With the assumption of annual event rate of 6% in the placebo group, 
a 42-month accrual period, an approximate 6 years total study duration (from the 
first subject randomized), and an annualized lost to follow-up rate of 2%, a total of 
approximately 2500 responders (1250 per group) were planned to be randomized into the 
DB-Period to achieve the 425 required events.
However, during the course of the trial, the rate of the primary endpoint was observed to 
be lower than expected and, as a result, a much longer duration of follow-up would be 
required to collect the originally planned 425 primary endpoints.  The sponsor decided 
that this extended follow-up would exceed the originally planned study length beyond 
what was feasible.  A decision was made in December 2017 to stop the trial and conduct 
an orderly close-out, with final follow-up of the last patient concluding in the first half of 


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2018.  The final analyses will be conducted using the final number of events accrued at 
the time of trial closure.
In the meantime, additional internal analyses were performed (under blinded condition for 
SONAR) on actual data acquired in the trial to date and a critical was undertaken to 
account for other relevant developments in the field.  This led to the following revised 
conclusions regarding the anticipated treatment effect size and study power:
1.
A meta-regression7 of 21 adequate and well-controlled clinical trials concluded that 
for each 30% reduction in albuminuria, an approximately 25% reduction in the 
hazard of ESRD may be expected.  
2.
Based on data from the Phase 2 study (RADAR) using atrasentan, an 
approximately 50% average reduction in albuminuria was anticipated among 
responders prior to randomization in SONAR.  Review of the SONAR enrichment 
period data the responder population confirmed an approximately 50% reduction in 
albuminuria.  In conjunction with the analysis described in 1., this finding suggests 
that this degree of reduction in urinary albumin excretion should translate into a 
larger reduction in the risk of renal progression than the 27% risk reduction 
originally anticipated in the power calculations.
3.
In support of this possibility, external data from recent trials with sodium glucose 
co-transporter 2 inhibitors have shown that these drugs which lower albuminuria by 
30 to 40% along with reductions in blood pressure and glucose, lead to a 40% 
reduction in renal risk.
As mentioned above, the overall blinded event rate (i.e., in the placebo and atrasentan 
groups combined) is much lower than expected in the responder group.  While this could 
reflect a lower than anticipated event rate in the placebo group, it could also reflect a 
larger than predicted treatment effect size, consistent with the other data summarized 
above.  Therefore it is now expected that the treatment effect in the responder population 


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may be larger than 27% risk-reduction, and an effect size of between 35% to 50% risk-
reduction is more plausible.
The table below summarizes the updated power calculation with the number of events 
required to achieve 80% or 90% power based on the assumption of a larger treatment-
effect (27 – 45% relative risk-reduction).
Table 1.
Number of Events Required to Achieve 80% or 90% Power Based 
on Different Effect Size Assumptions (2-Sided Alpha = 0.05)
Effect Size
Number of Events Required for 
80% Power
Number of Events Required 
for 90% Power
HR = 0.73 (27% reduction)
317
425
HR = 0.65 (35% reduction)
170
227
HR = 0.60 (40% reduction)
121
162
HR = 0.55 (45% reduction)
88
118
It is expected that approximately 160 – 180 events will be observed in the responder 
population at the end of the study.  This will provide approximately 90% power if the true 
treatment effect has 40% risk reduction, or approximately 80% power for 35% risk
reduction.
In addition as noted earlier, 1,000 non-responders will also be randomized in a 1:1 ratio to 
atrasentan or placebo to estimate the effect of atrasentan in reducing long-term CKD 
progression in this population.  In the original study protocol and Amendments 1 and 2, 
randomization of non-responders was arbitrarily capped per geographic region based on 
pre-study projections of enrollment of responders for each region (stratification factor).  
This essentially meant that, for each region, all non-responders would be enrolled until the 
caps are filled and none after that.  Since such a process would have led to a temporal bias 
and longer exposure for non-responders, Amendment 4 introduced a "start-and-stop" 
procedure to be implemented via the interactive response technology (IRT) system – so 
that 50 non-responders would be enrolled for every 150 responders (Section 8.3 of Study 
Protocol Amendment 4).  Specific caps per geographic region were removed, except for 


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Japan.  Changes to the IRT system to this effect were implemented on 19 November 2014.  
Following observations made by the IDMC on 23 February 2015, the ratio was further 
changed to enroll 5 non-responders every 21 responders to offset the essentially 
unrestricted enrollment during the initial stages of the study and finish enrollment of both 
groups approximately simultaneously.  This change was implemented as of 15 June 2015.  
Since July 2016, the 21:5 R/NR ratio cap has been removed from IRT and the overall 
randomization cap for non-responders remained as 1000.
4.4
Planned Interim Analysis
The interim analysis as previously planned in the protocol and SAP version 2 has been 
removed since the number of events required to trigger the interim analysis will not be 
reached.
4.5
Type I Error Adjustment Procedures for Multiple Testing
Since statistical testing for comparison of efficacy between atrasentan and placebo will be 
solely based on data available from the DB-Period, the following type I error adjustment 
procedures only apply to analysis of data from this period. 
SONAR has a single primary efficacy endpoint and one primary treatment comparison 
between placebo and atrasentan among responders.  The final analysis will be tested at a 
two-sided alpha level of 0.05.  
Secondary efficacy endpoints will be tested at the final analysis only when the primary 
endpoint is statistically significant at the corresponding analysis.  To control the family-
wise type I error rate at two-sided 0.05 for all the tests, each secondary endpoint will be 
tested using the same alpha level as the alpha spent for the primary endpoint at the final 
analysis in a stage-wise hierarchical (step-down, by the same order of the secondary 
endpoints as specified in Section 6.7.2) fashion (Glimm et al 2010).  More specifically, 
the secondary endpoints will be tested with the following procedures: 


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a.
If the primary endpoint is significant at the alpha level that is specified for the final 
analysis based on an overall alpha level = 0.05 (two-sided), each secondary 
endpoint will be tested in a hierarchical fashion at the same alpha level that is used 
for the primary endpoint. 
b. If the primary endpoint is not significant, no formal test for the secondary 
endpoints will be performed.
Unless otherwise specified, multiplicity adjustments are not planned for additional 
(exploratory) efficacy endpoints, subgroup analyses, supportive analyses or sensitivity 
analyses.
5.0
Definitions, Derivations and Data-Handling 
Conventions
This section provides general considerations for data handling, data summaries and data 
analysis.  This also includes general definitions of certain kinds of endpoints.  More 
details about specific endpoints and additional analysis methods, as needed, will be 
specified within the description of analysis of data for each epoch.
5.1
Definition of Study Treatment Dates
5.1.1
Date of First Dose of Atrasentan in EP
The date of first dose of atrasentan in EP is defined as the first date when a nonzero dose 
of atrasentan was taken as per "Atrasentan Dosing (Enrichment Period)" electronic case 
report form (eCRF).  This date will also be referred as first date of atrasentan, or 
first date of study treatment.
5.1.2
Date of Last Dose of Atrasentan in EP
The date of last dose of atrasentan in EP is defined as the last date when a nonzero dose of 
atrasentan was taken as per "Atrasentan Dosing (Enrichment Period)" eCRF. 


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5.1.3
Date of First Dose of Study Treatment in DB-Period
The date of first dose of study treatment in DB-Period is defined as the first date when a 
nonzero dose of atrasentan or placebo was taken as per "Atrasentan Dosing (Double-Blind 
Treatment Period)" eCRF.
5.1.4
Date of Last Dose of Study Treatment in DB-Period
The date of last dose of study treatment in DB-PERIOD is defined as the last date when a 
nonzero dose of atrasentan or placebo was taken as per "Atrasentan Dosing (Double-Blind 
Treatment Period)" eCRF.
5.1.5
Date of Last Dose of Study Treatment
The date of last dose of study treatment is defined as the date of last dose of atrasentan in 
EP for subjects who did not receive the study treatment in DB-Period, or the date of last 
dose of study treatment in DB-Period for subjects who did receive the study treatment in 
DB-Period.  This date will also be referred as last date of study treatment.
5.2
Describing Study Time Points
For each subject, the study day of a specific study time point (date of interest on study) is 
defined as the number of days from the first date of atrasentan (defined in Section 5.1).  
For dates after the first date of atrasentan, study day is calculated as, 
Study day = Date of interest – first date of atrasentan + 1.
Dates prior to the first dose date are represented by a negative study day, computed as 
Study day = Date of interest – first date of atrasentan.
By these conventions, there is no Study Day 0.


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Similarly, days from randomization for a specific study time point (date of interest on 
study) is defined as the number of days from the date of randomization.  This is of course, 
only defined for subjects who enter the DB-Period.  It is calculated as, 
Days from randomization = Date of interest – date of randomization.
5.3
Baseline
5.3.1
Baseline for Summaries in DB-Period
For treatment comparisons and summaries for efficacy based on the DB-Period, baseline 
values refer to the last non-missing value observed prior to or at the time of randomization 
unless specified otherwise.  Some exceptions/notes are:  
●
For determination of doubling of serum creatinine, the reference value is the 
last non-missing value observed prior to or pre-dose on the date of first dose of 
atrasentan in EP
●
For secondary or additional efficacy endpoints of time to 50% (or 40%) eGFR 
reduction, unless otherwise specified, the reference value is the last non-
missing value observed prior to or pre-dose on the date of first dose of 
atrasentan in EP.
●
For quality of life data, baseline values refer to the last non-missing value 
observed prior to or pre-dose on the date of first dose of study treatment in 
DB-Period.  If the first dose date in DB-Period is not available, then 
randomization date will be used as the reference date.
For the safety summaries in the DB-Period, baseline values refer to the last non-missing 
value observed prior to or pre-dose on the first dose of study treatment in DB-Period.
5.3.2
Baseline for Summaries in EP/Entire Study Period
For purposes of summarizing safety and efficacy for the EP and the entire study treatment 
period (EP and DP combined), baseline values refer to the last non-missing value 
observed prior to or pre-dose on the first day of atrasentan in EP.


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5.4
Urine Albumin to Creatinine Ratio (UACR) and UACR 
Related Randomization Stratification
The UACR for each subject plays a fundamental role in SONAR and is calculated in all 
epoch's of the study.  For calculating UACR at the screening visit, the geometric mean of 
UACR from two consecutive first morning void (FMV) urine samples collected prior to 
that visit is used.  For each subsequent scheduled visit that collects FMV urine samples, 
the geometric mean from all samples available for that visit is used.
For the EP, initial UACR is computed as the geometric mean of UACR collected at Visits 
R6 and E1, and final UACR is computed as the geometric mean of the UACR values 
collected at Visits E4 and E5.
For the randomization stratification factor of UACR reduction in EP, the percent UACR 
reduction is calculated as:
(Initial UACR in EP – Final UACR in EP) / (Initial UACR in EP) * 100
The geometric mean value of UACR for the relevant visits and the value of UACR 
reduction in EP are calculated by Covance and included in the laboratory data.  The 
derived randomization stratifications (UACR reduction level in EP, UACR level at the 
beginning of EP) are transferred from Covance to the randomization IRT vendor. 
At the time when randomization was almost complete it was noticed that Covance's 
calculation of geometric mean of the UACR was not correct.  Instead of calculating 
geometric mean, the calculation was actually based on arithmetic mean.  This caused 
incorrect randomization stratifications for an estimated small proportion (~3%) of the 
study population.  Covance will provide correct calculations for the analysis, but since 
randomization is complete and to avoid jeopardizing the stratified randomization, the 
process of calculating the randomization strata remains the same for the rest of 
randomization.  Thus for the small set of the study population the UACR related 
stratifications remain incorrect in the randomization. 


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Both the randomized strata and the intended (actual) strata will be incorporated in the 
analyses (see Section 6.7.1).
5.5
Randomization Stratifications and Analysis Stratifications
Randomization of the study is stratified by the following stratification factors: 
●
Geographic region (North America, Latin America, Europe, Asia Pacific, and 
Japan),
●
UACR level at the beginning of the EP ≤ or > 1000 mg/g, and
●
UACR reduction during the EP:  < 0%; 0% to < 15% and 15% to < 30%, 30% 
to < 45%, 45% to < 60% and ≥ 60%.
For the efficacy analysis of the time-to-event endpoints (primary, secondary or additional 
endpoints) that will use stratified log-rank test (refer to Section 6.2.3 and Section 6.6), the 
strata are defined as below
●
(As randomized UACR strata):  UACR-related strata that are used in the 
randomization (i.e., strata derived based on arithmetic mean of UACR values, 
refer Section 5.4)
○
UACR level at the beginning of the EP ≤ or > 1000 mg/g, and
○
UACR reduction during the EP:  < 0%; 0% to < 15% and 15% to < 30%, 
30% to < 45%, 45% to < 60% and ≥ 60%.
●
(As intended UACR strata):  UACR related strata that are derived based on the 
geometric mean of UACR values, refer to Section 5.4)
○
UACR level at the beginning of the EP ≤ or > 1000 mg/g, and
○
UACR reduction during the EP:  < 0%; 0% to < 15% and 15% to < 30%, 
30% to < 45%, 45% to < 60% and ≥ 60%.
5.6
Last Contact Date
The last contact date will be derived for subjects not known to have died at the analysis 
cut-off using the latest complete date among the following:


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●
Date of randomization 
●
Last date of study treatment
●
All assessment dates (e.g., assessment date of vital signs, QoL questionnaires, 
central laboratory, ECG, and adjudicated primary/secondary events, ECG etc.)
●
Start or stop date of adverse events (AEs)
●
Medication dates including study medication, concomitant 
medications/procedures)
●
Death date
●
Date of visit
●
Date of discontinuation from 'Study Completion' or 'Study Drug Completion' 
eCRF.
Only dates associated with subject visits or actual examinations of the subject will be used 
in the derivation.  The assessment dates after the cutoff date will not be applied to derive 
the last contact date.  The last contact date will be used for censoring of subjects in the 
analysis of CV endpoints.
6.0
Analysis of Data from the DB-Period
6.1
Visit Windows
To perform visit-wise analyses of data, data collected throughout the study will be 
assigned to scheduled visits (per the protocol) based on time windows specified below. 


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Table 2.
Nominal Time and Visit Windows (as Days from First Dose of 
Study Treatment in DB-Period) for eGFR and Other 
Measurements* Performed at Each Scheduled Visit
Visit Name
Nominal Time
Window
T1
30
2 – 60
T3
90
61 – 135
T6
180
136 – 225
T9
270
226 – 315
T12
360
316 – 405
T15
450
406 – 495
…
…
…
T48
1440
1396 – 1485
…
…
…
T72
2160
2116 – 2205
*
Data collected at this visit schedule include vital signs, hematology, and limited chemistry.
Table 3.
Nominal Time and Visit Windows (as Days from First Dose of 
Study Treatment in DB-Period) for Laboratory Measurements 
Performed Annually, at T3 and then Annually, or at T1 and then 
Annually
Annual Assessments*
T3 and Annual 
Assessments**
T1 and Annual 
Assessments***
Visit Name
Nominal 
Time
Window
Nominal 
Time
Nominal 
Time
Nominal 
Time
Window
T1
30
2 – 195
T3
90
2 – 225
T12
360
2 – 540
360
226 – 540
360
196 – 540
T24
720
541 – 900
720
541 – 900
720
541 – 900
T36
1080
901 – 1260
1080
901 – 1260
1080
901 – 1260
T48
1440
1261 – 1620
1440
1261 – 1620
1440
1261 – 1620
…
T72
2160
1981 – 2340
2160
1981 – 2340
2160
1981 – 2340
*
Data collected at this visit schedule include ECG, HbA1c, and urinalysis.
**
Data collected at this visit schedule include serum and urine biomarkers.
*** Data collected at this visit schedule include complete chemistry, lipid profile, BNP, UACR.


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Table 4.
Interval and Nominal Day (as Days from First Dose of Study 
Treatment in DB-Period) for Quality of Life Questionnaires
Visit Name
Nominal Day
Time Window 
(Rx Randomization Day Range)
T3
90
2 – 135
T6
180
136 – 225
T9
270
226 – 315
T12
360
316 – 540
T24
720
541 – 900
T36
1080
901 – 1260
T48
1440
1261 – 1620
…
T72
2160
1981 – 2340
If more than one assessment is included in a time window, the assessment closest to the 
nominal day should be used.  If there were two observations equally distant from the 
nominal day the latest one will be used in the analyses.  If more than one assessment is 
collected on the same day, then the average of those assessments will be used in the 
analyses.
The study protocol (see Table 1 – Study Activities of the protocol) should be referred to in 
determining which scenario described above will apply for a specific measurement in this 
study.
For post-treatment assessments to be performed at the 45-Day Follow-up visit, the 
nominal time is Post-Treatment Day 45 (i.e., 45 days from the last date of study 
treatment) and the window is ≥ 14 – 90 days post last date of study treatment.  When there 
is more than one measurement collected for the 45-Day Follow-up visit window for 
assessments, the measurement closest to the nominal day will be used for analysis.


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6.2
General Statistical Methods
6.2.1
Methods of Categorical Endpoints
Categorical data (e.g., gender, race, age categories) will be summarized using frequencies 
and percentages by treatment group, where treatment group is defined as either atrasentan 
or placebo.  The number and percentage of subjects with missing information will also be 
summarized.  Each subject will be counted only once in any category, for all variables 
other than the subject's race.  Each subject has the option to identify him/herself as 
belonging to multiple races and hence the categories are not mutually exclusive.
Treatment comparisons will be performed using Fisher's exact test only when explicitly 
specified.  Hereafter, these summaries will be referred to as categorical summaries.
6.2.2
Methods of Continuous Endpoints
Continuous data (e.g., age, weight, height) will be summarized using sample size, mean, 
standard deviation, median, 1st quartile, 3rd quartile, minimum and maximum among non-
missing observations.  The number and percentage of subjects with missing information 
will also be summarized.  Only one raw or mean observation per subject will be used to 
compute these summaries.  Treatment comparisons will be performed using a two-sample 
t-test (with Satterthwaite's approximation) only when explicitly specified.  Hereafter, 
these summaries will be referred to as continuous summaries.
6.2.3
Methods of Time-to-Event Endpoints
All time to event (TTE) endpoints considered in SONAR are defined using a time variable 
and an event indicator.  The time variable represents the time from a pre-defined time 
origin to the onset of a predefined event of interest or the last time when adequate 
assessments have been made to rule out the onset of the event.  The latter case indicates 
that the endpoint has been right-censored.  The event indicator is set to 1 if the event has 
been observed during the course of the study and 0 if it is censored.  In general, when 
multiple assessments are needed to ascertain the occurrence of an event, the earliest date 
among all of these assessments is taken to be date of the event or censoring.  The time 


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variable will be computed in days and converted into months (1 month = 30.4375 days) 
for analysis of TTE endpoints.  When no post-randomization observations are available 
for a subject for any given endpoint, then the endpoint is taken to be censored on the date 
of randomization.
All TTE endpoints defined in this study are concerned with only the first incidence of an 
event of interest, and recurrence of the same event is not considered.  An event however 
may be defined in a composite fashion, i.e., as the occurrence of one among several 
different outcomes (hereafter referred to as component events).  The composite event is 
observed when at least one of the component events occurs, and the time to the earliest 
among the occurring component events is considered to be the TTE for the composite 
event.
In general, all TTE endpoints will be analyzed using the stratified log-rank test for 
treatment comparison.  Two-sided P-values will be rounded to 3 decimal points for 
display and comparison to appropriate thresholds for statistical tests (refer to Section 4.5).  
The stratification used in the analysis will be as follows (refer to Section 5.5 for "as 
randomized/actual UACR strata," Section 6.3 for "as randomized/actual" analysis sets):
●
"As randomized UACR strata" will be used for intent-to-treat (ITT) Responder 
Set ("as randomized"), ITT Non-responder set ("as randomized"), ITT Pooled 
Set, and per-protocol set (PPS) set
●
"As intended UACR strata" will be used for ITT Responder Set ("as 
intended"), and ITT Non-responder set ("as intended")
In addition, a Cox proportional-hazards regression model will be used to estimate the 
hazard ratio of atrasentan to placebo and its 95% confidence interval for all TTE 
endpoints.  In general, the treatment effect in this model will be adjusted for the following 
covariates:  log[UACR] values at the beginning of EP (logarithm of the geometric mean 
of UACR values at Visits R6 and E1) and at the end of EP (logarithm of the geometric 
mean of UACR values at Visits E4 and E5), eGFR, serum albumin and age (values at 
randomization), provided that adding them as a group to the Cox model as covariates will 


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improve the goodness of fit of the model as measured by the Bayesian Information 
Criterion (BIC) (Chris et al 2000).  SAS PROC PHREG with Breslow's method of 
handling ties will be used.  More endpoint-specific covariates are described in Section 6.7.
Median TTE (if estimable) and its 95% confidence interval, as well as Kaplan-Meier 
(KM) estimates of the incidence function (cumulative event rates over time) will be 
calculated.  KM estimates of event incidence rates at the certain follow-up time 
(e.g., 1 year, 2 year) and the time from randomization to the highest quartile or decile of 
cumulative incidence for each TTE (and each treatment group, where applicable) will be 
obtained. 
Frequency and percentage of subjects with events observed and of subjects who are 
censored will be summarized for each treatment group.  For composite endpoints events 
observed will be summarized according to type of first event.  In general, censored 
observations will be summarized according to the reasons for censoring:
●
Ongoing without an event (for subjects who are still in the study and haven't 
experienced an event)
●
Study discontinued without an event (for subjects who discontinued the study 
prior to experiencing an event)
Furthermore, for composite endpoints, time to each component event may also be 
analyzed individually as a separate endpoint following the methods described above.  
Note that the time to the first occurrence of a component event may in fact occur after the 
composite event (since other component events can occur earlier).  Unless otherwise 
stated, the occurrence of one component event may not be censored due to the occurrence 
of other component events prior to it.
6.2.4
Methods of Longitudinal Repeated Measurements
Longitudinal repeated measurements (e.g., physical and laboratory assessment) from the 
two treatment groups, as needed, will be compared using the mixed-effects maximum 
likelihood repeated measures (MMRM) analysis carried on by SAS PROC MIXED.  


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Repeated measurements from each subject will be identified by subject identifier.  The 
unstructured covariance matrix (TYPE = UN) will be used to estimate the within subject 
correlations.  In cases where this model does not converge, an autoregressive 
(1) (TYPE = AR(1)) structure will be used, which is more restrictive and assumes 
measurements from samples taken closer together in time are more highly correlated than 
those from samples taken farther apart.  The Satterthwaite method for computing the 
denominator degrees of freedom for the test of fixed effects will be used, and the Type III 
sum-of-squares for the Least Squares (LS) means will be used to estimate treatment group 
differences.  The model will include the fixed effects of treatment, time as defined by visit 
windows, treatment by time interaction, baseline measurement, and baseline measurement 
by time interaction.  The treatment difference at each post-baseline visit will be estimated 
from the model using a CONTRAST statement.  This approach will be referred to as 
MMRM.
6.3
Analysis Sets
6.3.1
Efficacy/Non-Safety Analysis Sets
The following datasets will be used for the analysis of all efficacy and other non-safety 
endpoints in the DB-Period.  For these analyses, subjects will be classified according to 
the treatment group to which they were randomized even if a subject does not receive the 
correct treatment, is not compliant to the protocol procedures, or does not follow the
protocol until completion.
Unless otherwise specified, analyses of all efficacy and non-safety variables will be 
performed using all three ITT analysis sets – ITT responder set, ITT non-responder set 
and ITT pooled set – and by the two randomized treatment arms (atrasentan or placebo).
Intent-to-Treat (ITT) Responder Set comprises all randomized responders and will 
serve as the primary dataset for the analysis of efficacy of the DB-Period, as well as the 
overall study.  Responders are defined as subjects who achieve at least 30% reduction in 
UACR in the EP, and will be derived via two sources: 


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●
(As randomized) based on randomization stratification:  subjects who have the 
randomization strata of UACR reduction in EP as 30% – < 45%, 45% –
< 60%, or ≥60% (Note:  a small proportion of subjects may have been 
assigned into the wrong randomization strata of UACR reduction in EP, refer 
to Section 5.4 for more details)
●
(As intended) based on actual correct UACR reduction values in EP 
(i.e., based on geometric mean of UACR rather than arithmetic mean of 
UACR, refer to Section 5.4) included in the laboratory data:  subjects with 
UACR reduction in EP ≥ 30%
The "as randomized" set will be the primary analysis set, and the 'as intended' set will be 
used for the sensitivity analyses.
Per-Protocol Set (PPS) is a subset of the ITT Responder Set (based on ITT Responder 
Set defined "as randomized" above) and comprises subjects with at least 70% compliance 
overall in taking medication throughout the course of their treatment without major 
protocol deviation.  Here are the criteria to be considered a major protocol deviation:
●
Inclusion 5
●
Inclusion 7
ITT Non-Responder Set comprises all randomized non-responders.  Non-responders are 
defined as subjects who achieve < 30% reduction in UACR in EP, and will be derived via 
two sources: 
●
(As randomized) based on randomization stratification:  subjects who have the 
randomization strata of UACR reduction in EP as < 0%, 0% – < 15%, 15% –
< 30%.  (Note:  a small proportion of subjects may have been assigned into the 
wrong randomization strata of UACR reduction in EP, refer to Section 5.4 for 
more details)
●
(As intended) based on actual correct UACR reduction values in EP 
(i.e., based on geometric mean of UACR rather than arithmetic mean of 


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UACR, refer to Section 5.4) included in the laboratory data:  subjects with 
UACR reduction in EP < 30%
The "as randomized" set will be the primary analysis set, and the 'as intended' set will be 
used for the sensitivity analyses.
ITT Pooled Set comprises all randomized subjects and will be used for analysis of 
efficacy and non-safety endpoints in the total population (both responders and non-
responders).
6.3.2
Safety Analysis Sets
The following datasets will be used for the analysis of safety endpoints.  For these 
analyses, subjects will be analyzed according to the treatment they actually receive, 
defined as the randomized treatment if it was received at least once, otherwise, the 
treatment received at the first dose in DB-Period during the DB-Period.
●
All Treated Responder Set includes all randomized subjects who achieve at 
least 30% reduction in UACR in the EP and receive at least one dose of study 
drug during DB-Period.
●
All Treated Non-Responder Set includes all randomized subjects who achieve 
less than 30% reduction in UACR in the EP and receive at least one dose of study 
drug during DB-Period.
●
All Treated Set includes all randomized subjects who receive at least one dose of 
study drug during DB-Period.
The All Treated Responder or Non-responder Sets will be based on as randomized 
responder or non-responder definitions described in the ITT analysis sets above.
6.4
Demographics and Baseline Characteristics
Continuous summaries (refer Section 6.2.2) will be provided for age (collected at 
screening), height, weight, body mass index (BMI), blood pressure, and laboratory 
assessments (e.g., serum creatinine, albumin, UACR, eGFR, BNP, cholesterol, 


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triglyceride, HbA1c) at baseline.  Summaries may be provided for both EP baseline and 
DB-Period baseline for applicable data.  In addition, the baseline UACR and final UACR 
in EP (refer Section 5.4) as well as UACR reduction in EP will be summarized.
Categorical summaries will be provided for gender (sex), age (≤ 50, 51 – 60, 61 – 70, 
> 70), age (≤ 65 or > 65), race, ethnicity, region UACR related stratification factors (as 
randomized and as intended), diabetic retinopathy (Yes), nicotine use (Yes, No), and 
alcohol use (Light, Moderate, Heavy).  Categorical summaries will also be provided for 
subject medical history using body systems and diagnosis/condition within body system 
(a lexicographic ordering will be used).
Summary of demographics and baseline characteristics will be provided based on ITT 
analysis sets (ITT Responder Set, ITT Non-responder Set, and ITT Pooled Set).  The 
baseline data between responders and non-responders will be visually compared and 
contrasted.  If imbalance is observed, appropriate statistical test will be performed as 
needed.
6.5
Subject Disposition
The number and percentage of subjects enrolled by geographic region, country and 
investigator/institution will be provided.  In addition, the following summaries will be 
provided. 
●
The number and percentage of subjects who are randomized, receive study 
treatment in the DB-Period, discontinue the study treatment in the DB-Period 
along with the reasons (by primary reason and by any reason), and discontinue 
the study along with the reasons (by primary reason and by any reason) in the 
DB-Period (ITT analysis sets).
6.6
Study Treatment and Concomitant Medications
6.6.1
Study Treatment and Compliance
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Treatment duration in DB-Period = Date of last dose in DB-Period – date of first dose in 
DB-Period + 1. 
The summary of duration of treatment will be provided using descriptive statistics.  In 
addition, the number and percentage of subjects exposed to study drug in DB-Period will 
be summarized for the following categories of exposure duration:  0 to 4 weeks, 
> 4 weeks to 8 weeks, > 8 weeks to 12 weeks, > 12 weeks to 6 months, > 6 months to 
1 year, > 1 to 2 years, > 2 to 3 years, > 3 to 4 years, …, etc.
Total subject-years of exposure will be calculated by summing the duration of treatment 
for all subjects and dividing this sum by 365.25.
The number and percentage of subjects with at least 70% compliance per visit and 
throughout the study (i.e., at all visits) in DB-Period will be summarized.  Percent 
compliance will be computed across all bottles for each visit as follows:
Percent (%) compliance for certain visit = # of pills taken / # of days for this visit * 100%
where
# of pills taken= # of pills dispensed for this visit- # of pills returned for this visit
# of days for this visit = next visit start date –  current visit start date 
Percent (%) compliance overall = total # of pills taken / treatment duration in DB-Period 
All the summaries will be based on All Treated Set, All Treated Responder Set, and All 
Treated Non-responder Set.
6.6.2
Prior and Concomitant Medications
A concomitant medication is defined as any medication other than study drug that is 
taken from the first dose of atrasentan to the final study visit.  Concomitant medications 
will be coded and reported by the generic name assigned following the World Health 
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Prior therapies or medications are those that are collected on the case report forms to 
have been taken within 4 weeks of the screening visit and ending prior to the first dose of 
atrasentan.
Concomitant medication will be summarized by ATC class level 2 and generic name 
assigned by the World Health Organization (WHO) dictionary (2016Q1 version or higher) 
and their usage in the DB-Period will be summarized by treatment group for the ITT 
analysis sets.  Subjects who report taking more than one medication will be counted only 
once in the total number of subjects who are taking any concomitant medication.  For 
each specific concomitant medication, the frequency and percentage of subjects who take 
at least one dose of that medication will be summarized.  Subjects who report a 
medication two or more times will be counted only once for that medication.  No 
statistical comparisons will be performed.  A similar summarization will be performed for 
prior therapies or medications.
In addition, the concomitant use of RAS inhibitors will be summarized for the ITT 
analysis sets as follows:
●
For each medication in the RAS inhibitor class, the average daily dose will be 
calculated across the DB-Period and summary statistics of the average daily 
dose will be provided by treatment group.
●
The number and percentage of subjects who change their dosage or initiate 
prescriptions of another RAS inhibitor during the DB-Period of the study will 
be tabulated by treatment group.
The concomitant use of diuretics will be summarized for the ITT analysis sets as follows:
●
For each medication in the diuretics class, the average daily dose will be 
calculated across the days that diuretics are taken during the DB-Period and 
summary statistics for the average daily dose will be provided by treatment
group.
●
The number of days that a subject is on any diuretics during the DB-Period and 
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will be computed. Summary statistics will be provided for the percentage of 
days on any diuretics by treatment group.
●
The number and percentage of subjects who take diuretics, change their 
dosage, or initiate prescriptions of another diuretic medication during the 
DB-Period will be tabulated by treatment group.
●
The number and percentage of subjects who take oral antidiabetic medications, 
including but not limited to SU's, TZD's, GLP-1's, DPP-4 inhibitors and 
SGLT2 inhibitors.  Subjects taking insulin will also be tabulated by treatment 
group
6.7
Efficacy Analyses
All primary and secondary endpoints in SONAR are TTE endpoints and are defined with 
the date of randomization as the time origin.
6.7.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the time to the first occurrence of a renal composite 
endpoint.  The event comprises either a) doubling of serum creatinine (confirmed by a 
30-day serum creatinine) or b) the onset of ESRD (eGFR < 15 ml/min/1.73 m2 confirmed 
by a 90 day eGFR, receiving chronic dialysis, renal transplantation or renal death).  Only 
events adjudicated by the Events Adjudication Committee (EAC) will be considered in 
defining this endpoint.
The primary endpoint will be analyzed and tested based on ITT Responder Set (as 
randomized) using the methods described in Section 6.2.3.  In addition, the endpoint will 
be summarized based on other ITT analysis sets, i.e., ITT Responder Set (as intended), 
ITT Non-responder sets (as randomized, as intended), and PPS as the 
supportive/sensitivity analyses. 
For the primary endpoint, the events will be censored if the subjects either are ongoing 
without an event or discontinued the study without experiencing an event.  The censor 


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time will be the minimum date of last laboratory sample collection with available serum 
creatinine or eGFR values and date of analysis cut off. 
Individual components of the primary endpoint will be analyzed separately using similar 
methods as the primary endpoint.  The following individual components will be 
summarized: 
●
Time to doubling of serum creatinine
●
Time to ESRD (eGFR < 15 ml/min/1.73 m2 confirmed by a 90 day eGFR, 
receiving chronic dialysis, renal transplantation or renal death)
For the analysis of time to doubling of serum creatinine, time to onset will be censored at 
the minimum date of last laboratory sample collection with available serum creatinine 
values, date of ESRD (as receiving chronic dialysis, renal transplantation or renal death 
will make assessment of serum creatinine impossible or unreliable), and date of analysis 
cutoff.  The censoring reasons will be as following:
●
Ongoing without an event (censored at minimum of last lab sample date and 
analysis cutoff date)
●
ESRD (censored at ESRD onset date)
●
Study discontinued without an event (censored at minimum of last lab sample 
date and analysis cutoff date)
For the analysis of time to ESRD, time to onset will be censored at minimum date of last 
laboratory sample collection with available serum creatinine or eGFR values and date of 
analysis cut off.  The censoring reasons for time to ESRD will be summarized in the same 
way as for the primary renal composite endpoint.
6.7.2
Secondary Efficacy Endpoints
Secondary efficacy endpoints will be analyzed and tested sequentially (refer to 
Section 4.5) using methods described in Section 6.2.3 with additional specifications 
included in this section.  The hierarchical order of the secondary endpoints is:


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●
Time to a 50% eGFR reduction.
●
Time to cardio-renal composite endpoint:  confirmed doubling of serum 
creatinine, ESRD, CV death, nonfatal myocardial infarction (MI), nonfatal 
stroke.
●
Time to first occurrence of a component of composite renal endpoint:  
confirmed doubling of serum creatinine or the onset of ESRD for all 
randomized subjects (pooled responders and non-responders).
●
Time to the CV composite endpoint:  CV death, nonfatal MI and nonfatal 
stroke.
In general, all the secondary endpoints will be tested based on ITT Responder Set (as 
randomized) except for the endpoint of time to a component of the renal composite 
endpoint in the combined responder and non-responder population.  Summary will be also 
provided for the other ITT analysis sets and PPS as the supportive/sensitivity analyses.
6.7.2.1
Time to 50% eGFR Reduction
The event of interest for this endpoint is a 50% reduction in a subject's eGFR value 
compared to baseline, confirmed by a repeated value at least 20 days apart.
The event time is the first time when a 50% reduction in eGFR is observed.  Subjects will 
be censored (with censoring reasons same as described in Section 6.2.3) at the minimum 
of date of last laboratory sample collection with available eGFR values and date of 
analysis cut off, if no event is observed prior to that date.
6.7.2.2
Time to Cardio-Renal Composite Endpoint
The composite event of interest in this case consists of doubling of serum creatinine, 
ESRD, cardiovascular (CV) death (including CV death and presumed CV death), nonfatal 
MI and nonfatal stroke.  Presumed sudden cardiac death will be included as a sub-
category of presumed CV death.  Only events adjudicated by the EAC will be used.


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In addition to the covariates described in Section 6.2.3 for the Cox proportional hazards 
model, the model for time to cardio-renal composite endpoint will also include the 
covariate for the history of CV disease (Y/N).
For event censoring, the censor time and reasons will be defined as the same as for the 
primary renal composite endpoint. 
6.7.2.3
Time to Renal Composite Endpoint in the Combined 
Responder and Non-Responder Population
This endpoint is the same as the primary efficacy endpoint, except that it will now be 
tested using the ITT pooled set.
Based on initial trends from the EP, the percent of responders is expected to be 
approximately 65%.  However, per the ratio implemented in the randomization the 
responder to non-responder ratio in the ITT pooled will be approximately 2.5:1, i.e., a 
response rate of approximately 71%.  To account for the non-proportional sampling of 
non-responders, a weighted approach will be used to combine the log-rank statistics 
(Z-scores) for the ITT responder and non-responder sets, provided a positive trend is 
observed (not expected to be statistically significant) in the ITT non-responder set.  The 
weighted Z-score will be computed as follows:
                                            1)
R
NR
R
NR
NR
R
R
NR
R
NR
R
NR
NR
R
R
NR
R
NR
R
NR
U
U
z
V
V
V
V
Z
Z
V
V
V
V
d
d
Z
Z
d
d
d
d
!
∀
!
∀
!
!
!
∀
!
!
!
where ZR, ZNR and dR, dNR represent the z-scores and number of events, respectively, for 
the responder and non-responder groups in a proportionate sample.  However, the z-scores 


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for responder and non-responder groups are not observed directly due to disproportionate 
sampling.  If the z-scores and number of events among responders and non-responders in 
the disproportionate sample (i.e., in the ITT pooled set) are denoted by Z'R, Z'NR, d'R and 
d'NR, respectively, and if p denotes the expected proportion of responders in a 
proportionate sample, and p' denotes the same proportion in the ITT pooled set, then it can 
be derived that
1
 
'
 ,        
'
 ,
'
1
'
1
'
'
    and   
'
'
 
'
'
'
1
'
R
R
NR
NR
NR
R
R
R
R
NR
NR
NR
R
NR
p
p
d
d
d
d
p
p
d
d
p
p
Z
Z
Z
Z
Z
Z
d
p
d
p
#
∃
∃
#
#
∃
∃
∃
∃
#
These estimates may now be plugged into equation (1) to compute the weighted adjusted 
z-score from the ITT pooled set and to use for inference.
The KM curves and incidence rate of events, and their 95% CIs, for the ITT pooled set 
will be obtained in a similarly weighted fashion, where the weights will be the proportions 
of responders and non-responders at the end of the EP. 
Additional characterization of the treatment effect in the combined population will be 
provided using a Cox regression analysis of the renal composite endpoint in the ITT 
pooled set adjusting for the UACR related stratification factor (as randomized). 
6.7.2.4
Time to CV Composite Endpoint
The composite event of interest in this case consists of CV death (CV death, presumed 
CV death), nonfatal MI and nonfatal stroke.  Presumed sudden cardiac death will be 
included as a sub-category of presumed CV death.  Only events adjudicated by the EAC 
will be used.  Time to onset will be censored at minimum date of last contact date and 
analysis cutoff date.  The censoring reasons will be as follows:
●
Ongoing without an event


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●
Study discontinued without an event
In addition to the covariates described in Section 6.2.3 for the Cox proportional hazards 
model, the model for time to CV composite endpoint will also include the covariate for 
the history of CV disease (Y/N).
6.7.3
Additional Supportive/Sensitivity Analyses
In order to further characterize the treatment effect, the following additional 
supportive/sensitivity analyses will be performed.
●
Time to the renal composite endpoint or all-cause mortality (ITT Responder 
Set)
●
If more than 10% of subjects discontinued the study without contributing a 
primary event or all-cause mortality, the analysis of the primary endpoint (time 
to renal composite endpoint) will be performed with an event imputed on the 
date of the next scheduled visit (3 months after the last assessment, had it been 
performed as scheduled) (ITT Responder Set).  In addition, the pattern of 
discontinuation will be assessed and additional sensitivity analyses of the 
primary endpoint may be performed to evaluate the impact of subject 
discontinuation.
●
If for more than 5% of the primary endpoint, there is more than a 6 month gap 
(i.e., approximately 2 missing assessments) between the date of an event and 
the last assessment prior to it showing no event, an analysis of the primary 
endpoint will be performed with an event imputed on the date of the earliest 
one of those missing assessments (3 months after the last assessment prior to 
the event, had it performed as scheduled).  (ITT Responder Set)
●
Analysis of the secondary CV composite endpoint with deaths of unknown 
cause included as CV deaths. 
●
If more than 5% of the secondary endpoint of CV composite event occurred on 
or after renal dialysis or renal transplant, an analysis of the secondary endpoint 
of time to CV composite will be performed with those events censored at the 
time of the renal dialysis/transplant.  (ITT Responder Set)


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●
If the treatment effect on the primary renal endpoint is correlated with the 
change in UACR level observed at the time of randomization (i.e., during the 
EP), the treatment effect on all primary and secondary endpoints as a function 
of albuminuria reduction over 6 weeks will be further explored.  Details of this 
exploratory analysis will be specified prior to the final analysis of study data.
6.7.4
Subgroup Analyses
The following subgroup analyses will be performed for the primary and all secondary 
efficacy endpoints in the ITT responder set (as randomized), ITT non-responder set (as 
randomized) and ITT pooled set:
●
Gender (Male or Female);
●
Age (≤ 65 or > 65);
●
Race (White or Non-white);
●
Geographical region (North America, Latin America, Europe,1 Asia Pacific, 
and Japan);
●
BMI (< 30, ≥ 30);
●
Blood pressure control (SBP ≥ 140 or DBP ≥ 90; SBP < 140 and DBP < 90);
●
UACR level (≤ 1000 mg/g or > 1000 mg/g) used for stratification;
●
UACR reduction during the EP (< 0%, 0% to < 15% and 15% to < 30%; 30% 
to < 45%, 45% to < 60% and ≥ 60%).  Here only the relevant categories are 
used depending on the analysis set;
●
eGFR (< 45 ml/min, ≥ 45 ml/min);
●
History of CV disease (yes or no);
●
History of diabetic retinopathy (yes or no);
●
HbA1C level at screening (≤ 7 or > 7);
●
Potassium at E1 (≤ 4.5 or > 4.5);
●
Use of the following medications prior to randomization
○
SGLT2 inhibitors (Yes/No);
                                               
1 This includes South Africa, Turkey, Russia and Israel.


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○
Statins (Yes/No);
○
Beta blockers (Yes/No);
○
Diuretics (Yes/No);
○
Non-steroidal anti-inflammatory drugs including aspirin (Yes/No)
The same methods as described for the primary and secondary endpoints will be used.  
The results will be pictorially displayed using a forest plot.
6.7.5
Additional Endpoints
Per discussion with the study team and the study Steering Committee, some of the 
additional protocol-specified endpoints have been clarified, and/or modified, or removed 
from the analyses.  Unless otherwise stated, the endpoints will be analyzed for the ITT 
responder (as randomized), ITT non-responder (as randomized) and ITT pooled sets.
Time to 40% eGFR reduction
The event of interest for this endpoint is a 40% reduction in a subject's eGFR value 
compared to baseline, confirmed by a repeated value at least 20 days apart.  The analysis 
method is the same as described for the secondary endpoint of time to 50% eGFR 
reduction.
Change in eGFR 
Absolute change in eGFR from baseline (randomization) across all post-baseline 
measurements will be analyzed by MMRM (refer Section 6.2.4).  The following models 
will be performed:
●
Only on-treatment measurements will be included
●
All post-baseline measurements will be included
In addition, the following change in eGFR will be analyzed by ANCOVA (treatment as 
the fixed effect, baseline measurement as the covariate):


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●
Change from baseline to final treatment visit.  Final treatment visit is defined 
as 
○
Premature Discontinuation (PD) visit if it is within 9 days of last dose of 
study treatment, or
○
Last visit prior to last dose of study treatment
●
Change from baseline to final study visit 
●
For subjects who discontinued study treatment: 
○
Change from baseline to final treatment visit
○
Change from baseline to F1 visit
○
Change from final treatment visit to F1
○
Change from final treatment visit to final study visit
Plots of eGFR over the course of the study will also be provided.
Change in UACR
Absolute change in Log-transformed UACR will be analyzed similarly as the analyses 
described for change in eGFR.  The output will be transformed to present the percentage 
of change in UACR from baseline. 
Time to congestive heart failure (hospitalized and hospitalized-equivalent)
Only adjudicated events will be used.  The same analysis methods described for the 
secondary endpoint of time to CV composite endpoint will be used.  This can be 
considered as a safety analysis as well. 
Time to major coronary disease events:  fatal coronary event, nonfatal MI, 
The event of interest in this case is a composite of major coronary events, namely any 
fatal coronary event (i.e., fatal MI, adjudicated) and nonfatal MI (adjudicated).  The same 
analysis methods described for the secondary endpoint of time to CV composite endpoint 
will be used.


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Time to total stroke:  fatal and non-fatal stroke
Only events adjudicated by the EAC will be considered.  The same analysis methods 
described for the secondary endpoint of time to CV composite endpoint will be used.
Cumulative number of acute kidney injury (AKI) events after randomization that 
are associated with temporary dialysis (< 30 days duration of dialysis)
The number and percentage of subjects who experience AKI events will be summarized
by treatment arm.  Also, for the set of subjects who experience AKI events, continuous 
summaries of the cumulative number of AKI events will be provided.  Here a temporary 
dialysis (< 30 days duration of dialysis) is defined to be associated with an AKI event, if 
they occur within 3 weeks of each other.
Change from baseline to each post-baseline assessment in EQ-5D-5L Index Score 
and AQOL-4D (Australia only) and KDQOL SF™ version 1.3 parameters
MMRM described in Section 6.2.4 will be used for analysis of this endpoint.  Treatment 
group differences in the change from baseline to each post-baseline visit in the EQ-5D 
index scores, each KDQOL subscales, and AQOL-4D scores, as available, will be 
compared.
Time to all-cause mortality
Methods described in Section 6.2.3 will be used for analysis of this endpoint.  For subjects 
who are alive at the end of the study, the endpoint will be censored on the last contact 
date, or analysis cutoff date, whichever is earlier.
Time to first laser photocoagulation for diabetic retinopathy
The event of interest for this endpoint is any laser photocoagulations performed no sooner 
than 10 weeks from the first dose of study treatment.  Methods described in Section 6.2.3
will be used.  For subjects who never had laser photocoagulation, the endpoint will be 
censored on the last contact date, or analysis cutoff date, whichever is earlier.


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Cumulative number of laser photocoagulations for diabetic retinopathy (where a
laser treatment is considered new if it occurs more than 10 weeks after the last 
treatment)
Continuous summaries and treatment comparisons using the 2-sample t-test (per 
Section 6.2.2) of the cumulative number of photocoagulations for diabetic retinopathy will 
be provided.
Changes in biomarkers (risk markers)
The following laboratory measurements, blood pressures and weight change are 
potentially related to cardio-renal functioning, and changes thereof can be considered as 
part of the efficacy of atrasentan therapy.  Analyses of these measurements are covered in 
Section 6.8 (Safety Analyses).
●
systolic and diastolic BP
●
lipid:  LDL, HDL, TG
●
potassium
●
body weight
●
hematocrit
●
serum albumin
●
Hemoglobin
●
HbA1c
●
BNP
6.8
Safety Analyses
All safety analyses will be performed on All Treated Responder Set, All Treated 
Non-responder Set, and All Treated Set.


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6.8.1
Summaries of AEs and SAEs
Per the study protocol, all AEs (non-serious and serious) reported from the time of study 
drug administration until 45 days following discontinuation of study drug administration 
have elapsed will be collected, whether solicited or spontaneously reported by the subject.  
In addition, SAEs will be collected from the time the subject signed the study-specific 
informed consent.  However, in practice, AEs occurring more than 45 days after drug 
discontinuation are also collected to facilitate adjudication of primary and secondary 
endpoints.  All AEs and SAEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA), Version 16.0 or higher.
Treatment emergent AE (TEAE) in DB-Period is defined as AEs that first occur or 
worsen on or after the first dose of study treatment in DB-Period and within 45 days after 
the last study treatment.
Events where the onset date is the same as the study drug start date are assumed to be 
treatment-emergent.  If an incomplete onset date was collected for an AE, the AE will be 
assumed to be treatment-emergent unless there is evidence that confirms that the AE was 
not treatment-emergent (e.g., the AE end date was prior to the date of the first dose of 
study drug). 
TEAEs and serious TEAEs will be summarized by treatment group and overall in 
descending order of overall frequency by MedDRA preferred term, as well as in a 
lexicographic order by system organ class (SOC) and MedDRA preferred term (PT).  The 
incidence rates of TEAEs for each treatment group will be summarized.  Additionally, the 
TEAEs will also be summarized by the relationship to study drug and their maximum 
severity.
Because the study is expected to have a long duration, the exposure-adjusted incidence 
rate for each treatment group will be also provided.  The exposure-adjusted incidence rate 
(EAIR) is defined as the number of subjects with a particular TEAE divided by the total 


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exposure-time among subjects in the respective treatment group at risk of an initial 
occurrence of the event.  More specifically, 
 =
	

 = / ∑,  
where  is the number of subjects with the event,  is a subject's exposure time to have an 
event, and T is the total exposure time.  If a subject has multiple events,  is the time of 
the first event.  For a subject with no event,  is censored at the time of last contact date, 
or last dose date + 45 days, whichever is earlier. 
AEs reported as reasons for discontinuation will be summarized by treatment group.  AEs 
leading to dosing delays and interruptions will also be summarized.  SAEs will be 
evaluated in a similar manner. 
Specifically, TEAEs will be summarized by treatment group as described below:
1.
An overview of the number and percentage of subjects with TEAEs
2.
A summary of the number and percentage of subjects with TEAEs in descending 
order of overall incidence frequency (with at least 1% incidence) by MedDRA PT
3.
A summary of the number and percentage of subjects with TEAEs by primary 
MedDRA SOC and PT
4.
A summary of the number and percentage of subjects with serious TEAEs in 
descending order of overall incidence frequency (with at least 1% incidence) by 
MedDRA PT
5.
A summary of the number and percentage of subjects with serious TEAEs by 
primary MedDRA SOC and PT
6.
A summary of the number and percentage of subjects with TEAEs leading to 
discontinuation of study drug by primary MedDRA SOC and PT
7.
A summary of the number and percentage of subjects with TEAEs leading to 
dosing delays and interruptions by primary MedDRA SOC and PT


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8.
A summary of the number and percentage of subjects with drug-related (i.e., with 
reasonable possibility to be related to study drug) TEAEs by primary MedDRA 
SOC and PT
9.
A summary of the number and percentage of subjects with TEAEs by primary 
MedDRA SOC, PT and maximum severity
6.8.2
Listing of TEAEs
The following additional listings will be prepared.
●
List of all TEAEs by treatment arm and subject ID
●
Listing of all serious TEAEs by treatment arm and subject ID
●
Listing of all TEAEs that led to discontinuation of study drug by treatment arm 
and subject ID
●
Listing of all fatal TEAEs 
●
Listing of all deaths by treatment arm and subject ID
●
List of subject numbers associated with each PT for all TEAEs by treatment 
arm
●
List of subject numbers associated with each PT for all TEAEs assessed by the 
investigator as having a reasonable possibility of being related to study drug by 
treatment arm
6.8.3
TEAEs of Special Interest
Specific TEAEs of special interest (TEAESI) will be identified by the following search 
criteria:


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Table 5.
TEAESI Search Criteria
Adverse Event of 
Special Interest
Search Criteria
Event Definition/Medical Concept
Hypervolemia/Fluid 
Retention
Hypervolemia/Fluid Retention 
CMQ and Cardiac failure SMQ 
(broad) 
Any AE report identified by search 
criterion
Cardiac Failure
Cardiac failure SMQ (narrow)
Any AE report identified by search 
criterion
Dilutional Anemia
Non-hemolytic and non-aplastic 
anemia CMQ
Any AE report identified by search 
criterion
Vasodilation
Hypotension CMQ 
Any AE report identified by search 
criterion
Cardiovascular Toxicity
Cardiac Arrhythmias SMQ 
(narrow), Cardiomyopathy SMQ 
(narrow), and Ischemic Heart 
Disease SMQ (narrow)
Any AE report identified by search 
criterion
Liver Toxicity
Liver function tests (LFTs) and 
hepatobiliary adverse events by 
using Drug Related Hepatic 
Disorders SMQ (narrow)
Any AE report identified by search 
criterion
A summary of TEAESI will be summarized by each treatment group and across all 
treatment groups ("overall") when appropriate.
6.8.4
Laboratory Results
Laboratory test variables as well as their statistical analysis methods including 
hematology, chemistry, urinalysis, and additional test variables are specified in Table 6.


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Table 6.
Laboratory Variables and Corresponding Statistical Analyses
Laboratory Test Variables
Statistical Method (Brief)
Hematology
Hematocrit
Hemoglobin
Red Blood Cells (RBC)
White Blood Cells (WBC)
Neutrophils
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet Count
(estimate not acceptable)
Change from baseline to final 
measures on treatment and to 
final measurement on study of 
these variables will be analyzed 
by ANOVA;
Change from baseline across all 
post-baseline measurements of 
those variables will be analyzed 
by MMRM.
Complete Chemistry
(obtained under fasting 
conditions)
Albumin
Alkaline Phosphatase*
ALT (SGPT)*
AST (SGOT)*
Bicarbonate
Blood Urea Nitrogen (BUN)
Calcium
Cystatin C
Potassium
Chloride
Cholesterol**
Creatinine
eGFR
Direct Bilirubin*
Glucose**
HDL**
Insulin (HOMA-IR)**
LDH
Lipoprotein A**
LDL**
Phosphorus
Sodium
Total Bilirubin*
Total Protein
Triglycerides**
Uric Acid
VLDL**
Change from baseline to final 
measures on treatment and to 
final measurement on study of 
these variables will be analyzed 
by ANOVA.
Change from baseline across all 
post-baseline measurements of 
those variables will be analyzed 
by MMRM for Albumin, 
Cholesterol, HDL, LDL.


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Table 6.
Laboratory Variables and Corresponding Statistical Analyses 
(Continued)
Laboratory Test Variables
Statistical Method (Brief)
Limited Chemistry
Sodium
Albumin
Potassium
Bicarbonate
Creatinine
Chloride
BUN
Change from baseline across all 
post-baseline measurements of 
those variables will be analyzed 
by MMRM.
Urine Tests
First Morning Void Urine:
UACR
24-hour Urine: 
Albumin
Creatinine
Sodium 
Potassium
Chloride
BUN
Change from baseline to final 
measures on treatment and to 
final measurement on study of 
these variables will be analyzed 
by ANOVA.
Change from baseline across all 
post-baseline measurements of 
those variables will be analyzed 
by MMRM for UACR
Additional Tests
BNP
HbA1C
Change from baseline to final 
measures on treatment and to 
final measurement on study of 
these variables will be analyzed 
by ANOVA;
Change from baseline across all 
post-baseline measurements will 
be analyzed by MMRM.
*
Liver enzymes.
**
Lipid and metabolic profile tests (obtained under fasting conditions).
For all the laboratory parameters, the mean change from baseline to each visit post-
baseline, from baseline to the minimum/maximum value post-baseline, from baseline to 
the final treatment visit, and from baseline to the final post-baseline values will be 
summarized by treatment group with the baseline mean, min/max/final mean, change 
from baseline mean, standard deviation, and median.  Treatment group differences for
mean changes from baseline will be analyzed using ANOVA and will be summarized 
using the mean, standard error, 95% confidence interval, and p-value for the 


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between-group difference.  Type III sum-of-squares for the least-squares means will be 
used.
Where it is applicable to categorize a laboratory assessment by Normal, High, or Low 
according to the normal range provided by the central laboratory, the status at the final 
value will be compared with that at the baseline and the "shifts" (i.e., changed from 
baseline category) will be summarized by treatment group.
For the laboratory measurements specified in Table 6 above, MMRM (Section 6.2.4) will 
be used to evaluate treatment group differences in change from baseline to each 
post-baseline visit.  In addition, within group LS mean change from baseline to each 
post-baseline visit as output from MMRM for hemoglobin will be presented graphically.
6.8.5
Vital Signs
The mean change from baseline to each visit in vital signs, including weight, will be 
summarized by treatment group.  Vital sign variables include systolic blood pressure 
(SBP), diastolic blood pressure (DBP), pulse rate, temperature, and weight.
Treatment differences between atrasentan and placebo in change from baseline to 
minimum, maximum and final observation will be analyzed using one-way ANOVA with 
treatment as the main effect.
An MMRM (Section 6.2.4) analysis of vital signs data (SBP, DBP, and weight) collected 
at each visit will be performed.  In addition, within group LS mean change from baseline 
to each post-baseline visit for SBP and DBP as output from MMRM will be presented 
graphically. 
Frequencies and percentages of subjects meeting Criteria for Potentially Clinically 
Significant (PCS) values as listed in Table 7 at any time after the first dose of study drug 
and no more than 3 days after the last dose of study drug will be summarized by treatment 
group.  Treatment group comparisons will be performed using Fisher's exact tests.  Only 


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p-values < 0.100 when rounded to three digits will be presented.  A separate listing will be 
provided that presents all of the subjects and values meeting PCS criteria.
Table 7.
Criteria for Potentially Clinically Significant (PCS) Vital Sign and 
Weight Values
Vital Signs
Low
High
Systolic Blood Pressure (mmHg)
≤ 100
≥ 180
Diastolic Blood Pressure (mmHg)
≤ 50
≥ 120
Pulse (bpm)
≤ 60
≥ 120
Temperature (C/F)
≤ 36.1/97
≥ 38.9/102
Weight (kg)
Decreased ≥ 7% from baseline
Increased ≥ 7% from baseline
6.8.6
ECG Parameters
The number and percentage of subjects with shifts from baseline to the final in the 
categories of normal, abnormal (clinically significant, not clinically significant, as 
indicated by the study site investigators) will be summarized.  Shifts from baseline at each 
visit where ECG data is collected will be summarized similarly.  In addition, a summary 
of the number and percent of subjects with each abnormality will be provided.
6.9
Pharmacokinetic (PK) Parameters
Plasma concentrations of atrasentan and its possible metabolites will be obtained at all 
treatment visits.  The pharmacokinetic profile of atrasentan will be summarized in a 
separate report produced by AbbVie's Clinical Pharmacology group.
7.0
Analysis of Data from the EP
7.1
Analysis Set
The All Atrasentan Set comprises all subjects who receive at least one dose of 
atrasentan, including both Enrichment and Double-Blind Treatment Periods.


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All Atrasentan Set is the primary dataset for analysis of data from the EP.  No treatment 
group comparisons will be performed for analysis of data from the EP.
7.2
Demographics and Baseline Characteristics
Similar summaries as described in Section 6.4 for DB-Period will be provided for EP 
demographics and baseline characteristics data.
7.3
Subject Disposition
The number and percentage of subjects enrolled by geographic region, country and 
investigator/institution will be provided.  In addition, the number of patients who 
discontinue the study treatment in EP along with the reasons (by primary reason and by 
any reason) will be provided. 
In addition, the following summary related to inclusion criteria 7 will be summarized for 
those subjects who discontinued the study treatment in EP:
●
Number of subjects who have a weight change ≥ 3 kg from the beginning of 
Enrichment (E1) to the end of the Enrichment Period AND absolute serum 
BNP ≥ 300 pg/mL (300 ng/L) at the last Enrichment visit;
●
Number of subjects who 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.
7.4
Study Treatment and Concomitant Medications
7.4.1
Drug Exposure and Compliance
Duration of treatment with study drug during EP will be computed as follows:
Treatment duration in EP = Date of last dose in EP– date of first dose in EP + 1.
The summary of duration of treatment will be provided using descriptive statistics.  In 
addition, the number and percentage of subjects exposed to study drug in EP will be 


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summarized for the following categories of exposure duration:  ≤ 1 weeks, > 1 to 2 weeks, 
> 2 to 3 weeks, > 3 to 4 months, > 4 to 5 weeks, ≥ 6 weeks,
Similarly as in the summary of DB-Period, the total patient-years of exposure, and 
number and percent of subjects with at least 70% compliance per visit and throughout the 
EP (i.e., at all visits in EP) will be summarized in a similar fashion.
7.4.2
Concomitant Medications
Concomitant medications taken during the EP will be summarized in a similar fashion as 
the summaries in DB-Period.
7.5
Efficacy
7.5.1
UACR
Continuous summaries will be provided for UACR, eGFR, serum creatinine at each visit 
in EP, the initial UACR (i.e., baseline UACR) and final UACR in EP.  In addition, the 
percentage reduction in UACR from the initial UACR to the final UACR in EP will be 
summarized using descriptive statistics. 
Categorical summaries (number and percentage of subjects) will be provided for the 
following categories:
●
UACR reduction in EP:  < 0%; 0% to < 15% and 15% to < 30%; 30% to 
< 45%, 45% to < 60% and ≥ 60%
7.5.2
Other Key Laboratory Data and Vital Sign
Continuous summaries will be provided for eGFR, serum creatinine and other key 
laboratory/vital sign data (listed below) at each visit in EP.  The absolute change from 
baseline at each visit, and absolute change from baseline to the last visit in EP will be 
summarized by descriptive statistics as well. 
●
Serum albumin 


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●
Hematocrit
●
Hemoglobin
●
BNP
●
Cholesterol (Total, LDL, HDL)
●
Triglycerides
●
HbA1c
●
Potassium
●
Blood glucose
●
Blood pressure (SBP, DBP)
●
Weight
7.6
Safety
For summaries of TEAE in EP, TEAE is defined as AEs that first occur or worsen on or 
after the first dose of atrasentan in EP and prior to DB-Period (if subjects entered 
DB-Period), or within 45 days after the last study treatment (if subjects did not enter 
DB-Period).
Safety data in EP will be summarized for TEAEs and serious TEAEs, TEAESI, laboratory 
results, vital signs, as well as ECG parameters, in a similar fashion as described in 
Section 6.8, except that there is no treatment group.  In addition, the cumulative incidence 
of TEAE and serious TEAE adjusting for the duration of exposure on atrasentan during 
the EP will be summarized.
In addition, time to congestive heart failure (hospitalized and hospitalized-equivalent) 
based on adjudicated events will be summarized. 
7.7
PK
Plasma concentrations of atrasentan and its possible metabolites will be obtained at all 
treatment visits.  The pharmacokinetic profile of atrasentan will be summarized in a 
separate report produced by AbbVie's Clinical Pharmacology group.


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8.0
Analysis of Data from the Screening Period and RP
All screen failures will be summarized by reason of screen failure, and also by screening 
period and RP. 
For each subject entering the run-in period, concomitant medications will be summarized 
as described in Section 6.6.2.  In addition, the concomitant use of RAS inhibitors and 
diuretics will be summarized in a similar fashion as described in Section 6.6.2.
For safety, SAEs experienced by a subject during the RP (anytime from Visits R1 to E1) 
will be summarized in descending order of overall frequency by MedDRA PT, as well as 
in a lexicographic order by SOC and PT.  The number and percentage of subjects with 
SAEs will be presented according to primary MedDRA SOC and PT and overall.
9.0
Analysis of Data for the 24-Hour Urine Sub Study
Twenty-four-hour urine will be collected prior to dosing in the EP (Visit E1), and during 
enrichment at Visit E5, 12 months after randomization (Visit T12), yearly thereafter and 
at the follow-up visit (Visit F1) for each subject that consents to participate in this 
optional sub-study up to a limit of 800 subjects.  Longitudinal analyses of change from 
baseline in mean 24-hour urine indices (albumin, creatinine, sodium, potassium and 
chloride) will be performed using MMRM and ANOVA similarly as the other laboratory 
parameters described in Section 6.8.4.
The mean of each 24-hour urine component for each subject is calculated as the average 
of all the valid measurements taken in that 24-hour period.


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10.0
References
1.
US Food and Drug Administration (USFDA).  Guidance on Enrichment Strategies 
for Clinical Trials to Support Approval of Human Drugs and Biological Products.  
2012.  US FDA:  Rockville, MD.
2.
Brenner BM, Cooper ME, De Zeeuw D, et al; RENAAL Study Investigators.  
Effects of losartan on renal and cardiovascular outcomes in patients with type 2 
diabetes and nephropathy.  N Engl J Med.  2001;345(12):861-9.
3.
Parving HH, Brenner BM, McMurray JJ, et al; ALTITUDE Investigators.  
Cardiorenal end points in a trial of aliskiren for type 2 diabetes.  N Engl J Med.  
2012;367(23):2204-13.
4.
Hwang IK, Shih WJ, De Cani JS.  Group sequential designs using a family of 
type I error probability spending functions.  Stat Med.  1990;9(12):1439-45.
5.
Westfall PH, Krishen A.  Optimally weighted, fixed sequence and gatekeeper 
multiple testing procedures.  J Stat Plan Inference.  2001;99:25-40.
6.
Volinsky CT, Raftery AE.  Bayesian information criterion for censored survival 
models.  Biometrics.  2000;56(1):256-62.
7.
Heerspink HJ, Kröpelin TF, Hoekman J, et al.  Drug-induced reduction in 
albuminuria is associated with subsequent renoprotection:  a meta-analysis.  J Am 
Soc Nephrol.  2015;26(8):2055-64.