Conditions: Nephropathy Diabetes
Keywords: Diabetic Nephropathies Kidney Diseases Urologic Diseases Diabetes Complications Diabetes Mellitus Endocrine System Diseases
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: no

Brief summary:
This study is being conducted to evaluate the effects of Atrasentan on sperm production and testicular function in male subjects with Type 1 or 2 Diabetes and Nephropathy.

This study included 2 periods: a Treatment Period (up to 26 weeks) followed by an Observational Period (up to an additional 52 weeks).

Detailed description:

Arms:
arm 1: Atrasentan 0.75 mg administered orally once daily (QD) for 26 weeks

Interventions: intervention 1: Atrasentan
Intervention descriptions: intervention 1: Atrasentan

Protocol document:
Prot_000.pdf: 
Atrasentan
M12-919 Protocol Amendment 4
EudraCT 2016-000722-19
1
1.0
Title Page
Clinical Study Protocol M12-919
A Multicenter, Single-Arm Study of the Effects of 
Atrasentan on Spermatogenesis and Testicular 
Function
Incorporating Administrative Change 1 and 
Amendments 1, 2, 3 and 4
AbbVie Investigational
  Product:
Atrasentan (ABT-627)
Date:
08 April 2016
Development Phase:
2
Study Design:
Phase 2, single-arm, multicenter study.
EudraCT Number:
2016-000722-19
Investigators:
Multicenter (Investigator information is on file at AbbVie).
Sponsor:
AbbVie*
Sponsor/Emergency 
  Contact:
*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.
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.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
NCT02118714


Atrasentan
M12-919 Protocol Amendment 4
EudraCT 2016-000722-19
2
1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions 
Protocol
Date 
Original
14 February 2014
Amendment 1
25 April 2014
Amendment 2
15 October 2014
Amendment 3
06 May 2015
The purpose of this amendment is to: 
●
Revise, clarify and describe in more detail the overall study design and plan.
Rationale:  With more safety data available on Atrasentan and considering the 
study objectives, it was determined the selection criteria can be amended to 
enhance participation in the trial while maintaining subject's safety.
The changes are as follows:
Study Design Changes:
●
Broaden the duration of the screening period to up to 4 weeks
Rationale:  Allow time for repeat testing and potential subject schedule
●
Redefine visit windows.
Rationale:  Enhance subject compliance to the visit schedule.
●
Remove collection of duplicate semen samples at T4/Week 6 visit 
Rationale:  Align semen sample collection with the spermatogenesis cycle to 
every 13 weeks.
●
Remove collection of duplicate semen samples at T6/EOT visit if subjects 
prematurely discontinues study drug as a result of entering the Observational 
Period
Rationale:  it is determined collection of semen samples from these subjects is 
not necessary as these subjects would be providing two sets of semen samples 
within 2 weeks


Atrasentan
M12-919 Protocol Amendment 4
EudraCT 2016-000722-19
3
●
Remove Week 6 visit from the Observational Period
Rationale:  Align semen sample collection to spermatogenesis cycle every 
13 weeks.
●
Replace the O5/EOS visit with a phone contact for subjects who return to 
within 15% of baseline or above
Rationale:  Safety can be adequately monitored via a telephone contact.
●
Update the following study procedures
○
Move Physical Examination to the T1/Day 1 visit from Screening.
○
Add measurement of hormone levels to the T1/Day 1 visit
○
Remove lipid profile assessments
○
Update the requirement for two FMV urine collections to one FMV urine 
collection during the Screening Period
○
Update the requirement for limited chemistry to completed chemistry at 
each visit during the Observational Period
○
Move Hb A1c and urinalysis to the O1/Week 13 visit from the 
EOS/Week 52 visit 
Rationale:  Ensure appropriate timing of baseline physical examination 
(immediately before first dose administration) and eliminate laboratory tests 
that have been deemed not necessary based on study objectives.
●
Study Design Clarifications:
○
Individual tests may be repeated within the screening window instead of a 
full rescreening of all procedures.
○
Provide clear direction on when a subject enters the Observational Period
○
Provide clear definition of when the follow-up contact is performed
Selection Criteria Changes:
●
Inclusion Criterion 3:  remove requirement for being on a stable dose of ACE 
or ARB prior to the Screening Period.
Rationale:  Align with scientific objectives of the study while maintaining the 
target study population


Atrasentan
M12-919 Protocol Amendment 4
EudraCT 2016-000722-19
4
●
Inclusion Criterion 4:  lowered eGFR criterion to ≥ 35 mL/min/1.73 m2
Rationale:  To expand the study population to subjects that are more closely 
aligned with the target atrasentan population.
●
Inclusion Criterion 6:  increase the upper limit of SBP to 180 mmHg
Rationale:  To accept expected fluctuations in blood pressure and align with 
blood pressure targets across atrasentan studies.
●
Inclusion Criterion 7:  increase the serum potassium upper limit to 6.0 mEq/L
Rationale:  To accept expected fluctuations in serum chemistry 
●
Inclusion Criterion 10:  streamline description for male contraception 
requirements
Rationale:  details are provided in Section 5.2.4 of the protocol
●
Inclusion Criterion 15:  redefine acceptable testosterone levels 
Rationale:  subjects with kidney disease have lower levels of testosterone that 
may not correlate with baseline sperm concentration 
●
Inclusion Criterion 16:  lessen required duration for being on alpha-blockers to 
at least 2 weeks prior to the initial screening visit.
Rationale:  Two weeks of alpha-blockers is considered stable treatment for the 
purposes of excluding effect on spermatogenesis
●
Inclusion Criterion 17:  lessen required duration for being on 5 alpha reductase 
inhibitors to at least 3 months prior to the initial screening visit.
Rationale:  Three months of 5 alpha reductase inhibitors is considered stable 
treatment for the purposes of excluding effect on spermatogenesis
●
Exclusion Criterion 5:  only exclude subjects currently symptomatic and on 
treatment.
Rationale:  History of resolved infection is not confounding to the inclusion of 
the target patient population
●
Exclusion Criterion 8:  lessen duration of drug, alcohol or substance abuse to 
3 months prior to the initial screening.
Rationale:  Three months of lack of abuse is a reasonable timeframe to 
determine subject's potential compliance with study requirements.


Atrasentan
M12-919 Protocol Amendment 4
EudraCT 2016-000722-19
5
●
Exclusion Criterion 11:  only exclude subjects who are currently receiving or 
have received hormone replacement therapy within the 6 months prior to the 
initial screening visit.
Rationale:  Past hormone therapy use is not confounding to the study 
objective; only subjects with current or recent use need to be excluded.
●
Exclusion Criterion 15:  remove moderate edema and pulmonary edema and to 
revise the required time frame to 4 weeks prior to the initial screening visit
Rationale:  A subject with a history of pulmonary edema, which would be 
identified as part of the diagnosis of heart failure, would not be allowed into 
the study per Exclusion Criterion 17.  Adequate medical management of 
peripheral or facial edema within the 4 weeks prior to screening is an 
acceptable length of time for assessment of subject eligibility at the initial 
screening visit. 
●
Selection Criteria Clarifications:
○
Inclusion Criterion 5:  the BNP upper limit should be less or equal than 
200 pg/L
○
Exclusion Criterion 2:  only exclude subjects unable to provide semen 
samples
○
Exclusion Criterion 3:  only exclude subjects with azoospermia.
○
Exclusion Criterion 16:  all subjects with pulmonary hypertension are 
excluded and not only those who are receiving oxygen
○
Exclusion Criterion 25:  allergies should be known to both thiazide and 
loop diuretics
○
Additional updates to the selection criteria have been made to provide 
definitive time frames for some criteria. 
●
Selection Criteria that have been deleted:
○
Inclusion Criterion 12:  HbA1c
Rationale:  It is acceptable to allow all patients with diabetes into this 
study, regardless of glucose control, as subjects will receive close medical 
oversight on the management of diabetes. 
○
Inclusion Criterion 13:  Follicle Stimulating Hormone (FSH)


Atrasentan
M12-919 Protocol Amendment 4
EudraCT 2016-000722-19
6
Rationale:  To align with the scientific objectives of the study without 
excluding potentially eligible subjects.
○
Inclusion Criterion 14:  Luteinizing Hormone (LH)
Rationale:  To align with the scientific objectives of the study without 
excluding potentially eligible subjects
○
Exclusion Criterion 4:  Prior history of radiation to the testes
Rationale:  To align with the scientific objectives of the study without 
excluding potentially eligible subjects.
○
Exclusion Criterion 6:  History of male infertility
Rationale:  The subject's fertility history is not confounding to the study 
objective, provided the subject meets the inclusion criteria for sperm 
concentration and semen sample provision.   
○
Exclusion Criterion 7:  Prior history of occupational exposure to 
environmental toxins
Rationale:  The subject's toxin exposure history is not confounding to the 
study objective, provided the subject meets the inclusion criteria for sperm 
concentration and semen sample provision. 
○
Exclusion Criterion 10:  BMI
Rationale:  To align with the target population of atrasentan across 
clinical trials
○
Exclusion Criterion 12:  Evidence or history of hypogonadism
Rationale:  Diagnosis of hypogonadism is not confounding to the study 
objective, provided the subject meets inclusion criteria for sperm 
concentration and semen sample provision.  
○
Exclusion Criterion 13:  Current use of hot tub/Jacuzzi/sauna or within the 
previous 12 weeks 
Rationale:  use of hot tub/Jacuzzi/sauna is not confounding to the study 
objective, provided the subject meets inclusion criteria for sperm 
concentration and semen sample provision.  


Atrasentan
M12-919 Protocol Amendment 4
EudraCT 2016-000722-19
7
Other Changes:
●
Remove "Single Country" from study title
Rationale:  Allow for conducting the study in multiple countries
●
Revise Section 5.2.3, Prior and Concomitant Therapy 
○
Addition of Prior Therapy Section (now known as Section 5.2.3.1)
Rationale:  Consistency with revised inclusion and exclusion criteria
○
Addition of Concomitant Therapy Section (now known as Section 5.2.3.2) 
Rationale:  administrative; separate from prior therapy and prohibited 
therapy text
○
Change to numbering for Prohibited Therapy Section (now known as 
Section 5.2.3.3) 
Rationale:  administrative
○
Addition of Guidance for Managing Edema or Weight Gain Section (now 
known as Section 5.2.3.4) 
Rationale:  administrative
●
Addition of Section 5.2.4, Contraception Recommendations
Rationale:  revision per AbbVie policies to provide clear and full description 
on contraception requirements
●
Revise criteria for discontinuation of subjects 
○
Subjects will not be discontinued at the T4/Week 6 visit if the subject has a 
weight gain of > 3 kg from baseline and a BNP > 300 ng/L.
○
Subjects will not be discontinued at the T4/Week 6 visit if subject has an 
increase in serum creatinine > 0.5 mg/dL (> 48 umol/L) and > 20% 
increase from baseline
Rationale:  To allow for continued participation of subjects in the study 
with continued medical oversight by the principal investigator.
Other Clarifications:
●
Section 5.3.1.1, Study Procedures, weight gain and assessment of edema will 
be assessed during the Treatment Period


Atrasentan
M12-919 Protocol Amendment 4
EudraCT 2016-000722-19
8
●
Section 5.3.2.6, Handling/Processing of Samples, provide direction for local 
lab handling and name/contact information for central morphology laboratory
●
Section 5.5.2.2, Storage and Disposition of Study Drugs, provide specific 
details for the storage of study drug on site and management of study drug 
exposed to temperatures outside the allowed range and allow for local 
destruction of study drug.
●
Section 5.5.6, Treatment Compliance, removed directions for calculation, as 
information is not being collected 
●
Complete Section 5.6, Discussion and Justification of Study Design
●
Section 6.4, Adverse Event Collection Period, clarify the collection period and 
reporting of adverse events
●
Section 6.6, Pregnancy, add statement regarding the requirement for obtaining 
written informed consent from the subject's pregnant partner prior to releasing 
medical information
●
Section 9.3, Subject Information and Consent:
○
Clarify that information regarding incentives and compensation can be 
found in the informed consent form 
○
Clarify the use of samples collected and stored in the event a subject 
withdraws consent.
●
First secondary variable/endpoint: clarify that subjects whose sperm 
concentration returns to levels above 15% of their baseline are included.  
Administrative changes are made throughout the protocol to remove duplicative 
information and reordering of information to provide clearer understanding of the 
procedures, to include, but not limited to the following:
●
Streamline the synopsis by including only the main selection criteria,
●
Reorganize text throughout,
●
Clarify required procedures,
●
Add standard international units to eligibility lab values,
●
Update Table 1, Study Activities, to align with study design changes,
●
Streamline footnotes,


Atrasentan
M12-919 Protocol Amendment 4
EudraCT 2016-000722-19
9
●
Update Abbreviations and Definition of Terms subsections (Section 1.3),
●
Update contact information (Section 7.0),
●
Update and re-organize Section 15.0, Reference List
●
Update signatory.
Rationale:  Administrative/clarification
An itemized list of changes made to this amendment can be found in Appendix C.


Atrasentan
M12-919 Protocol Amendment 4
EudraCT 2016-000722-19
10
1.2
Synopsis
AbbVie
Protocol Number:  M12-919
Name of Study Drug:  Atrasentan
Phase of Development:  2
Name of Active Ingredient:  Atrasentan
Date of Protocol Synopsis:  08 April 2016
Protocol Title:  A Multicenter, Single-Arm Study of the Effects of Atrasentan on Spermatogenesis and 
Testicular Function
Objectives:  The study objective is to evaluate the effect of Atrasentan on spermatogenesis and 
testicular function in men with diabetic nephropathy.
Investigators:  Multicenter
Study Sites:  Approximately 20 sites.
Study Population:  Subjects with type 1 or 2 diabetes and nephropathy (e-GFR ≥ 35 ml/min/1.73 m2
and a urinary albumin to creatinine ratio (UACR) ≥ 30 mg/g creatinine and < 5,000 mg/g 
(≥3.4 mg/mmol and < 565 mg/mmol)).
Number of Subjects to be Enrolled:  Approximately 20 subjects will be enrolled to complete 
15 evaluable subjects.
Methodology:
This is a prospective, open-label, multicenter, single-arm study.  Eligible subjects will be treated with 
Atrasentan 0.75 mg once daily (QD) for 26 weeks while remaining on their RAS inhibitors.  Semen 
samples will be collected at Screening (baseline), Week 13 and Week 26/End of Treatment (EOT) visits.  
Semen samples will be collected at two time-points over a 7-day period with each sample being 
separated by at least 2 days (48 hours) for each scheduled collection period.  The average of the 2 semen 
samples will be used as the value for that collection period.  If at any time during the Treatment Period 
or at the Week 26/EOT visit, the subjects' sperm concentration drops below 15 million/mL, the subject 
will be discontinued from study drug and enter into an Observational Period of up to an additional 
52 weeks.  If at the end of the 26-Week Treatment Period, there is a ≥ 50% reduction in sperm 
concentration from baseline, the subject will enter into the Observational Period.  During the 
Observational Period semen samples will be collected (at two time-points over a 7-day period with each 
sample being separated by at least 2 days [48 hours]) every 13 weeks until the subject's sperm 
concentration returns to within 15% of baseline or above, or until the end of the Observational Period.  
Subjects who do not meet the criteria to enter the Observational Period will have a follow-up contact 
from the Investigator (or designee) 30 to 35 days after the last dose of study drug.  Subjects, whose 
sperm concentration returns to within 15% of baseline or above during the Observational Period, will 
have a follow-up contact from the Investigator (or designee) within 14 days of the collection of the 
second semen sample.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
!
Male subject 30 to 75 years of age, inclusive at the time of Screening.
!
Subject has type 1 or 2 diabetes and is receiving treatment with at least one anti-hyperglycemic 
medication and ACEi or ARB (RAS inhibitor).


Atrasentan
M12-919 Protocol Amendment 4
EudraCT 2016-000722-19
11
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
!
Subject has an eGFR ≥ 35 mL/min/1.73 m2 with the CKD-EPI formula and UACR ≥ 30 to 
< 5,000 mg/g creatinine (≥ 3.4 mg/mmol and < 565 mg/mmol).
!
Subject is able to provide a semen specimen at the required intervals.
!
Subject has a baseline sperm concentration ≥ 30 million per mL at Screening.
Main Exclusion:
!
Subject has had treatment with hormone suppressive agents, including androgens, estrogens, 
anabolic steroids, glucocorticoids, ketoconazole, cyclosporine, or cancer chemotherapy within 
the 6 months prior to the initial screening visit or planned during the study.
!
Subject is currently receiving or has received hormone replacement therapy within the last 
6 months prior to the Screening Period.
!
Subject has a history of severe peripheral edema or facial edema unrelated to trauma or a 
history of myxedema in the prior 4 weeks to the initial screening visit.
!
Subject has a history of pulmonary hypertension, pulmonary fibrosis or any lung disease 
requiring either 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.
Investigational Product:
Atrasentan
Dose:
0.75 mg QD
Mode of Administration:
Oral
Reference Therapy:
Not applicable
Dose:
Not applicable
Mode of Administration:
Not applicable
Duration of Treatment:  26 weeks
Criteria for Evaluation:
Safety:
Primary Safety Endpoint:
The proportion of subjects who have a sperm concentration < 15 × 106/mL during the 26-week 
Treatment Period.


Atrasentan
M12-919 Protocol Amendment 4
EudraCT 2016-000722-19
12
Criteria for Evaluation (Continued):
Safety (Continued):
Secondary Safety Measures up to the End of Study:
!
The proportion of subjects who enter the Observational Period and do not return to within 15% 
of baseline or above during the 52-week Observational Period.  
!
Change from baseline to each visit in sperm concentration.
!
Change from baseline to each visit in each of the components of the semen analysis (sperm 
motility, sperm morphology, sperm count, semen volume).
!
Change from baseline to each visit in serum testosterone, estradiol, LH, FSH, and inhibin B.
Pharmacokinetic:
Atrasentan apparent oral clearance (CL/F) and volume of distribution (V/F) may be estimated using 
population pharmacokinetic techniques.
Statistical Methods:
Analysis Datasets:
The following datasets will be used for the analysis of safety endpoints:
!
The Evaluable Set will consist of all subjects who achieve the following:  1) ≥ 70% overall 
study drug compliance; and 2) having completed the 26-week treatment period and having all 
planned sperm samples collected; or having a sperm concentration value < 15 × 106/mL 
observed by the end of the Treatment Period.
!
The Safety Analysis Set includes all subjects who receive at least one dose of Atrasentan.
Sample Size Justification:
The proportion of subjects with sperm concentration < 15 × 106/mL in an unscreened population of 
healthy male subjects is reported to be approximately 10%.  With 15 evaluable subjects, this open label, 
single-arm study will have approximately 80% power to detect a 20% difference between the incidence 
rates in the Atrasentan group and the null hypothesis of 10% at 2-sided significance level of 0.2.
Safety:
Primary Safety Analysis:  
The primary safety analysis will be conducted on the evaluable set for the primary safety endpoint.  The 
simple percentage of subjects and a 2-sided 80% exact confidence interval will be calculated.  When 
15 evaluable subjects are available, if 4 or more subjects have a sperm concentration < 15 × 106/mL, the 
trial will claim that Atrasentan has a statistically significant effect on the primary endpoint.
Secondary Safety Analysis: 
The secondary analysis on the proportion of subjects who enter the Observational Period and do not 
return to within 15% of baseline or above during the 52-week Observational Period will be performed on 
the evaluable set.  The other secondary safety analyses will be conducted on the Safety population.  For 
proportion endpoints, the simple percentage of subjects and a 2-sided exact 80% confidence interval will 
be calculated.
The continuous variable of the secondary endpoints will be summarized by sample size (N), mean, 
standard deviation, minimum and maximum.


Atrasentan
M12-919 Protocol Amendment 4
EudraCT 2016-000722-19
13
Statistical Methods (Continued):
Adverse Events (AEs) Analysis:
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 
30 days after the last dose of the study drug will be summarized in descending order by MedDRA 
preferred term, as well as by system organ class (SOC) and MedDRA preferred term.  The incidence 
rates of treatment-emergent AEs 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.  Serious adverse events 
will be evaluated in a similar manner.
For the Observational Period, the protocol related AEs will be summarized similarly from 30 days after 
the last dose of study drug through study completion.  The number and percentage of subjects who report 
protocol-related adverse events in the Observational Period will also be summarized.
Laboratory Data:
For each laboratory test, the mean change from baseline to the minimum, maximum, and to each visit 
will be summarized.  Additionally for selected laboratory tests of particular 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.  The mean change from baseline to each visit in vital signs, including 
weight, will be summarized.
Interim Analysis:
An interim analysis will be performed after all the subjects have completed or prematurely discontinued 
from the 26-week Treatment Period.  The database will be formally locked and versioned.  The primary, 
applicable secondary and other safety analyses will be performed on this version of the clinical database.  
There is no need to adjust significance level since the only comparison is in the primary analysis which 
will be conducted using data from the 26-week Treatment Period.


Atrasentan
M12-919 Protocol Amendment 4
EudraCT 2016-000722-19
14
1.3
List of Abbreviations and Definition of Terms
Abbreviations
ACEi
Angiotensin-converting enzyme inhibitor
AE
Adverse event
ALT
Serum alanine aminotransaminase
AST
Serum aspartate aminotransaminase
ARB
Angiotensin II receptor blocker
BNP
Brain natriuretic peptide
BP
Blood pressure
BUN
Blood urea nitrogen 
CAD
Coronary artery disease
CFR
Code of federal regulations
CHF
Congestive heart failure
CKD
Chronic kidney disease
CL/F
Oral clearance
CRA
Clinical Research Associate
CRF
Case report form
CV
Cardiovascular
CVD
Cerebrovascular disease
DBP
Diastolic blood pressure
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EDTA
Edetic acid (ethylenediaminetetraacetic acid)
eGFR
Estimated glomerular filtration rate
EPI
Epidemiology collaboration
EOS
End of Study
EOT
End of Treatment
ESRD
End stage renal disease
ET
Endothelins
ETA
Endothelin-A
ETB
Endothelin-B
FMV
First morning void 


Atrasentan
M12-919 Protocol Amendment 4
EudraCT 2016-000722-19
15
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GI
Gastrointestinal
HBA1c
Glucosylated hemoglobin A1c
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
IND
Investigational new drug
IRB
Institutional Review Board
IUD
Intrauterine device
IWRS
Interactive voice response/Interactive Web Response System
IVRS
Interactive voice response system
LH
Luteinizing hormone
MI
Myocardial infarction
MTLDD
Maximum tolerated labeled daily dose
OLE
Open-label extension
PD
Premature discontinuation
PK
Pharmacokinetic
QD
Once daily
MedDRA
Medical dictionary for regulatory activities
RAS
Renin angiotensin system
RBC
Red blood cell
SAE
Serious adverse event
SBP
Systolic blood pressure
SGPT
Serum glutamic pyruvic transaminase
SGOT
Serum glutamic oxaloacetic transaminase
SI
Standard International Units
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reactions
T
Testosterone
TGF-β
Transforming growth factor beta
UACR
Urinary albumin to creatinine ratio
ULN
Upper limit of normal 
US
United States


Atrasentan
M12-919 Protocol Amendment 4
EudraCT 2016-000722-19
16
V/F
Volume of distribution
WBC
White blood cell
Definition of Terms
First morning void urine
The first void of the morning collected after 5:00 am or upon raising for 
the day.
Stable dose
Same type and regimen of medication.
Duplicate semen samples
Set of two semen samples collected over a 7-day period with each sample 
being separated by at least 2 days (48 hours) for a scheduled collection 
period.  Each collection period lasts up to 14 days and is associated with a 
specific study visit.


Atrasentan
M12-919 Protocol Amendment 4
EudraCT 2016-000722-19
17
2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................2
1.2
Synopsis ...................................................................................................10
1.3
List of Abbreviations and Definition of Terms........................................14
2.0
Table of Contents...................................................................17
3.0
Introduction ...........................................................................21
3.1
Differences Statement..............................................................................26
3.2
Benefits and Risks....................................................................................26
4.0
Study Objective......................................................................27
5.0
Investigational Plan...............................................................27
5.1
Overall Study Design and Plan:  Description ..........................................27
5.2
Selection of Study Population..................................................................32
5.2.1
Inclusion Criteria .....................................................................................32
5.2.2
Exclusion Criteria ....................................................................................34
5.2.3
Prior and Concomitant Therapy...............................................................36
5.2.3.1
Prior Therapy ...........................................................................................37
5.2.3.2
Concomitant Therapy...............................................................................37
5.2.3.3
Prohibited Therapy...................................................................................37
5.2.3.4
Guidance for Managing Edema or Weight Gain .....................................38
5.2.4
Contraception Recommendations ............................................................39
5.3
Efficacy and Safety Assessments/Variables ............................................40
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................40
5.3.1.1
Study Procedures .....................................................................................44
5.3.2
Drug Concentration Measurements .........................................................47
5.3.2.1
Collection of Samples for Pharmacokinetic Analysis .............................47
5.3.2.2
Handling/Processing of Samples .............................................................48
5.3.2.3
Disposition of PK Samples ......................................................................49
5.3.2.4
Measurement Methods.............................................................................49
5.3.2.5
Collection of Semen Samples for Analysis .............................................49
5.3.2.6
Handling/Processing of Samples .............................................................50
5.3.3
Efficacy Variables....................................................................................51


Atrasentan
M12-919 Protocol Amendment 4
EudraCT 2016-000722-19
18
5.3.4
Safety Variables.......................................................................................51
5.3.4.1
Primary Safety Variable...........................................................................51
5.3.4.2
Secondary Safety Variables .....................................................................51
5.3.5
Pharmacokinetic Variables ......................................................................51
5.4
Removal of Subjects from Therapy or Assessment.................................52
5.4.1
Discontinuation of Individual Subjects....................................................52
5.4.2
Discontinuation of Entire Study...............................................................53
5.5
Treatments................................................................................................53
5.5.1
Treatments Administered.........................................................................53
5.5.2
Identity of Investigational Products.........................................................54
5.5.2.1
Packaging and Labeling...........................................................................54
5.5.2.2
Storage and Disposition of Study Drugs..................................................54
5.5.3
Method of Assigning Subjects to Treatment Groups...............................55
5.5.4
Selection and Timing of Dose for Each Subject......................................55
5.5.5
Blinding....................................................................................................55
5.5.5.1
Blinding of Investigational Product.........................................................55
5.5.6
Treatment Compliance.............................................................................55
5.5.7
Drug Accountability.................................................................................56
5.6
Discussion and Justification of Study Design..........................................56
5.6.1
Discussion of Study Design and Choice of Control Groups....................56
5.6.2
Appropriateness of Measurements...........................................................57
5.6.3
Suitability of Subject Population .............................................................57
5.6.4
Selection of Doses in the Study ...............................................................57
6.0
Adverse Events.......................................................................58
6.1
Definitions................................................................................................58
6.1.1
Adverse Event..........................................................................................58
6.1.2
Serious Adverse Events ...........................................................................59
6.2
Adverse Event Severity............................................................................60
6.3
Relationship to Study Drug......................................................................61
6.4
Adverse Event Collection Period.............................................................61
6.5
Adverse Event Reporting.........................................................................62
6.6
Pregnancy.................................................................................................64
7.0
Protocol Deviations................................................................64


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8.0
Statistical Methods and Determination of Sample 
Size ..........................................................................................65
8.1
Statistical and Analytical Plans................................................................65
8.1.1
Analysis Datasets.....................................................................................66
8.1.2
Demographic, Other Baseline Characteristics, Subject 
Disposition, and Concomitant Medication ..............................................67
8.1.3
Safety Analyses........................................................................................67
8.1.3.1
Primary Safety Analyses..........................................................................67
8.1.3.2
Secondary Safety Endpoints ....................................................................68
8.1.3.3
Adverse Events (AEs) Analyses ..............................................................68
8.1.3.4
Clinical Laboratory Data..........................................................................70
8.1.3.5
Vital Signs Data .......................................................................................70
8.1.3.6
ECG Analyses..........................................................................................70
8.1.4
Interim Analysis.......................................................................................70
8.2
Determination of Sample Size .................................................................70
9.0
Ethics.......................................................................................71
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) .............................................................................................71
9.2
Ethical Conduct of the Study ...................................................................71
9.3
Subject Information and Consent.............................................................72
10.0
Source Documents and Case Report Form 
Completion .............................................................................72
10.1
Source Documents ...................................................................................72
10.2
Case Report Forms...................................................................................73
11.0
Data Quality Assurance ........................................................74
12.0
Use of Information.................................................................75
13.0
Completion of the Study .......................................................75
14.0
Investigator's Agreement......................................................77
15.0
Reference List ........................................................................78
List of Tables
Table 1.
Study Activities........................................................................................41


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Table 2.
Clinical Laboratory Tests.........................................................................47
Table 3.
Semen Analysis Tests ..............................................................................50
Table 4.
Identity of Investigational Products.........................................................54
List of Figures
Figure 1.
Study Schematic.......................................................................................29
Figure 2.
Adverse Event Collection ........................................................................62
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator............................................80
Appendix B.
List of Protocol Signatories......................................................................82
Appendix C.
Protocol Amendment:  List of Changes...................................................83


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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 1 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-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N,N-
di-(N-butyl)-aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid] 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 TGFb).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, (Study M96-499) 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.  The most commonly experienced 
treatment-emergent adverse events in the Atrasentan group were peripheral edema (64%), 
rhinitis (36%) and headache (18%), whereas in the placebo group the rates were:  
peripheral edema (0%), rhinitis (11%) and headache (56%).
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, 1-sided P = 0.023) and 
1.75 mg per day (35% reduction, 1-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 Study M12-812, 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 Study M12-830, 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).
The Phase 3 study (Study M11-352) is ongoing to characterize the safety and efficacy of 
Atrasentan in delaying renal disease progression in subjects with type 2 diabetes and 
nephropathy who have residual albuminuria while receiving MTLDD of RAS inhibitors.  
The primary endpoint will be the time to doubling of serum creatinine or end stage renal 
disease (ESRD).
Effect of Atrasentan on Testicular Function in Clinical Studies
Because of the nonclinical findings affecting male fertility, a Phase 2a clinical study, 
Study M10-815, included assessment of the neurohormonal axis in a subset of male 
subjects.  These assessments evaluated FSH and inhibin B, which were measured at 
baseline and after 8 weeks of treatment or early termination and again at 30 days after the 


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last dose of study drug.  In this study, the mean changes from baseline to final value in 
both FSH and inhibin B were not statistically significantly different between placebo and 
Atrasentan, nor were they clinically relevant.
At 30 days after the last dose of study drug, mean FSH decreased in all groups during the 
30-day follow-up period, with greater decreases in all Atrasentan groups compared with 
placebo; the difference between placebo (least squares mean change of –0.03 mIU/mL) 
and the 0.75 mg Atrasentan group (–1.75 mIU/mL) was statistically significant 
(P = 0.002).  Mean inhibin B increased in all groups during the 30-day follow-up period, 
with smaller increases in all Atrasentan groups compared with placebo and with no 
statistically significant differences between groups.
One Phase 2b study, Study M12-812, also included evaluation of testosterone for all male 
subjects.  Mean testosterone levels measured at baseline were at the higher range of 
normal in all treatment groups (470 ng/dL in the Atrasentan 0.75 mg group, 513 ng/dL in 
the placebo group, and 584 ng/dL in the Atrasentan 1.25 mg group).  By Week 8, there 
was a decline in testosterone observed in both Atrasentan groups; however, a statistically 
significant decrease in testosterone from baseline was observed only in the Atrasentan 
1.25 mg group (–83 ng/dL, P = 0.020 for difference from baseline) with a further 
statistically significant decline (–120 ng/dL from baseline) at post treatment follow-up 
visit compared with baseline visit observed only in this treatment group.  Despite the 
observed decreases in testosterone in the Atrasentan 1.25 mg group toward the end of 
treatment and at the follow-up visit, the mean values for all treatment groups remained 
within the normal range.
A Phase 2 study from the original prostate cancer clinical development program also 
included evaluation of testosterone levels.  Study M01-366 was a randomized, 
double-blind, placebo-controlled study of 10 mg Atrasentan QD versus placebo QD in 
men with hormone-naïve prostate cancer who had undergone a radical prostatectomy, but 
had not begun hormonal therapy and who were exhibiting signs of biochemical failure 
defined as both prostate-specific antigen (PSA) between 0.4 ng/mL and 5 ng/mL and a 
PSA doubling time ≤ 12 months.  Testosterone levels were measured at baseline, during 


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Weeks 2, 6, 12, and 24 and every 12 weeks thereafter.  One hundred ninety-nine men with 
a mean age of 65 years were enrolled.  Mean testosterone at baseline was within normal 
range and was similar between the treatment groups (approximately 354 ng/dL in the 
placebo group [n = 107] and approximately 372 ng/dL in the Atrasentan group [n = 111]).  
The mean exposure to Atrasentan was 442 days.  Among all randomized subjects, the 
testosterone levels with Atrasentan were significantly increased relative to placebo at 
Week 12, Week 24, and Final Visit.  A subset of subjects enrolled into an open-label 
extension (OLE) study, during which all subjects received Atrasentan 10 mg, including 
those originally randomized to receive placebo.  Among those who entered the open-label 
extension study, in an analysis that compared groups according to their original 
randomization, at the Final Visit, there was a mean decrease in testosterone levels for the 
72 subjects originally randomized to Atrasentan (–54 ng/dL) that was statistically 
significantly different (P = 0.008) from a small mean increase for the 75 subjects 
originally randomized to placebo (19.6 ng/dL).  Among all subjects who enrolled into the 
open-label extension, a mean increase in testosterone was observed at Week 12 (original 
treatment groups analyzed as one), but testosterone declined compared with baseline at 
Week 96 and Week 108 in the small number of subjects still on study.  Of note, subjects 
enrolled in the OLE were permitted to start hormone ablative treatment at the discretion of 
the PI.  Thus average testosterone values during the OLE will be confounded by these 
androgen reducing therapies.
In a clinical study evaluating the effect of bosentan, a dual endothelin antagonist, on 
spermatogenesis, 25% of male subjects experienced a ≥ 50% decrease in sperm count, yet 
their counts remained within the normal range after 6 months of treatment without 
changes in sperm morphology, motility, or serum hormone levels.  One subject developed 
marked oligospermia after 3 months of therapy, which was reversible following 
discontinuation of bosentan.  These results are noted in the US prescribing information for 
both bosentan and ambrisentan.19,20  In ARIES-E, a clinical study with chronic 
ambrisentan administration, there was no clear evidence of a detrimental effect on sperm 
count; however, a decrease in plasma inhibin B and an increase in plasma FSH not 
associated with a change in testosterone were observed.21


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The purpose of this study (Study M12-919) is to evaluate the effect of prolonged 
administration of Atrasentan on spermatogenesis and testicular function (Section 4.0).
3.1
Differences Statement
This study is designed to evaluate the effect of Atrasentan (0.75 mg once daily [QD]) on 
spermatogenesis and testicular function in men with diabetic nephropathy.  Prior studies 
in this population have not evaluated the effect of Atrasentan on spermatogenesis and 
testicular function.
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.  This study will provide 
safety information of Atrasentan administration for 26 weeks on spermatogenesis and 
testicular function.
Atrasentan has been evaluated in 5 studies in patients with diabetic nephropathy:  
one Phase 2a study in subjects with type 1 diabetic nephropathy who were not receiving 
renin-angiotensin-aldosterone system (RAS) inhibitors (Study M96-499), 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 patients 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.
The primary toxicities of Atrasentan in animals are effects on the reproductive system of 
both males and females and teratogenic effects on the fetus.  The effects of Atrasentan on 
male fertility are similar to those seen with other drugs in this class; seminiferous tubule 
atrophy as well as reduced male fertility are considered to be class effects of 
ET antagonists.  Effects observed in animals with Atrasentan are similar to those reported 


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for the –entans bosentan and ambrisentan.  As indicated above, testicular toxicity leading 
to impaired male fertility is a common feature of this class.
4.0
Study Objective
The study objective is to evaluate the effect of Atrasentan on spermatogenesis and 
testicular function in men with diabetic nephropathy.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 2, prospective, open-label, multicenter, single-arm study designed to 
evaluate the effect of Atrasentan on spermatogenesis and testicular function in men with 
diabetic nephropathy.  Approximately 20 subjects (to complete 15 evaluable subjects) 
with diabetic nephropathy who are taking RAS inhibitors are planned to be enrolled in the 
study at approximately 20 sites.  
Subjects who provide consent, will enter a Screening Period to assess eligibility.  Eligible 
subjects will enter a 26-week Treatment Period, followed by an Observational Period if 
the subject qualifies.  General laboratory tests (including hematology, chemistry and 
urinalysis) will be collected for safety monitoring and semen samples will be collected 
throughout the subject's study participation.
If at any time during the Treatment Period or at the T6/End of Treatment (EOT) 
(Week 26) visit the subject's sperm concentration drops below 15 million/mL, the subject 
will be discontinued from study drug and enter into an Observational Period of up to an 
additional 52 weeks.  If at the end of the 26-week Treatment Period there is a ≥ 50% 
reduction in sperm concentration from baseline the subject will also enter into the 
Observational Period.  
During the Observational Period, laboratory tests and semen samples will be collected. 


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Subjects who do not meet the criteria for entering the Observational Period will have a 
contact from the Investigator (or designee) 30 to 35 days after their last dose of study 
drug.
The study was designed to enroll approximately 20 subjects to obtain 15 evaluable 
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 enrolled, there is a possibility that additional subjects in screening will 
not be enrolled.
A schematic of the study design is shown below in Figure 1.


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Figure 1.
Study Schematic


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Screening Period
The Screening Period will last up to 4 weeks.  Procedures to be performed during the 
Screening Period are outlined in the Study Activities Table (Table 1).  Subjects will be 
given supplies and instructions for obtaining the first morning void urine sample and 
scheduled to return to the site within the 4-week Screening Period to return the 
first morning void urine sample.  In addition, the subject will provide the semen samples 
according to the specific windows for semen collection (Section 5.3.2.1) within the 
4-week Screening Period.  Tests for eligibility may be repeated within the subject's 
4-week Screening Period.  Subjects who fail to meet eligibility criteria will be allowed to 
re-screen at the investigator's discretion.
Treatment Period
Eligible subjects will return for the T1 visit (Day 1) no more than 4 weeks from the initial 
screening visit.  The procedures to be performed at the T1 visit are outlined in the Study 
Activities Table (Table 1), including initial administration of open-label study drug 
(Atrasentan).
The Treatment Period consists of five additional site visits over a 26 week period.
●
The T2 (Week 2) visit will take place 2 weeks (± 7 days) after the T1 visit.
●
The T3 (Week 4) visit will take place 2 weeks (± 7 days) after the T2 visit.
●
The T4 (Week 6) visit will take place 2 weeks (± 7 days) after the T3 visit.  
●
The T5 (Week 13) visit will take place 7 weeks (± 7 days) after the T4 visit.  
At this visit, subjects will be provided with supplies and instructions for the 
collection of the duplicate semen samples and will be scheduled for the 
collection of the semen samples according to the specific windows for semen 
collection (Section 5.3.2.1).  Supplies and instructions for obtaining the 
first morning void urine sample within 1 day of the T6 visit will also be given 
to the subjects.  The site will also call into IVRS/IWRS at this visit and 
dispense study drug to the subject.


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If the average of the two semen samples is < 15 million/mL, the subject will 
discontinue from study drug and return to the End of Treatment Visit (EOT) 
5 days (± 3 days) of the last dose of study drug.  For this subject, semen 
samples will not be collected at the EOT visit.
The T6/EOT (Week 26) visit will take place 13 weeks (± 7 days) after the 
T5 visit.  Subjects will be provided with supplies and instructions for the 
collection of the duplicate semen samples, and will be scheduled for the 
collection of the semen samples according to the specific windows for semen 
collection (Section 5.3.2.1).  If the average of the two semen samples is 
< 15 million/mL or there is a ≥ 50% reduction in sperm concentration from 
Screening at T6/EOT (Week 26) visit, the subject will enter the Observational 
Period.
The procedures to be performed at each visit are outlined in the Study Activities Table 
(Table 1).
Follow-Up Contact
Only those subjects who do not meet criteria to enter the Observational Period will be 
contacted by the Investigator (or designee) approximately 30 to 35 days after their last 
dose of study drug to solicit changes to concomitant medications and AEs and SAEs.  
This follow-up contact will be the final contact for these subjects.
Observational Period
Only those subjects with a sperm concentration below 15 million/mL at any time during 
the Treatment Period or with a ≥ 50% reduction from Screening (baseline) at the end of 
the 26-week Treatment Period will enter the Observational Period. 
The Observational Period will consist of up to 4 study visits and last up to 52 weeks. 
●
The O1 (Week 13) visit will take place 13 weeks (± 7 days) after the subject's 
EOT visit.


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●
The O2 (Week 26) visit will take place 13 weeks (± 7 days) after the O1 visit 
with the remaining visits (O3 [Week 39] and O4 /End of Study [EOS; 
Week 52]) following every 13 weeks (± 7 days) thereafter.
The procedures to be performed at these visits are outlined in the Study Activities Table 
(Table 1). 
During the Observational Period duplicate semen samples will be collected until the 
subject's sperm concentration returns to within 15% of baseline or above, or until the end 
of the Observational Period.  At each visit, subjects will be provided with supplies and 
instructions for the collection of the semen samples, and will be scheduled for the 
collection of the semen samples according to the specific windows for semen collection 
(Section 5.3.2.1).  If at any time during the Observational Period the sperm concentration 
returns to within 15% of baseline or above, subjects will have completed their 
participation in the Observational Period.  The visit at which their sperm concentration 
returned to within 15% of baseline or above will be considered their End of Study visit.  
These subjects will also be contacted by the Principal Investigator (or designee) within 
14 days of the collection of the second semen sample.  This contact will be the final 
contact for these subjects.
All other subjects will continue study visits until the End of Study visit.
5.2
Selection of Study Population
Subjects will be males who meet all of the inclusion criteria and none of the exclusion 
criteria.
5.2.1
Inclusion Criteria
1.
Male subject 30 to 75 years of age, inclusive at the time of Screening.
2.
Subject has voluntarily signed and dated an Informed Consent Form, approved by 
an Institutional Review Board (IRB)/Independent Ethics (IEC), after the nature of 
the study has been explained and the subject has had the opportunity to ask 


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questions.  The informed consent must be signed before any study-specific 
procedures are performed.
3.
Subject has type 1or 2 diabetes and is receiving treatment with at least 
one anti-hyperglycemic medication and ACEi or ARB (RAS inhibitor).
4.
Subject has an eGFR ≥ 35 mL/min/1.73 m2 with the CKD-EPI formula and UACR 
≥ 30 to < 5,000 mg/g creatinine (≥ 3.4 mg/mmol and < 565 mg/mmol).
5.
Subject has a serum BNP ≤ 200 pg/L (200 ng/mL).
6.
Subject has systolic blood pressure ≥ 110 and ≤ 180 mmHg at Screening.
7.
Subject has a serum potassium ≥3.5 (3.5 mmol/L) and ≤ 6.0 mEq/L (6.0 mmol/L).
8.
Subject is able to provide a semen specimen at the required intervals.
9.
Subject has a baseline sperm concentration ≥ 30 million per mL at Screening.
10.
If the subject is sexually active with female partner(s) of childbearing potential, he 
must agree, from initial study drug administration through 90 days after the last 
dose of study, to practice the protocol specified contraception (Section 5.2.4).
11.
Subject must agree not to donate sperm from initial study drug administration 
through 90 days after the last dose of study drug.
12.
(intentionally left blank; criterion deleted)
13.
(intentionally left blank; criterion deleted)
14.
(intentionally left blank; criterion deleted)
15.
Subject has a total Testosterone > 150 ng/dL (5.20 nmol/L).
16.
Subjects currently using alpha blockers must be on a stable dose for at least 
2 weeks prior to the initial screening visit and expected to remain on a stable dose 
during the study.
17.
Subject currently using 5 alpha reductase inhibitors must be on a stable dose for at 
least 3 months prior to the initial screening visit and expected to remain on a stable 
dose during the study.  


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Rationale for the Inclusion Criteria
(1, 3 – 7)  To select the appropriate subject population with diabetes-related kidney 
disease.
(2)  In accordance with harmonized GCP.
(8, 9, 15 – 17) To select a patient population with an acceptable sperm concentration for 
the evaluation.
(10, 11)  The impact of Atrasentan on pregnancies is unknown.
5.2.2
Exclusion Criteria
1.
Prior history of prostate cancer with or without treatment.
2.
Untreated retrograde ejaculation or anejaculation; history of prostatectomy with 
aspermia.  Subjects with treated retrograde ejaculation will be allowed with 
approval of the Study Designated Physician.
3.
Prior history of vasectomy unless subject has undergone reversed vasectomy.
4.
(intentionally left blank; criterion deleted)
5.
Currently symptomatic and receiving treatment for sexually transmitted disease 
(STD), prostatitis, orchitis or epididymitis.
6.
(intentionally left blank; criterion deleted)
7.
(intentionally left blank; criterion deleted)
8.
Drug, alcohol or substance abuse within the 3 months prior to the initial screening 
visit.
9.
Subject has had treatment with hormone suppressive agents, including androgens, 
estrogens, anabolic steroids, glucocorticoids, ketoconazole, cyclosporine, or cancer 
chemotherapy within the 6 months prior to the initial screening visit or planned 
during the study.


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10.
(intentionally left blank; criterion deleted)
11.
Subject is currently receiving or has received hormone replacement therapy within 
the 6 months prior to the initial screening visit.
12.
(intentionally left blank; criterion deleted)
13.
(intentionally left blank; criterion deleted)
14.
Renal transplant.
15.
Subject has a history of severe peripheral edema or facial edema unrelated to 
trauma or a history of myxedema in the prior 4 weeks prior to the initial screening 
visit.
16.
Subject has a history of pulmonary hypertension, pulmonary fibrosis or any lung 
diseases requiring oxygen therapy (e.g., chronic obstructive pulmonary disease, 
emphysema).
17.
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.
18.
Subject has elevated liver enzymes (serum alanine aminotransaminase [ALT] 
and/or serum aspartate aminotransaminase [AST]) > 3 × the upper limit of normal 
(ULN) during the Screening Period.
19.
Subject has a hemoglobin < 9 g/dL during the Screening Period.
20.
Subject has a history of an allergic reaction or significant sensitivity to Atrasentan 
(or its excipients) or similar compounds.
21.
Subject has significant comorbidities (e.g., advanced malignancy, advanced liver 
disease) with a life expectancy of less than 1 year.


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22.
Subject has clinically significant cerebrovascular disease (CVD) or coronary artery 
disease (CAD) within 3 months prior to the initial screening visit, defined as one of 
the following:
●
Hospitalization for Myocardial Infarction or unstable angina; or
●
New onset angina with positive functional study or coronary angiogram 
revealing stenosis; or
●
Coronary revascularization procedure; or
●
Transient ischemic attack (TIA) or stroke.
23.
Subject has received any investigational drug within 3 months prior to the initial 
screening visit.
24.
Subject is currently receiving rosiglitazone, moxonidine, aldosterone blockers, 
aliskiren or a combination of ACEi and ARB.
25.
Subjects with known allergy to both thiazide and loop diuretics.
26.
The subject is considered by the Investigator unsuitable to participate in the trial for 
any other reason, for instance due to a significant serious underlying condition.
Rationale for the Exclusion Criteria
(1 – 3, 5, 8, 26)  To exclude an inappropriate subject population.
(9, 11)  To avoid bias for the evaluation of safety by concomitant use of other 
medications.
(14 – 25)  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 Screening, 
or receives during the study, must be recorded along with the reason for use, date(s) of 


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administration including start and end dates, and dosage information including dose, route 
and frequency. 
The AbbVie study designated physician (listed in Section 6.5) should be contacted if there 
are any questions regarding concomitant or prior therapy(ies).
5.2.3.1
Prior Therapy
Subjects currently using alpha blockers should have been on a stable dose for at least 
2 weeks prior to the initial screening visit and must be on a stable dose during the study.
Subjects currently using 5-alpha reductase inhibitors should have been on a stable dose for 
at least 3 months prior to the initial screening visit and must be on a stable dose during the 
study. 
5.2.3.2
Concomitant Therapy
If medically necessary, changes to or interruption of ACEi or ARB doses during the 
Treatment or Observational Periods of the study will be allowed.  Plasma levels of 
Atrasentan may be affected by concomitant use of CYP3A or OATP inhibitors 
(e.g., protease inhibitors, clarithromycin, ketoconazole, gemfibrozil, ciclosporin).  Potent 
P-gp inhibitors may potentially increase the plasma exposure of Atrasentan.  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 patients taking any of these 
medications during the trial.
5.2.3.3
Prohibited Therapy
Subjects should not enter into the study if they are currently receiving or have received 
testosterone or hormone replacement therapy within 6 months of the initial screening visit.  
In addition, subjects should not receive hormone replacement therapy while enrolled in 
the study.


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Treatment with hormone suppressive agents, including androgens, estrogens, anabolic 
steroids, glucocorticoids, ketoconazole, cyclosporine, or cancer chemotherapy during the 
study is prohibited.
Combinations of ACEi/ARB medications and/or concomitant use of aldosterone blockers 
or aliskiren are not allowed.
Use of hot tub/Jacuzzi/sauna are prohibited during the study.
5.2.3.4
Guidance for Managing Edema or Weight Gain
Weight will be measured at each visit during the Treatment Period of 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.  If 
there is an increase of ≥ 2 kg during the Treatment Period, it is recommended to 
implement the following activities:
●
Rule out measurement errors or obvious reasons for the increase (i.e., diet 
transgression, different clothing than previously).
Evaluate for the presence of edema.  This may be indicative of fluid retention as the cause 
for weight gain.
Ascertain whether the subject has exceeded the recommended daily dietary salt intake 
(≤5 grams of sodium chloride).
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.
If the 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):


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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
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.
If weight continues to increase (i.e., > 3 kg in 6 weeks or the previous visit during the 
Treatment Period) despite the modification in the doses of diuretics, contact the study 
designated physician.
Discontinuation of an existing diuretic may be allowed under the following conditions or 
at the discretion of the investigator:
●
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.
The AbbVie study designated physician should be contacted if there are any questions.
5.2.4
Contraception Recommendations
If the male subject has a female partner who is postmenopausal or permanently sterile 
(bilateral oophorectomy, bilateral salpingectomy or hysterectomy), no contraception is 
required.


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If the subject is sexually active with female partner(s) of childbearing potential, he must 
agree from initial study drug administration through 90 days after the last dose of study 
drug to practice contraception with:
●
Condom use and female partner(s) using at least one of the following 
contraceptive measures
○
Intrauterine device (IUD);
○
hormonal contraceptives (oral, vaginal, parenteral or transdermal);
○
Barrier method (contraceptive sponge, diaphragm, or vaginal ring with 
spermicidal jellies or creams).
●
True abstinence:  refraining from sexual intercourse when this is line with the 
preferred and usual lifestyle of the subject.  (Note:  Periodic abstinence 
[e.g., calendar, ovulation, symptothermal, post-ovulation methods] and 
withdrawal are not acceptable).
Additionally, subject agrees not to donate sperm from initial study drug administration 
through 90 days after the last dose of study drug.
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
Activity
Screening 
Period 
(Up to 
4 Weeks)a
Treatment Periodb
Observational Periodb,c
FU 
Contactd
T1e
(Day 1)
T2 
(Week 2)
T3 
(Week 4)
T4 
(Week 6)
T5 
(Week 13)
T6/EOT 
(Week 26)f
O1 
(Week 13)
O2, O3 
(Weeks 
26, 39)
O4/End 
of Study 
(Week 52)
Informed Consentg
X
Medical History
X
Xh
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Complete Physical Exam
X
X
Vital Signsi
X
X
X
X
X
X
X
X
X
X
Semen Sample Collectionj
X
X
X
X
X
X
Assess Peripheral Edema
X
X
X
X
X
X
X
12-Lead ECG
X
X
Hematology
X
X
X
X
X
X
X
X
X
Limited Chemistry
X
X
Complete Chemistry
X
X
X
X
X
X
X
BNP
X
X
X
HbA1c
X
X
X
Urinalysis
X
X
X
FMV Urine Collection for 
UACRk
X
X
Serum total T, estradiol, LH, 
FSH, inhibin Bl
X
X
X
X
X
X
X
X
X
IVRS Call
X
X
X
X


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Table 1.
Study Activities (Continued)
Activity
Screening 
Period 
(Up to 
4 Weeks)a
Treatment Periodb
Observational Periodb,c
FU 
Contactd
T1e
(Day 1)
T2 
(Week 2)
T3 
(Week 4)
T4 
(Week 6)
T5 
(Week 13)
T6/EOT 
(Week 26)f
O1 
(Week 13)
O2, O3 
(Weeks 
26, 39)
O4/End 
of Study 
(Week 52)
Monitor AEs and SAEsm
X
X
X
X
X
X
X
X
X
X
X
PK Analysisn
X
X
X
Dispense Study Drug
X
X
Drug Accountability/Compliance 
Assessment
X
X
X
X
X
a.
Screening procedures and laboratory tests may be repeated during the Screening Period, per the Investigator's discretion.  Semen samples may be repeated per Section 5.3.2.5.
b.
All Treatment and Observational Period visits must be completed within ± 7 days of the expected visit date.
c.
If at any time during the Observational Period, the sperm concentration returns to within 15% of baseline or above, subjects will have completed their participation in the 
Observational Period.  The visit at which their sperm concentration returned to within 15% of baseline or above will be considered their End of Study visit.
d.
Subjects not entering the Observational Period should be contacted by the Principal Investigator (or designee) 30 – 35 days after the last dose of study drug.  Subjects who 
have returned to within 15% of their baseline sperm concentration or above during the Observational Period should be contacted by the Principal Investigator (or designee) 
within 14 days of the collection of the second semen sample.
e.
The T1/Day 1 visit should be completed within 4 weeks from the initial screening visit.
f.
Subjects completing the End of Treatment Visit because their sperm concentration has dropped below 15 million/mL during the Treatment Period will not provide duplicate 
semen samples at the T6/EOT visit.
g.
Informed consent can be collected up to 30 days prior to conduct of initial study procedures.
h.
Updates only.
i.
Vital signs include BP, weight, temperature and pulse rate will be collected at every visit.  Height will be collected at initial Screening visit only.  Weight gain will be assessed 
at each visit during the Treatment Period.  
j.
Subjects will be scheduled for the collection of the duplicate semen samples according to the specific windows for semen collection noted in Section 5.3.2.5. 


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Table 1.
Study Activities (Continued)
k.
For Screening, subjects will be given supplies and instructions for the FMV urine collection, which should be collected and returned to the study site within the 4-week 
Screening Period.  For the T6/EOT visit, the first morning void (FMV) urine collection will be collected within 1 day before the visit.
l.
Total testosterone sample should be collected at approximately the same time of day at each visit.
m.
Protocol-related non-serious and serious adverse events (SAEs) will be collected from the time the subject signs the study-specific informed consent.  All adverse events 
(serious and nonserious) will be captured from the time of study drug administration through 30 days after the last dose of study drug.  Forsubjects entering the Observational 
Period, protocol-related non-serious and serious adverse events will be collected beginning 30 days after the last dose of study drug through the post-therapy Observational 
Period.
n.
Blood samples only to be collected for atrasentan PK analysis and possible metabolites of atrasentan at the following visits:  T3/Week 4 (immediately before dose and 
15 minutes, 30 minutes, 1 hour post dose), T4/Week 6 (immediately before dosing) and T5/Week 13 (immediately before dosing).


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5.3.1.1
Study Procedures
Informed Consent
A signed informed consent will be obtained from the patient before any study procedures 
are undertaken at the initial screening visit.  Informed consent can be collected up to 
30 days prior to Screening.  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 patient during the initial Screening visit 
and updated during the Screening Period and at the T1/Day 1 visit, as necessary.  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
For the purposes of the study, it is the clinical discretion of the investigator to define what 
constitutes alcohol abuse.
Physical Examination
A complete physical examination will be performed at the T1/Day 1 visit (baseline) and 
the T6/EOT visit.
Any clinically significant changes will be documented as adverse events.


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Vital Signs
Vital sign determination of sitting BP, weight, temperature and pulse rate will be obtained 
at all on-site visits.  Vital signs performed at the T1/Day 1 Visit will serve as the baseline.  
Weight gain will be assessed at every visit during the Treatment Period.  Careful 
consideration should be used to ensure that the appropriate cuff size is used for all sitting 
BP determinations.  Resting BP will be measured two times in the non-dominant arm 
using the appropriate cuff size at least 2 minutes apart.  All BP readings should be 
collected by trained and qualified personnel with standard equipment.  BP should be 
measured consistently by the same method for all visits.  Height will be collected at the 
initial Screening visit only.
Assessment of Edema
Assessment of edema will be performed at Screening and at every Treatment Visit.  The 
assessment of edema should be performed by the same 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;
●
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.


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12-Lead Electrocardiogram (ECG)
A 12-lead resting ECG will be obtained at the T1/Day 1 visit prior to initial dose of study 
drug and at the T6/EOT visit.  The ECG measurements at the T1/Day 1 visit will serve as 
the baseline measurements for clinical assessment.
First Morning Void (FMV) Urine Sample Collection
One first morning void urine collection will be obtained during the Screening Period, and 
prior to the T6/EOT visit.  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.  The UACR values will be reported 
to the Investigator by the central laboratory on the laboratory reports.
If a subject did not collect the required FMV sample(s), re-dispense supplies and 
instructions for collection of the FMV sample.  Once the FMV sample is collected by the 
subject, he/she will return to the site to return the sample for the respective visit.
Laboratory Tests
A central laboratory will be utilized for the clinical laboratory tests.  Samples will be 
obtained for the laboratory tests listed in Table 2 at the visits specified in Table 1.  Blood 
draws should be performed after vital sign determinations have been completed for each 
visit.
The Investigator will review all laboratory test results in a timely manner.  All laboratory 
test results that are considered clinically significant by the Investigator will be followed to 
a satisfactory resolution. 
Instructions regarding the collection, processing, and shipping of these samples will be 
provided by the central laboratory chosen for this study.


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Table 2.
Clinical Laboratory Tests
Hematology
Clinical 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
Potassium
Chloride
Cholesterol
Creatinine
Direct Bilirubin
Glucose
LDH
Phosphorus
Sodium
Total bilirubin
Total protein
Triglycerides
Uric acid
Blood
Glucose
Ketones
pH
Protein
Specific gravity
Urine Tests
First morning void urine:
UACR
Limited Chemistry
Sodium
Albumin
Potassium
Bicarbonate
Creatinine
Chloride
BUN
Additional Tests
BNP
Pharmacokinetic measurement
HbA1c
Serum total T*
Estradiol
LH
FSH
Inhibin B
*
The testosterone sample should be collected at approximately the same time of the day at each visit.
The CKD-EPI formula will be used to calculate eGFR at the Screening visit to determine 
eligibility for the study.  The central laboratory will also calculate the eGFR on the 
laboratory profile report at each visit during the Treatment and Observational Periods.
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 the T3 (Week 4) visit at immediately prior to dose and 15 minutes, 


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30 minutes and 1 hour post dose and at the T4 (Week 6) visit immediately before dosing 
and the T5 (Week 13) immediately before dosing.
A total of 6 blood samples per subject are planned to be collected for pharmacokinetic 
(PK) analysis.  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, and will be 
placed in an ice bath.  The date and time of collection of 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 the shipment of samples to 
AbbVie:
AbbVie Sample Receiving
c/o Delivery Services
1150 S. Northpoint Blvd.
Waukegan, IL  60085
Phone:
Fax:
Email:
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.


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5.3.2.3
Disposition of PK 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 
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.
5.3.2.5
Collection of Semen Samples for Analysis
Semen samples will be obtained for the tests listed in Table 3 during the scheduled 
collection period for the visits specified in Table 1.  Semen samples should be collected at 
2 time-points over a 7-day period with each sample being separated by at least 2 days.  If 
for any reason one of the duplicate samples is inadequate or not obtained, then a 
replacement sample will be collected to ensure that two samples are available for each 
scheduled collection period.  If clinically relevant confounding symptoms, illness or 
conditions are suspected, replacement sample/samples may be obtained at the 
investigator's discretion.  All semen samples for a scheduled collection period must be 
collected within 14 days of the collection of the first semen sample.  Subjects must abstain 
from ejaculation for at least 2 days but not more than 7 days prior to semen sample 
collection.  The average of the 2 semen samples will be used as the value for that 
collection period.  If the semen sample is collected at the scheduled study visit, the sample 
should be obtained after all study procedures have been completed.  
The semen sample will be sent for processing as soon as possible after collection.  Semen 
motility analysis should be started with 1 hour of sample collection.  The full ejaculate 
must be captured at each semen collection.  Subjects should be evaluated, per the site's 
standard procedure, for retrograde ejaculation if the full ejaculate is < 1.0 mL.  The Study 


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Designated Physician should be consulted if retrograde ejaculation is identified or 
diagnosed at any time during the study.  If the full ejaculate is not captured in the 
collection container, then a replacement specimen should be collected.
Table 3.
Semen Analysis Tests
Semen Volume
Sperm Concentration
Sperm Motility
Sperm Morphology
5.3.2.6
Handling/Processing of Samples
Detailed instructions regarding collection and preparation of the semen samples will be 
provided by the local laboratory processing the semen specimen.  The specimen container 
should be kept at ambient temperature, between 30° and 37°C, to avoid temperature 
changes that may affect the spermatozoa.  
The local laboratory processing the semen specimens will analyze the samples for 
volume, concentration and motility following their standard operating procedures, and 
will prepare 4 slides for morphology analysis to be conducted by the central morphology 
laboratory (Tulane Andrology Laboratory).  Written instructions on preparation and fixing 
of sperm morphology slides and shipment to the central morphology laboratory will be 
provided to the site semen analysis laboratory.  Slides must be labeled, per the instructions 
provided by the morphology laboratory, with the subject's initials, subject number, study 
visit, sample identifier, and the date and time of collection.
Morphology slides will be sent for morphology analysis to:
Tulane Andrology Laboratory
1430 Tulane Ave., SL-42; 
 
New Orleans, LA  70112-2699
United States


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5.3.3
Efficacy Variables
This is a safety study and no efficacy data will be collected.
5.3.4
Safety Variables
5.3.4.1
Primary Safety Variable
The primary safety variable is the proportion of subjects who have a sperm concentration 
< 15 × 106/mL during the 26-week Treatment Period.
5.3.4.2
Secondary Safety Variables
●
The proportion of subjects who enter the Observational Period and do not 
return to within 15% of baseline or above during the 52-week Observational 
Period.   
●
Change from baseline to each visit in sperm concentration.
●
Change from baseline to each visit in each of the components of the semen 
analysis (sperm motility, sperm morphology, sperm count, semen volume).
●
Change from baseline to each visit in serum testosterone, estradiol, LH, FSH, 
and inhibin B.
Safety data will be analyzed for the data collected throughout Treatment Period and up to 
35 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.
5.3.5
Pharmacokinetic Variables
Plasma concentrations of Atrasentan and its possible metabolites will be obtained at the 
times indicated in Section 5.3.2.1.  Population pharmacokinetic modeling techniques may 


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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 pharmacokinetic variables may be calculated if useful in the interpretation of 
the data.
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Subjects will be discontinued from study drug immediately if any of the following events 
occur:
●
Clinically significant deterioration of the subject's medical status that is 
thought to possibly or probably be related to study drug by the Investigator.
●
The subject requests withdrawal from the study.
●
Investigator request (for any reason).
●
Achievement of the primary study endpoint (sperm concentration 
< 15 × 106/mL).
●
Chronic dialysis or renal transplant.
●
Subject is lost to follow-up.
If the subject is permanently discontinued from study drug and does not meet the criteria 
to enter the Observational Period, the procedures outlined for the T6/End of Treatment 
visit must be completed 5 days (± 3 days) of the last dose of study drug.  Additionally, the 
subject will be contacted by the Investigator (or designee) approximately 30 to 35 days 
after their last dose of study drug.
If the subject meets the criteria to enter the Observational Period during the Treatment 
Period, the subject will permanently discontinue from study drug and the procedures 
outlined for the T6/End of Treatment visit should be completed 5 days (± 3 days) of the 
last dose of study drug.  Following discontinuation of the study drug, the subject will 


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continue to be monitored during the Observational Period until sperm concentration 
returns to within 15% of baseline or above, or through the O4/EOS visit, whichever 
occurs first unless the subject withdraws consent.
Subjects who prematurely discontinue from the Treatment Period for other reasons than 
achievement of the primary study endpoint, will not be replaced unless the discontinuation 
rate exceeds 25% in the Treatment Period.  Subjects may be added to ensure that 
15 evaluable subjects are assessed.  
If the subject is permanently discontinued from the Observational Period for other reasons 
than returning to within 15% of their baseline sperm concentration or above, the 
procedures outlined for the O4/End of Study visit must be completed 5 days (± 3 days) of 
the discontinuation.  
The date and reason for premature discontinuation in either period will be recorded in the 
subject's source documents and on the appropriate eCRF.   
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 provided that written notice is submitted 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 will immediately 
notify the Investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
5.5.1
Treatments Administered
Each subject will receive 0.75 mg Atrasentan once daily for up to 26 weeks.


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5.5.2
Identity of Investigational Products
The individual study drug information is presented in Table 4.
Table 4.
Identity of Investigational Products
Study Drug
Dosage Strength
Formulation
Manufacturer
Atrasentan
0.75 mg
Film-coated tablet
AbbVie
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.
Subjects will receive open-label Atrasentan 0.75 mg.  Subjects will be instructed to take 
1 tablet daily.
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), 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, affected study drug should be 


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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.
5.5.3
Method of Assigning Subjects to Treatment Groups
This is a single arm study.  Subjects meeting entry criteria will be centrally registered 
using an Interactive Voice Response System/Interactive Web Response System 
(IVRS/IWRS).  Before the study is initiated, the telephone number and call-in directions 
for the IVRS/IWRS will be provided to each site.  Study drug will be dispensed at the 
study visits summarized in Table 1.  Returned study drug should not be re-dispensed to 
the subject.
5.5.4
Selection and Timing of Dose for Each Subject
Each subject will receive Atrasentan 0.75 mg.  Subjects will be instructed to take study 
drug once per day at approximately the same time each day (preferably in the morning).
5.5.5
Blinding
5.5.5.1
Blinding of Investigational Product
This is an open-label study.
5.5.6
Treatment Compliance
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.


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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 treatment visit.  The 
study site personnel will document compliance by recording the total number of doses 
dispensed and returned (brought back) per bottle during each visit during the Treatment 
Period in IVRS/IWRS and on the appropriate eCRF page.
Subjects will be encouraged to take study drug as prescribed.  At each visit, compliance 
will be assessed and counseled if the subject has taken more study drug than expected or 
if subject's non-compliant rate is < 100% compliant.  Overall compliance will be 
calculated at the end of the Treatment Period.
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 in 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 drug unit doses 
must be inventoried, accounted for, and returned to AbbVie per instructions from AbbVie 
and according to local regulations.
The Investigator and/or subinvestigator(s) 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
This study is designed to assess the effects of Atrasentan on spermatogenesis and 
testicular function during treatment period and up to 52 weeks follow-up.  The open-label 


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design is chosen for this study because no change in spermatogenesis or testicular 
function is expected without treatment in healthy volunteers.
5.6.2
Appropriateness of Measurements
All safety measurements in this study are standard and validated.  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 effects of Atrasentan on spermatogenesis and 
testicular function by assessing sperm concentration in subjects with Type 1 or 2 diabetes 
and nephropathy who are also being treated with a RAS inhibitor.
Therefore, subjects who have been treated with a RAS inhibitor (ACEi or ARBs), who 
have an estimated GFR ≥ 35 mL/min/1.73 m2 with the CKD-EPI formula and UACR ≥ 30 
to < 5,000 mg/g creatinine (≥ 3.4 mg/mmol and < 565 mg/mmol) with sperm and 
testosterone levels within normal ranges have been selected as the target population.  
Subjects who have underlying diseases/conditions and/or on medications affecting 
spermatogenesis or testicular function, history of allergic reaction or significant sensitivity 
to atrasentan or drugs similar to the study drug will be excluded to avoid confounding 
factors related to the effects being studied.
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 Atrasentan for up to 26 weeks during theTreatment Period. 
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 


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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.  The 
simulations, however, also showed that the probability of edema increases with increasing 
atrasentan exposure with predicted incidences of 32% and 38% at a dose of 1.25 mg and 
1.5 mg per day.  Although a slightly higher efficacy is predicted at doses greater than 
1.25 mg per day, the predicted rate of edema is higher at these doses.
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 
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.


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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.
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.


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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).
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.


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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:
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 reported from the time of study drug administration until 30 days 
following discontinuation of study drug administration have elapsed will be collected, 
whether solicited or spontaneously reported by the subject.  In addition, protocol-related 
nonserious and serious adverse events will be collected from the time the subject signed 
the study-specific informed consent through the post-therapy Observational Period.
Adverse event information will be collected as shown in Figure 2.


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Figure 2.
Adverse Event Collection
SAEs and 
Protocol-
Related 
Nonserious 
AEs
SAEs and Nonserious AEs
Elicited and/or Spontaneously Reported
SAEs and 
Protocol-Related 
Nonserious AEs
∀
∀
∀
∀
∀
Consent 
Signed
Study 
Drug 
Start
Study 
Drug 
Stopped
30 Days
After 
Study
Drug 
Stopped
Observational 
Period
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 be documented 
on the SAE Non CRF paper forms and emailed (preferred route) or faxed to Clinical 
Pharmacovigilance within 24 hours of being made aware of the serious adverse event.
Email:  
FAX to:  


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For safety concerns, contact the Renal Safety Team at:
Renal Safety Management Team
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 emergency situations involving study subjects when the Study Designated Physician is 
unavailable, please contact the 24-hour AbbVie Medical Escalation Hotline where your 
call will be re-directed to a designated back-up AbbVie Renal Medical Director.
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.
6.6
Pregnancy
Pregnancy in a study subject partner must be reported to AbbVie within 1 working day of 
the site becoming aware of the pregnancy.
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.
Pregnancy in a study subject partner 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.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol.  The 
principal 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 principal investigator is 
responsible for notifying Independent Ethics Committee (IEC)/Independent Review 
Board (IRB) regulatory authorities (as applicable), the following AbbVie Clinical 
Monitor(s):


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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.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
This is a Phase 2, single arm, open-label, multicenter study designed to evaluate the effect 
of Atrasentan (0.75 mg QD) on spermatogenesis and testicular function in men with 
diabetic nephropathy.
There are no planned efficacy objectives for this study.  The primary safety endpoint is 
the proportion of subjects who have a sperm concentration < 15 × 106/mL by 26 weeks.  
Approximately 20 subjects (to complete 15 evaluable subjects) with diabetic nephropathy 
who are taking RAS inhibitors are planned to be enrolled in the study at approximately 
20 sites.  Subjects will receive 0.75 mg QD of Atrasentan during the 26-week Treatment 
Period.
In the Treatment Period, semen samples will be collected at Screening (baseline), T5 
(Week 13) and T6/EOT (Week 26).  Semen samples will be collected at 2 time-points 
over a 7-day period with each sample being separated by at least 2 days.  The average of 
the 2 samples will be used as the value for that scheduled collection period.  Inadequate or 
missed semen samples can be made up within 14 days of the initial semen sample for that 


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collection period.  In the Observational Period, semen samples will be collected according 
to the specific windows for semen collection (Section 5.3.2.1), starting at the O1 
(Week 13) visit and then every 13 weeks thereafter until the sperm concentration has 
returned to within 15% of baseline or above, or until the end of the 52-week 
Observational Period, whichever occurs earlier.
General Considerations
Treatment effects will be evaluated based on a 2-sided 80% exact confidence interval.
Unless otherwise specified, for Treatment Period, the baseline observation is defined as 
the last non-missing measurement collected on or before the date of the first dose of study 
drug.  The final observations are defined as the last non-missing observations taken 
between the first dose and no more than 3 days after the last dose of study drug.
Unless noted otherwise, all analyses will be performed using SAS version 9.2 or higher 
(SAS Institute Inc., Cary, NC  27513) under the UNIX operating system.
8.1.1
Analysis Datasets
Evaluable Set
A subject will be considered evaluable if the following is satisfied:  (1) the Overall Study 
Drug compliance status is ≥ 70%; and (2) completes the 26-week treatment period and has 
all planned sperm samples collected; or has sperm concentration value less than 
15 million/mL observed by the end of Treatment Period.
The Safety Analysis Set includes all subjects who receive at least one dose of study drug.  
Unless otherwise specified, the safety analysis set will serve as the primary population for 
the safety analysis in this study.


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8.1.2
Demographic, Other Baseline Characteristics, Subject 
Disposition, and Concomitant Medication
All demographic and baseline characteristics such as gender, race, age, weight, etc., will 
be summarized.  Subject disposition, completion of study, or discontinuation from the 
study, will be summarized.  The number and percentage of subjects who prematurely 
discontinue from the study will be summarized for the primary reason as well as for all 
reasons collected.
Concomitant medications reported by generic name assigned by the World Health 
Organization (WHO) dictionary will be summarized.  For each concomitant medication, 
the number and percentage of subjects who take this medication will also be summarized.
8.1.3
Safety Analyses
Study Drug Exposure and Compliance
The duration of study drug exposure and the average daily dose will be summarized for 
safety analyses set.  The number and percentage of subjects with at least 70% compliance 
with study drug at each visit during the Treatment Period will be summarized.  The
Overall Study Drug compliance for a subject (Yes or No) is defined as following:  if the 
subject has at least 70% compliance with study drug at the end of the Treatment Period, 
then this subject is considered to be overall compliant to study drug; otherwise, the 
Overall compliant status will be set to as No.
8.1.3.1
Primary Safety Analyses
The primary safety endpoint is the proportion of subjects who have a sperm concentration 
< 15 × 106/mL during the 26-week Treatment Period.  The simple percentage of subjects 
and a 2-sided 80% exact confidence interval will be calculated.  The primary safety 
analysis will be conducted on the evaluable set.  When 15 evaluable subjects are 
available, if 4 or more subjects have a sperm concentration < 15 × 106/mL, the trial will 
claim that Atrasentan has a statistically significant effect on the primary endpoint.


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8.1.3.2
Secondary Safety Endpoints
The secondary safety endpoints are:
●
The proportion of subjects who enter the Observational Period and do not 
return to within 15% of baseline or above during the 52-week Observational 
Period.
●
Change from baseline to each visit in sperm concentration.
●
Change from baseline to each visit in each of the components of the semen 
analysis (sperm motility, sperm morphology, sperm count, semen volume).
●
Change from baseline to each visit in serum testosterone, estradiol, LH, FSH, 
and inhibin B.
The secondary analysis on the proportion of subjects who enter the Observational Period 
and do not return to within 15% of baseline or above during the 52-week Observational 
Period will be performed on the evaluable set.  The other secondary safety analyses will 
be conducted on the Safety population.  For proportion endpoints, the simple percentage 
of subjects and a 2-sided exact 80% confidence interval will be calculated.
The continuous variable of the secondary endpoints will be summarized by sample 
size (N), mean, standard deviation, minimum and maximum.
8.1.3.3
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 30 days after the last dose of the study drug will be 
summarized in descending order by MedDRA preferred term, as well as by system organ 
class (SOC) and MedDRA preferred term.  The incidence rates of treatment-emergent 
AEs will be summarized.  Additionally, the treatment-emergent AEs will also be 
summarized by the relationship to study drug and their maximum severity.


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The adverse events reported as reasons for discontinuation will be summarized.  Serious 
adverse events will be evaluated in a similar manner.
Specifically, adverse events will be summarized as described below:
●
An overview of the number and percentage of subjects with treatment-
emergent adverse events.
●
A summary of the number and percentage of subjects with treatment-emergent 
adverse events by primary MedDRA system organ class and preferred term.
●
A summary of the number and percentage of subjects with treatment-emergent 
serious adverse events by primary MedDRA system organ class and preferred 
term.
●
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.
●
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.
●
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.
●
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.
●
A summary of subject numbers associated with treatment-emergent adverse 
events by primary MedDRA system organ class and preferred term.
For the Observational Period, the protocol-related adverse events will be summarized 
similarly from 30 days after the last dose of study drug through study completion.


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8.1.3.4
Clinical Laboratory Data
For each laboratory test, the mean change from baseline to the minimum, maximum, and 
to each visit will be summarized.  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.
8.1.3.5
Vital Signs Data
The mean change from baseline to each visit in vital signs, including weight, will be 
summarized.
8.1.3.6
ECG Analyses
The number and percentage of subjects with shifts from baseline in the categories of 
normal, abnormal as indicated by the study site investigators will be summarized.
8.1.4
Interim Analysis
An interim analysis will be performed after all the subjects have completed or prematurely 
discontinued from the 26-week Treatment Period.  The database will be formally locked 
and versioned.  The primary, applicable secondary and other safety analyses will be 
performed on this version of the clinical database.  There is no need to adjust significance 
level since the primary analysis will be conducted using data from the 26-week Treatment 
Period.
8.2
Determination of Sample Size
The proportion of subjects with sperm concentration < 15 million/mL in an unscreened 
population of otherwise healthy males is reported to be approximately 10%. 22  With 
15 evaluable subjects, this single-arm study will have approximately 80% power to detect 
a 20% difference between the incidence rate in the Atrasentan group and the null 
hypothesis of 10% at 2-sided significance level of 0.2.


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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 
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.


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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 
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.  Enrollment of subjects who 
cannot read, sponsor employees, site employees and employee family members are not 
permissible in this study.  In addition, the use of legally authorized representatives is 
prohibited for this protocol.
Information regarding incentives for the subject and provisions for treating and/or 
compensating subjects who are harmed as a consequence of participation in the study can 
be found in the informed consent form.
In the event a subject withdraws consent to participate from the study, stored samples will 
continue to be used for research and analysis.  In the event a subject would like to 
withdraw consent for research using these samples, the subject may request their samples 
be withdrawn.  Once AbbVie receives this request, the remaining samples will be 
destroyed.  If the subject changes his consent, and the samples have already been tested, 
those results will still remain as part of the overall research data.
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 


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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.
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.
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 


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Investigator will review the eCRFs for completeness and accuracy and provide his or her 
electronic signature and date to eCRFs as evidence thereof.
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.
11.0
Data Quality Assurance
Prior to the initiation of the study, the study personnel at each site will be trained on the 
study procedures by a CRA at a study initiation visit.  This training will include a detailed 
discussion of the protocol, performance of study procedures, CRF completion, and 
specimen collection methods.  In addition, the study personnel at each site 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, urinalysis, and other lab tests 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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Semen analysis will be conducted at qualified semen analysis laboratories.  Data from 
these analyses will be entered by the site into the eCRF.  A final review of all laboratory 
results will be conducted by a physician and clinical review team at AbbVie.
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.
13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the time frame specified in the contract between the Investigator and 


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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.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure 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 Multicenter, Single-Arm Study of the Effects of Atrasentan on 
Spermatogenesis and Testicular Function
Protocol Date:
08 April 2016
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(6163):411-5.
2.
Levin ER.  Endothelins.  N Engl J Med.  1995;333(6):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.  1991;49(11):PL61-5.
5.
Opgenorth TJ.  Endothelin receptor antagonism.  Adv Pharmacol.  1995;33:1-65.
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:S183-5.
7.
Bax WA, Saxena PR.  The current endothelin receptor classification:  time for 
reconsideration?  Trends Pharmacol Sci.  1994;15(10):379-86.
8.
Rabelink TJ, Kaasjager KAH, Stroes ES, et al.  Endothelin in renal 
pathophysiology:  from experimental to therapeutic application.  Kidney Int.  
1996;50(6):1827-33.
9.
Kaasjager KA, 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(1):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(2):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(1):16-8.
12.
Haak T, Jungmann E, Felber A, et al.  Increased plasma levels of endothelin in 
diabetic patients with hypertension.  Am J Hypertens.  1992;5(3):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(2):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(2):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(3):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(5):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(1):143-54.
19.
Tracleer® [package insert].  South San Francisco, CA; Actelion Pharmaceuticals 
US, Inc., 2011.
20.
Letairis® [package insert].  Foster City, CA; Gilead Sciences Inc., 2012.
21.
Volibris® [package insert].  Brentford, Middlesex, UK; Glaxo Group Ltd, 2013.
22.
Cooper TG, Noonan E, von Eckardstein S, et al.  World Health Organization 
reference values for human semen characteristics.  Hum Reprod Update.  
2010;16(3):231-45.


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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
Clinical
Clinical
Clinical
Pharmacokinetics
Statistics


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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
Protocol title previously read:
A Single-Country, Multicenter, Single-Arm Study of the Effects of Atrasentan on 
Spermatogenesis and Testicular Function
Has been changed to read:
A Multicenter, Single-Arm Study of the Effects of Atrasentan on Spermatogenesis and 
Testicular Function
Section 1.0  Title Page
Add:  "EudraCT Number:"
EudraCT Number:
2016-000722-19
Section 1.0  Title Page
"Investigators:," "Sponsor:," and "Sponsor/Emergency Contact:" previously read:
Investigators:
Multicenter (Investigator information on file at AbbVie).
Sponsor:
AbbVie Inc. (AbbVie)
Sponsor/Emergency 
  Contact:


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Has been changed to read:
Investigators:
Multicenter (Investigator information is on file at AbbVie).
Sponsor:
AbbVie*
Sponsor/Emergency 
  Contact:
Section 1.0  Title Page
Add:  new table note "*"
*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.


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Section 1.2  Synopsis
Previously read:
AbbVie Inc.
Protocol Number:  M12-919
Name of Study Drug:  Atrasentan
Phase of Development:  2
Name of Active Ingredient:  Atrasentan
Date of Protocol Synopsis:  06 May 2015
Protocol Title:  A Single-Country, Multicenter, Single-Arm Study of the Effects of Atrasentan on 
Spermatogenesis and Testicular Function
Objectives:  The study objective is to evaluate the effect of Atrasentan on spermatogenesis and 
testicular function in men with diabetic nephropathy.
Investigators:  Multicenter
Study Sites:  Approximately 10 sites.
Study Population:  Subjects that have diabetic nephropathy as defined by micro or macro albuminuria.
Number of Subjects to be Enrolled:  Approximately 20 subjects will be enrolled to complete 
15 evaluable subjects.
Methodology:
This is a prospective, single-country, multicenter, single-arm study.  Eligible subjects will be treated 
with Atrasentan 0.75 mg once daily (QD) for 26 weeks.  Semen samples will be collected at Screening 
(baseline), Week 6, Week 13, and Week 26/End of Treatment (EOT) visit.  Duplicate samples will be 
collected at each time-point over a 7-day period with each sample being separated by at least 2 days.  
The average of the 2 samples will be used as the value for that time-point.  Subjects will be discontinued 
from study drug and enter into an Observational Period of up to an additional 52 weeks if sperm 
concentration drops below 15 million/mL at any time during the Treatment Period or at the 
Week 26/EOT visit.  If at the end of the 26-Week Treatment Period, there was a ≥ 50% reduction in 
sperm concentration from baseline the subject will also enter into the Observational Period.  During the 
Observational Period, semen samples will be collected at Weeks 6 and 13 and then every 13 weeks until 
sperm concentration returns to baseline (± 15%) or until the end of the Observational Period.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Male subject 30 to 75 years of age, inclusive at the time of Screening.
2.
Subject 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 1or 2 diabetes and has been treated with at least one anti-hyperglycemic 
medication and ACEi or ARB (RAS inhibitor) for at least 2 months prior to the Screening Period.
4.
Subject has an eGFR ≥ 50 mL/min with the CKD-EPI formula and UACR ≥ 30 to < 5,000 mg/g 
creatinine.
5.
Subject has a serum BNP < 200 ng/L.
6.
Subject has systolic blood pressure ≥ 110 and ≤ 160 mmHg.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
7.
Subject has a serum potassium ≥ 3.5 and ≤ 5.5 mEq/L.
8.
Subject is able to provide a semen specimen at the required intervals.
9.
Subject has baseline sperm concentration ≥ 30 million per mL.
10. Subject must be practicing at least two of the following methods of contraception, from initial study 
drug administration through 90 days after the last dose of study drug unless the 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.
11. Subject must agree not to donate sperm from initial study drug administration through 90 days after 
last dose of study drug.
12. HbA1C ≤ 12%.
13. Subject has a Follicle Stimulating Hormone (FSH) between 1.30 – 19.30 IU/L.
14. Subject has a Luteinizing Hormone (LH) between 1.2 – 8.6 IU/L.
15. Subject has a total Testosterone between 3.0 – 10.0 ng/mL (300 – 1000 ng/dL) inclusive.
16. Subjects currently using alpha blockers must be on a stable dose for at least 3 months prior to 
screening and expected to remain on a stable dose during the study.
17. Subject currently using 5 alpha reductase inhibitors must be on a stable dose for at least 6 months 
prior to screening and expected to remain on a stable dose during the study.  
Main Exclusion:
1.
Prior history of prostate cancer with or without treatment.
2.
Untreated retrograde ejaculation or prior prostate surgery.  Subjects with treated retrograde 
ejaculation will be allowed with approval of the Study Designated Physician.
3.
Prior history of vasectomy.
4.
Prior history of radiation to the testes.
5.
Recent history (within 6 months) of STD, UTI, documented prostatitis, orchitis, epididymitis.
6.
History of male infertility.
7.
Prior history of occupational exposure to environmental toxins within the past 6 months.
8.
Drug, alcohol or substance abuse within the last 6 months.
9.
Treatment with hormone suppressive agents, including androgens, estrogens, anabolic steroids, 
glucocorticoids, ketoconazole, cyclosporine, or cancer chemotherapy within the past 6 months or 
planned during the study.
10. Subject has a body mass index (BMI) > 45.
11. Subject has a history of hormone replacement therapy.
12. Subject has evidence or history of hypogonadism.
13. Current hot tub/Jacuzzi/sauna use or within the previous 12 weeks.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
14. Renal transplant.
15. Subject has a history of moderate or severe peripheral edema, pulmonary edema or facial edema 
unrelated to trauma or a history of myxedema in the prior 6 months to Screening.
16. Subject has a history of pulmonary hypertension requiring either oxygen therapy and/or endothelin 
receptor antagonist or phosphodiesterase therapy or any lung diseases requiring oxygen therapy 
(e.g., chronic obstructive pulmonary disease, emphysema, pulmonary fibrosis).
17. 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.
18. Subject has elevated liver enzymes (serum alanine aminotransaminase [ALT] and/or serum 
aspartate aminotransaminase [AST]) > 3 × the upper limit of normal (ULN).
19. Subject has a hemoglobin < 9 g/dL.
20. Subject has a history of an allergic reaction or significant sensitivity to Atrasentan (or its excipients) 
or similar compounds.
21. Subject has significant comorbidities (e.g., advanced malignancy, advanced liver disease) with a 
life expectancy of less than 1 year.
22. Subject has clinically significant cerebrovascular disease (CVD) or coronary artery disease (CAD) 
within 3 months prior to the Screening Period, defined as one of the following:
a.
Hospitalization for MI or unstable angina; or
b.
New onset angina with positive functional study or coronary angiogram revealing stenosis; or
c.
Coronary revascularization procedure; or
d.
Transient ischemic attack (TIA) or stroke.
23. Subject has received any investigational drug within 3 months prior to Screening.
24. Subject is currently receiving rosiglitazone, moxonidine, aldosterone blockers, aliskiren or a 
combination of ACEi and ARB.
25. Subjects with known allergy to thiazide or loop diuretics.
26. Is considered by the Investigator unsuitable to participate in the trial for any other reason, for 
instance due to a significant serious underlying condition.
Investigational Product:
Atrasentan
Dose:
0.75 mg QD
Mode of Administration:
Oral
Reference Therapy:
Not applicable
Dose:
Not applicable
Mode of Administration:
Not applicable
Duration of Treatment:  26 weeks


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Criteria for Evaluation:
Primary Safety Endpoint:
The proportion of subjects who have a sperm concentration < 15 × 106/mL by 26 weeks.
Criteria for Evaluation (Continued):
Secondary Safety Measures up to the End of Study:
1.
The proportion of subjects who enter the Observation Period and do not return to within 15% of 
baseline by 52 weeks after treatment discontinuation.  
2.
Change from baseline to each visit in sperm concentration.
3.
Change from baseline to each visit in each of the components of the semen analysis (sperm 
motility, sperm morphology, sperm concentration, semen volume).
4.
Change from baseline to each visit in serum testosterone, estradiol, LH, FSH, and inhibin B.
Pharmacokinetic:
Atrasentan apparent oral clearance (CL/F) and volume of distribution (V/F) may be estimated using 
population pharmacokinetic techniques.
Statistical Methods:
Sample Size Justification:
The proportion of subjects with sperm concentration < 15 million/mL in an unscreened population of 
healthy male subjects is reported to be approximately 10% (Cooper et al 2010).  With 15 evaluable 
subjects, this single-arm study will have approximately 80% power to detect a 20% difference between 
the incidence rates in the Atrasentan group and the null hypothesis of 10% at 2-sided significance level 
of 0.2.
Safety:
Primary Safety Endpoint:  The proportion of subjects who have a sperm concentration 
< 15 million /mL by 26 weeks.  The primary safety analysis of primary endpoint will be performed on 
evaluable subjects.  A subject will be considered evaluable for the primary analysis if the following is 
satisfied:  (1) The Overall Study Drug compliance status = YES; and (2) Completes the 26-week TP and 
has all planned sperm samples collected; or has a sperm concentration value less than 15 million/mL 
observed prior to the end of treatment period.  The simple percentage of subjects and a 2-sided 80% 
exact confidence interval will be calculated.  Thus, when 15 subjects are evaluable, if 4 or more subjects 
have a sperm concentration < 15 million/mL, the trial will claim that Atrasentan has a statistically 
significant effect on the primary endpoint.
Adverse events will be coded using the most current version of the Medical Dictionary for Regulatory 
Activities (MedDRA).  The number and percentage of subjects who report treatment-emergent adverse 
events in treatment period will be tabulated by system organ class (SOC) and preferred term by 
treatment group.  The number and percentage of subjects who report protocol-related adverse events in 
Observational Period will be also be summarized.
For each laboratory test, the mean change from baseline to the minimum, maximum, and to each visit 
will be summarized.  Additionally for selected laboratory tests of particular 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.  The mean change from baseline to each visit in vital signs, including 
weight, will be summarized.


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Reference:
1.
Cooper TG, Noonan E, von Eckardstein S, et al.  World Health Organization reference values for 
human semen characteristics.  Hum Reprod Update.  2010;16(3):231-45.


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Has been changed to read:
AbbVie
Protocol Number:  M12-919
Name of Study Drug:  Atrasentan
Phase of Development:  2
Name of Active Ingredient:  Atrasentan
Date of Protocol Synopsis:  08 April 2016
Protocol Title:  A Multicenter, Single-Arm Study of the Effects of Atrasentan on Spermatogenesis and 
Testicular Function
Objectives:  The study objective is to evaluate the effect of Atrasentan on spermatogenesis and 
testicular function in men with diabetic nephropathy.
Investigators:  Multicenter
Study Sites:  Approximately 20 sites.
Study Population:  Subjects with type 1 or 2 diabetes and nephropathy (e-GFR ≥ 35 ml/min/1.73 m2
and a urinary albumin to creatinine ratio (UACR) ≥ 30 mg/g creatinine and < 5,000 mg/g 
(≥3.4 mg/mmol and < 565 mg/mmol)).
Number of Subjects to be Enrolled:  Approximately 20 subjects will be enrolled to complete 
15 evaluable subjects.
Methodology:
This is a prospective, open-label, multicenter, single-arm study.  Eligible subjects will be treated with 
Atrasentan 0.75 mg once daily (QD) for 26 weeks while remaining on their RAS inhibitors.  Semen 
samples will be collected at Screening (baseline), Week 13 and Week 26/End of Treatment (EOT) visits.  
Semen samples will be collected at two time-points over a 7-day period with each sample being 
separated by at least 2 days (48 hours) for each scheduled collection period.  The average of the 2 semen 
samples will be used as the value for that collection period.  If at any time during the Treatment Period 
or at the Week 26/EOT visit, the subjects' sperm concentration drops below 15 million/mL, the subject 
will be discontinued from study drug and enter into an Observational Period of up to an additional 
52 weeks.  If at the end of the 26-Week Treatment Period, there is a ≥ 50% reduction in sperm 
concentration from baseline, the subject will enter into the Observational Period.  During the 
Observational Period semen samples will be collected (at two time-points over a 7-day period with each 
sample being separated by at least 2 days [48 hours]) every 13 weeks until the subject's sperm 
concentration returns to within 15% of baseline or above, or until the end of the Observational Period.  
Subjects who do not meet the criteria to enter the Observational Period will have a follow-up contact 
from the Investigator (or designee) 30 to 35 days after the last dose of study drug.  Subjects, whose 
sperm concentration returns to within 15% of baseline or above during the Observational Period, will 
have a follow-up contact from the Investigator (or designee) within 14 days of the collection of the 
second semen sample.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
!
Male subject 30 to 75 years of age, inclusive at the time of Screening.
!
Subject has type 1 or 2 diabetes and is receiving treatment with at least one anti-hyperglycemic 
medication and ACEi or ARB (RAS inhibitor).


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
!
Subject has an eGFR ≥ 35 mL/min/1.73 m2 with the CKD-EPI formula and UACR ≥ 30 to < 
5,000 mg/g creatinine (≥ 3.4 mg/mmol and < 565 mg/mmol).
!
Subject is able to provide a semen specimen at the required intervals.
!
Subject has a baseline sperm concentration ≥ 30 million per mL at Screening.
Main Exclusion:
!
Subject has had treatment with hormone suppressive agents, including androgens, estrogens, 
anabolic steroids, glucocorticoids, ketoconazole, cyclosporine, or cancer chemotherapy within 
the 6 months prior to the initial screening visit or planned during the study.
!
Subject is currently receiving or has received hormone replacement therapy within the last 
6 months prior to the Screening Period.
!
Subject has a history of severe peripheral edema or facial edema unrelated to trauma or a 
history of myxedema in the prior 4 weeks to the initial screening visit.
!
Subject has a history of pulmonary hypertension, pulmonary fibrosis or any lung disease 
requiring either 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.
Investigational Product:
Atrasentan
Dose:
0.75 mg QD
Mode of Administration:
Oral
Reference Therapy:
Not applicable
Dose:
Not applicable
Mode of Administration:
Not applicable
Duration of Treatment:  26 weeks
Criteria for Evaluation:
Safety:
Primary Safety Endpoint:
The proportion of subjects who have a sperm concentration < 15 × 106/mL during the 26-week 
Treatment Period.


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Criteria for Evaluation (Continued):
Safety (Continued):
Secondary Safety Measures up to the End of Study:
!
The proportion of subjects who enter the Observational Period and do not return to within 15% 
of baseline or above during the 52-week Observational Period.  
!
Change from baseline to each visit in sperm concentration.
!
Change from baseline to each visit in each of the components of the semen analysis (sperm 
motility, sperm morphology, sperm count, semen volume).
!
Change from baseline to each visit in serum testosterone, estradiol, LH, FSH, and inhibin B.
Pharmacokinetic:
Atrasentan apparent oral clearance (CL/F) and volume of distribution (V/F) may be estimated using 
population pharmacokinetic techniques.
Statistical Methods:
Analysis Datasets:
The following datasets will be used for the analysis of safety endpoints:
!
The Evaluable Set will consist of all subjects who achieve the following:  1) ≥ 70% overall 
study drug compliance; and 2) having completed the 26-week treatment period and having all 
planned sperm samples collected; or having a sperm concentration value < 15 × 106/mL 
observed by the end of the Treatment Period.
!
The Safety Analysis Set includes all subjects who receive at least one dose of Atrasentan.
Sample Size Justification:
The proportion of subjects with sperm concentration < 15 × 106/mL in an unscreened population of 
healthy male subjects is reported to be approximately 10%.  With 15 evaluable subjects, this open label, 
single-arm study will have approximately 80% power to detect a 20% difference between the incidence 
rates in the Atrasentan group and the null hypothesis of 10% at 2-sided significance level of 0.2.
Safety:
Primary Safety Analysis:  
The primary safety analysis will be conducted on the evaluable set for the primary safety endpoint.  The 
simple percentage of subjects and a 2-sided 80% exact confidence interval will be calculated.  When 
15 evaluable subjects are available, if 4 or more subjects have a sperm concentration < 15 × 106/mL, the 
trial will claim that Atrasentan has a statistically significant effect on the primary endpoint.
Secondary Safety Analysis: 
The secondary analysis on the proportion of subjects who enter the Observational Period and do not 
return to within 15% of baseline or above during the 52-week Observational Period will be performed on 
the evaluable set.  The other secondary safety analyses will be conducted on the Safety population.  For 
proportion endpoints, the simple percentage of subjects and a 2-sided exact 80% confidence interval will 
be calculated.
The continuous variable of the secondary endpoints will be summarized by sample size (N), mean, 
standard deviation, minimum and maximum.


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Statistical Methods (Continued):
Adverse Events (AEs) Analysis:
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 
30 days after the last dose of the study drug will be summarized in descending order by MedDRA 
preferred term, as well as by system organ class (SOC) and MedDRA preferred term.  The incidence 
rates of treatment-emergent AEs 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.  Serious adverse events 
will be evaluated in a similar manner.
For the Observational Period, the protocol related AEs will be summarized similarly from 30 days after 
the last dose of study drug through study completion.  The number and percentage of subjects who report 
protocol-related adverse events in the Observational Period will also be summarized.
Laboratory Data:
For each laboratory test, the mean change from baseline to the minimum, maximum, and to each visit 
will be summarized.  Additionally for selected laboratory tests of particular 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.  The mean change from baseline to each visit in vital signs, including 
weight, will be summarized.
Interim Analysis:
An interim analysis will be performed after all the subjects have completed or prematurely discontinued 
from the 26-week Treatment Period.  The database will be formally locked and versioned.  The primary, 
applicable secondary and other safety analyses will be performed on this version of the clinical database.  
There is no need to adjust significance level since the only comparison is in the primary analysis which 
will be conducted using data from the 26-week Treatment Period.


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Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Previously read:
ACEi
Angiotensin-converting enzyme
AE
Adverse event
AKI
Acute kidney injury
ALT
Serum alanine aminotransaminase
AQOL-4D
Assessment of Quality of Life – 4 Dimensions
AST
Serum aspartate aminotransaminase
ARB
Angiotensin II receptor blocker
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
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)
eGFR
Estimated glomerular filtration rate
EMEA
European agency for the evaluation of medicinal products
EPI
Epidemiology collaboration


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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
HBA1c
Glucosylated hemoglobin A1c
HDL
High density lipoprotein
HOMA-IR
Homeostatic model assessment
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IEF
Index of Erectile Function 
IMP
Investigational medicinal product
IND
Investigational new drug
IRB
Institutional Review Board
IUD
Intrauterine device
IWRS
Interactive voice response/Interactive Web Response System
IVRS
Interactive voice response system
LDL
Low density lipoprotein
LDH
Lactic dehydrogenase
LH
Luteinizing hormone
MI
Myocardial infarction
MMRM
Mixed model of repeated measures
MTLDD
Maximum tolerated labeled daily dose
NSAIDS
Non-steroidal anti-inflammatory drugs 
OLE
Open-label extension
PD
Premature discontinuation
PG
Pharmacogenetic
PI
Principal investigator
PK
Pharmacokinetic
QD
Once daily
MedDRA
Medical dictionary for regulatory activities


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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
SGPT
Serum glutamic pyruvic transaminase
SGOT
Serum glutamic oxaloacetic transaminase
SI
Standard International Units
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reactions
T
Testosterone
TGF-β
Transforming growth factor beta
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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Has been changed to read:
ACEi
Angiotensin-converting enzyme inhibitor
AE
Adverse event
ALT
Serum alanine aminotransaminase
AST
Serum aspartate aminotransaminase
ARB
Angiotensin II receptor blocker
BNP
Brain natriuretic peptide
BP
Blood pressure
BUN
Blood urea nitrogen 
CAD
Coronary artery disease
CFR
Code of federal regulations
CHF
Congestive heart failure
CKD
Chronic kidney disease
CL/F
Oral clearance
CRA
Clinical Research Associate
CRF
Case report form
CV
Cardiovascular
CVD
Cerebrovascular disease
DBP
Diastolic blood pressure
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EDTA
Edetic acid (ethylenediaminetetraacetic acid)
eGFR
Estimated glomerular filtration rate
EPI
Epidemiology collaboration
EOS
End of Study
EOT
End of Treatment
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


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GI
Gastrointestinal
HBA1c
Glucosylated hemoglobin A1c
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
IND
Investigational new drug
IRB
Institutional Review Board
IUD
Intrauterine device
IWRS
Interactive voice response/Interactive Web Response System
IVRS
Interactive voice response system
LH
Luteinizing hormone
MI
Myocardial infarction
MTLDD
Maximum tolerated labeled daily dose
OLE
Open-label extension
PD
Premature discontinuation
PK
Pharmacokinetic
QD
Once daily
MedDRA
Medical dictionary for regulatory activities
RAS
Renin angiotensin system
RBC
Red blood cell
SAE
Serious adverse event
SBP
Systolic blood pressure
SGPT
Serum glutamic pyruvic transaminase
SGOT
Serum glutamic oxaloacetic transaminase
SI
Standard International Units
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reactions
T
Testosterone
TGF-β
Transforming growth factor beta
UACR
Urinary albumin to creatinine ratio
ULN
Upper limit of normal 
US
United States
V/F
Volume of distribution
WBC
White blood cell


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Section 1.3  List of Abbreviations and Definition of Terms
Subsection Definition of Terms
"First morning void urine" previously read:
First morning void urine The first void of the morning collected after 5:00 am.
Has been changed to read:
First morning void urine The first void of the morning collected after 5:00 am or upon 
raising for the day.
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Definition of Terms
Delete:  "Observation Period criteria"
Observation Period criteria
Subjects whose sperm concentration drops below 
< 15 million/mL at any time during the Treatment Period.  Subjects who experience a 
≥50% reduction in sperm concentration from baseline at the end of the 26-week 
Treatment Period will enter the Observational Period.
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Definition of Terms
Add:  "Duplicate semen samples"
Duplicate semen samples
Set of two semen samples collected over a 7-day period 
with each sample being separated by at least 2 days (48 hours) for a scheduled collection 
period.  Each collection period lasts up to 14 days and is associated with a specific study 
visit.
Section 3.0  Introduction
Last paragraph, first sentence previously read:
The Phase 3 study (Study M11-352) is ongoing 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.


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Has been changed to read:
The Phase 3 study (Study M11-352) is ongoing to characterize the safety and efficacy of 
Atrasentan in delaying renal disease progression in subjects with type 2 diabetes and 
nephropathy who have residual albuminuria while receiving MTLDD of RAS inhibitors.
Section 3.0  Introduction
Subsection Effect of Atrasentan on Testicular Function in Clinical Studies
Fifth paragraph, third and fourth sentence previously read:
These results are noted in the US prescribing information for both bosentan and 
ambrisentan.  In ARIES-E, a clinical study with chronic ambrisentan administration, there 
was no clear evidence of a detrimental effect on sperm count; however, a decrease in 
plasma inhibin B and an increase in plasma FSH not associated with a change in 
testosterone were observed.
Has been changed to read:
These results are noted in the US prescribing information for both bosentan and 
ambrisentan.19,20  In ARIES-E, a clinical study with chronic ambrisentan administration, 
there was no clear evidence of a detrimental effect on sperm count; however, a decrease in 
plasma inhibin B and an increase in plasma FSH not associated with a change in 
testosterone were observed.21
Section 3.0  Introduction
Subsection Effect of Atrasentan on Testicular Function in Clinical Studies
Last paragraph previously read:
The purpose of this study (Study M12-919) is to evaluate the effect of prolonged 
administration of Atrasentan on spermatogenesis and testicular function.
Has been changed to read:
The purpose of this study (Study M12-919) is to evaluate the effect of prolonged 
administration of Atrasentan on spermatogenesis and testicular function (Section 4.0).


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Section 5.1  Overall Study Design and Plan:  Description
Previously read:
This is a Phase 2, open-label, single-country, single-arm study designed to demonstrate 
the effect of Atrasentan on spermatogenesis and testicular function in men with diabetic 
nephropathy.  Approximately 20 subjects (to complete 15 evaluable subjects) with 
diabetic nephropathy who are taking RAS inhibitors are planned to be enrolled in the 
study at approximately 15 sites.  Subjects will receive 0.75 mg once daily (QD) of 
Atrasentan for 26 weeks.  The duration of the study will be up to approximately 80 weeks.  
Semen samples will be collected at Screening (baseline), Week 6, Week 13, and 
Week 26/End of Treatment (EOT).  A duplicate sample will be collected at each 
time-point over a 7-day period with each sample being separated by at least 2 days.  If for 
any reason one of the two required samples is inadequate or not obtained, then a 
replacement sample will be collected to ensure that two samples are available for each 
time-point.  All semen samples for a time-point must be collected within a 14-day period.  
Subject must abstain from ejaculation for at least 2 days but not more than 7 days prior to 
semen sample collection.  The average of the 2 semen samples will be used as the value 
for that time-point.  Subjects will be discontinued from study drug and enter into an 
Observational Period of up to an additional 52 weeks if sperm concentration drops below 
15 million/mL at any time during the Treatment Period or at the Week 26/EOT visit.  If at 
the end of the 26-Week Treatment Period there is a ≥ 50% reduction in sperm 
concentration from baseline the subject will also enter into the Observational Period.  
During the Observational Period, semen samples will be collected 6 weeks after the end of 
treatment visit, Week 13 and then every 13 weeks until all values have returned to the 
baseline sperm concentration (± 15%) or until the end of the Observational Period.
The study was designed to enroll approximately 20 subjects to obtain 15 evaluable 
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 enrolled, there is a possibility that additional subjects in screening will 
not be enrolled.


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Figure 1.
Study Schematic
Screening 
Period 
(14 days)
Treatment Period (Up to 26 weeks)
Follow-up 
Period 
(30 days)
Observation Period (Up to 52 weeks)
T2
T1
T3
T4
T5
T6/EOT
30 day 
contact
O1
O2
O3
O4
O5/
EOS


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Screening Period
The Screening Period will last up to 14 days.  Procedures to be performed at the Screening 
visit are noted in Table 1.  Subjects will return to the site within the 14-day Screening 
Period to return the two consecutive first morning void urine samples.  In addition, the 
two semen samples should be scheduled within the 14-day window.  See Section 5.3.2.1 
for semen collection requirements and time windows.  Subjects who fail to meet 
eligibility criteria will be allowed to re-screen twice.
Treatment Period
Subjects should return for the Day 1 visit after all eligibility criteria has been reviewed 
and the subject is deemed eligible within 14 days from the initial screening laboratory 
assessments.  Subjects who return for the Day 1 visit outside of 14 days from the initial 
screening laboratory assessments, must repeat Screening laboratory assessments.  In 
addition, if 14 days have passed from the second semen sample, the subjects must repeat 
the Screening semen assessments.
All subjects will be contacted 30 to 35 days after their last dose of study drug to solicit 
AEs and SAEs.  This follow-up contact will be the final visit for subjects who do not meet 
the criteria for entering the Observational Period.
Observational Period
Subjects meeting the criteria for entering the Observational Period will complete study 
visits and assessments as noted in Table 1.  Subjects who have a sperm concentration 
returning to baseline (± 15%) will return for their O5/End of Study visit within 14 days.  
All other subjects will continue study visits until the End of Study visit.
Has been changed to read:
This is a Phase 2, prospective, open-label, multicenter, single-arm study designed to 
evaluate the effect of Atrasentan on spermatogenesis and testicular function in men with 
diabetic nephropathy.  Approximately 20 subjects (to complete 15 evaluable subjects) 


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with diabetic nephropathy who are taking RAS inhibitors are planned to be enrolled in the 
study at approximately 20 sites.  
Subjects who provide consent, will enter a Screening Period to assess eligibility.  Eligible 
subjects will enter a 26-week Treatment Period, followed by an Observational Period if 
the subject qualifies.  General laboratory tests (including hematology, chemistry and 
urinalysis) will be collected for safety monitoring and semen samples will be collected 
throughout the subject's study participation.
If at any time during the Treatment Period or at the T6/End of Treatment (EOT) 
(Week 26) visit the subject's sperm concentration drops below 15 million/mL, the subject 
will be discontinued from study drug and enter into an Observational Period of up to an 
additional 52 weeks.  If at the end of the 26-week Treatment Period there is a ≥ 50% 
reduction in sperm concentration from baseline the subject will also enter into the 
Observational Period.  
During the Observational Period, laboratory tests and semen samples will be collected. 
Subjects who do not meet the criteria for entering the Observational Period will have a 
contact from the Investigator (or designee) 30 to 35 days after their last dose of study 
drug.
The study was designed to enroll approximately 20 subjects to obtain 15 evaluable 
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 enrolled, there is a possibility that additional subjects in screening will 
not be enrolled.
A schematic of the study design is shown below in Figure 1.


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Figure 1.
Study Schematic


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Screening Period
The Screening Period will last up to 4 weeks.  Procedures to be performed during the 
Screening Period are outlined in the Study Activities Table (Table 1).  Subjects will be 
given supplies and instructions for obtaining the first morning void urine sample and 
scheduled to return to the site within the 4-week Screening Period to return the 
first morning void urine sample.  In addition, the subject will provide the semen samples 
according to the specific windows for semen collection (Section 5.3.2.1) within the 
4-week Screening Period.  Tests for eligibility may be repeated within the subject's 
4-week Screening Period.  Subjects who fail to meet eligibility criteria will be allowed to 
re-screen at the investigator's discretion.
Treatment Period
Eligible subjects will return for the T1 visit (Day 1) no more than 4 weeks from the initial 
screening visit.  The procedures to be performed at the T1 visit are outlined in the Study 
Activities Table (Table 1), including initial administration of open-label study drug 
(Atrasentan).
The Treatment Period consists of five additional site visits over a 26 week period.
●
The T2 (Week 2) visit will take place 2 weeks (± 7 days) after the T1 visit.
●
The T3 (Week 4) visit will take place 2 weeks (± 7 days) after the T2 visit.
●
The T4 (Week 6) visit will take place 2 weeks (± 7 days) after the T3 visit.  
●
The T5 (Week 13) visit will take place 7 weeks (± 7 days) after the T4 visit.  
At this visit, subjects will be provided with supplies and instructions for the 
collection of the duplicate semen samples and will be scheduled for the 
collection of the semen samples according to the specific windows for semen 
collection (Section 5.3.2.1).  Supplies and instructions for obtaining the 
first morning void urine sample within 1 day of the T6 visit will also be given 
to the subjects.  The site will also call into IVRS/IWRS at this visit and 
dispense study drug to the subject.


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If the average of the two semen samples is < 15 million/mL, the subject will 
discontinue from study drug and return to the End of Treatment Visit (EOT) 
5 days (± 3 days) of the last dose of study drug.  For this subject, semen 
samples will not be collected at the EOT visit.
The T6/EOT (Week 26) visit will take place 13 weeks (± 7 days) after the 
T5 visit.  Subjects will be provided with supplies and instructions for the 
collection of the duplicate semen samples, and will be scheduled for the 
collection of the semen samples according to the specific windows for semen 
collection (Section 5.3.2.1).  If the average of the two semen samples is 
< 15 million/mL or there is a ≥ 50% reduction in sperm concentration from 
Screening at T6/EOT (Week 26) visit, the subject will enter the Observational 
Period.
The procedures to be performed at each visit are outlined in the Study Activities Table 
(Table 1).
Follow-Up Contact
Only those subjects who do not meet criteria to enter the Observational Period will be 
contacted by the Investigator (or designee) approximately 30 to 35 days after their last 
dose of study drug to solicit changes to concomitant medications and AEs and SAEs.  
This follow-up contact will be the final contact for these subjects.
Observational Period
Only those subjects with a sperm concentration below 15 million/mL at any time during 
the Treatment Period or with a ≥ 50% reduction from Screening (baseline) at the end of 
the 26-week Treatment Period will enter the Observational Period. 
The Observational Period will consist of up to 4 study visits and last up to 52 weeks. 
●
The O1 (Week 13) visit will take place 13 weeks (± 7 days) after the subject's 
EOT visit.


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●
The O2 (Week 26) visit will take place 13 weeks (± 7 days) after the O1 visit 
with the remaining visits (O3 [Week 39] and O4 /End of Study [EOS; 
Week 52]) following every 13 weeks (± 7 days) thereafter.
The procedures to be performed at these visits are outlined in the Study Activities Table 
(Table 1). 
During the Observational Period duplicate semen samples will be collected until the 
subject's sperm concentration returns to within 15% of baseline or above, or until the end 
of the Observational Period.  At each visit, subjects will be provided with supplies and 
instructions for the collection of the semen samples, and will be scheduled for the 
collection of the semen samples according to the specific windows for semen collection 
(Section 5.3.2.1).  If at any time during the Observational Period the sperm concentration 
returns to within 15% of baseline or above, subjects will have completed their 
participation in the Observational Period.  The visit at which their sperm concentration 
returned to within 15% of baseline or above will be considered their End of Study visit.  
These subjects will also be contacted by the Principal Investigator (or designee) within 
14 days of the collection of the second semen sample.  This contact will be the final 
contact for these subjects.
All other subjects will continue study visits until the End of Study visit.
Section 5.2.1  Inclusion Criteria
Previously read:
1.
Male subject 30 to 75 years of age, inclusive at the time of Screening.
2.
Subject has voluntarily signed and dated an Informed Consent Form, approved by 
an Institutional Review Board (IRB)/Independent Ethics (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.


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3.
Subject has type 1or 2 diabetes and has been treated with at least 
one anti-hyperglycemic medication and ACEi or ARB (RAS inhibitor) for at least 
2 months prior to the Screening Period.
4.
Subject has an eGFR ≥ 50 mL/min with the CKD-EPI formula and UACR ≥ 30 to 
< 5,000 mg/g creatinine.
5.
Subject has a serum BNP < 200 ng/L.
6.
Subject has systolic blood pressure ≥ 110 and ≤ 160 mmHg.
7.
Subject has a serum potassium ≥ 3.5 and ≤ 5.5 mEq/L.
8.
Subject is able to provide a semen specimen at the required intervals.
9.
Subject has baseline sperm concentration ≥ 30 million per mL.
10.
Subject must be 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.
11.
Subject must agree not to donate sperm from initial study drug administration 
through 90 days after last dose of study drug.
12.
HbA1C ≤ 12%.
13.
Subject has a Follicle Stimulating Hormone (FSH) between 1.30 – 19.30 IU/L.
14.
Subject has a Luteinizing Hormone (LH) between 1.2 – 8.6 IU/L.


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15.
Subject has a total Testosterone between 3.0 – 10.0 ng/mL (300 – 1000 ng/dL) 
inclusive.
16.
Subjects currently using alpha blockers must be on a stable dose for at least 
3 months prior to screening and expected to remain on a stable dose during the 
study.
17.
Subject currently using 5 alpha reductase inhibitors must be on a stable dose for at 
least 6 months prior to screening and expected to remain on a stable dose during 
the study.  
Rationale for the Inclusion Criteria
(1, 3 – 7, 12)  To select the appropriate subject population with diabetes-related kidney 
disease.
(2)  In accordance with harmonized GCP.
(8, 9) To select a patient population with an acceptable sperm concentration for the 
evaluation.
(10, 11, 13 – 15)  The impact of Atrasentan on pregnancies is unknown.
Has been changed to read:
1.
Male subject 30 to 75 years of age, inclusive at the time of Screening.
2.
Subject has voluntarily signed and dated an Informed Consent Form, approved by 
an Institutional Review Board (IRB)/Independent Ethics (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 1or 2 diabetes and is receiving treatment with at least 
one anti-hyperglycemic medication and ACEi or ARB (RAS inhibitor).


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4.
Subject has an eGFR ≥ 35 mL/min/1.73 m2 with the CKD-EPI formula and UACR 
≥ 30 to < 5,000 mg/g creatinine (≥ 3.4 mg/mmol and < 565 mg/mmol).
5.
Subject has a serum BNP ≤ 200 pg/L (200 ng/mL).
6.
Subject has systolic blood pressure ≥ 110 and ≤ 180 mmHg at Screening.
7.
Subject has a serum potassium ≥ 3.5 (3.5 mmol/L) and ≤ 6.0 mEq/L (6.0 mmol/L).
8.
Subject is able to provide a semen specimen at the required intervals.
9.
Subject has a baseline sperm concentration ≥30 million per mL at Screening.
10.
If the subject is sexually active with female partner(s) of childbearing potential, he 
must agree, from initial study drug administration through 90 days after the last 
dose of study, to practice the protocol specified contraception (Section 5.2.4).
11.
Subject must agree not to donate sperm from initial study drug administration 
through 90 days after the last dose of study drug.
12.
(intentionally left blank; criterion deleted)
13.
(intentionally left blank; criterion deleted)
14.
(intentionally left blank; criterion deleted)
15.
Subject has a total Testosterone > 150 ng/dL (5.20 nmol/L).
16.
Subjects currently using alpha blockers must be on a stable dose for at least 
2 weeks prior to the initial screening visit and expected to remain on a stable dose 
during the study.
17.
Subject currently using 5 alpha reductase inhibitors must be on a stable dose for at 
least 3 months prior to the initial screening visit and expected to remain on a stable 
dose during the study.  
Rationale for the Inclusion Criteria
(1, 3 – 7)  To select the appropriate subject population with diabetes-related kidney 
disease.


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(2)  In accordance with harmonized GCP.
(8, 9, 15 – 17) To select a patient population with an acceptable sperm concentration for 
the evaluation.
(10, 11)  The impact of Atrasentan on pregnancies is unknown.
Section 5.2.2  Exclusion Criteria
Previously read:
1.
Prior history of prostate cancer with or without treatment.
2.
Untreated retrograde ejaculation or prior prostate surgery.  Subjects with treated 
retrograde ejaculation will be allowed with approval of the Study Designated 
Physician.
3.
Prior history of vasectomy.
4.
Prior history of radiation to the testes.
5.
Recent history (within 6 months) of STD, UTI, documented prostatitis, orchitis, 
epididymitis.
6.
History of male infertility.
7.
Prior history of occupational exposure to environmental toxins within the past 
6 months.
8.
Drug, alcohol or substance abuse within the last 6 months.
9.
Treatment with hormone suppressive agents, including androgens, estrogens, 
anabolic steroids, glucocorticoids, ketoconazole, cyclosporine, or cancer 
chemotherapy within the past 6 months or planned during the study.
10.
Subject has a body mass index (BMI) > 45.
11.
Subject has a history of hormone replacement therapy.
12.
Subject has evidence or history of hypogonadism.


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13.
Current hot tub/Jacuzzi/sauna use or within the previous 12 weeks.
14.
Renal transplant.
15.
Subject has a history of moderate or severe peripheral edema, pulmonary edema or 
facial edema unrelated to trauma or a history of myxedema in the prior 6 months to 
Screening.
16.
Subject has a history of pulmonary hypertension requiring either oxygen therapy, 
and/or endothelin receptor antagonist or phosphodiesterase therapy or any lung 
diseases requiring oxygen therapy (e.g., chronic obstructive pulmonary disease, 
emphysema, pulmonary fibrosis).
17.
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.
18.
Subject has elevated liver enzymes (serum alanine aminotransaminase [ALT] 
and/or serum aspartate aminotransaminase [AST]) > 3 × the upper limit of normal 
(ULN).
19.
Subject has a hemoglobin < 9 g/dL.
20.
Subject has a history of an allergic reaction or significant sensitivity to Atrasentan 
(or its excipients) or similar compounds.
21.
Subject has significant comorbidities (e.g., advanced malignancy, advanced liver 
disease) with a life expectancy of less than 1 year.
22.
Subject has clinically significant cerebrovascular disease (CVD) or coronary artery 
disease (CAD) within 3 months prior to the Screening Period, defined as one of the 
following:
●
Hospitalization for MI or unstable angina; or


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●
New onset angina with positive functional study or coronary angiogram 
revealing stenosis; or
●
Coronary revascularization procedure; or
●
Transient ischemic attack (TIA) or stroke.
23.
Subject has received any investigational drug within 3 months prior to Screening.
24.
Subject is currently receiving rosiglitazone, moxonidine, aldosterone blockers, 
aliskiren or a combination of ACEi and ARB.
25.
Subjects with known allergy to thiazide or loop diuretics.
26.
Is considered by the Investigator unsuitable to participate in the trial for any other 
reason, for instance due to a significant serious underlying condition.
Rationale for the Exclusion Criteria
(10, 13 – 29)  To ensure the safety of subjects throughout the study.
(11, 12, 23)  To avoid bias for the evaluation of safety by concomitant use of other 
medications.
(1 – 10)  To exclude an inappropriate subject population.
Has been changed to read:
1.
Prior history of prostate cancer with or without treatment.
2.
Untreated retrograde ejaculation or anejaculation; history of prostatectomy with 
aspermia.  Subjects with treated retrograde ejaculation will be allowed with 
approval of the Study Designated Physician.
3.
Prior history of vasectomy unless subject has undergone reversed vasectomy.
4.
(intentionally left blank; criterion deleted)
5.
Currently symptomatic and receiving treatment for sexually transmitted disease 
(STD), prostatitis, orchitis or epididymitis.


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6.
(intentionally left blank; criterion deleted)
7.
(intentionally left blank; criterion deleted)
8.
Drug, alcohol or substance abuse within the 3 months prior to the initial screening 
visit.
9.
Subject has had treatment with hormone suppressive agents, including androgens, 
estrogens, anabolic steroids, glucocorticoids, ketoconazole, cyclosporine, or cancer 
chemotherapy within the 6 months prior to the initial screening visit or planned 
during the study.
10.
(intentionally left blank; criterion deleted)
11.
Subject is currently receiving or has received hormone replacement therapy within 
the 6 months prior to the initial screening visit.
12.
(intentionally left blank; criterion deleted)
13.
(intentionally left blank; criterion deleted)
14.
Renal transplant.
15.
Subject has a history of severe peripheral edema or facial edema unrelated to 
trauma or a history of myxedema in the prior 4 weeks prior to the initial screening 
visit.
16.
Subject has a history of pulmonary hypertension, pulmonary fibrosis or any lung 
diseases requiring oxygen therapy (e.g., chronic obstructive pulmonary disease, 
emphysema).
17.
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.


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18.
Subject has elevated liver enzymes (serum alanine aminotransaminase [ALT] 
and/or serum aspartate aminotransaminase [AST]) > 3 × the upper limit of normal 
(ULN) during the Screening Period.
19.
Subject has a hemoglobin < 9 g/dL during the Screening Period.
20.
Subject has a history of an allergic reaction or significant sensitivity to Atrasentan 
(or its excipients) or similar compounds.
21.
Subject has significant comorbidities (e.g., advanced malignancy, advanced liver 
disease) with a life expectancy of less than 1 year.
22.
Subject has clinically significant cerebrovascular disease (CVD) or coronary artery 
disease (CAD) within 3 months prior to the initial screening visit, defined as one of 
the following:
●
Hospitalization for Myocardial Infarction or unstable angina; or
●
New onset angina with positive functional study or coronary angiogram 
revealing stenosis; or
●
Coronary revascularization procedure; or
●
Transient ischemic attack (TIA) or stroke.
23.
Subject has received any investigational drug within 3 months prior to the initial 
screening visit.
24.
Subject is currently receiving rosiglitazone, moxonidine, aldosterone blockers, 
aliskiren or a combination of ACEi and ARB.
25.
Subjects with known allergy to both thiazide and loop diuretics.
26.
The subject is considered by the Investigator unsuitable to participate in the trial for 
any other reason, for instance due to a significant serious underlying condition.
Rationale for the Exclusion Criteria
(1 – 3, 5, 8, 26)  To exclude an inappropriate subject population.


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(9, 11)  To avoid bias for the evaluation of safety by concomitant use of other 
medications.
(14 – 25)  To ensure the safety of subjects throughout the study.
Section 5.2.3  Prior and Concomitant Therapy
Previously read:
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 Screening, 
or 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 Treatment or 
Observational Periods of the study will be allowed.  When returning to RASi therapy, 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).  Potent P-gp inhibitors may potentially increase the plasma exposure of 
Atrasentan.  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 patients taking 
any of these medications during the trial.
The AbbVie study designated physician should be contacted if there are any questions 
regarding concomitant or prior therapy(ies).


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Has been changed to read:
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 Screening, 
or 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. 
The AbbVie study designated physician (listed in Section 6.5) should be contacted if there 
are any questions regarding concomitant or prior therapy(ies).
5.2.3.1
Prior Therapy
Subjects currently using alpha blockers should have been on a stable dose for at least 
2 weeks prior to the initial screening visit and must be on a stable dose during the study.
Subjects currently using 5-alpha reductase inhibitors should have been on a stable dose for 
at least 3 months prior to the initial screening visit and must be on a stable dose during the 
study. 
5.2.3.2
Concomitant Therapy
If medically necessary, changes to or interruption of ACEi or ARB doses during the 
Treatment or Observational Periods of the study will be allowed.  Plasma levels of 
Atrasentan may be affected by concomitant use of CYP3A or OATP inhibitors 
(e.g., protease inhibitors, clarithromycin, ketoconazole, gemfibrozil, ciclosporin).  Potent 
P-gp inhibitors may potentially increase the plasma exposure of Atrasentan.  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 patients taking any of these 
medications during the trial.


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Section 5.2.3.1  Prohibited Therapy
First paragraph, first sentence previously read:
Subjects should not enter into the study if they have a documented history of receiving 
testosterone or hormone replacement therapy within 6 months of Screening.
Has been changed to read:
Subjects should not enter into the study if they are currently receiving or have received 
testosterone or hormone replacement therapy within 6 months of the initial screening visit.
Section 5.2.3.1  Prohibited Therapy
Add:  new third paragraph
Combinations of ACEi/ARB medications and/or concomitant use of aldosterone blockers 
or aliskiren are not allowed.
Section 5.2.3.1  Prohibited Therapy
Third paragraph previously read:
Hot tub/Jacuzzi/sauna use are prohibited 12 weeks prior to Screening and during the 
study.
Has been changed to read:
Use of hot tub/Jacuzzi/sauna are prohibited during the study.
Section 5.2.3.2  Guidance for Managing Edema or Weight Gain
First paragraph, first sentence previously read:
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).


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Has been changed to read:
Weight will be measured at each visit during the Treatment Period of 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).
Section 5.2.3.2  Guidance for Managing Edema or Weight Gain
Seventh paragraph previously read:
If weight continues to increase (i.e., > 3 kg in 6 weeks or the previous visit during the 
Treatment Period), despite the modification in the doses of diuretics, contact the study 
designated physician for the study.
Has been changed to read:
If weight continues to increase (i.e., > 3 kg in 6 weeks or the previous visit during the 
Treatment Period) despite the modification in the doses of diuretics, contact the study 
designated physician.
Section 5.2.4  Contraception Recommendations
Add:  new section title and text
5.2.4
Contraception Recommendations
If the male subject has a female partner who is postmenopausal or permanently sterile 
(bilateral oophorectomy, bilateral salpingectomy or hysterectomy), no contraception is 
required.
If the subject is sexually active with female partner(s) of childbearing potential, he must 
agree from initial study drug administration through 90 days after the last dose of study 
drug to practice contraception with:
●
Condom use and female partner(s) using at least one of the following 
contraceptive measures
○
Intrauterine device (IUD);
○
hormonal contraceptives (oral, vaginal, parenteral or transdermal);


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○
Barrier method (contraceptive sponge, diaphragm, or vaginal ring with 
spermicidal jellies or creams).
●
True abstinence:  refraining from sexual intercourse when this is line with the 
preferred and usual lifestyle of the subject.  (Note:  Periodic abstinence 
[e.g., calendar, ovulation, symptothermal, post-ovulation methods] and 
withdrawal are not acceptable).
Additionally, subject agrees not to donate sperm from initial study drug administration 
through 90 days after the last dose of study drug.
Section 5.3.1  Efficacy and Safety Measurements Assessed and Flow Chart
Add:  new first paragraph 
Study procedures described in this protocol are summarized in Table 1.


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Table 1.  Study Activities
Previously read:
Screening Period
(–14 Days)a
Treatment Periodb
Observational Periodb
Activity
Screening
T1c
(Day 1)
T2 
(Week 2)
T3 
(Week 4)
T4 
(Week 6)
T5 
(Week 13)
T6/EOT 
(Week 26)m
O1 
(Week 6)
O2, O3, O4
(Weeks 13, 
26, 39)
O5/End of 
Studyn
(Week 52)
Informed Consentd
X
Medical History
X
X
Concurrent Medications
X
X
X
X
X
X
X
X
X
X
Complete Physical Exam
X
X
Vital Signse
X
X
X
X
X
X
X
X
X
X
Semen Samplesf
X
X
X
X
X
X
Xg
Assess Peripheral Edema
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
Hematology
X
X
X
X
X
X
X
X
Limited Chemistry
X
X
X
Complete Chemistry
X
X
X
X
X
Lipid Profile (fasting)h
X
X
X
BNP
X
X
X
X
HbA1c
X
X
X
Urinalysis
X
X
X


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Screening Period
(–14 Days)a
Treatment Periodb
Observational Periodb
Activity
Screening
T1c
(Day 1)
T2 
(Week 2)
T3 
(Week 4)
T4 
(Week 6)
T5 
(Week 13)
T6/EOT 
(Week 26)m
O1 
(Week 6)
O2, O3, O4
(Weeks 13, 
26, 39)
O5/End of 
Studyn
(Week 52)
FMV Urine Collection for 
UACRi
X
X
X
Serum total T, estradiol, LH, 
FSH, inhibin Bj
X
X
X
X
X
X
X
X
IVRS Call
X
X
X
X
Monitor AEs and SAEsk
X
X
X
X
X
X
X
X
X
X
PK Analysisl
X
X
X
Drug Accountability/ 
Compliance Assessment
X
X
X
X
X
a.
Screening procedures and laboratory tests may be repeated during the Screening Period, per the Investigator's discretion.  Semen samples may be repeated per Section 5.3.2.5.
b.
All Treatment and Observation Period visits must be completed be completed with + 5/–0 days of the expected visit date.  
c.
Day 1 should be completed within 14 days from initial screening assessments or screening laboratory assessments must be repeated.
d.
Informed consent can be collected up to 30 days prior to Screening.  Informed consent should be obtained prior to performing any study procedures.
e.
Vital signs include BP, weight, temperature and pulse rate will be collected at every visit.  Height will be collected at initial Screening visit only.  Weight gain will be assessed 
at each visit.  Resting BP will be measured two times in the non-dominant arm using the appropriate cuff size at least 2 minutes apart.
f.
Two samples should be collected within a 7-day period, with each sample separated by at least 2 days.  Subject must abstain from ejaculation 2 days but no more than 7 days 
prior to collection.  For Screening, subjects will be scheduled for the duplicate semen collections to be completed within the 14 day Screening Period and adhering to the 
specific windows for semen collection noted in Section 5.3.2.1.  If Day 1 is not completed within 14 days from the second screening semen sample, the screening semen 
collections must be repeated.
g.
Subjects completing the End of Study visit after returning to sperm concentration baseline (± 15%) during the Observational Period will not provide a semen sample during 
the EOS visit.
h.
Lipid profile tests will be done under fasting conditions.


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i.
For Screening, subjects will be given supplies and instructions for the two consecutive FMV urine collections, which should be collected and returned to the study site within 
the 14-day Screening Period.  For Treatment and Observation visits, the first morning void (FMV) urine collection will consist of one first morning void sample collected 
within 1 day of the visit.
j.
Total testosterone sample should be collected at approximately the same time of day at each visit.
k.
Only serious adverse events (SAEs) will be collected from informed consent until Day 1.  All adverse events (serious and nonserious) will be captured beginning the time of 
informed consent through 30 days after the last dose of study drug.  For subjects entering the Observational Period, protocol-related adverse events (serious and nonserious) 
will be collected beginning 30 days after the last dose of study drug through the End of Study.
l.
Blood samples only to be collected for Atrasentan PK analysis and possible metabolites of atrasentan at the following visits:  T3 (immediately before dose and 15 minutes, 
30 minutes, 1 hour post dose), T4 (immediately before dosing), T5 (immediately before dosing).
m.
All subjects should be contacted 30 to 35 days after the last dose of study drug to solicit AEs and SAEs.  For subjects not entering the Observational Period, this contact will 
be the final study contact. 
n.
During the Observational Period, when subjects return to their baseline sperm concentration value (± 15%), they will return within 14 days for the End of Study visit.


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Has been changed to read:
Activity
Screening 
Period 
(Up to 
4 Weeks)a
Treatment Periodb
Observational Periodb,c
FU 
Contactd
T1e
(Day 1)
T2 
(Week 2)
T3 
(Week 4)
T4 
(Week 6)
T5 
(Week 13)
T6/EOT 
(Week 26)f
O1 
(Week 13)
O2, O3 
(Weeks 
26, 39)
O4/End 
of Study 
(Week 52)
Informed Consentg
X
Medical History
X
Xh
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Complete Physical Exam
X
X
Vital Signsi
X
X
X
X
X
X
X
X
X
X
Semen Sample Collectionj
X
X
X
X
X
X
Assess Peripheral Edema
X
X
X
X
X
X
X
12-Lead ECG
X
X
Hematology
X
X
X
X
X
X
X
X
X
Limited Chemistry
X
X
Complete Chemistry
X
X
X
X
X
X
X
BNP
X
X
X
HbA1c
X
X
X
Urinalysis
X
X
X
FMV Urine Collection for 
UACRk
X
X
Serum total T, estradiol, LH, 
FSH, inhibin Bl
X
X
X
X
X
X
X
X
X
IVRS Call
X
X
X
X


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Activity
Screening 
Period 
(Up to 
4 Weeks)a
Treatment Periodb
Observational Periodb,c
FU 
Contactd
T1e
(Day 1)
T2 
(Week 2)
T3 
(Week 4)
T4 
(Week 6)
T5 
(Week 13)
T6/EOT 
(Week 26)f
O1 
(Week 13)
O2, O3 
(Weeks 
26, 39)
O4/End 
of Study 
(Week 52)
Monitor AEs and SAEsm
X
X
X
X
X
X
X
X
X
X
X
PK Analysisn
X
X
X
Dispense Study Drug
X
X
Drug Accountability/Compliance 
Assessment
X
X
X
X
X
a.
Screening procedures and laboratory tests may be repeated during the Screening Period, per the Investigator's discretion.  Semen samples may be repeated per Section 5.3.2.5.
b.
All Treatment and Observational Period visits must be completed within ± 7 days of the expected visit date.
c.
If at any time during the Observational Period, the sperm concentration returns to within 15% of baseline or above, subjects will have completed their participation in the 
Observational Period.  The visit at which their sperm concentration returned to within 15% of baseline or above will be considered their End of Study visit.
d.
Subjects not entering the Observational Period should be contacted by the Principal Investigator (or designee) 30 – 35 days after the last dose of study drug.  Subjects who 
have returned to within 15% of their baseline sperm concentration or above during the Observational Period should be contacted by the Principal Investigator (or designee) 
within 14 days of the collection of the second semen sample.
e.
The T1/Day 1 visit should be completed within 4 weeks from the initial screening visit.
f.
Subjects completing the End of Treatment Visit because their sperm concentration has dropped below 15 million/mL during the Treatment Period will not provide duplicate 
semen samples at the T6/EOT visit.
g.
Informed consent can be collected up to 30 days prior to conduct of initial study procedures.
h.
Updates only.
i.
Vital signs include BP, weight, temperature and pulse rate will be collected at every visit.  Height will be collected at initial Screening visit only.  Weight gain will be assessed 
at each visit during the Treatment Period.  
j.
Subjects will be scheduled for the collection of the duplicate semen samples according to the specific windows for semencollection noted in Section 5.3.2.5. 
k.
For Screening, subjects will be given supplies and instructions for the FMV urine collection, which should be collected and returned to the study site within the 4-week 
Screening Period.  For the T6/EOT visit, the first morning void (FMV) urine collection will be collected within 1 day before the visit.
l.
Total testosterone sample should be collected at approximately the same time of day at each visit.


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m.
Protocol-related non-serious and serious adverse events (SAEs) will be collected from the time the subject signs the study-specific informed consent.  All adverse events 
(serious and nonserious) will be captured from the time of study drug administration through 30 days after the last dose of study drug.  For subjects entering the Observational 
Period, protocol-related non-serious and serious adverse events will be collected beginning 30 days after the last dose of study drug through the post-therapy Observational 
Period.
n.
Blood samples only to be collected for atrasentan PK analysis and possible metabolites of atrasentan at the following visits:  T3/Week 4 (immediately before dose and 
15 minutes, 30 minutes, 1 hour post dose), T4/Week 6 (immediately before dosing) and T5/Week 13 (immediately before dosing).


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Section 5.3.1.1  Study Procedures
Subsection Informed Consent
First sentence previously read:
A signed informed consent will be obtained from the patient before any study procedures 
are undertaken at the Screening visit.
Has been changed to read:
A signed informed consent will be obtained from the patient before any study procedures 
are undertaken at the initial screening visit.
Section 5.3.1.1  Study Procedures
Subsection Medical History
First paragraph, first sentence previously read:
A complete medical history, including history of tobacco and alcohol use and 
colonoscopy history, will be obtained from each patient during the initial Screening visit 
and updated during the Screening Period and Day 1 visit, as necessary.
Has been changed to read:
A complete medical history, including history of tobacco and alcohol use and 
colonoscopy history, will be obtained from each patient during the initial Screening visit 
and updated during the Screening Period and at the T1/Day 1 visit, as necessary.
Section 5.3.1.1  Study Procedures
Subsection Physical Examination
First paragraph, first sentence previously read:
A complete physical examination will be performed at the Screening visit (baseline) and 
the T6/EOT visit.
Has been changed to read:
A complete physical examination will be performed at the T1/Day 1 visit (baseline) and 
the T6/EOT visit.


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Section 5.3.1.1  Study Procedures
Subsection Vital Signs
First, second, and third sentence previously read:
Vital sign determination of sitting BP, weight, temperature and pulse rate will be obtained 
at all visits.  Vital signs performed at the Day 1 visit will serve as the baseline.  Weight 
gain will be assessed at every visit.
Has been changed to read:
Vital sign determination of sitting BP, weight, temperature and pulse rate will be obtained 
at all on-site visits.  Vital signs performed at the T1/Day 1 Visit will serve as the baseline.  
Weight gain will be assessed at every visit during the Treatment Period.
Section 5.3.1.1  Study Procedures
Subsection Assessment of Edema
First paragraph, first sentence previously read:
Assessment of edema will be performed at every visit.
Has been changed to read:
Assessment of edema will be performed at Screening and at every Treatment Visit.
Section 5.3.1.1  Study Procedures
Subsection 12-Lead Electrocardiogram (ECG)
Previously read:
A 12-lead resting ECG will be obtained at the Day 1 visit and the T6/EOT visit.  The 
ECG measurements at the Day 1 visit will serve as the baseline measurements for clinical 
assessment.
Has been changed to read:
A 12-lead resting ECG will be obtained at the T1/Day 1 visit prior to initial dose of study 
drug and at the T6/EOT visit.  The ECG measurements at the T1/Day 1 visit will serve as 
the baseline measurements for clinical assessment.


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Section 5.3.1.1  Study Procedures
Subsection First Morning Void (FMV) Urine Sample Collection
First paragraph, first, second, and third sentence previously read:
Two first morning void urine collections will be obtained during the Screening Period.  
One first morning void urine sample will be obtained prior to the T6 (EOT) and O1 visits.  
The first morning void is defined as the subject's first void after 5:00 AM.
Has been changed to read:
One first morning void urine collection will be obtained during the Screening Period, and 
prior to the T6/EOT visit.  The first morning void is defined as the subject's first void after 
5:00 AM or upon rising for the day.
Section 5.3.1.1  Study Procedures
Subsection Safety Contact
Delete:  subsection title and text
Safety Contact
All subjects should be contacted 30 – 35 days after the last dose of study drug to solicit 
adverse events (serious and nonserious).
Section 5.3.1.1  Study Procedures
Subsection Randomization and Assignment of Subject Numbers
Delete:  subsection title and text
Randomization and Assignment of Subject Numbers
All inclusionary screening laboratory results must be reviewed prior to registering the 
subject for treatment in IVRS/IWRS.  At the Screening visit, each subject will be assigned 
a unique 4-digit subject number by the IVRS/IWRS.  The first 2 digits will be the site 
number (i.e., 10 to 99), the third and fourth digits will be assigned in ascending numerical 
order at each site.


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Section 5.3.1.1  Study Procedures
Subsection Laboratory Tests
Previously read:
Samples will be obtained for the laboratory tests listed in Table 2 at the visits specified in 
Table 1.  Blood draws should be performed after vital sign determinations have been 
completed for each visit.
The CKD-EPI formula will be used to calculate eGFR at the Screening visit to determine 
eligibility for the study.
One hormone measurement will be taken at each visit as noted in Table 1.  The 
testosterone sample should be collected at approximately the same time of the day at each 
visit.
A central laboratory will be utilized for the clinical laboratory tests.  Instructions 
regarding the collection, processing, and shipping of these samples will be provided by 
the central laboratory chosen for this study.
The Investigator will review all laboratory test results in a timely manner.  All laboratory 
test results that are considered clinically significant by the Investigator will be followed to 
a satisfactory resolution.


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Table 2.
Clinical Laboratory Tests
Hematology
Clinical 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,
sodium,
potassium,
chloride, urea nitrogen
Limited Chemistry
Sodium
Albumin
Potassium
Bicarbonate
Creatinine
Chloride
BUN
Additional Tests
BNP
Pharmacokinetic measurement
HbA1c
Serum total T
Estradiol
LH
FSH
Inhibin B
*
Lipid and metabolic profile tests (obtained under fasting conditions).
Has been changed to read:
A central laboratory will be utilized for the clinical laboratory tests.  Samples will be 
obtained for the laboratory tests listed in Table 2 at the visits specified in Table 1.  Blood 
draws should be performed after vital sign determinations have been completed for each 
visit.
The Investigator will review all laboratory test results in a timely manner.  All laboratory 
test results that are considered clinically significant by the Investigator will be followed to 
a satisfactory resolution. 


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Instructions regarding the collection, processing, and shipping of these samples will be 
provided by the central laboratory chosen for this study.
Table 2.
Clinical Laboratory Tests
Hematology
Clinical 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
Potassium
Chloride
Cholesterol
Creatinine
Direct Bilirubin
Glucose
LDH
Phosphorus
Sodium
Total bilirubin
Total protein
Triglycerides
Uric acid
Blood
Glucose
Ketones
pH
Protein
Specific gravity
Urine Tests
First morning void urine:
UACR
Limited Chemistry
Sodium
Albumin
Potassium
Bicarbonate
Creatinine
Chloride
BUN
Additional Tests
BNP
Pharmacokinetic measurement
HbA1c
Serum total T*
Estradiol
LH
FSH
Inhibin B
*
The testosterone sample should be collected at approximately the same time of the day at each visit.
The CKD-EPI formula will be used to calculate eGFR at the Screening visit to determine 
eligibility for the study.  The central laboratory will also calculate the eGFR on the 
laboratory profile report at each visit during the Treatment and Observational Periods.
Section 5.3.2.1  Blood Samples for Pharmacokinetic Analysis
Section title previously read:
Blood Samples for Pharmacokinetic Analysis


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Has been changed to read:
Collection of Samples for Pharmacokinetic Analysis
Section 5.3.2.1  Blood Samples for Pharmacokinetic Analysis
First paragraph previously read:
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 the T3 (Week 4) visit at immediately prior to dose and 15 minutes, 
30 minutes and 1 hour post dose and at the T4 (Week 6) visit and the T5 (Week 13) 
immediately before dosing.
Has been changed to read:
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 the T3 (Week 4) visit at immediately prior to dose and 15 minutes, 
30 minutes and 1 hour post dose and at the T4 (Week 6) visit immediately before dosing 
and the T5 (Week 13) immediately before dosing.
Section 5.3.2.1  Blood Samples for Pharmacokinetic Analysis
Second paragraph, last sentence previously read:
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.
Has been changed to read:
The date and time of collection of 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.


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Section 5.3.2.5  Collection of Semen Samples for Analysis
Previously read:
Samples will be obtained for the tests listed in Table 3 at the time-points specified in 
Table 1.  Duplicate semen samples should be collected at each time-point over a 7-day 
period with each sample being separated by at least 2 days.  If for any reason one of the 
duplicate samples is inadequate or not obtained, then a replacement sample will be 
collected to ensure that two samples are available for each time-point.  If clinically 
relevant confounding symptoms, illness or conditions are suspected, a replacement 
sample/samples may be obtained at the investigator's discretion.  All semen samples for a 
time-point must be collected within a 14-day period.  Subjects must abstain from 
ejaculation for at least 2 days but not more than 7 days prior to semen sample collection.  
The average of the 2 semen samples will be used as the value for that time-point.  
Samples should be collected at the required visits after all study procedures have been 
completed.  Semen sample will be sent for processing as soon as possible after collection.  
Semen motility analysis should be started with 1 hour of sample collection.  The full 
ejaculate must be captured at each semen collection.  Subjects should be evaluated, per 
the site's standard procedure, for retrograde ejaculation if the full ejaculate is < 1.0 mL.  
The Study Designated Physician should be consulted if retrograde ejaculation is identified 
or diagnosed at any time during the study.  If the full ejaculate is not captured in the 
collection container, then a replacement specimen should be collected.
Has been changed to read:
Semen samples will be obtained for the tests listed in Table 3 during the scheduled 
collection period for the visits specified in Table 1.  Semen samples should be collected at 
2 time-points over a 7-day period with each sample being separated by at least 2 days.  If 
for any reason one of the duplicate samples is inadequate or not obtained, then a 
replacement sample will be collected to ensure that two samples are available for each 
scheduled collection period.  If clinically relevant confounding symptoms, illness or 
conditions are suspected, replacement sample/samples may be obtained at the 
investigator's discretion.  All semen samples for a scheduled collection period must be 


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collected within 14 days of the collection of the first semen sample.  Subjects must abstain 
from ejaculation for at least 2 days but not more than 7 days prior to semen sample 
collection.  The average of the 2 semen samples will be used as the value for that 
collection period.  If the semen sample is collected at the scheduled study visit, the sample 
should be obtained after all study procedures have been completed.  
The semen sample will be sent for processing as soon as possible after collection.  Semen 
motility analysis should be started with 1 hour of sample collection.  The full ejaculate 
must be captured at each semen collection.  Subjects should be evaluated, per the site's 
standard procedure, for retrograde ejaculation if the full ejaculate is < 1.0 mL.  The Study 
Designated Physician should be consulted if retrograde ejaculation is identified or 
diagnosed at any time during the study.  If the full ejaculate is not captured in the 
collection container, then a replacement specimen should be collected.
Section 5.3.2.6  Handling/Processing of Samples
Previously read:
Detailed instructions regarding collection and preparation of the semen samples will be 
provided by the local laboratory processing the semen specimen.  The specimen container 
should be kept at ambient temperature, between 30° and 37°C, to avoid temperature 
changes that may affect the spermatozoa.  It must be labeled, per the instructions provided 
by the morphology laboratory, with the subject's initials, subject number, study visit, 
sample identifier, and the date and time of collection.
Has been changed to read:
Detailed instructions regarding collection and preparation of the semen samples will be 
provided by the local laboratory processing the semen specimen.  The specimen container 
should be kept at ambient temperature, between 30° and 37°C, to avoid temperature 
changes that may affect the spermatozoa.  
The local laboratory processing the semen specimens will analyze the samples for 
volume, concentration and motility following their standard operating procedures, and 


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will prepare 4 slides for morphology analysis to be conducted by the central morphology 
laboratory (Tulane Andrology Laboratory).  Written instructions on preparation and fixing 
of sperm morphology slides and shipment to the central morphology laboratory will be 
provided to the site semen analysis laboratory.  Slides must be labeled, per the instructions 
provided by the morphology laboratory, with the subject's initials, subject number, study 
visit, sample identifier, and the date and time of collection.
Morphology slides will be sent for morphology analysis to:
Tulane Andrology Laboratory
1430 Tulane Ave., SL-42; 
 
New Orleans, LA  70112-2699
United States
Section 5.3.4.1  Primary Safety Variable
Previously read:
The proportion of subjects who have a sperm concentration < 15 × 106/mL by 26 weeks.
Has been changed to read:
The primary safety variable is the proportion of subjects who have a sperm concentration 
< 15 × 106/mL during the 26-week Treatment Period.
Section 5.3.4.2  Secondary Safety Variables
First bullet list 
First bullet previously read:
The proportion of subjects who enter the Observation Period and do not return to within 
15% of baseline by 52 weeks after treatment discontinuation.   
Has been changed to read:
The proportion of subjects who enter the Observational Period and do not return to within 
15% of baseline or above during the 52-week Observational Period.   


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Section 5.3.4.2  Secondary Safety Variables
First bullet list 
Third bullet previously read:
Change from baseline to each visit in each of the components of the semen analysis 
(sperm motility, sperm morphology, sperm concentration, semen volume).
Has been changed to read:
Change from baseline to each visit in each of the components of the semen analysis 
(sperm motility, sperm morphology, sperm count, semen volume).
Section 5.3.4.2  Secondary Safety Variables
First paragraph, first sentence previously read:
Safety data will be analyzed for the data collected throughout Treatment Period and up to 
30 days post-treatment.
Has been changed to read:
Safety data will be analyzed for the data collected throughout Treatment Period and up to 
35 days post-treatment.
Section 5.4.1  Discontinuation of Individual Subjects
Previously read:
Subjects will be discontinued from study drug immediately if any of the following events 
occur:
●
Subject has a weight gain of > 3 kg compared to T1/Day 1 AND a BNP of 
> 300 ng/L at the T4 (Week 6) visit.
●
Subject has an increase in serum creatinine > 0.5 mg/dL (> 48 umol/L) AND 
> 20% increase from baseline at the T4 (Week 6) visit.
●
Clinically significant deterioration of the subject's medical status that is 
thought to possibly or probably be related to study drug by the Investigator.
●
The subject requests withdrawal from the study.


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●
Investigator request (for any reason).
●
Achievement of the primary study endpoint (sperm concentration sperm 
concentration < 15 × 106/mL).
●
ESRD as defined by confirmed eGFR < 15 mL/min/1.73 m2.
●
Subject is lost to follow-up.
If the subject is permanently discontinued from study drug, the procedures outlined for the 
T6/End of Treatment visit must be completed within 5 days (±2 days) of the last dose of 
study drug.  Following discontinuation of the study drug, the subject will continue to be 
monitored until sperm concentration returns to baseline (±15%) or through the O5/EOS 
visit, whichever occurs first unless the subject withdraws consent.
Subjects who prematurely discontinue from the Treatment Period will not be replaced 
unless the discontinuation rate exceeds 25% in the Treatment Period.  Subjects may be 
added to ensure that 15 evaluable subjects are assessed.  
If the subject is permanently discontinued from the Observation Period, the procedures 
outlined for the O5/End of Study visit must be completed within 5 days (± 2 days) of the 
discontinuation.  The date and reason for premature discontinuation in either period will 
be recorded in the subject's source documents and on the appropriate eCRF.   
Has been changed to read:
Subjects will be discontinued from study drug immediately if any of the following events 
occur:
●
Clinically significant deterioration of the subject's medical status that is 
thought to possibly or probably be related to study drug by the Investigator.
●
The subject requests withdrawal from the study.
●
Investigator request (for any reason).
●
Achievement of the primary study endpoint (sperm concentration 
< 15 × 106/mL).
●
Chronic dialysis or renal transplant.


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●
Subject is lost to follow-up.
If the subject is permanently discontinued from study drug and does not meet the criteria 
to enter the Observational Period, the procedures outlined for the T6/End of Treatment 
visit must be completed 5 days (± 3 days) of the last dose of study drug.  Additionally, the 
subject will be contacted by the Investigator (or designee) approximately 30 to 35 days 
after their last dose of study drug.
If the subject meets the criteria to enter the Observational Period during the Treatment 
Period, the subject will permanently discontinue from study drug and the procedures 
outlined for the T6/End of Treatment visit should be completed 5 days (± 3 days) of the 
last dose of study drug.  Following discontinuation of the study drug, the subject will 
continue to be monitored during the Observational Period until sperm concentration 
returns to within 15% of baseline or above, or through the O4/EOS visit, whichever 
occurs first unless the subject withdraws consent.
Subjects who prematurely discontinue from the Treatment Period for other reasons than 
achievement of the primary study endpoint, will not be replaced unless the discontinuation 
rate exceeds 25% in the Treatment Period.  Subjects may be added to ensure that 
15 evaluable subjects are assessed.  
If the subject is permanently discontinued from the Observational Period for other reasons 
than returning to within 15% of their baseline sperm concentration or above, the 
procedures outlined for the O4/End of Study visit must be completed 5 days (± 3 days) of 
the discontinuation.  
The date and reason for premature discontinuation in either period will be recorded in the 
subject's source documents and on the appropriate eCRF.   
Section 5.5.1  Treatments Administered
Previously read:
Each subject will receive 0.75 mg Atrasentan once daily for 26 weeks.


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Has been changed to read:
Each subject will receive 0.75 mg Atrasentan once daily for up to 26 weeks.
Table 4.  Identity of Investigational Products
Delete:  table note
Note: All tablets will be identical in appearance.
Section 5.5.2.2  Storage and Disposition of Study Drugs
Previously read:
The study drug must be stored between (15° to 25°C/59° to 77°F), in the supplied bottle 
which contains a desiccant.  Desiccant canister should be returned to the bottle directly 
after each tablet removal.  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 or returned to AbbVie.
Has been changed to read:
The study drug must be stored between (15° to 25°C/59° to 77°F), 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, 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 


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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.
Section 5.5.3  Method of Assigning Subjects to Treatment Groups
Second sentence previously read:
Subjects meeting entry criteria will be will be centrally registered using an Interactive 
Voice Response System/Interactive Web Response System (IVRS/IWRS).
Has been changed to read:
Subjects meeting entry criteria will be centrally registered using an Interactive Voice 
Response System/Interactive Web Response System (IVRS/IWRS).
Section 5.5.6  Treatment Compliance
Delete:  third, fourth, and fifth paragraph 
To calculate compliance per bottle 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.
Section 5.6.1  Discussion of Study Design and Choice of Control Groups
Add:  new paragraph
This study is designed to assess the effects of Atrasentan on spermatogenesis and 
testicular function during treatment period and up to 52 weeks follow-up.  The open-label 
design is chosen for this study because no change in spermatogenesis or testicular 
function is expected without treatment in healthy volunteers.


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Section 5.6.3  Suitability of Subject Population
Add:  new first and second paragraph
The purpose of this study is to assess the effects of Atrasentan on spermatogenesis and 
testicular function by assessing sperm concentration in subjects with Type 1 or 2 diabetes 
and nephropathy who are also being treated with a RAS inhibitor.
Therefore, subjects who have been treated with a RAS inhibitor (ACEi or ARBs), who 
have an estimated GFR ≥ 35 mL/min/1.73 m2 with the CKD-EPI formula and UACR ≥ 30 
to < 5,000 mg/g creatinine (≥ 3.4 mg/mmol and < 565 mg/mmol) with sperm and 
testosterone levels within normal ranges have been selected as the target population.  
Subjects who have underlying diseases/conditions and/or on medications affecting 
spermatogenesis or testicular function, history of allergic reaction or significant sensitivity 
to atrasentan or drugs similar to the study drug will be excluded to avoid confounding 
factors related to the effects being studied.
Section 5.6.4  Selection of Doses in the Study
Add:  new first and second paragraph
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 Atrasentan for up to 26 weeks during theTreatment Period. 
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.  The 
simulations, however, also showed that the probability of edema increases with increasing 
atrasentan exposure with predicted incidences of 32% and 38% at a dose of 1.25 mg and 


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1.5 mg per day.  Although a slightly higher efficacy is predicted at doses greater than 
1.25 mg per day, the predicted rate of edema is higher at these doses.
Section 6.4  Adverse Event Collection Period
First paragraph previously read:
All serious adverse events and protocol-related nonserious adverse events will be 
collected from the signing of the study specific informed consent until study drug 
administration.  All adverse events (nonserious and serious) reported from the time of 
study drug administration until 30 days following discontinuation of study drug 
administration have elapsed will be collected, whether solicited or spontaneously reported 
by the subject.  In addition, protocol-related nonserious and serious adverse events will be 
collected through the post-therapy Observational Period.
Has been changed to read:
All adverse events reported from the time of study drug administration until 30 days 
following discontinuation of study drug administration have elapsed will be collected, 
whether solicited or spontaneously reported by the subject.  In addition, protocol-related 
nonserious and serious adverse events will be collected from the time the subject signed 
the study-specific informed consent through the post-therapy Observational Period.
Figure 2.  Adverse Event Collection
Previously read:
SAEs and 
Protocol-
Related 
AEs
Elicited and/or Spontaneously Reported SAEs and 
Nonserious AEs
Protocol-Related 
AEs and SAEs
∀
∀
∀
∀
∀
Consent 
Signed
Study 
Drug 
Start
Study 
Drug 
Stopped
30 Days
After Study
Drug 
Stopped


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Has been changed to read:
SAEs and 
Protocol-
Related 
Nonserious 
AEs
SAEs and Nonserious AEs
Elicited and/or Spontaneously Reported
SAEs and 
Protocol-Related 
Nonserious AEs
∀
∀
∀
∀
∀
Consent
Signed
Study 
Drug 
Start
Study 
Drug 
Stopped
30 Days
After 
Study
Drug 
Stopped
Observational 
Period
Section 6.5  Adverse Event Reporting
First paragraph, last sentence previously read:
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 fax to Clinical 
Pharmacovigilance within 24 hours of being made aware of the serious adverse event.
Has been changed to read:
Serious adverse events that occur prior to the site having access to the RAVE® system or 
if RAVE is not operable, should be documented on the SAE Non CRF paper forms and 
emailed (preferred route) or faxed to Clinical Pharmacovigilance within 24 hours of being 
made aware of the serious adverse event.
Section 6.5  Adverse Event Reporting
Contact box previously read:
FAX to:  
Email:  


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Has been changed to read:
Email:  
FAX to:  
Section 6.5  Adverse Event Reporting
"Primary Study Designated Physician:"
Title previously read:
Associate Medical Director
Has been changed to read:
Medical Director
Section 6.5  Adverse Event Reporting
Fourth paragraph previously read:
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:
Has been changed to read:
In emergency situations involving study subjects when the Study Designated Physician is 
unavailable, please contact the 24-hour AbbVie Medical Escalation Hotline where your 
call will be re-directed to a designated back-up AbbVie Renal Medical Director.
Section 6.6  Pregnancy
Second paragraph previously read:
Information regarding a pregnancy occurrence in a study subject partner and the outcome 
of the pregnancy will be collected.


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Has been changed to read:
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.
Section 7.0  Protocol Deviations
Contact information previously read:
Primary Contact:
Alternate Contact:
Has been changed to read:
Primary Contact:
Alternate Contact:


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Section 8.1  Statistical and Analytical Plans
First paragraph previously read:
This is a single arm, open-label, single-country Phase 2 study designed to evaluate the 
effect of Atrasentan (0.75 mg QD) on spermatogenesis and testicular function in men with 
diabetic nephropathy.
Has been changed to read:
This is a Phase 2, single arm, open-label, multicenter study designed to evaluate the effect 
of Atrasentan (0.75 mg QD) on spermatogenesis and testicular function in men with 
diabetic nephropathy.
Section 8.1  Statistical and Analytical Plans
Second paragraph, third sentence previously read:
Approximately 20 subjects (to complete 15 evaluable subjects) with diabetic nephropathy 
who are taking RAS inhibitors are planned to be enrolled in the study at approximately 
10 sites.
Has been changed to read:
Approximately 20 subjects (to complete 15 evaluable subjects) with diabetic nephropathy 
who are taking RAS inhibitors are planned to be enrolled in the study at approximately 
20 sites.
Section 8.1  Statistical and Analytical Plans
Third paragraph previously read:
In the Treatment Period, semen samples will be collected at Screening (baseline), 
T4 (Week 6), T5 (Week 13), and T6/EOT (Week 26).  Duplicate samples will be collected 
at each visit over a 7-day period with each sample being separated by at least 2 days.  The 
average of the 2 samples will be used as the value for that visit.  Inadequate or missed 
semen samples can be made up within 14 days of the initial semen sample from that 
time-point.  In the Observational Period, semen samples will be collected at 6 and 


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13 weeks after the last dose of study drug then every 13 weeks thereafter until all values 
have returned to baseline (± 15%) or until the end of the Observational Period, whichever 
occurs earlier.
Has been changed to read:
In the Treatment Period, semen samples will be collected at Screening (baseline), T5 
(Week 13) and T6/EOT (Week 26).  Semen samples will be collected at 2 time-points 
over a 7-day period with each sample being separated by at least 2 days.  The average of 
the 2 samples will be used as the value for that scheduled collection period.  Inadequate or 
missed semen samples can be made up within 14 days of the initial semen sample for that 
collection period.  In the Observational Period, semen samples will be collected according 
to the specific windows for semen collection (Section 5.3.2.1), starting at the O1 
(Week 13) visit and then every 13 weeks thereafter until the sperm concentration has 
returned to within 15% of baseline or above, or until the end of the 52-week 
Observational Period, whichever occurs earlier.
Section 8.1  Statistical and Analytical Plans
Subsection General Considerations
First paragraph previously read:
Treatment effects will be evaluated based on a 2-sided significance level of 0.200 (when 
rounded to 3 decimal places).
Has been changed to read:
Treatment effects will be evaluated based on a 2-sided 80% exact confidence interval.
Section 8.1.1  Analysis Datasets
Subsection Evaluable Set
First paragraph previously read:
A subject will be considered evaluable if the following is satisfied:  (1) the Overall Study 
Drug compliance status = YES; and (2) completes the 26-week treatment period and has 


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all planned sperm samples collected; or has sperm concentration value less than 
15 million/mL observed prior to the end of Treatment Period.
Has been changed to read:
A subject will be considered evaluable if the following is satisfied:  (1) the Overall Study 
Drug compliance status is ≥ 70%; and (2) completes the 26-week treatment period and has 
all planned sperm samples collected; or has sperm concentration value less than 
15 million/mL observed by the end of Treatment Period.
Section 8.1.3  Safety Analyses
Subsection Study Drug Exposure and Compliance
First sentence previously read:
The duration of study drug exposure and average daily dose will be summarized for safety 
analyses set.
Has been changed to read:
The duration of study drug exposure and the average daily dose will be summarized for 
safety analyses set.
Section 8.1.3.1  Primary Safety Analyses
First sentence previously read:
The primary safety endpoint is the proportion of subjects who have a sperm concentration 
< 15 × 106/mL by 26 weeks.
Has been changed to read:
The primary safety endpoint is the proportion of subjects who have a sperm concentration 
< 15 × 106/mL during the 26-week Treatment Period.


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Section 8.1.3.2  Secondary Safety Endpoints
First paragraph, first bullet previously read:
The proportion of subjects who enter the Observation Period and do not return to within 
15% of baseline by 52 weeks after treatment discontinuation.
Has been changed to read:
The proportion of subjects who enter the Observational Period and do not return to within 
15% of baseline or above during the 52-week Observational Period.
Section 8.1.3.2  Secondary Safety Endpoints
Second paragraph, first sentence previously read:
The secondary analysis on the proportion of subjects who enter the Observation Period 
and do not return to within 15% of baseline by 52 weeks after treatment discontinuation 
will be performed on the evaluable set.
Has been changed to read:
The secondary analysis on the proportion of subjects who enter the Observational Period 
and do not return to within 15% of baseline or above during the 52-week Observational 
Period will be performed on the evaluable set.
Section 8.1.3.3  Adverse Events (AEs) Analyses
Number list previously read:
1.
An overview of the number and percentage of subjects with treatment-emergent 
adverse events.
1.
A summary of the number and percentage of subjects with treatment-emergent 
adverse events by primary MedDRA system organ class and preferred term.
2.
A summary of the number and percentage of subjects with treatment-emergent 
serious adverse events by primary MedDRA system organ class and preferred term.


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3.
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.
4.
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.
5.
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.
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.
Has been changed to read:
●
An overview of the number and percentage of subjects with treatment-
emergent adverse events.
●
A summary of the number and percentage of subjects with treatment-emergent 
adverse events by primary MedDRA system organ class and preferred term.
●
A summary of the number and percentage of subjects with treatment-emergent 
serious adverse events by primary MedDRA system organ class and preferred 
term.
●
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.
●
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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●
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.
●
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.
●
A summary of subject numbers associated with treatment-emergent adverse 
events by primary MedDRA system organ class and preferred term.
Section 8.1.3.3  Adverse Events (AEs) Analyses
Fourth paragraph previously read:
For Observational Period, the protocol-related adverse events will be summarized 
similarly from 30 days after the last dose of study drug through study completion.
Has been changed to read:
For the Observational Period, the protocol-related adverse events will be summarized 
similarly from 30 days after the last dose of study drug through study completion.
Section 8.1.4  Interim Analysis
First sentence previously read:
An interim analysis will be performed after all the subjects have completed or prematurely 
discontinued from 26-week Treatment Period.
Has been changed to read:
An interim analysis will be performed after all the subjects have completed or prematurely 
discontinued from the 26-week Treatment Period.
Section 8.1.4  Interim Analysis
Last sentence previously read:
There is no need to adjust significance level since the primary analysis will be conducted 
using data from 26-week Treatment Period.


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Has been changed to read:
There is no need to adjust significance level since the primary analysis will be conducted 
using data from the 26-week Treatment Period.
Section 8.2  Determination of Sample Size
First sentence previously read:
The proportion of subjects with sperm concentration < 15 million/mL in an unscreened 
population of otherwise healthy males is reported to be approximately 10% 
(Cooper et al 2010).
Has been changed to read:
The proportion of subjects with sperm concentration < 15 million/mL in an unscreened 
population of otherwise healthy males is reported to be approximately 10%. 22
Section 9.3  Subject Information and Consent
Add:  new second and third paragraph
Information regarding incentives for the subject and provisions for treating and/or 
compensating subjects who are harmed as a consequence of participation in the study can 
be found in the informed consent form.
In the event a subject withdraws consent to participate from the study, stored samples will 
continue to be used for research and analysis.  In the event a subject would like to 
withdraw consent for research using these samples, the subject may request their samples 
be withdrawn.  Once AbbVie receives this request, the remaining samples will be 
destroyed.  If the subject changes his consent, and the samples have already been tested, 
those results will still remain as part of the overall research data.
Section 14.0  Investigator's Agreement
Item "1." previously read: 
I have received and reviewed the Investigator's Brochure for Atrasentan and the product 
labeling for marketed drug name.


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Has been changed to read:
I have received and reviewed the Investigator's Brochure for Atrasentan.
Section 14.0  Investigator's Agreement
"Protocol Title:" previously read: 
Protocol Title:
A Single-Country, Multicenter, Single-Arm Study of the Effects of 
Atrasentan on Spermatogenesis and Testicular Function
Has been changed to read:
Protocol Title:
A Multicenter, Single-Arm Study of the Effects of Atrasentan on 
Spermatogenesis and Testicular Function
Section 15.0  Reference List
Reference 19, 20, 21, 22, and 23 previously read:
19.
Cooper TG, Noonan E, von Eckardstein S, et al.  World Health Organization 
reference values for human semen characteristics.  Hum Reprod Update.  
2010;16(3):231-45.
20.
Anantharanman P, Schmidt RJ.  Sexual function in chronic kidney disease.  Adv 
Chronic Kidney Dis.  2007;14(2):119-25.
21.
Hellstrom WJ, Overstreet JW, Yu A, et al.  Tadalafil has no detrimental effect on 
human spermatogenesis or reproductive hormones.  J Urol.  2003;170(3):887-91.
22.
Pierik FH, Vreeburg JT, Stijnen Y, et al.  Serum inhibin B as a marker of 
spermatogenesis.  J Clin Endocrinol Metab.  1998;83(9):3110-4.
23.
Letairis® [package insert].  Foster City, CA; Gilead Sciences Inc., 2012.
Has been changed to read:
19.
Tracleer® [package insert].  South San Francisco, CA; Actelion Pharmaceuticals 
US, Inc., 2011.


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20.
Letairis® [package insert].  Foster City, CA; Gilead Sciences Inc., 2012.
21.
Volibris® [package insert].  Brentford, Middlesex, UK; Glaxo Group Ltd, 2013.
22.
Cooper TG, Noonan E, von Eckardstein S, et al.  World Health Organization 
reference values for human semen characteristics.  Hum Reprod Update.  
2010;16(3):231-45.
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Clinical
Clinical
Clinical
Pharmacokinetics
Statistics
Has been changed to read:
Name
Title
Functional Area
Clinical
Clinical
Clinical
Pharmacokinetics
Statistics

SAP_001.pdf: 
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1.0
Title Page
Statistical Analysis Plan
Study M12-919
A Multicenter, Single-Arm Study of the Effects of 
Atrasentan on Spermatogenesis and Testicular 
Function
Date:  08 Jun 2018
Version 1.0
NCT02118714


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2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................4
4.0
Study Background.................................................................4
4.1
Study Objective...................................................................................... 4
4.2
Study Design.......................................................................................... 4
4.3
Sample Size............................................................................................ 6
4.4
Interim Analysis ..................................................................................... 6
4.5
Multiplicity Testing Procedures for Type-I Error Control....................... 6
4.6
Missing Data Imputation ........................................................................ 6
5.0
Definitions and Derivations ..................................................7
5.1
Definition of Study Dates ....................................................................... 7
5.1.1
Date of First Dose of Atrasentan in TP ................................................... 7
5.1.2
Date of Last Dose of Study Drug............................................................ 7
5.1.3
Date of End of Study Visit...................................................................... 7
5.2
Definition of Study Time Points ............................................................. 7
5.3
Baseline and Final Observations in TP and OP ....................................... 8
6.0
Analysis of Data from the Treatment Period and 
Observational Period ............................................................8
6.1
General Statistical Methods.................................................................... 8
6.1.1
Methods for Categorical Endpoints......................................................... 8
6.1.2
Methods for Continuous Endpoints......................................................... 8
6.2
Analysis Sets.......................................................................................... 9
6.3
Demographics, Baseline Characteristics and Medical History................. 9
6.4
Subject Disposition............................................................................... 10
6.5
Overall Study Drug Exposure and Compliance..................................... 10
6.6
Concomitant Medications..................................................................... 11
6.7
Efficacy Analysis ................................................................................. 11
6.8
Safety Analyses.................................................................................... 12
6.8.1
Primary Safety Endpoint....................................................................... 12
6.8.2
Secondary Safety Endpoints ................................................................. 12


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6.9
Sensitivity Analyses ............................................................................. 13
7.0
Adverse Events Analyses .................................................... 13
7.1
Analysis of Adverse Events (AEs)........................................................ 13
7.2
Listing of TEAEs ................................................................................. 14
7.3
Clinical Laboratory Data ...................................................................... 15
7.4
Vital Signs............................................................................................ 15
7.5
ECG Data............................................................................................. 15
8.0
Appendix.............................................................................. 16
List of Figures
Figure 1.
Study Schematic..................................................................................... 5


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3.0
Introduction
Study M12-919 is a prospective, single-arm, open-label, multicenter, phase 2 study 
designed to evaluate the effect of Atrasentan (0.75 mg QD) on spermatogenesis and 
testicular function in men with diabetic nephropathy.  This statistical analysis plan (SAP) 
describes the analysis to be performed by AbbVie clinical statisticians and programmers 
for the Study M12-919 study protocol Amendment 4. 
The purpose of this document is to pre-specify all statistical analyses and data summaries 
of the primary and secondary safety endpoints to be included in the clinical study report 
(CSR). 
Safety analyses will be performed using SAS Version 9.4 or higher (SAS Institute, Inc., 
Cary, NC 27513) under the UNIX operating system.
4.0
Study Background
4.1
Study Objective
The study objective is to evaluate the effect of Atrasentan on spermatogenesis and 
testicular function in men with diabetic nephropathy.
4.2
Study Design
This is a Phase-2, single-arm, open-label, multicenter study designed to evaluate the effect 
of Atrasentan (0.75 mg QD) on spermatogenesis and testicular function in men with 
diabetic nephropathy. 
Subjects who provide consent will enter a Screening Period to assess eligibility.  Eligible 
subjects will enter a 26-week Treatment Period (TP), followed by an Observational Period 
(OP) up to an additional 52 weeks if the subject qualifies. 


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In the Treatment Period, semen samples will be collected at two time-points over a 7-day 
period with each sample being separated by at least 2 days (48 hours) at Screening 
(baseline), T5 (Week 13) and T6/End of Treatment (EOT, Week 26). 
If at any time during the Treatment Period or at the T6/ EOT (Week 26) visit the subject's 
sperm concentration drops below 15 × 106 mL, the subject will be discontinued from 
study drug and enter into an Observational Period of up to an additional 52 weeks.  If at 
the end of the 26-week Treatment Period there is a ≥ 50% reduction in sperm 
concentration from Screening (baseline), the subject will also enter into the Observational 
Period.
During the Observational Period, semen samples will be collected (at two time-points 
over a 7-day period with each sample being separated by at least 2 days [48 hours]) every 
13 weeks until the subject's sperm concentration returns to within 15% of baseline or 
above, or until the end of the Observational Period. 
General laboratory tests (including hematology, chemistry and urinalysis) will be 
collected for safety monitoring.
A schematic of the study design is shown below in Figure 1.
Figure 1.
Study Schematic


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4.3
Sample Size 
Approximately 20 subjects (15 evaluable subjects) with diabetic nephropathy who are 
taking RAS inhibitors are planned to be enrolled in the study at approximately 20 sites. 
The proportion of subjects with sperm concentration < 15 × 106/mL in an unscreened
population of healthy male subjects is reported to be approximately 10%.  With 
15 evaluable subjects, this study will have approximately 80% power to detect a 20% 
difference between the incidence rates in the Atrasentan group and the null hypothesis of 
10% at 2-sided significance level of 0.2.
4.4
Interim Analysis
It is specified in the protocol that an interim analysis (IA) will be performed after all the 
subjects have completed or prematurely discontinued from the 26-week Treatment Period.  
The purpose of the IA was to include preliminary data to support registration in the EU.
In November 2017, AbbVie prematurely terminated the Phase 3 registration study 
(Study M11-352) with less than 25% of the planned number of primary endpoints 
achieved.  Future development plans for atrasentan are unknown at this time.  For study 
Study M12-919, it has been decided that the IA will not be performed.  The decision has 
been documented in the Key Decision document (Appendix).
4.5
Multiplicity Testing Procedures for Type-I Error Control
There is no multiple testing in the study thus no adjustment is needed. 
4.6
Missing Data Imputation
Missing data will not be imputed.


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5.0
Definitions and Derivations
5.1
Definition of Study Dates
5.1.1
Date of First Dose of Atrasentan in TP
The date of first dose of atrasentan in TP is defined as the first date when a nonzero dose 
of atrasentan was taken as per "Atrasentan Dosing (Treatment Period)" electronic case 
report form (eCRF).  This date is referred to as the Treatment 1 (T1) visit date (Day 1).
5.1.2
Date of Last Dose of Study Drug 
The date of last dose of atrasentan in TP is defined as the last date when a nonzero dose of 
atrasentan was taken as per "Atrasentan Dosing (Treatment Period)" electronic case report 
form (eCRF). 
5.1.3
Date of End of Study Visit
Subjects who do not meet the criteria to enter the Observational Period will be contacted 
by the Investigator (or designee) approximately 30 - 35 days after their date of last dose of 
study drug.  This follow-up contact date will be the final contact date for these subjects.
For subjects who enter the Observational Period, the visit as which their sperm 
concentration returns to within ± 15% of the baseline or above will be the End of Study 
(EOS) visit date; otherwise the date of Observational Period Visit 4 (O4/Week 52) will be 
the date of EOS visit. 
5.2
Definition of 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 date for first dose of atrasentan (defined in 
Section 5.1.1).  For dates after the first date of atrasentan, study day is calculated as:
Study day= Date of interest – first date of atrasentan + 1.
There is no Study Day 0.


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5.3
Baseline and Final Observations in TP and OP
For Treatment Period, the baseline observation is defined as the last non-missing 
measurement collected on or before the date of first dose of study drug (T1/Day 1 
Visit/Screening visit).  The final observations in TP are defined as the last non-missing 
observations taken between the first dose and no more than 3 days after the last dose of 
study drug.
The final observation in Observational Period is defined as the last non-missing 
observations taken on or before the End of Study visit date.  
6.0
Analysis of Data from the Treatment Period and 
Observational Period 
6.1
General Statistical Methods
6.1.1
Methods for Categorical Endpoints
Categorical data (e.g., race, age categories) will be summarized using frequencies and 
percentages.  Then 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 himself as belonging 
to multiple races and hence the categories are not mutually exclusive.  These summaries 
will be referred to as categorical summaries.
6.1.2
Methods for Continuous Endpoints
Continuous data (e.g., age, sperm concentration) 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.  These summaries will be referred to as continuous 
summaries.


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6.2
Analysis Sets
Evaluable Set
The Evaluable Set (ES) includes subjects for whom either one of the following conditions 
is satisfied: 
●
The Overall Study Drug compliance status are ≥ 70%, and complete the 
26-week treatment period and has all planned sperm samples collected; OR
●
Receive at least one dose of study drug, and have a sperm concentration value 
less than 15 × 106/mL observed by the end of the Treatment Period or have a 
≥50% reduction from baseline in sperm concentration at the end of the 
Treatment Period.
Safety Analysis Set
The Safety Analysis Set includes all subjects who receive at least one dose of atrasentan. 
Sensitivity Analysis Set
The Sensitivity Analysis Set includes subjects who satisfy the following conditions: 
●
Achieve ≥ 70% overall study drug compliance; AND
●
Complete the 26-week treatment period and have all planned sperm samples 
collected; or have a sperm concentration value < 15 × 106/mL observed by the 
end of the Treatment Period.
6.3
Demographics, Baseline Characteristics and Medical 
History 
All demographic and baseline characteristics such as gender, race, age, weight, etc., will 
be summarized.  Subject disposition, completion of study, or discontinuation from the 
study, will be summarized.  The number and percentage of subjects who prematurely 
discontinue from the study will be summarized for the primary reason as well as for all 
reasons collected.


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Concomitant medications reported by generic name assigned by the World Health 
Organization (WHO) dictionary will be summarized.  For each concomitant medication, 
the number and percentage of subjects who take this medication will also be summarized.
Categorical summaries will be provided for race and ethnicity at baseline; and for 
assessment of peripheral edema (none, mild, moderate, severe), tobacco and alcohol use 
(unknown, never, current, former) at baseline.  Categorical summaries will also be 
provided for subject medical history using body system and diagnosis/condition within 
body system using a lexicographic order.
Summaries of the demographic baseline characteristics and medical history will be based 
on the Safety Analysis Set.
6.4
Subject Disposition
For Treatment Period, accountability by investigator, completion of study drug, and 
discontinuation from the study drug will be summarized.  The number and percentage of 
subjects who prematurely discontinued from the study drug will be summarized for the 
primary reason as well as for all reasons collected. 
For Observational Period, the number of subjects entered Observational Period, reasons 
for entering the Observational Period, completion and discontinuation from the 
Observational Period will be summarized.  The number and percentage of subjects who 
prematurely discontinued from the Study will be summarized for the primary reason and 
for all reasons collected.
6.5
Overall Study Drug Exposure and Compliance
Duration of treatment with study drug will be computed as follows:
Treatment duration in TP = Date of last dose of Atrasentan in TP ─ date of first dose 
of Atrasentan in TP + 1.
At each visit, compliance will be assessed as follows:


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Percent (%) compliance for certain visit = # of pills taken / # of days for this visit × 
100%
# of days for this visit = next visit start date ─ current visit start date.
Overall compliance will be calculated at the end of the Treatment Period as:
Percent (%) overall compliance = total # of pills taken / treatment duration in TP.
The number and percentage of subjects with at least 70% compliance with study drug at 
each visit during the Treatment Period will be summarized.  The Overall Study Drug 
compliance for a subject (Yes or No) is defined as following:  if the subject has at least 
70% compliance with study drug at the end of the Treatment Period, then this subject is 
considered to be overall compliant to study drug; otherwise, the overall compliant status 
will be set to as No.
6.6
Concomitant Medications
A concomitant medication is defined as any medication other than the study drug that is 
taken from the first dose of atrasentan to the End of Treatment or End of Study visit.  
Concomitant medications reported by generic name assigned by the World Health 
Organization (WHO) dictionary will be summarized.  Subjects who report taking more 
than one medication will be counted once in total number of subjects who are taking any 
concomitant medication.  For each concomitant medication, the number and percentage of 
subjects who take this medication will also be summarized.
6.7
Efficacy Analysis
This is a safety study and no efficacy data will be collected.


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6.8
Safety Analyses
6.8.1
Primary Safety Endpoint
The primary safety endpoint is the proportion of subjects in the Evaluable Set who have a 
sperm concentration < 15 × 106/mL during the 26-week Treatment Period.  Number and 
percentage of subjects with primary safety endpoint, along with the 2-sided 80% and 95% 
exact confidence interval will be calculated. 
6.8.2
Secondary Safety Endpoints
The secondary safety endpoints are:
●
The proportion of subjects who enter the Observational Period and do not 
return to within 15% of baseline or above during the 52-week Observational 
Period.
●
Change from baseline to each visit in sperm concentration.
●
Change from baseline to each visit in each of the components of the semen 
analysis (sperm motility, sperm morphology, sperm count, semen volume).
●
Change from baseline to each visit in serum testosterone, estradiol, LH, FSH, 
and inhibin B.
Number and percentage of subjects who enter the Observational Period and do not return 
to within 15% of baseline or above during the 52-week Observational Period, along with 
the 2-sided 80% and 95% exact confidence interval will be calculated based on the 
Evaluable Set. 
The other secondary safety endpoints will be analyzed based on the Safety Analysis Set.  
Continuous summaries will be provided for the changes from baseline to each visit; as 
well as the change from baseline to the last visit.  Plots of mean sperm concentration with 
standard deviation at each visit will be provided.


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6.9
Sensitivity Analyses
The same analysis for the primary safety endpoint and the first secondary safety endpoint 
will be performed using the Sensitivity Analysis Set.
7.0
Adverse Events Analyses
7.1
Analysis of Adverse Events (AEs)
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Treatment-emergent adverse events (TEAEs, i.e., AEs that begin or worsen in severity 
after initiation of study drug throughout 30 days after the last dose of the study drug) will 
be summarized in descending order by MedDRA preferred term, as well as by system 
organ class (SOC) and MedDRA preferred term (PT). 
The incidence rates of TEAEs will be summarized.  Additionally, the TEAEs 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.  Serious 
treatment-emergent adverse events will be evaluated in a similar manner.
Treatment-emergent adverse events (non-serious and serious) will be summarized as 
described below:
●
An overview of the number and percentage of subjects with treatment-
emergent adverse events.
●
A summary of the number and percentage of subjects with treatment-emergent 
adverse events by primary MedDRA system organ class and preferred term.
●
A summary of the number and percentage of subjects with treatment-emergent 
serious adverse events by primary MedDRA system organ class and preferred 
term.
●
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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●
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.
●
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.
●
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.
●
A summary of subject numbers associated with treatment-emergent adverse 
events by primary MedDRA system organ class and preferred term.
●
A summary of protocol-related adverse events in the Observational Period by 
primary MedDRA system organ class, preferred term and maximum severity.
For the Observational Period, the protocol-related adverse events will be summarized 
similarly from 30 days after the last dose of study drug through study completion.
7.2
Listing of TEAEs 
The following additional listings will be prepared.
●
List of all TEAEs by subject ID.
●
Listing of all serious TEAEs by subject ID.
●
Listing of all TEAEs that led to discontinuation of study drug by treatment arm 
and subject ID.
●
Listing of subject numbers associated with each PT for all TEAEs.
●
Listing 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.


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7.3
Clinical Laboratory Data
Continuous summaries will be provided for laboratory assessments including semen 
sample analysis, hematology, chemistry and urianalysis at baseline and at each visit.
For each laboratory test, the mean change from baseline to each post-baseline visit will be 
summarized.  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.
7.4
Vital Signs 
Continuous summaries will be provided for age and height (collected at screening), 
weight, body mass index (BMI), blood pressure at baseline and at each treatment visit.
The mean change from baseline to each visit in vital signs, including sitting blood 
pressure, weight, will be summarized.  Weight gain and edema will be assessed at every 
visit during the Treatment Period.
7.5
ECG Data
The number and percentage of subjects with shifts from baseline in the categories of 
normal, abnormal (not clinically significant/clinically significant) as indicated by the 
study site investigators will be summarized.