Conditions: Anterior Ischemic Optic Neuropathy
Keywords: Non-arteritic Anterior Ischemic Optic Neuropathy NAION PDE5 inhibitors vardenafil Levitra sildenafil Viagra Tadalafil Cialis acute vision loss vision loss blurred vision optic neuropathy erectile dysfunction.
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

Brief summary:
The primary objective of this study is to determine whether the use of PDE5 inhibitors (vardenafil, sildenafil, or tadalafil) increases the risk for the development of NAION.

Detailed description:
Collected data will be compared to historic data of the same participant in case-crossover design.

Arms:
arm 1: None

Interventions: intervention 1: Diagnostic procedures
Intervention descriptions: intervention 1: The patients will not receive any study drug in this study. The patients will have ophthalmological (eye) examinations, blood work and will complete an interview

Protocol document:
Prot_000.pdf: 
 
Document Type: 
Study Protocol 
Official Title: 
Prospective Case Crossover Study to Assess Whether PDE5 
Inhibitor Exposure in Men increase the Risk for the Development of 
Non-arteritic Anterior Ischemic Optic Neuropathy (NAION) 
NCT Number: 
NCT00867815 
Document Date: 
02-MAR-2016 
 


Bayer 
CLINICAL STUDY PROTOCOL 
Title: 
Prospective Case Crossover Study to Assess Whether 
PDE5 Inhibitor Exposure in Men Increases the Risk for 
the Development ofNon-arteritic Anterior Ischemic 
Optic New·opathy (NAION) (Note: Erectile Dysfunction was 
removed in amendment 4) 
Test Drugs: 
Non-investigational drugs: vardenafil (e.g. Levitra®), 
sildenafil (e.g. Viagra®), tadalafil (e.g. Cialis®), avanafil 
(e.g. Stendra/Spedra®) (Note: Avanqfil was added in 
amendment 4) 
Sponsor's Name and Address: 
Bayer HealthCare AG, D-51368 Leverkusen 
Sponsor's Telephone Number: 
(Study Manager) 
 (Medical Expert) (Note: Telephone 
numbers were changed in amendment 4) 
Study N umberN ersion/Date: 
12912 I Integrated Protocol Version 4.0 I 02 MAR 2016 
This document is an integrated protocol containing the 
modifications mandated in amendment 4.0 
Supersedes: Version 3.0 I 01Feb2011 
Development Phase: 
Phase IV 
EudraCT number: 2010-023586-22 (Note: This number was 
included as described in amendment 2) 
The undersigned co1ifirm that they agree to conduct the study under the conditions 
1k nm80f ;;.zoj?d;nafffflMmem4) 
Date 
I 
Date 
Date 
Tluoughout this document, symllols indicating proprietary names(®, TM) may not be displayed. 
Hence, the appearance of product names without these symbols does not imply that these names are not protected. 
BAY 38-9456 / 12912 /Integrated Protocol Version 4.0 (02 March 2016) 
Page 1 of59 
PPD
PPD


Confidentiality 
statement: 
Tilefollowi11i: co11jitle11ti1tl i11f11r11111tio11 is tile property of Bayer. As 1011g flS tile i11formfllim1 co11tai11etl i11 
this pratocol ilus 1101 beett p11bli.<lte1l, it may 011ly be used wile11 permissio11 has bee11 obtai11edfrom Bayer. 
It is 1101 possible lo make reprotl11ctio11s of all or sectio11s of //tis protocol. Commerci11f 11.<e of tile 
i11fnrmatin11 is n11ly possible wit/1 tile permission of tile proprietor 11111/ is subjec/ lo 11 /ice11sefee. 
Additional Signatures 
Name: 
Function: 
Address: 
Telephone: 
Name: 
Function: 
Address: 
Telephone: 
 
Coordinating Investigator 
US 
 
Global Clinical Lead 
Bayer Pharma 
Berlin, Germany (Note: .,Schering" 
was re111vvedfro111 the company name) 
 
Signature: 
Date: 
Signature: 
Date: 
BAY 38-9456 I 12912 I Integrated Protocol Version 4.0 (02 March 2016) 
/C- /Y)q,.c'1f 20 /C. 
-
-{ c_ 
( 6 
Pngc 2 of 59 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 3 of 59
Table of Contents
1.
INTRODUCTION .............................................................................................................. 6
2.
STUDY OBJECTIVE(S).................................................................................................. 10
3.
INVESTIGATOR(S) AND OTHER STUDY PARTICIPANTS..................................... 10
4.
INVESTIGATIONAL PLAN........................................................................................... 11
Study Design and Plan............................................................................................... 11
4.1
Selection of Study Population ................................................................................... 13
4.2
4.2.1
Inclusion Criteria................................................................................................ 13
4.2.2
Exclusion Criteria............................................................................................... 14
Removal of Subjects from Study............................................................................... 16
4.3
Premature Termination of Study/Closure of Center.................................................. 16
4.4
Treatments ................................................................................................................. 17
4.5
4.5.1
Treatments to be Administered .......................................................................... 17
4.5.2
Method of Assigning Subjects to Treatment Groups......................................... 17
4.5.3
Selection of Doses in the Study.......................................................................... 17
4.5.4
Selection and Timing of Dose for Each Subject ................................................ 17
4.5.5
Blinding.............................................................................................................. 17
4.5.6
Prior and Concomitant Therapy......................................................................... 17
4.5.7
Treatment Compliance ....................................................................................... 18
Study Variables.......................................................................................................... 18
4.6
4.6.1
Efficacy Variable................................................................................................ 18
4.6.2
Safety Variables ................................................................................................. 18
4.6.3
Assessment Periods............................................................................................ 18
4.6.3.1
Visit 1 (Day 1) ............................................................................................ 18
4.6.3.2
Visit 2 (Day 90 30) .................................................................................. 21
4.6.3.3
Expert Panel................................................................................................ 21
4.6.4
Observations and Measurements........................................................................ 22
4.6.5
Drug Concentration Measurements.................................................................... 23
Data Quality............................................................................................................... 23
4.7
Documentation........................................................................................................... 23
4.8
5.
ETHICAL AND LEGAL ASPECTS ............................................................................... 23
Ethics Committee (EC) or Institutional Review Board (IRB)................................... 23
5.1
Ethical Conduct of the Study..................................................................................... 24
5.2
Regulatory Authority Approvals/Authorizations ...................................................... 24
5.3
Subject Information and Consent .............................................................................. 24
5.4
Insurance.................................................................................................................... 25
5.5
Confidentiality........................................................................................................... 25
5.6
6.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE................. 25
Statistical and Analytical Plans ................................................................................. 26
6.1
6.1.1
Populations for Analysis .................................................................................... 26
6.1.2
Derived Data and Data Sets ............................................................................... 26
6.1.3
Demography, Medical History, Concomitant Medication................................. 27
6.1.4
Efficacy Analysis ............................................................................................... 27
6.1.5
Safety Analysis................................................................................................... 27
6.1.5.1
Risk Contribution of PDE5 Inhibitor Exposure to NAION........................ 27


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 4 of 59
6.1.5.2
Adverse Events ........................................................................................... 28
6.1.5.3
Laboratory Data .......................................................................................... 29
6.1.5.4
Vital Signs................................................................................................... 29
6.1.5.5
ECG Data.................................................................................................... 29
6.1.5.6
Other Safety Data........................................................................................ 29
6.1.6
Interim Analysis ................................................................................................. 29
6.1.7
Blind Review...................................................................................................... 29
6.1.8
Handling of Dropouts and Missing Data............................................................ 30
Determination of Sample Size................................................................................... 30
6.2
7.
ADVERSE EVENTS........................................................................................................ 31
Warnings/Precautions................................................................................................ 31
7.1
Adverse Event Monitoring ........................................................................................ 31
7.2
Adverse Event Definitions......................................................................................... 32
7.3
7.3.1
Adverse Event .................................................................................................... 32
7.3.2
Serious Adverse Event ....................................................................................... 32
7.3.3
Unexpected Adverse Event................................................................................ 33
7.3.4
Relationship of Adverse Event to Investigational Product ................................ 34
7.3.5
Severity of the Adverse Event............................................................................ 36
7.3.6
Adverse Event Documentation........................................................................... 36
Reporting of Serious Adverse Events........................................................................ 36
7.4
7.4.1
Reporting of Suspected NAION Cases prior to Informed Consent ................... 37
7.4.2
Reporting of Worsening Cases of NAION ........................................................ 37
8.
USE OF DATA AND PUBLICATION ........................................................................... 37
9.
REFERENCES ................................................................................................................. 38
10.
APPENDICES............................................................................................................... 40
Study Flow Chart....................................................................................................... 41
10.1
Package Inserts for PDE5 Inhibitors ......................................................................... 42
10.2
10.2.1
Package insert for sildenafil (e.g. Viagra®)........................................................ 42
10.2.2
Package insert for tadalafil (e.g. Cialis®)........................................................... 42
10.2.3
Package insert for vardenafil (e.g. Levitra®)...................................................... 42
10.2.4
Package insert for avanafil (e.g. Stendra® / Spedra®) ........................................ 42
Laboratory Parameters............................................................................................... 43
10.3
12912 NAION Interview........................................................................................... 44
10.4
Instruction on How to Perform Perimetry................................................................. 55
10.5
Sample Narrative to Expert Panel ............................................................................. 56
10.6


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 5 of 59
Glossary and Abbreviations (Note: Some abbreviations were added or removed in 
amendment 4)
AE
adverse event
AION
arteritic anterior ischemic optic neuropathy
CBC
complete blood count
CCDS
Company Core Data Sheet
CI
confidence interval
CRF
Case Report Form (electronic)
CRP
C-reactive protein
EC
Ethics Committee
ECG
electrocardiogram
ED
erectile dysfunction
eg, e.g.
exempli gratia, for example
EOS
end of the study
ESR
erythrocyte sedimentation rate
EU
European Union
GCP
Good Clinical Practice
GMS
Global Medical Standards
GPRD
General Practice Research Database
HR
hazard ratio
IB
Investigator Brochure
ID
identification
ie, i.e.
id est, that is
IOP
intraocular pressure
IP
Investigational Product
IRB
Institutional Review Board
LPLV
last patient last visit
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mmHg
millimeter hydrargyrum, millimeter of mercury
MS
multiple sclerosis
NAION
non-arteritic anterior ischemic optic neuropathy
OR
odds ratio
PASS
Power Analysis and Sample Size
PDE5
phosphodiesterase type 5
PRN
pro re nata, as needed
RAPD
relative afferent pupillary defect
RBC
red blood cells
SAE
serious adverse event
SmPC
Summary of Product Characteristics
SUSAR
suspected unexpected serious adverse reaction
US
United States of America
vs.
versus, compared with, as opposed to
WBC
white blood cells
WHOART
World Health Organization Adverse Reactions Terminology

phi-coefficient, correlation coefficient to express the degree of 


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 6 of 59
1. INTRODUCTION
Erectile dysfunction (ED) has been noted to be a common disorder in adult men.  
According to one estimate, it affects 17% of men in the United States (US) (more 
than 16 million men, age range 20-79 years).(1) Note: Reference to the IB was
removed in amendment 4. According to the Men’s Attitudes to Life Events and 
Sexuality (MALES) study, ED affects 16% of men in Europe, North America, and 
South America, with rates varying markedly from one country to another.(2-5)  The 
incidence of ED increases with increasing age.  Co-morbidities that contribute to ED 
include diabetes, cardiovascular disease, hypertension, dyslipidemia, and 
depression.(2)  Other factors associated with an increased risk of ED include 
smoking and high dietary intake of cholesterol and unsaturated fats.(6)
Currently, several phosphodiesterase type 5 (PDE5) inhibitors are available for the 
treatment of ED. Note: The sentence was modified in amendment 4.The number of 
men seeking medical consultation for the condition is highly variable.(1,6) In the US 
population, it is estimated that approximately 27% of men with ED will take a PDE5 
inhibitor.(7) 
Non-arteritic anterior ischemic optic neuropathy (NAION) is a form of acute optic 
neuropathy that affects an estimated 5700 patients a year in the US(8), generally over 
age 50.  It affects men and women equally, with onset of clinical manifestations 
occurring on average at 60 years of age. Clinical manifestations include acute
unilateral loss of visual field with acuity variably affected associated with a swollen 
optic nerve.(9,10)  Risk factors for NAION include small cup to disc ratio of the 
optic nerve head, diabetes, hypertension, hypercholesterolemia, and smoking.(11)
The diagnosis of NAION involves differentiation from arteritic ischemic optic 
neuropathy from temporal arteritis or other forms of arteritis, demylinating optic 
neuritis, or other inflammatory optic neuropathies, eg, sarcoid or syphilis, 
compressive or infiltrative optic neuropathy, and post-papilledema optic atrophy on 
the basis of setting, clinical course, physical examination findings, and laboratory 
test results.  Sometimes NAION must be distinguished from branch or central retinal 


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 7 of 59
artery occlusion if the patient is seen late after the visual loss.  There is no specific 
laboratory test definitive for NAION.
The epidemiology of NAION is not well described in the literature.  By one 
estimate, the age- and sex-adjusted incidence of NAION is 10.2 cases per 
100,000 patients per year in people aged 50 and older.(8)  Another, earlier study that 
used surveys of referring physicians, estimated the mean annual incidence as 
2.30 cases per 100,000 population for subjects aged 50 and older.(12)
Several case reports have been published in the last few years on a potential 
association between the use of the PDE5 inhibitor sildenafil, used for the treatment 
of ED, and the development of NAION.(13-16)  Similar reports have also been 
published for tadalafil, another PDE5 inhibitor.(11,17-19)  Subsequently, a pooled 
analysis of data on sildenafil, collected from 103 clinical trials involving more than 
13,000 men and observational studies generating more than 35,000 person-years 
found an estimated incidence rate of 2.8 cases of NAION per 100,000 person-years 
of sildenafil use.(20) This rate in men using PDE5 inhibitors was deemed to be 
similar to that expected in the general US population, where estimates range from 
2.5 to 11.8 per 100,000 men over the age of 50.  Most recently, a small case-control 
study of 38 cases of NAION and 38 matched controls determined an odds ratio (OR)
of NAION associated with sildenafil or tadalafil of 1.81 (95% confidence interval 
[CI]: 0.51 - 6.37).  However, the OR was 10.7 (95% CI: 1.3 – 95.8) among subjects 
with a history of myocardial infarction and 6.9 (95% CI: 0.8 – 63.6) among those 
with a history of hypertension.(21)
As a result of these reports, precautionary statements have been added to the product 
labeling of all PDE5 inhibitors.(22-24) (See Appendix 10.2).  Individuals with a 
history of NAION are advised not to use these products, and those individuals who 
are using a PDE5 inhibitor and experience the loss of vision are advised to stop their 
medication and see their physician.
To further address this matter, Bayer sponsored a pilot study by 3 independent 
medical experts to explore the feasibility of conducting a retrospective epidemiology


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 8 of 59
study by using the General Practice Research Database (GPRD) in the United 
Kingdom to provide a more recent incidence rate estimate of NAION.
A case validation algorithm for establishing a diagnosis of NAION was used by 
independent medical experts. The GPRD pilot study found an incidence rate of
6.9 cases of NAION per 100,000 person-years for men and 4.8 cases per 
100,000 person-years for women.  However, the data available were significantly 
deficient for diagnosis of NAION.  Contributing to the difficulties identified in the 
pilot study is the difficulty in establishing a diagnosis of NAION retrospectively, 
even by medical experts.
Other methodological difficulties in performing an epidemiologic study include a 
multitude of confounding factors, the as-needed (PRN) use of PDE5 inhibitors, 
potential selection bias, and the large sample size required.  Thus, the results of 
almost any epidemiology database study would be difficult to interpret.
Because the study herein described is to provide information on a possible 
association between a rare medical condition (NAION) and a relatively uncommon 
drug exposure (PDE5 inhibitors), a prospective field study has been chosen.  A 
prospective approach will optimize the potential to assess timing of exposure to 
PDE5 inhibitors and provide a more reliable means of diagnosing NAION.  
Different study designs, in particular a case-crossover design and a case-control 
design, were assessed.  The following difficulties with a prospective case-control 
design are described below:

Selection bias:  Subjects without the outcome of interest would be asked to give 
consent to participate in a study involving questionnaires dealing with ED and 
PDE5 inhibitor use.  It is not clear that subjects who self-select for participation 
as controls in such a study would be comparable to the cases.  It is also not clear 
whether a sufficient number of control subjects could be identified.

Confounding:  Though controls could be matched to cases with respect to ED, 
and multiple control subjects could be matched to the cases, the prospective 


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 9 of 59
case-control design does not permit matching on the wide range of covariates 
(risk factors) that may be associated with NAION.  Imbalances between cases 
and controls could be addressed only in the analysis by logistic regression, 
which, in the case of major imbalances, cannot reliably protect against 
confounding.

Diagnostic bias:  It is possible that the likelihood of a diagnosis of NAION may 
itself depend upon exposure history, given the knowledge of reports suggesting a 
possible association between NAION and the use of PDE5 inhibitors became 
wide-spread among health care providers and consumers in 2005.
The following difficulties with a prospective case-crossover design are described 
below:

Recall bias:  Subjects are asked to recall the exposure just prior to onset of the 
event as well as exposure at some earlier time. Of necessity, the time period for 
which the subject is questioned about earlier exposure is more remote from the 
event, and the subject’s ability to recall and accurately report the details of 
exposure for the more remote time period is less reliable than his ability to report 
a recent exposure, especially an exposure just prior to the onset of symptoms of 
changes in vision.

Diagnostic bias:  Subjects experiencing symptoms may be more likely to seek 
medical care and to receive a diagnosis of NAION if the symptoms develop 
shortly after the use of a PDE5 inhibitor.
The case-crossover design provides some advantages over a case-control design.  
Since it would be difficult to find a comparable control population balanced with the 
NAION population with respect to multiple confounding factors, a case-crossover 
design is preferable.  In a case-crossover study, each case serves as its own control.  
A relative strength of this design is that it controls for known and unknown 
covariates (provided that these do not change with time), reducing the likelihood of 
confounding on this basis.  The problem of recall bias and diagnostic bias remain.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 10 of 59
The case-crossover design examines PDE5 inhibitor exposure at the time of NAION 
onset compared with prior time points for the same subject. The study design calls 
for a narrow exposure window that is consistent for each subject and each 
assessment period. This is in contrast to a case-control design, in which the lack of a 
narrow exposure window could result in enhancement of the effects of other 
underlying, confounding disease states.
Based on this assessment, a case-crossover design was chosen for this study.
The case-crossover study to be conducted under this protocol will examine only 
subjects with a NAION event. A 3-person, blinded expert panel will confirm the 
diagnosis of NAION.  To enhance the capacity of the study to detect a safety signal 
between NAION and the use of PDE5 inhibitors, it will focus on a narrow exposure 
window (a 2-day time frame for NAION onset) that will prevent dilution of the time 
span from ingestion of PDE5 inhibitor to the onset of NAION and it will include 
control periods in the proceeding months.(25)
2. STUDY OBJECTIVE(S)
The primary objective of this study is to determine whether the use of PDE5 
inhibitors (vardenafil, sildenafil, tadalafil or avanafil) increases the risk for the 
development of NAION. Note: The text was changed in amendment 4.
3. INVESTIGATOR(S) AND OTHER STUDY PARTICIPANTS
Coordinating Principal Investigator responsible for signing the Study Report:
Name:
Title:
Address:
 United States
Telephone:
Fax:
PPD
PPD
PPD
PPD
PPD


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 11 of 59
The sponsor will set up an independent expert panel of 3 experts in neuro-
ophthalmological diseases. Note: This text was modified as described in 
amendment 2.
Information regarding additional key personnel involved in the conduct of the study, 
including names and contact details of participating investigators, monitors, clinical 
laboratories, technical departments and/or institutions, as well as information on 
members of additional study committees, will be found in the study files of the 
sponsor and on site if requested.  This information will include contact details for 
serious adverse event reporting.
4. INVESTIGATIONAL PLAN
Study Design and Plan
4.1
This will be a case-crossover prospective field study, in which each subject will 
serve as his own control.
The primary study variable is the relative risk (as measured by the hazard ratio 
[HR]) of NAION, contrasting PDE5 inhibitor exposure in the risk period with PDE5 
inhibitor exposure during the control periods for each NAION case.
Suspicion of NAION (event onset prior to the signing of informed consent for this 
study) will be reported by the investigator. These events will be processed as 
solicited post-marketing adverse events (please refer to Section 7.4.1).
Subjects to be screened must meet the following criteria:

Preliminary diagnosis of NAION by an ophthalmologist
Note: “History of ED according to the subject” was removed in amendment 4.

Use of a PDE5 inhibitor within the past year


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 12 of 59
The following times will be determined for this study:

Date of onset of suspected NAION (must be within 45 days of initial 
presentation to the investigator) Note: The time point of onset was changed in 
amendment 2.

Date of initial presentation for medical evaluation in the study

Date of NAION diagnosis as conducted by a study investigator

Risk period: the 2 calendar days including the day of onset of suspected NAION
symptoms and the preceding day (If the subject can specify onset only to within 
a 2-day window, then those 2 days constitute the risk period.)
Each subject will have 2 clinical visits. Visit 1 (Day 1) will include screening for 
NAION and other inclusion and exclusion criteria, enrollment, and conduct of a 
telephone interview for collection of data on PDE5 inhibitor use. Visit 2 (Day 90
30) will be a follow-up visit to document the persistence of vision loss. Visits and 
procedures are described in Section 4.6.3, and in the Study Flow Chart 
(Appendix 10.1).
The final adjudication of NAION events will be done through an anonymous, 
independent assessment of medical records by an expert panel of 3 experts in neuro-
ophthalmological diseases. Note: This text was modified as described in
amendment 2.
About 300 subjects will be enrolled in at least 60 sites globally. Note: The 
information on number of centers and country scope was changed in amendment 2.
In the case-crossover design of this study, the day of NAION onset and the day 
before (Days 0-1) are defined as risk period (Figure 4–1). Control periods are the 
same two days of the week in the preceding three weeks (Days 7-8, 14-15, 21-22). 
The relative risk (as measured by the HR) contrasts PDE5 inhibitor exposure in the 
risk period with PDE5 inhibitor exposure in the control periods of each NAION 
case.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 13 of 59
Figure 4–1: Study Design
D
a
y
NAION
onset
-22 -21
-20
-19
-18
-17
-16 -15 -14
-13
-12
-11
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
Control
period 3
Washout period
Control
period 2
Control
period 1
Risk period
Note: This figure was modified in amendment 2.
The 2-day control periods were chosen taking into account the terminal half-lives of 
PDE5 inhibitor drug products, ie approximately 4 hours for vardenafil, sildenafil and 
avanafil, and 17.5 hours for tadalafil. Note: This text was changed as described in 
amendment 4.
An interim evaluation will be done after 100 confirmed NAION cases have been 
collected.  The purpose of the interim evaluation is to determine whether the 
parameter settings for the sample size calculation are adequate and the 10% 
inaccuracy rate for diagnosis of potential NAION cases is appropriate.
The primary outcome will be determined after last patient last visit (LPLV); the end 
of the study (EOS) will be the date when the expert panel has provided their final 
assessments and the clean data base is available.
Selection of Study Population
4.2
The study population will consist of adult men, first diagnosed with NAION which 
started within 45 days before study start, and who took PDE5 inhibitors in the 1 year 
prior to enrollment in the study. Note: The time point for first diagnosis was 
changed in amendment 2. ED was removed and “1 year prior to NAION onset” was 
replaced by “1 year prior to enrollment in the study” in amendment 4.
4.2.1
Inclusion Criteria
To be enrolled in the study, subjects must meet all of the following criteria:
1. NAION onset within 45 days before entry to the study defined as including all of
the following: Note: The time point of onset was changed in amendment 2.
a) Visual field defect consistent with optic neuropathy


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 14 of 59
b) Relative Afferent Pupillary Defect (RAPD) Subjects without RAPD may be 
included in the study if: 1) optic neuropathy was present in the non-study 
eye, preventing an RAPD in the study eye, or  2) an RAPD could not be 
measured because the subject had a non-study prosthetic eye or postsurgical 
pupils. Note: The modification of this inclusion criterion is described under 
amendment 2.
c) Optic disc edema. Subjects without optic disc edema may be included in the 
study if optic disc edema was documented by another qualified physician 
after the onset of NAION and before entry into the study. Note: The 
modification of this inclusion criterion is described under amendment 2.
2. NAION onset definable by the subject within a 2 calendar day window. (If the 
subject specifies an exact day of onset, the risk period will include that day and 
the preceding day.)
Note: Criterion 3 “Men with a history of ED at least 1 year prior to enrollment” 
was removed in amendment 4.
4. Men who have taken at least 1 dose of PDE5 inhibitor(s) at any time in the 
1 year prior to enrollment in the study Note: This criterion was modified in 
amendment 4.
5. Age 40 years or older
6. Ability to complete a phone interview and recall history adequately
7. Documented, signed and dated written Informed Consent
4.2.2
Exclusion Criteria
Medical
1. History of multiple sclerosis (MS) or suggestive for MS (probable or possible 
MS) or optic neuritis (or any of the following symptoms or signs suggestive of 
these diagnoses)
a) Pain on motion of the globe within 3 days of loss of vision
b) Marked recovery of field loss and vision
c) Marked delays on visual evoked potential


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 15 of 59
2. Evidence of temporal arteritis, as indicated by any of the following findings:
a) Positive temporal artery biopsy
b) Jaw claudication or temporal tenderness
c) Polymyalgia rheumatica
d) High ESR (40 mm/h) platelets (>400 x 109 L), and/or CRP (>10 mg/dL). 
Subjects with an ESR above 40 mm/hr are allowed to be included if 1) the 
elevated sedimentation rate could be attributed to some other cause and/or 2) 
the subject had no other symptoms or indications of temporal arteritis or if 
temporal arteritis has been excluded by appropriate diagnostic methods. 
Note: The modification of this exclusion criterion is described under 
amendment 2.
e) Large cup in fellow eye with a >50% cup to disc ratio
3. History of vasculitis or collagen vascular disease (eg, systemic lupus 
erythematosus, polyarteritis nodosa), or any other inflammatory disease
associated with arteritic anterior ischemic optic neuropathy (AION) or disc 
swelling
4. Evidence of elevated intracranial pressure
Note: Criterion 5 “Use of PDE5 inhibitors from other than a sample or 
prescription” was removed in amendment 4.
6. Daily dosing of PDE5 inhibitor for benign prostatic hyperplasia and/or pulmonary 
arterial hypertension Note: This criterion was added in amendment 4.
Opthalmological
1. Any of the following orbital signs
a) Proptosis or resistance to retropulsion which may be associated with Graves 
eye disease or Graves-related exophthalmos
b) Arterialized conjunctival vessels
c) Choroidal folds
d) Orbital mass


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 16 of 59
2. Ocular inflammation that may be associated with any of the following 
conditions:
a) Iritis or vitritis
b) Evidence of active sarcoidosis
c) Evidence of active syphilis
3. Acute glaucoma or intraocular pressure (IOP) 30 mmHg
4. Retinal vein occlusion
5. Previous history of NAION
6. Retinal detachment
7. Uveitis
8. Lens opacities (which prevent an adequate examination)
9. Use of any drugs known to affect the optic nerve or retina that cannot be 
excluded
Removal of Subjects from Study
4.3
A subject who withdraws is one who discontinues in a clinical study for any reason.
Subjects may be withdrawn from the study for the following reasons:

At their own request

If, in the investigator’s opinion, continuation in the study would be detrimental 
to the subject’s well-being

At the specific request of the sponsor
In all cases, the reason for withdrawal must be recorded in the Case Report Form 
(CRF) and in the subject’s medical records.
Premature Termination of Study/Closure of Center
4.4
The sponsor has the right to close this study, and the investigator/sponsor has the 
right to close a center, at any time, although this should occur only after consultation 
between involved parties. The Ethics Committee (EC)/Institutional Review Board 
(IRB) must be informed. Should the study/center be closed prematurely, all study 
materials (except documentation that has to remain stored at site) must be returned 
to the sponsor. The investigator will retain all other documents until notification 
given by the sponsor for destruction.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 17 of 59
Treatments
4.5
4.5.1
Treatments to be Administered
No interventional treatment will be administered in the context of this study.  Only 
the subject’s history of PDE5 inhibitor use will be assessed and recorded as 
specified in Section 4.5.6.
Subjects must not take PDE5 inhibitors while participating in the study, ie between 
Visit 1 and Visit 2. Subjects will continue with their usual medical therapies,
including any treatment for NAION.
4.5.2
Method of Assigning Subjects to Treatment Groups
Not applicable.
4.5.3
Selection of Doses in the Study
Not applicable.
4.5.4
Selection and Timing of Dose for Each Subject
Not applicable.
4.5.5
Blinding
Not applicable.
4.5.6
Prior and Concomitant Therapy
All medications taken by the subjects prior to signing informed consent (including 
during the event and historical control period) are to be documented as medication 
history.  Within the first 2 months before Visit 1, PDE5 inhibitors use and/or any 
intermittent use of additional medications will be recorded according to the subject’s 
best recollection on the CRF.  The source of PDE5 inhibitors should be recorded
(documented source, i.e. sample or prescription vs. non-documented, i.e. other
source). Note: This sentence was added in amendment 4. All medications used at 
study entry will be recorded.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 18 of 59
All medications taken by the subjects during the study (from Visit 1 to Visit 2) are 
termed concomitant medication. All concomitant medications must be documented 
on the CRF (name, start and stop date and daily dose) throughout the study duration.
Concomitant medications also have to be recorded in the subject’s medical records.
4.5.7
Treatment Compliance
Not applicable.
Study Variables
4.6
4.6.1
Efficacy Variable
As this is a safety study, no assessment of efficacy will be made.
4.6.2
Safety Variables
The primary study variable is the relative risk (as measured by the HR) of NAION, 
contrasting PDE5 inhibitor exposure in the risk period with PDE5 inhibitor exposure 
during the control periods for each NAION case.
Any additional safety information provided by the subject will be collected through 
the medical history taken at Visit 1 and any adverse events reported at Visit 2.
4.6.3
Assessment Periods
Subjects will be assessed at 2 visits, as summarized in the Study Flow Chart 
(Appendix 10.1).  Visit 1 (Day 1) will include screening, confirmation of the 
diagnosis of NAION (with date and time of onset), enrollment, and collection of 
data on PDE5 inhibitor and other concomitant medication use.  Visit 2 (Day 90) will 
be a follow-up visit to document the persistence of vision loss and confirm the 
diagnosis of NAION.
4.6.3.1 Visit 1 (Day 1)
Subjects with possible NAION will be assessed at clinical eye centers including 
referrals from the surrounding community.  Subjects will be enrolled in the trial, if 
they fulfill the inclusion criteria and if none of the exclusion criteria apply.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 19 of 59
Informed consent will be obtained from each subject before any study-related 
assessment is done, ie, before screening of inclusion / exclusion criteria.
Clinical and laboratory examinations will be made initially according to the 
standards usually applied at each investigational site.  Procedures must include the 
following:

Suspicion of NAION (event onset prior to the signing of informed consent for 
this study) will be reported by the investigator. These events will be processed as 
solicited post-marketing adverse events (please refer to Section 7.4.1).

Obtain informed consent

Enrollment

Complete detailed medical history and surgical measures (including dental 
interventions)

Complete medication history, including medications taken on an intermittent 
basis (including herbal/naturopathic medications and vitamins)

History of erectile dysfunction as reported by the subject

Examination of visual acuity

Examination of formal visual field

Ophthalmic examination, including pupil evaluation, slit lamp examination, 
applanation tonometry, fundus examination under dilated condition, with 
description of retinal vessel caliber and cup-to-disc ratio

If applicable, ophthalmic examination documentation from another qualified 
physician to document the presence of optic disc edema after the onset of 
NAION symptoms before entry into the study. Note: This text was added as 
described amendment 2.

Physical examination including weight, height, and vital signs

Fundus photography

Report any adverse event that starts after signing informed consent


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 20 of 59
Laboratory tests will include the following:

Erythrocyte sedimentation rate (ESR)

C-reactive protein (CRP)

Complete blood count (CBC) with platelet count
After preliminary confirmation of the suspected diagnosis of NAION, subjects will 
be interviewed by telephone to assess their history of PDE5 inhibitor use (tadalafil, 
sildenafil, vardenafil or avanafil) and other relevant conditions, including new 
conditions and concomitant medications and changes in existing conditions or 
concomitant medications during the 4 weeks before the onset of visual symptoms 
and including the day of NAION onset. Note: Trade names were replaced by 
generic names, and avanafil was added in amendment 4. This interview should take 
place on the enrollment day.
A subject will be enrolled in the study if the preliminary diagnosis of NAION is 
made (final diagnosis will be made after Visit 2) and the phone interview on the 
history of PDE5 inhibitor use and other concomitant therapies has been completed.
Subject exposure to PDE5 inhibitor will be assessed during the 2-day event window 
and 3 control periods (Figure 4–1), as follows:

Risk period: 2 consecutive calendar days, including the day of onset of NAION 
(Each subject must be able to specify the time of onset to within the 2-day 
window. If the subject specifies the exact day of onset, the risk period will 
include that day and the proceeding day). Must be no more than 45 days before 
entry to the study, ie the day of onset of NAION must be within 45 days of the 
Visit 1. Note: The extension of the time points before onset of symptoms is 
described amendment 2.

Control periods: 2 consecutive calendar days corresponding to the same days of 
the week as in the event window, for 1, 2, and 3 weeks preceding the event onset 
(designated Week -1, Week -2, and Week -3).


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 21 of 59
4.6.3.2 Visit 2 (Day 90 30)
Approximately 3 months after first diagnosis, the subject will be examined again to 
document the persistence of vision loss and the conversion of the disc edema to 
optic atrophy.
At this second visit, clinical examinations to support the persistence of vision loss 
can be performed, if required.  Procedures will include the following:

Examination of formal visual acuity

Examination of visual field

Ophthalmic examination including pupil evaluation, slit lamp examination, 
applanation tonometry, and fundus examination under dilated condition with 
description of retinal vessel caliber and cup to disc ratio

Physical examination including weight and vital signs

Fundus photography

Collection of adverse events and concomitant medications
4.6.3.3 Expert Panel
The final diagnosis of NAION will be made by an independent expert panel of 
3 experts in neuro-ophthalmological diseases. Note: This text was modified as 
described in amendment 2.
A charter will be developed defining the review process by the expert panel.
The expert panel will receive all information recorded on all cases in a blinded 
fashion.
Experts will be blinded to the following information:

Date of event

PDE5 inhibitor use related to the event and during control periods or event 
period and history of use


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 22 of 59

Presence of ED Note: This text was modified as described in amendment 4.

Concomitant medication

Date and duration of concomitant diseases
The final adjudication of events will be done by the expert panel, with an 
anonymous, independent assessment from medical records by all 3 experts. In case 
of conflicting assessments, the experts are requested to discuss those cases in detail 
with the goal of finding agreement.
Three categories of assessment are possible:

Definite NAION – 3 experts confirm diagnosis

Probable NAION – 2 experts confirm diagnosis

Unlikely NAION – fewer than 2 experts confirm diagnosis
4.6.4
Observations and Measurements
The principal variables to be assessed are the following:

Occurrence of NAION

Use of PDE5 inhibitor on specified days

Source of PDE5 inhibitor Note: This text was added in amendment 4.
Other observations and measurements will include the following:

General medical history and current medications, focusing on prior 4 weeks

Diagnosis of erectile dysfunction

Examination of visual acuity

Examination of formal visual fields

Ophthalmic examination, including pupil evaluation, slit lamp examination, 
applanation tonometry, and fundus examination under dilated condition with 
description of retinal vessel caliber and cup to disc ratio

Physical examination


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 23 of 59

Fundus photography

Laboratory values: ESR, CRP, and CBC with platelets

Adverse events reported at Visit 2
4.6.5
Drug Concentration Measurements
Not applicable.
Data Quality
4.7
Monitoring and auditing procedures defined/agreed by the sponsor will be followed, 
in order to comply with Good Clinical Practice (GCP) guidelines. Each center will 
be visited at regular intervals by a monitor to ensure compliance with the study 
protocol, GCP, and legal aspects. This will include on-site checking of the CRF for 
completeness and clarity, cross-checking with source documents, and clarification of 
administrative matters.
Documentation
4.8
Entries made in the CRF must be either verifiable against source documents or have 
been directly entered into the CRF, in which case the entry in the CRF will be 
considered as the source data.  The source data parameter to be verified and the 
identification of the source document must be documented. The study file and all 
source data should be retained until notification given by the sponsor for destruction.
5. ETHICAL AND LEGAL ASPECTS
Ethics Committee (EC) or Institutional Review Board (IRB)
5.1
Documented approval from appropriate ECs/IRBs will be obtained for all 
participating centers/countries prior to study start, according to GCP, local laws, 
regulations and organizations. When necessary, an extension, amendment or 
renewal of the EC/IRB approval must be obtained and also forwarded to the 
sponsor.  The EC/IRBs must supply to the sponsor, upon request, a list of the 
EC/IRBs members involved in the vote and a statement to confirm that the EC/IRB 
is organized and operates according to GCP and applicable laws and regulations.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 24 of 59
Ethical Conduct of the Study
5.2
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator 
abide by GCP Guidelines and under the guiding principles detailed in the 
Declaration of Helsinki.  The study will also be carried out in keeping with 
applicable local law(s) and regulation(s).  This may include an inspection by the 
sponsor representatives and/or Regulatory Authority representatives at any time.  
The investigator must agree to the inspection of study-related records by the 
Regulatory Authority/sponsor representatives, and must allow direct access to 
source documents to the Regulatory Authority/sponsor representatives.  
Additionally, this study is designed to ensure that good pharmacoepidemiology 
practices are met.
Modifications to the study protocol will not be implemented by either the sponsor or 
the investigator without agreement by both parties. However, the investigator may 
implement a deviation from, or a change to, the protocol to eliminate an immediate 
hazard(s) to the trial subjects without prior EC/IRB/Sponsor approval/favorable 
opinion. As soon as possible, the implemented deviation or change, the reasons for 
it, and if appropriate the proposed protocol amendment should be submitted to the 
EC/IRB/Sponsor. Any deviations from the protocol must be fully explained and 
documented by the investigator.
Regulatory Authority Approvals/Authorizations
5.3
Regulatory Authority approvals/ authorizations/ notifications, where required, must 
be in place and fully documented prior to study start.
Subject Information and Consent
5.4
A core information and Informed Consent Form will be provided. Prior to the 
beginning of the study, the investigator must have the EC/IRB written 
approval/favorable opinion of the written Informed Consent Form and any other 
written information to be provided to subjects.  The written approval of the EC/IRB 
together with the approved subject information/Informed Consent Forms must be 
filed in the study files.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 25 of 59
Written informed consent must be obtained before any study specific procedure 
takes place.  Participation in the study and date of informed consent given by the 
subject should be documented appropriately in the subject’s files.
Insurance
5.5
All subjects participating in the study have insurance coverage by the sponsor, 
which is in line with applicable laws and/or regulations.
Confidentiality
5.6
All records identifying the subject will be kept confidential and, to the extent 
permitted by the applicable laws and/or regulations, will not be made publicly 
available.
Subject names will not be supplied to the sponsor. Only the subject number will be 
recorded in the CRF, and if the subject name appears on any other document (eg, 
pathologist report), it must be obliterated before a copy of the document is supplied 
to the sponsor.  Study findings stored on a computer will be stored in accordance 
with local data protection laws.  The subjects will be informed in writing that 
representatives of the sponsor, EC/IRB, or Regulatory Authorities may inspect their 
medical records to verify the information collected, and that all personal information 
made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws.
If the results of the study are published, the subject’s identity will remain 
confidential.
The investigator will maintain a list to enable subjects’ records to be identified.
6. STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 26 of 59
Statistical and Analytical Plans
6.1
In the case-crossover design of this study, the day of NAION onset and the day 
before are defined as the risk period.  Control periods are the same 2 days of the 
week in the preceding 3 weeks.  The relative risk (as measured by the HR), contrasts 
PDE5 inhibitor exposure in the risk period with PDE5 inhibitor exposure in the 
control periods for each NAION case.  In this sense the case-crossover design is a 
matched case-control study in which each subject serves as his own control.
Primary statistical analysis will investigate whether use of PDE5 inhibitors increases 
the risk for the occurrence of NAION.
6.1.1
Populations for Analysis
Valid for NAION analysis set
The principal statistical analysis will be based on the valid for NAION analysis set, 
ie, the subset of subjects with a unanimous NAION assessment (ie, “definite 
NAION”) and probable NAION assessment (2 of 3 experts confirm the diagnosis).  
Subjects fulfilling all the criteria for NAION at Visit 1 who are subsequently lost to 
follow-up (no follow-up information available on visual status after 3 months) will 
be interpreted as definite NAION cases.  Subjects not returning after 3 months for 
Visit 2 will be contacted by telephone and questioned about their visual status.  This 
information can be used for analysis instead of Visit 2.
Safety analysis set
All subjects who sign informed consent and who have any of the following collected 
at Visit 1 will be valid for safety: laboratory values, physical exam, any eye exams, 
or adverse events.
6.1.2
Derived Data and Data Sets
None planned.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 27 of 59
6.1.3
Demography, Medical History, Concomitant Medication
Demographic variables, medical history, ED history, and findings will be tabulated 
overall and by stratum. Note: the text was modified in amendment 4. Sample size, 
mean values, standard deviations, minimum, median, and maximum values will be 
calculated for quantitative variables.  Frequencies and percentages will be reported 
for binary variables.
6.1.4
Efficacy Analysis
Not applicable.  Determination of sample size is based on the primary safety 
variable.
6.1.5
Safety Analysis
6.1.5.1 Risk Contribution of PDE5 Inhibitor Exposure to NAION
The primary analysis will be conducted using a conditional logistic regression model 
(Proc PHREG; SASInstitute).  The dependent variable (outcome) distinguishes 
between “case” and “control” phase.  The predictor will be “exposed” or “not 
exposed” to PDE5 inhibitor.  According to the case-crossover design, subject 
(patient) will be the stratum variable.  Association of PDE5 inhibitor exposure and 
NAION will be concluded if the lower limit of the 90% confidence interval of the 
HR of an increased risk under PDE5 inhibitors exceeds 1.0.
As a secondary analysis, time-variant covariates, as the intermediate (non-regular) 
ingestion of other medications, treatments, or critical external events, as well as their 
interaction, will be included in the logistic model to test the independence from 
confounding factors.  The final model will be selected via backward elimination.
If a significant HR indicating an increased risk with PDE5 inhibitors is found, 
stratified analyses will be conducted on an exploratory basis, including those 
subjects constituting subsamples with comparable time-invariant medical conditions 
(eg, diabetes, hypertension, hyperlipidemia, cardiovascular disease, and cup to disc 
ratio).


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 28 of 59
Sensitivity Analysis Note: The text was modified as described in amendment 4.
Depending on sample composition, the primary analysis will be repeated by:  
1. Subjects with ED taking a PDE5 inhibitor versus subjects without ED taking a 
PDE5 inhibitor, to assess the impact of ED on primary analysis,  
2. Source of PDE5 inhibitor (patients who always used a documented source of 
PDE5 inhibitor, that is, sample or prescription, versus those with at least one 
non-documented source of PDE5 inhibitor), to assess the impact of source of 
PDE5 inhibitor.
3.
Age (eg, 40 – 49 years and 50 years),
It is known that the study may not be adequately powered in these subgroups and 
that these results should only be considered as descriptive.
6.1.5.2 Adverse Events
Adverse conditions starting prior to informed consent will be captured as part of the 
medical history; adverse conditions reported after informed consent will be recorded 
as adverse events on the CRF.  Accordingly, NAION starting before informed 
consent will be reported by the investigator and processed as a solicited post-
marketing serious adverse event.  Please refer to Section 7.4.1 for investigator 
reporting requirements.  Worsening of NAION after signing of informed consent 
will be recorded on the Adverse Event page of the CRF as a serious adverse event 
and reported according to guidelines in Section 7.4.2 for investigator reporting 
requirements.
Concomitant diseases, pre-existing diseases, and laboratory data reported as medical 
history or reported as an adverse event will be classified according to Medical 
Dictionary for Regulatory Activities (MedDRA).  Conditions that worsen or occur 
between Visit 1 and Visit 2, after the subjects had signed the informed consent form,
will be recorded as adverse events on the CRF.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 29 of 59
6.1.5.3 Laboratory Data
Baseline laboratory data (Visit 1) will be summarized as means, standard deviations, 
minimum, median, and maximum values, per stratum (Global Medical Standards 
[GMS]) provided they are quantitative variables. Note: “Strata” was replaced by 
“stratum” in amendment 4.
6.1.5.4 Vital Signs
Vital signs data (systolic/diastolic blood pressure and heart rate) will be tabulated as 
means, standard deviations, minimum, median, and maximum values per visit and 
stratum (GMS).
6.1.5.5 ECG Data
Not applicable
6.1.5.6 Other Safety Data
Ophthalmic data will be summarized as means, standard deviations, minimum, 
median, and maximum values per visit and stratum (GMS) provided they are 
quantitative variables.  Qualitative variables will be tabulated as frequencies and 
percentages.
6.1.6
Interim Analysis
After inclusion of 100 confirmed NAION cases, an interim evaluation will be done 
by an analyst who will be blinded to the use of PDE5 inhibitor exposure in the risk 
period, to determine whether the parameter settings for the sample size calculation 
are adequate (that is, the 1-day prevalence of PDE5 inhibitor use in the control 
period) and to determine whether the 10% inaccuracy rate for diagnosis of potential 
NAION cases is appropriate. Note: This text was modified as described in 
amendment 4. This is a technical interim analysis that is not scheduled for deciding 
on potential early termination.  If necessary, the study will be extended but not 
significantly reduced with regard to the number of cases estimated in this protocol.
6.1.7
Blind Review
Not applicable.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 30 of 59
Each case will be assessed by an independent panel of 3 experts in neuro-
ophthalmological diseases to confirm the diagnosis of NAION (please refer to 
Section 4.6.3.3). Note: This text was modified as described in amendment 2.
6.1.8
Handling of Dropouts and Missing Data
Subjects who do not complete Visit 2 will still be evaluated by the expert panel and 
may contribute to the analysis, if this is supported by the Expert Panel.
Determination of Sample Size
6.2
In the case-crossover design in this study the day of NAION onset and the day 
before (Days 0-1) are defined as the risk period. Control periods are the same 
2 days of the week in the preceding 3 weeks (Days 7-8, 14-15, 21-22). The relative 
risk (as measured by the HR) contrasts PDE5 inhibitor exposure in the risk period 
with PDE5 inhibitor exposure in the control periods of each NAION case.(26-28)
According to the US Government Census for 2000(29), the prevalence of ED is 
estimated to be about 17.21% (N=16,104,421; age range: 20-79 years) in all adult 
male US citizens. It is also expected that about 71% of all diseased subjects will ask
for medical consultation (N=11,434,139), and a final set of 27% of the total will take
PDE5 inhibitors (N=3,087,218).An internal analysis on the average use of PDE5
inhibitors, neglecting the type of PDE5 inhibitor treatment (ie, vardenafil, sildenafil, 
tadalafil), estimated an average annual prescription rate of 3.71. The average overall 
prescription number in all ED subjects within the target age range is then calculated 
as N= 11,359,884 prescriptions per calendar year. This estimation is based on 5 
tablets per blister pack and prescription. The average prevalence of PDE5 inhibitor 
use in the ED population estimated for a 1-day risk was then calculated as 
0.00965625.(1) 
The sample size estimation is based on the assumptions of a matched case-control 
design, which are also applicable to case-crossover designs.(30, 31)
According to the proposal of Dupont(32) for retrospective matched case-control 
study and using the statistics programs PS(33) and Power Analysis and Sample Size 


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 31 of 59
(PASS)(34) the study will require 258 confirmed NAION cases with ED to detect an 
increased risk of 3.0 (OR) under exposure with PDE5 inhibitors and considering 
3 within-control periods per NAION case, a type 1 error rate of 5% (1-sided), a 
power of 80%, a correlation coefficient for exposure of 0.2, and a 1-day prevalence 
of PDE5 inhibitor use in ED patients of 0.0097 (2 days: 0.0194).  The correlation 
coefficient was calculated based on the PDE5 inhibitor drug prevalence in the risk-
and control period.(32) Although the calculation supported the view of 
independence, it was recommended to use tentatively =0.2.
Summarizing, the study is designed to test the superiority hypothesis that ED 
subjects exposed to any PDE5 inhibitor will have an increased risk () of suffering 
from NAION. Thus the null hypothesis is:
H0 : = 1
The alternative hypothesis is:
H1 : > 1
The alternative hypothesis will be accepted if the 1-sided lower 95% confidence 
interval of the estimated HR does not include 1.
Assuming an accuracy of 90% for the NAION diagnosis that includes definite and 
probable cases, the number of potential NAION cases with ED to be included in this 
study is increased from 258 to 284.  This corresponds to an inter-rater reliability of 
approximately 0.9.
7. ADVERSE EVENTS
Warnings/Precautions
7.1
Not applicable.
Adverse Event Monitoring
7.2
Subjects will be monitored for adverse events.  Adverse events should be assessed in 
terms of their seriousness and severity.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 32 of 59
Adverse Event Definitions
7.3
7.3.1
Adverse Event
An adverse event is any untoward medical occurrence in a subject or clinical 
investigation subject and can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
occurring during the trial.
Adverse events associated with the use of a drug in humans, whether or not 
considered drug related, include the following:

An adverse event occurring in the course of the use of a drug product in 
professional practice.

An adverse event occurring from an overdose whether accidental or intentional.

An adverse event occurring from drug abuse.

An adverse event occurring from drug withdrawal.

An adverse event where there is a reasonable possibility that the event occurred 
purely as a result of the subject participation in the study (eg, adverse event or 
serious adverse event due to discontinuation of anti-hypertensive drugs during 
wash-out phase) must also be reported as an adverse event.
7.3.2
Serious Adverse Event
A serious adverse event is any untoward medical occurrence that:

Results in death.

Is life-threatening.

Requires in-patient hospitalization or prolongation of existing hospitalization.

Results in persistent or significant disability or incapacity.

Is a congenital anomaly or birth defect.

Is an important medical event.
Life-threatening: The term “life-threatening” in the definition of “serious” refers to 
an adverse event in which the subject was at risk of death at the time of the event.  It 


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 33 of 59
does not refer to an adverse event which hypothetically might have caused death if it 
were more severe.
Hospitalization:  Any adverse event leading to hospitalization or prolongation of 
hospitalization will be considered as “serious”, unless at least one of the following 
exceptions is met:

The admission results in a hospital stay of less than 12 hours.
OR

The admission is pre-planned (ie, elective or scheduled surgery arranged prior to 
the start of the study).
OR

The admission is not associated with an adverse event (eg, social hospitalization 
for purposes of respite care).
However it should be noted that invasive treatment during any hospitalization may 
fulfil the criteria of “medically important” and as such may be reportable as a serious 
adverse event dependent on clinical judgment.  In addition where local regulatory 
authorities specifically require a more stringent definition, the local regulation takes 
precedent.
Disability means a substantial disruption of a person’s ability to conduct normal 
life’s functions.
Important medical event:  Any adverse event may be considered serious because it 
may jeopardize the subject and may require intervention to prevent another serious 
condition.  As guidance for determination of important medical events refer to the 
World Health Organization Adverse Reaction Terminology (WHOART) – Critical 
Terms List.  These terms either refer to or might be indicative of a serious disease 
state.
Such reported events warrant special attention because of their possible association 
with a serious disease state and may lead to more decisive action than reports on 
other terms.
7.3.3
Unexpected Adverse Event
Expectedness of adverse events and serious adverse events will be assessed on the 
basis of the Investigator Brochure (IB)/Company Core Data Sheet (CCDS).


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 34 of 59
Worsening of NAION during the study is to be recorded in the CRF as serious 
adverse event and the procedures for serious adverse event reporting should be 
followed (see Section 7.4).
7.3.4
Relationship of Adverse Event to Investigational Product
No investigational product will be administered during the course of this study;
therefore, no assessment of causal relationship to the investigational product is 
applicable.  
Sponsor’s Fulfillment of Pharmacovigilance Reporting Requirements
As this study is non-interventional and observational, some definitions and 
processes need to be outlined and explained.  As a prerequisite for the special 
conditions a few agreements have been made beforehand.

All events dealing with NAION and /or the suspicion of NAION with the use of 
PDE5 inhibitors are considered ‘serious’. The Bayer HealthCare Global 
Pharmacovigilance system requires cases to be assessed as associated by either 
the investigator or by Bayer HealthCare to trigger distribution for expedited 
reporting to health authorities, depending upon local reporting requirements. 
Therefore, Bayer HealthCare will assess the serious NAION (suspected or 
confirmed) cases as associated to the PDE5 inhibitor.  This includes screen 
failures.

Although no investigational product will be administered during the course of 
this study, for pharmacovigilance reporting purposes PDE5 inhibitors are 
considered the ‘Investigational Product’ (IP).  This is reasonable from a medical 
point of view concerning the issue and questioning of this study and is to ensure 
that all events concerning NAION will be processed and handled in the context 
of PDE5 inhibitor use.  Furthermore, a ‘suspect drug’ is a ‘minimum 
requirement’ for defining a case internally within the Bayer HealthCare Global 
Pharmacovigilance system.

Definitions and wording are taken from the EU Directive 2001/20 and the 
respective document ‘Detailed guidance on the collection, verification, and 


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 35 of 59
presentation of adverse reaction reports arising from clinical trials on medicinal 
products for human use (April 2006, revision 2)’as Bayer HealthCare is an EU-
based pharmaceutical company.  This shall not be in conflict with fulfilment of 
reporting requirements to all concerned authorities, boards and committees.  
Bayer HealthCare will follow a very conservative strategy of reporting to ensure 
maximum possible transparency in terms of safety-relevant information.
Events/case reports will be processed as follows:
Suspected NAION Prior to the Signing of the Informed Consent
Enrolment of an individual into the study is linked to three main conditions:  male 
person, prior intake of PDE5 inhibitor and the suspicion of NAION.  Note: This text 
was modified as described in amendment 4. Consequently, every subject enrolled in 
this study will have had suspicion of NAION and will have taken at least 1 dose of 
PDE5 inhibitor prior to suspicion of NAION (although the PDE5 inhibitor may have 
been taken as much as 1 year before the suspicion of NAION).  These adverse 
events will therefore be processed as solicited post-marketing adverse events.  As 
Bayer HealthCare is actively looking for such case reports they are considered 
‘solicited’ and will be assessed as ‘serious’ and associated to the PDE5 inhibitor (as 
noted above) to allow for distribution for expedited reporting.  They will be reported 
expeditedly to all parties involved (please refer to Section 7.4.1).  This includes 
screen failures with NAION and/or the suspicion of NAION with a history of PDE5 
inhibitor use.
If there is follow-up information on the course of NAION at any time after 
enrolment this will trigger a follow-up report of the ‘solicited’ post-marketing 
adverse event report.  From a medical and procedural point of view it is reasonable 
not to consider this a new serious adverse event (SAE) or suspected unexpected 
serious adverse reaction (SUSAR), as no new exposure to a PDE5 inhibitor took 
place.  This does not refer to a worsening of NAION which is considered a new 
SAE and should be reported according to the procedures in Section 7.4.2.  The 
condition of “worsening” is based on the investigator’s clinical judgment.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 36 of 59
Adverse Events/SAEs Occurring After the Signing of the Informed Consent
Use of PDE5 inhibitors during the study is not allowed.  However, if a subject 
reports side-effects after PDE5 inhibitor intake during the study, they will be 
processed as adverse event or SAE.
7.3.5
Severity of the Adverse Event
The following classification should be used:
The severity of adverse events should be graded as follows:

Mild: usually transient in nature and generally not interfering with normal 
activities.

Moderate: sufficiently discomforting to interfere with normal activities.

Severe: prevents normal activities.
7.3.6
Adverse Event Documentation
All adverse events occurring after the subject has signed the informed consent must 
be fully recorded in the subject’s CRF.
Documentation must be supported by an entry in the subject’s file.  A laboratory test 
abnormality considered clinically relevant, eg, causing the subject to withdraw from 
the study, requiring treatment or causing apparent clinical manifestations, or judged 
relevant by the investigator, should be reported as an adverse event.  Each event 
should be described in detail along with start and stop dates, severity, action taken 
and outcome.
Reporting of Serious Adverse Events
7.4
Serious adverse events, including laboratory test abnormalities fulfilling the 
definition of serious, after signing the informed consent must immediately (within 
24 hours of the investigator’s awareness) be reported to the person detailed in the 
study file.  A Serious Adverse Event Form must also be completed within 24 hours 
of the investigator awareness and forwarded to the designated person as detailed in 
the study file.  Each serious adverse event must be followed up until resolution or 
stabilization by submission of updated reports to the designated person.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 37 of 59
When required, and according to local law and regulations, serious adverse events 
must be reported to the EC/IRB and Regulatory Authorities.
7.4.1
Reporting of Suspected NAION Cases prior to Informed 
Consent
Suspicion of NAION (event onset prior to the signing of informed consent for this 
study) in subjects who have a history of taking a PDE5 inhibitor will be reported by 
the investigator within 24 hours of investigator’s awareness.  The suspected NAION 
events are to be recorded on the CRF on the history page only (NOT on the Adverse 
Event CRF page) and on the solicited post-marketing adverse event form. These 
reports will be processed by Bayer HealthCare as solicited post-marketing reports.
Subject with suspicion of NAION but not qualifying or not consenting for enrolment 
will be recorded on standard “subject pre-screening failure log”.
7.4.2
Reporting of Worsening Cases of NAION
The investigator is to complete and submit the Serious Adverse Event Form within 
24 hours of investigator’s awareness of the event (see Section 7.4 above for further 
details).  The condition of “worsening” is based on the investigator’s clinical 
judgment.
In addition, after signing of informed consent, any cases of worsening of NAION 
will be recorded on the Adverse Event Form of the CRF and will be assessed as 
serious.
8. USE OF DATA AND PUBLICATION
All data and results and all intellectual property rights in the data and results derived 
from the study will be the property of the sponsor, who may utilize the data in 
various ways, such as for submission to government regulatory authorities or 
disclosure to other investigators.  The investigator, while free to utilize data derived 
from the study for scientific purposes, must discuss any publication with the sponsor 
prior to release and obtain written consent of the sponsor on the intended 
publication.  The sponsor recognizes the right of the investigator to publish the 
results upon completion of the study.  However, the investigator must send a draft 
manuscript of the publication or abstract to the sponsor 30 days in advance of 
submission in order to obtain approval prior to submission of the final version for 
publication.  This will be reviewed promptly, and approval will not be withheld 


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 38 of 59
unreasonably.  In case of a difference of opinion between the sponsor and the 
investigator(s), the contents of the publication will be discussed in order to find a 
solution which satisfies both parties.
9. REFERENCES
1.
Bayer-GSK. Utilization of vardenafil and other phosphodiesterase-5 inhibitors. 
Vardenafil Final Report.: Bayer-GSK Collaboration; 2006 2006 February 8, 
PhIRM.
2.
Rosen RC, Fisher WA, Eardley I, Niederberger C, Nadel A, Sand M. The 
multinational Men's Attitudes to Life Events and Sexuality (MALES) study: I. 
Prevalence of erectile dysfunction and related health concerns in the general 
population. Curr Med Res Opin 2004;20(5):607-17.
3.
Akkus E, Kadioglu A, Esen A, Doran S, Ergen A, Anafarta K, et al. 
Prevalence and correlates of erectile dysfunction in Turkey: a population-
based study. Eur Urol 2002;41(3):298-304.
4.
Braun M, Wassmer G, Klotz T, Reifenrath B, Mathers M, Engelmann U. 
Epidemiology of erectile dysfunction: results of the 'Cologne Male Survey'. Int 
J Impot Res 2000;12(6):305-11.
5.
Chew KK, Earle CM, Stuckey BG, Jamrozik K, Keogh EJ. Erectile 
dysfunction in general medicine practice: prevalence and clinical correlates. 
Int J Impot Res 2000;12(1):41-5.
6.
Feldman HA, Johannes CB, Derby CA, Kleinman KP, Mohr BA, Araujo AB, 
et al. Erectile dysfunction and coronary risk factors: prospective results from 
the Massachusetts male aging study. Prev Med 2000;30(4):328-38.
7.
Bayer. Data on file; 2005 October 24, 2005.
8.
Hattenhauer MG, Leavitt JA, Hodge DO, Grill R, Gray DT. Incidence of 
nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol 
1997;123(1):103-7.
9.
Arnold AC. Ischemic optic neuropathy. In: Miller NR, Newman NJ, editors. 
Clinical Neuro-ophthalmology. Baltimore, MD: Williams & Wilkins; 2005.
10.
IONDTRG. Ischemic Optic Neuropathy Decompression Trial Research Group. 
Characteristics of patients with non-arteritic anterior ischemic optic 
neuropathy eligible for the ischemic optic neuropathy decompression trial. 
Arch Ophthalmol 1996;114:1366-1374.
11.
Laties A, Sharlip I. Ocular safety in patients using sildenafil citrate therapy for 
erectile dysfunction. J Sex Med 2006;3(1):12-27.
12.
Johnson LN, Arnold AC. Incidence of nonarteritic and arteritic anterior 
ischemic optic neuropathy. Population-based study in the state of Missouri and 
Los Angeles County, California. J Neuroophthalmol 1994;14(1):38-44.
13.
Boshier A, Pambakian N, Shakir SA. A case of nonarteritic ischemic optic 
neuropathy (NAION) in a male patient taking sildenafil. Int J Clin Pharmacol 
Ther 2002;40(9):422-3.
14.
Janaky M, Fulop Z, Palffy A, Benedek K, Benedek G. Non-arteritic ischaemic 
optic neuropathy (NAION) in patients under 50 years of age. Acta Ophthalmol 
Scand 2005;83(4):499-503.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 39 of 59
15.
Pomeranz HD, Smith KH, Hart WM, Jr., Egan RA. Sildenafil-associated 
nonarteritic anterior ischemic optic neuropathy. Ophthalmology 
2002;109(3):584-7.
16.
Pomeranz HD, Bhavsar AR. Nonarteritic ischemic optic neuropathy 
developing soon after use of sildenafil (viagra): a report of seven new cases. J 
Neuroophthalmol 2005;25(1):9-13.
17.
Bollinger K, Lee MS. Recurrent visual field defect and ischemic optic 
neuropathy associated with tadalafil rechallenge. Arch Ophthalmol 
2005;123(3):400-1.
18.
Escaravage GK, Jr., Wright JD, Jr., Givre SJ. Tadalafil associated with 
anterior ischemic optic neuropathy. Arch Ophthalmol 2005;123(3):399-400.
19.
Peter NM, Singh MV, Fox PD. Tadalafil-associated anterior ischaemic optic 
neuropathy. Eye 2005;19(6):715-7.
20.
Gorkin L, Hvidsten K, Sobel RE, Siegel R. Sildenafil citrate use and the 
incidence of nonarteritic anterior ischemic optic neuropathy. Int J Clin Pract 
2006;60(4):500-3.
21.
McGwin G, Jr., Vaphiades MS, Hall TA, Owsley C. Non-arteritic anterior 
ischaemic optic neuropathy and the treatment of erectile dysfunction. Br J 
Ophthalmol 2006;90(2):154-7.
22.
Pfizer-Labs. VIAGRA® (sildenafil citrate) Tablets. [package insert]; 2007.
23.
Bayer-Pharmaceuticals-Corporation. LEVITRA® (vardenafil HCl) TABLETS 
[package insert]; 2007.
24.
Lilly-ICOS-LLC. CIALIS® (tadalafil) tablets [package insert]; 2007.
25.
Mittleman MA. Personal communication. 13 July. In; 2007.
26.
Maclure M. The case-crossover design: a method for studying transient effects 
on the risk of acute events. Am J Epidemiol 1991;133(2):144-53.
27.
Maclure M, Mittleman MA. Should we use a case-crossover design? Annu 
Rev Public Health 2000;21:193-221.
28.
Murray DM, Jacobs DR, Perry CL, Pallonen U, Harty KC, Griffin G, et al. A 
statewide approach to adolescent tobacco-use prevention: the Minnesota-
Wisconsin Adolescent Tobacco-Use Research Project. Prev Med 
1988;17(4):461-74.
29.
US-Census. Accessed at http://www.census.gov/prod/2002pubs/c2kprof00-
us.pdf. August 8, 2007. 2002.
30.
Whitaker HJ, Farrington CP, Spiessens B, Musonda P. Tutorial in biostatistics: 
the self-controlled case series method. Stat Med 2006;25(10):1768-97.
31.
Musonda P, Farrington CP, Whitaker HJ. Sample sizes for self-controlled case 
series studies. Stat Med 2006;25(15):2618-31.
32.
Dupont WD. Power calculations for matched case-control studies. Biometrics 
1988;44(4):1157-68.
33.
Dupont WD, Plummer WD, Jr. Power and sample size calculations. A review 
and computer program. Control Clin Trials 1990;11(2):116-28.
34.
Hintze JL. PASS 2000. Power analysis and sample size for Windows. User's 
Guide. Kaysville, UT 84037; 2002.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 40 of 59
10. APPENDICES


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 41 of 59
Study Flow Chart
10.1
Procedures and assessments
Visit 1
Day 1
Visit 2
Day 90 30
Report suspected NAION cases as a solicited post-marketing cases
X
Obtain Informed Consent
X
Enrollment
X
Medical history (including NAION history)
X
ED history
X
Medication history (including during the risk and control periods)
X
PDE5 inhibitor use history
X
Concomitant medications
X
Physical examination (including weight, height a and vital signs)
X
X
Examination of visual acuity
X
X
Examination of visual fields
X
X
Ophthalmic examination including pupil evaluation, slit lamp examination, 
applanation tonometry, fundus examination under dilated condition with description 
of retinal vessel caliber and cup to disc ratio
X
X
Fundus photography
X
X
Adverse events starting after signing informed consent
X
X
Laboratory tests (ESR, CRP, CBC)
X
Phone interview
X
a Height only at Visit 1
Abbreviations:
ED: erectile dysfunction, PDE5: phosphodiesterase type 5, NAION: non-arteritic anterior ischemic optic neuropathy
ESR: erythrocyte sedimentation rate, CRP: C-reactive protein, CBC: complete blood count


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 42 of 59
Package Inserts for PDE5 Inhibitors
10.2
Note: The following text was added to this section in amendment 2. Generic names 
were added in the following sections headings in amendment 4.
10.2.1
Package insert for sildenafil (e.g. Viagra®)
US package insert accessed on 6 Oct 2010 from the following web site:
http://media.pfizer.com/files/products/uspi_viagra.pdf
EU SmPC accessed on 6 Oct 2010 from the following web site:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000202/WC500049830.pdf
10.2.2
Package insert for tadalafil (e.g. Cialis®)
US package insert accessed on 6 Oct 2010 from the following web site:
http://pi.lilly.com/us/cialis-pi.pdf
EU SmPC accessed on 6 Oct 2010 from the following web site:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000436/WC500026318.pdf
10.2.3
Package insert for vardenafil (e.g. Levitra®)
US package insert accessed on 26 Oct 2015 from the following web site:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021400s017lbl.pdf
Note: the URL to US package was changed in amendment 4.
EU SmPC accessed on 6 Oct 2010 from the following web site:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000475/WC500039992.pdf
10.2.4
Package insert for avanafil (e.g. Stendra® / Spedra®)
Note: this section was added in amendment 4.
US package insert accessed on 9 Oct 2015 from the following website:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202276s013lbl.pdf
EU SmPC accessed on 9 Oct 2015 from the following website:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/002581/WC500145206.pdf


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 43 of 59
Laboratory Parameters
10.3
Complete blood count (CBC)

Hemoglobin

Hematocrit

RBC

MCV

MCHC

WBC

Neutrophils

Bands

Lymphocytes

Monocytes

Eosinophils

Basophils

Platelets

Cell morphology
Erythrocyte sedimentation rate (ESR)
C-reactive protein (CRP)


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 44 of 59
12912 NAION Interview
10.4
Date:___________
Time:_______________
Subject number:________________  
Date of Birth:____________
DD/MMM/YYYY
Instructions how to complete the interview (for the interviewer): will be italics 
throughout and will not be read aloud to patient
The intent of this phone interview is to help the subject remember the dates and time when he 
took his medications.  In particular, please ask detailed question about the medications, 
medical/surgical/dental interventions and alcohol consumption taken in the 4 weeks before 
the eye problem date of onset.  Determine which medications to ask about by reviewing the 
start dates from the Con Med page and only asking about those that were being taken from 
the “Date of suspected NAION Onset” and back 4 weeks.
A call/fax will be received from the site indicating that a patient is being seen for the Bayer 
study and that data will be available for review.
When contact is received from site, verify with the Study Coordinator the following:

Subject Number / and Date of Birth

Site contact call back number
Upon contact, ensure the site has provided the information via edc or fax if necessary:

Medical History page (including the date of suspected NAION onset)

Previous Medication page

Demography page

Previous or concomitant sexually enhancing medication page
If any of the above cannot be provided, call cannot take place at that time.
Contingency plans:

Site can re-fax medical history/concomitant medication list but interviewer needs 
time to review prior to speaking with patient
Note: Questions and text in the interview marked as W are considered as supporting 
questions and answers to these questions should not be recorded in the CRF pages.  The 
answers to questions and text marked as Q should be recorded in the CRF pages.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 45 of 59
Introductory statement:
Thank you for agreeing to participate in this research study. You have been seen in the eye 
specialist’s office because of your eye problem and had all or will have all of the necessary 
diagnostic assessments done. As a final part of this assessment, I would like to find out which 
medications you were taking at the time when you experienced your eye problem. I will ask 
you a few questions about these medications as well as any medical visits that happened 
during that time, including dental or specialist visits.  In addition, I will ask you about alcohol 
consumption.
W: Do you have any questions for me at this time regarding this interview?  If you have any 
questions regarding the study or your condition, please direct these to your study doctor.  
Yes    No
(Allow time for questions.)
W: Can we continue with the interview?  
Yes    No
If “yes” start the interview.
If “No”:  W:  I understand that you are not ready to complete the interview at this time.  It is 
important that we review your medications as soon as possible.  Do you think that you could 
take time tonight (preferably) or tomorrow to speak with me?” 
If “Yes” confirm time: W: Here is the number where I can be reached (give number).  
When you call, please be sure to have the calendar page given to you by the study 
staff with you as we will be referring to it during the call. 
W: Do I have your permission to call you if we do not hear from you as expected? 
W: What is the number where can I reach you? 
W: Is it acceptable to leave a message regarding the Bayer study on this line’s 
voicemail? 
If “No”, continue to encourage the subject to call up to 3 days in future.  If the interview 
cannot be scheduled within 45 days of NAION onset, thank caller and direct him to Study 
Coordinator. Note: The time of onset was changed in amendment 2.
Note: for the purpose of the interview scheduling, the interviewer should use the “date of 
NAION onset” obtained by the investigator.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 46 of 59
Note: Please ensure that the interview is scheduled within 48 days of NAION onset (45 days 
plus 3 days for scheduling the interview). Note: The time of onset was changed in 
amendment 2.
Start of the interview:
Review NAION onset date on medical history CRF page provided by study coordinator. 
If onset date was narrowed to 1 day proceed to question Onset 1
If NAION onset date was narrowed to 2 days proceed to question Onset 2
Q: Onset 1: You have reported an eye problem which started on [date (see date of 
onset  NAION History EDC screen) ].Is it correct? Yes    No
If “Yes, go to section A.
If “No”, write down the new date of Suspected NAION onset as reported by the patient and 
use that date to count back the weeks that medication will need to be reviewed for. 
Q: New onset 1: What is the new onset date? 
__________________________________________(enter date)
Now clarify with the patient the reason for the onset date change:
Q: You are saying that your eye problem began on [date just given] and not on [date 
given to investigator]. Can you please confirm this change and give a reason? (enter 
free text)
__________________________________________ (enter reason)
Go to section A.
Q: Onset 2:You have reported an eye problem which started on either of these 2 
days[date(see date of onset  NAION History EDC screen) ]. 
Is it correct? Yes    No
If “Yes”, go to section A.
If “No”write down the new date of Suspected NAION onset as reported by the patient and 
use that date to count back the weeks that medication will need to be reviewed for.
Q: New onset 2: What is the new onset date? 
__________________________________________(enter date)
Now clarify with the patient the reason for the onset date change:
Q: You are saying that your eye problem began on [date just given] and not on [date 
given to investigator].  Can you please confirm this change and give a reason? (enter 
free text)


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 47 of 59
__________________________________________ (enter reason)
Go to section A.
IMPORTANT: If the suspected NAION onset date has been narrowed down to 2 days , for 
the purpose of collecting the data, the date of suspected NAION onset is considered as the 
latter of the two days.
If during the phone interview the patient reported a different date of suspected NAION onset 
than what was reported to the investigator, request the patient update the calendar under 
direction of interviewer (the calendar should include the date of suspected NAION onset and 
the time period covering 4 weeks prior to NAION onset). 
A.
Previous medications (Duplicate page as needed)
Begin by asking about a drug from the received list that is expected to be taken daily.  Once 
all questions are asked for that drug, ask about PDE5 inhibitors, (i.e. tadalafil, vardenafil, 
sildenafil or avanafil). Note: trade names were replaced by generic in amendment 4.
Then ask about cardiovascular drugs, then etc. based on prioritization list provided by 
Bayer.
I will now begin asking you questions about the medications your doctor has recorded.  

If beginning of interview: I’d like to begin with [drug name-drug 1 on Previous 
Medication page].  
OR  

If subsequent drugs:  Now I’ll be asking you about [drug name-drug 2, etc. on 
Previous Medication page].
A1.
Q: Do you take this drug every day?
Yes    No
If “Yes”, continue interview using Questions for Medications Taken Daily. Ask questions B 
for EACH drug.
If “No”, continue interview using Questions for Medications Taken PRN.  Ask questions C 
for EACH drug.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 48 of 59
B.
Questions for Medications Taken Daily (Duplicate page as needed)
Q: (enter the drug name here)__________________________________________
Q: (total daily dose)_________________________________________________
B1.
Q: Did you start this medication before, on or after you first noticed the eye 
problem?
before on after 
If the start date  is before the day of  suspected NAION onset, ask the question B2
If the start date  is on  the day of  suspected NAION onset, ask the question B3
If the start date is after the suspected NAION onset (do not enter this drug into the phone 
interview page), go to section A ands ask about the next medication on the Previous 
Medication page
B2:
Q: I see that you have started your medication before the day you first 
noticed the eye problem. Can you please provide the date you started this 
medication.
Start date (if within 28 days of eye problem onset)_________________
or started more than 28 days before eye problem onset
Go to question B4
B3:
Q: I see that you started your medication on the day you first notice the eye 
problem. On that day, did you take the medication before or after you first 
noticed the eye problem?
before after 
If “before” go to question B4
If “after” (do not enter this drug into the phone interview page).Go to section A and ask 
about the next drug.
B4: 
Did you stop this medication before, on or after you first noticed the eye 
problem? 
before on after/continuing
If the stop date  is before the day of suspected NAION onset, ask the question B5
If the stop date  is on  the day of  suspected NAION onset, ask the question B6
If the stop  date is after/continuing the suspected NAION onset, go to question A and ask 
about the next medication on the conmed page.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 49 of 59
B5:
Q: I see that you stopped your medication before the day you first noticed the 
eye problem. Can you please provide the date when you stopped this 
medication?
Stop date_________________
Go to section A and ask about the next medication on the Previous Medication page
B6:
Q: I see that you stopped your medication on the day you first notice the eye 
problem. On that day, did you stop the medication before or after the you first 
noticed the eye problem?
before after
Go to section A and ask about the next medication on the Previous Medication page
.
C:
Questions for Medications Taken PRN (Duplicate page as needed)
Q: (enter the drug name here)__________________________________________
Q: (total daily dose)_________________________________________________
W: Please look carefully at calendar to help you to remember better and take your time. 
C1:
Q: Looking at the calendar, in the 28 days prior to first noticing the eye 
problem 
were there any days that you took this medication? 
Yes    No  Don't remember  
If “Yes”, continue interview with question C2.
Note: If the answer is “No” or “Don’t remember”, go to C3.a
C2.
Q: Can you please tell me which days you took this drug?  
enter days_______________________________________
C3.
Q: You have reported that you took medication on [repeat days reported in 
C2]? Are there any other days that you took this drug? 
Yes    No  Don't remember  
If “Yes”, return to C2.
If patient answers “No” or “Don’t remember” make additional efforts to help him to recall 
using the calendar and asking questions from C3.a through C3.d.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 50 of 59
W: Please look carefully at calendar to help you to remember better and take your 
time
C3.a
Q: Looking at the calendar did you take this drug on the day of or on the day 
before you noticed your eye problem started? This would be (state date from 
calendar- Day 0 & -Day 1. 
Allow some time for patient to think, if necessary
Yes    No Don't remember
If Yes, please enter the date and go to C3.b.
(enter date)_________________________________________
If No or Don’t remember, go to the C3.b
C3.b
Q: Looking at the calendar did you take this drug seven or eight days before 
the day your eye problem started? This would be (state date from calendar-
Day 7 & -Day 8)
Allow some time for patient to think, if necessary
Yes    No Don't remember
If Yes, please enter the date and go to C3.c.
(enter date)_________________________________________
If No or Don’t remember,  go to the C3.c
C3.c
Q: Looking at the calendar did you take this drug fourteen or fifteen days 
before the day your eye problem started? This would be (state date from 
calendar- Day 14 & -Day 15)
Allow some time for patient to think, if necessary
Yes    No Don't remember
If Yes, please enter the date and go to C3.d.
(enter date)_________________________________________
If No or Don’t remember, go to the C3.d
C3.d
Q: Looking at the calendar did you take this drug twenty-one or twenty-two 
days before the day your eye problem started? This would be (state date from 
calendar- Day 21 & -Day 22)
Allow some time for patient to think, if necessary
Yes    No Don't remember


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 51 of 59
If Yes, please enter the date and see the notes below.
(enter date)_________________________________________
If No or Don’t remember , see the notes below.
Note: If the answer is “Don’t remember” for all the questions from C1 through C3d, and the 
medication is PDE5 inhibitor, please complete the interview, but the patient will be 
considered a Screen Failure.
If this medication was taken on the same day as the suspected NAION onset ask patient:
C4.
Q: I see you took this medication on the day you first noticed the eye 
problem. On that day did you take this medication before or after you first 
noticed the eye problem? 
before after I don't know.
Continue asking the Daily or PRN questions for all drugs listed on the received list. Please 
communicate to the investigator the names of all medications which were not reported to the 
investigator initially.
After all drugs listed have been discussed:
D.
Homeopathic treatments, vitamins etc. 
D1.
W:Looking at the calendar, in the 28 days prior to first noticing the eye 
problem were there any drugs, prescription, over the counter or other types (including 
homeopathic treatments or vitamins) that you took during that time that we have not 
talked about? Yes    No Don't remember
If “Yes”, continue interview with question A.
Review Medical History for past 4 weeks.  Ask question E1 for each procedure from the 
“Date of Onset” and back 4 weeks.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 52 of 59
E.
Questions for medications during procedures/surgical/dental etc. 
(Duplicate page as needed)
E1. W: Looking at the calendar, in the 28 days prior to first noticing the eye problem 
were there any days that you had any medical/dental procedure (e.g. surgeries, tooth 
extractions, cavities being filled, etc.)? 
Yes    No  Don't remember  
If “Yes”, continue interview with question E2.
If “No”, continue interview with question F.
E2.
Q: Can you please tell me which days you had this procedure?  
(Enter procedure)___________________________________
(enter days)_______________________________________
E3.
Q: You have reported that you had a procedure on [repeat days reported in E2]? 
Are there any other days that you had any procedures? (if “Yes”, enter 
procedure and enter days)
(enter procedure)__________________________________________________
(enter days)______________________________________________________
If any procedure occurred on the same day as the suspected NAION onset, ask the patient 
question E4 for each procedure reported in E2 and E3:
E4.
Q: I see you had this procedure on the day you first noticed the eye problem. 
On that day, did you have this procedure before or after you first noticed the 
eye problem? 
before after I don't know.
E5.
W: During your procedure on the [date], did your medical professional give 
you any type of medication, including anaesthesia that we have not discussed?  
Yes    No  Don't remember
If “No”, continue interview with question F.
If “Yes”, will need to ask Questions for Medications Taken PRN for each drug.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 53 of 59
F
Alcohol consumption 
F1:
Q: Looking at the calendar, in the 28 days prior to first noticing the eye 
problem did you consume alcoholic beverages daily or occasionally?
daily    occasionally  none at all
If used daily  go to F2.
If occasional use go to F9
If “none at all” go to G
F2.
Q: Did you start taking the alcohol beverage on a daily basis before, on or 
after you first noticed the eye problem?
before on after 
If the start date  is before the day of  suspected NAION onset, ask the question F3
If the start date  is on  the day of  suspected NAION onset, ask the question F4
If the start  date is after the suspected NAION onset, go to question G.
F3:
Q: I see that you have started taking alcoholic beverages before the day you 
first noticed the eye problem. Can you please provide the date you started 
drinking alcoholic beverages
Start date_________________
or started more than 28 days before eye problem onset   
Level of consumption :
How many drinks per day did you drink?___________
(Answer will be entered by interviewer in one of three categories:  1-2 
drinks =mild, 3-4 drinks = moderate,5+ drinks =heavy 
Go to question F5
F4:
Q: I see that you started drinking alcoholic beverages on a daily basis on the 
day you first notice the eye problem . On that day, did you drink alcoholic 
beverages before or after you first noticed the eye problem?
before after 
Go to question F5
F5: 
Q: Did you stop drinking alcoholic beverages on a daily basis before, on or 
after you first noticed the eye problem? 
before on after 
If the stop date  is before the day of  suspected NAION onset, ask the question F6


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 54 of 59
If the stop date  is on  the day of  suspected NAION onset, ask the question F7
If the stop  date is after the suspected NAION onset, please check the check box under 
question F8 and then go to question .
F6:
Q: I see that you stopped drinking alcoholic beverages on a daily basis 
before the day you first noticed the eye problem. Can you please provide the 
date when you stopped drinking alcoholic beverages?
Stop date_________________
Go to question G.
F7:
Q: I see that you stopped drinking alcoholic beverages on a daily basis on 
the day you first notice the eye problem. On that day, did you stop drinking 
alcoholic beverages before or after you first noticed the eye problem?
before after
Go to question G.
F8:
Q: Check box below:
stopped after eye problem onset 
Go to question G.
F9:
Q: Looking at the calendar, in the 28 days prior to first noticing the eye 
problem 
were there any individual days that you consumed alcoholic beverages? 
Yes    No  Don't remember  
If “Yes”, continue interview with question F10.
If “No”, continue interview with question G
F10.
Q: Can you please tell me which days you consumed alcoholic beverages?  
enter days_______________________________________
Level of consumption :
How many drinks per day did you drink?___________
(Answer will be entered by interviewer in one of three categories:  1-2 drinks =mild, 3-4 
drinks = moderate,5+ drinks =heavy 
F11.
Q: You have reported that you consumed alcohol on [repeat days reported in 
F10]? Are there any other individual days that you consumed alcoholic beverages? 
Yes    No  Don't remember  (Duplicate page as needed)
If “Yes”, please return to F10.
If “No” or “Don’t remember” please go to section G.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 55 of 59
If alcohol was consumed on the same day as the suspected NAION onset ask patient:
F12.
Q: I see you consumed alcohol on the day you first noticed the eye problem. 
On that day, did you consume alcohol before or after you first noticed the eye 
problem? 
before  after I don't know.
Go to section G
G. Other
G1:
W: Looking at the calendar, are there any drugs/dr/dentist/other medical 
appointments that we did not discuss? 
Yes    No Don't remember
If “No”, continue interview with Conclusion.
If “Yes”, will need to go back to appropriate section.
________________________________________________________________________
H. Conclusion
I’d like to thank you for your participation in this study and taking the time to speak with 
me today.  If you have any questions regarding our conversation or the medications 
discussed, please speak with your study staff or eye doctor before leaving the office today.
Instruction on How to Perform Perimetry
10.5
In this study, Humphrey’s Field Analyzer and Octopus perimeters will be used for 
the visual field assessments. Note: Octopus perimetry was added in amendment 2. 
The perimetry should be performed by a trained and experienced staff.
Copies of all perimetry printouts must be signed and dated by the investigator (or 
his/her delegate) and kept in the Investigator’s Study File for source data 
verification.  The printouts must be marked with study code, patient number, as 
well as date of measurement.
In order to standardize how the perimetry testing will be performed in this study, 
technicians at each site will be provided with an instruction manual.


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 56 of 59
Sample Narrative to Expert Panel
10.6
The sample narrative below is to illustrate how partial blinding of the Expert Panel 
should be ensured.
PPD


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 57 of 59
PPD


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 58 of 59
PPD


BAY 38-9456 / 12912 / Integrated Protocol Version 4.0 (02 March 2016)
Page 59 of 59
PPD

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
Prospective Case Crossover Study to Assess Whether PDE5 
Inhibitor Exposure in Men increase the Risk for the Development of 
Non-arteritic Anterior Ischemic Optic Neuropathy (NAION) 
NCT Number: 
NCT00867815 
Document Date: 
20-MAR-2018 
 


Statistical Analysis Plan
Protocol No.: BAY 38-9456/12912
Page: 1 of 8
Title Page 
Prospective Case Crossover Study to Assess Whether PDE5 Inhibitor 
Exposure in Men increase the Risk for the Development of Non-arteritic
Anterior Ischemic Optic Neuropathy (NAION) 
[NAION]
Bayer study drug
BAY 38-9456/vardenfil/Levitra 
Study purpose:
Post Marketing Follow-up study
Clinical study 
phase:
IV
Date:
20 March 2018
Study No.:
12912
Version:
1.0
Author:
 
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation.  Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


Statistical Analysis Plan
Protocol No.: BAY 38-9456/12912
Page: 2 of 8
Table of Contents
Title Page................................................................................................................................... 1
Abbreviations............................................................................................................................ 3
1.
Introduction ....................................................................................................................... 4
2.
Study Objectives................................................................................................................ 4
3.
Study Design ...................................................................................................................... 4
4.
General Statistical Considerations .................................................................................. 5
4.1
General Principles............................................................................................................ 5
4.2
Handling of Dropouts ...................................................................................................... 5
4.3
Handling of Missing Data................................................................................................ 6
4.4
Interim Analyses and Data Monitoring............................................................................ 6
4.5
Data Rules........................................................................................................................ 6
4.6
Blind Review ................................................................................................................... 6
5.
Analysis Sets....................................................................................................................... 7
6.
Statistical Methodology..................................................................................................... 7
6.1
Population characteristics ................................................................................................ 8
6.2
Efficacy............................................................................................................................ 8
6.3
Pharmacokinetics/pharmacodynamics............................................................................. 8
6.4
Safety ............................................................................................................................... 8
7.
Document history and changes in the planned statistical analysis ............................... 8
8.
References .......................................................................................................................... 8


Statistical Analysis Plan
Protocol No.: BAY 38-9456/12912
Page: 3 of 8
Abbreviations
AE
Adverse event
CI
Confidence Interval
CSR
ED
Clinical Study Report
Erectile Dysfunction
LOS
Listing only set
MedDRA
Medical Dictionary for Regulatory Activities
N/A
NAION
PDE5
Not applicable
Non-Arteritic Ischemic Optic Neuropathy
Phosphodiesterase type 5 
PPS
Per-protocol set
PT
Perferred Term
SAE
Serious adverse event
SOC
System Organ Class
SAP
Statistical Analysis Plan


Statistical Analysis Plan
Protocol No.: BAY 38-9456/12912
Page: 4 of 8
1.
Introduction
This SAP is based on the 12912 Integrated Protocol Version 4.0 02 MAR 2016. That protocol 
is an integrated protocol containing the modifications mandated in amendment 4.0.
This SAP refers to the final analysis to be completed after FDA released Bayer from this post-
marketing commitment on 15 NOV 2017. The FDA  concluded that Study 12912 is unlikely 
to provide value for further risk assessment of NAION associated with the class of PDE5 
inhibitors indicated for the treatment of erectile dysfunction. Due to the limited number of 
patients valid for analysis (safety n=10 and Valid for NAION n=7) in this study an 
abbreviated set of tables and listing will be prepared.
2.
Study Objectives
The primary objective of this study is to determine whether the use of PDE5 inhibitors 
(vardenafil, sildenafil, tadalafil or avanafil) increases the risk for the development of NAION. 
Because of the small sample size at termination of the study, the principal statistical analysis 
based on the valid for NAION analysis will not be performed. However, a summary of the 
frequency of PDE5 Inhibitor exposure during all 3 control and 1 risk periods will be provided 
for the valid for NAION analysis set, ie, the subset of subjects with unanimous NAION 
assessment (ie, “definite NAION” – 3 out of 3 experts confirm the diagnosis) and probable
NAION assessment (2 of 3 experts confirm the diagnosis). 
3.
Study Design
This is a case-crossover prospective field study, in which each subject will serve as his own 
control.Patients suffering from a suspected case of NAION are medically examined and 
interviewed for confirmation of suspected NAION and PDE5 Inhibitor use in the 28 days 
prior to onset of suspected NAION. Each subject will have 2 clinical visits. Visit 1 (Day 1) 
will include screening for NAION and other inclusion and exclusion criteria, enrollment, and 
conduct of a telephone interview for collection of data on PDE5 inhibitor use. Visit 2 (Day 90
+/- 30) will be a follow-up visit to document the persistence of vision loss. 
In the case-crossover design of this study, the day of NAION onset and the day before (Days 
0-1) are defined as the risk period* (Figure 3–1). Control periods are the same two days of the 
week in the preceding three weeks (Days 7-8, 14-15, 21-22).
Thus, there is one risk period, and 3 control periods 1 to 3 weeks prior to the risk period. 
These control periods will serve as artificial or ‘matched’ controls simulating a matched case-
control study with the advantage of time invariant subject traits. 
Study Design
Figure 3–1：Study Design


Statistical Analysis Plan
Protocol No.: BAY 38-9456/12912
Page: 5 of 8
*Risk period: the 2 calendar days including the day of onset of suspected NAION
symptoms and the preceding day (If the subject can specify onset only to within
a 2-day window, then those 2 days constitute the risk period.)
Subjects to be screened must meet the following criteria:

Preliminary diagnosis of NAION by an ophthalmologist
Note: “History of ED according to the subject” was removed in amendment 4. But no patients 
were enrolled under amendment 4.

Use of a PDE5 inhibitor within the past year
The following times will be determined for this study:

Date of onset of suspected NAION (must be within 45 days of initial presentation to 
the investigator) 

Date of initial presentation for medical evaluation in the study

Date of NAION diagnosis as conducted by a study investigator

Risk period: the 2 calendar days including the day of onset of suspected NAION
symptoms and the preceding day (If the subject can specify onset only to within a 2-
day window, then those 2 days constitute the risk period.)

Last visit will be defined as the date of last contact with the subject
The final adjudication of NAION events will be done through an anonymous, independent 
assessment of medical records by an expert panel of 3 experts in neuroophthalmological
diseases..
4.
General Statistical Considerations
4.1
General Principles
The statistical tabulation and listing will be performed by using the software package SAS 
release 9.2 or higher (SAS Institute Inc., Cary, NC, USA). The number of data available and 
missing data, mean, standard deviation, minimum, quartiles, median, and maximum will be 
calculated for metric data. Frequency tables will be generated for categorical data.
4.2
Handling of Dropouts
A subject who withdraws is one who discontinues the study before visit 2 for any of the 
following reasons:

At his/her own request

If, in the investigator’s opinion, continuation in the study would be detrimental to the 
subject’s well-being

At the specific request of the sponsor
In all cases, the reason for withdrawal must be recorded in the Case Report Form (CRF) and 
in the subject’s medical records. 
There are no special instructions for handling dropouts in the TLF.


Statistical Analysis Plan
Protocol No.: BAY 38-9456/12912
Page: 6 of 8
4.3
Handling of Missing Data
Subjects who fulfill all the criteria for NAION at Visit 1 who are subsequently lost to follow-
up (no follow-up information available on visual status after 3 months) will be interpreted as 
definite NAION cases. Subjects not returning for Visit 2 will be contacted by telephone and 
questioned about their visual status. This information can be used for analysis instead of Visit 
2 if supported by the Expert Panel. 
The NAION onset date in main CRF (NAION history) pages are to be updated based on 
interview information. The updated NAION onset date should be used for all tables and 
listing except for NAION history listing where a footnote will explain that this date comes
from NAION history but could have been updated in the Interview.
4.4
Interim Analyses and Data Monitoring
An interim analysis was initially scheduled to be performed after the inclusion of 100 
confirmed NAION cases, however, no interim analysis was conducted as the trial was 
terminated early due to low enrollment. Furthermore, there was no data monitoring
committee.
4.5
Data Rules
Unless otherwise specified baseline is Visit 1.
Enrolled is defined as all patients who signed the informed consent (including screen failures).
4.6
Blind Review
The final diagnosis of NAION will be made by an independent expert panel of 3 experts in 
neuro-ophthalmological diseases. A charter will be developed defining the review process by 
the expert panel. The expert panel will receive all information recorded on all cases in a 
blinded fashion. Experts will be blinded to the following information: The final adjudication 
of events will be done by the expert panel, with an anonymous, independent assessment from 
medical records by all 3 experts. In case of conflicting assessments, the experts are requested 
to discuss those cases in detail with the goal of finding agreement. Three categories of 
assessment are possible:

Date of event

PDE5 inhibitor use related to the event and during control periods or event period and 
history of use

Presence of ED

Concomitant medication

Date and duration of concomitant diseases
The final adjudication of events will be done by the expert panel, with an anonymous, 
independent assessment from medical records by all 3 experts. In case of conflicting 
assessments, the experts are requested to discuss those cases in detail with the goal of finding 
agreement. Three categories of assessment are possible:


Statistical Analysis Plan
Protocol No.: BAY 38-9456/12912
Page: 7 of 8

Definite NAION – 3 experts confirm diagnosis (resulting in inclusion in the valid for 
NAION dataset)

Probable NAION – 2 experts confirm diagnosis (resulting in inclusion in the valid for 
NAION dataset)

Unlikely NAION – fewer than 2 experts confirm diagnosis (not included in the valid 
for NAION dataset)
5.
Analysis Sets
Assignment of analysis sets
Valid for NAION analysis set
While no statistical analysis will be performed due the small sample, the frequency of 
exposure to PDE5 inhibitors at risk and control periods will be tabulated for the Valid for 
NAION analysis set (also known as the Per Protocol set), defined as the subset of subjects 
with a unanimous NAION assessment (ie, “definite NAION”) and probable NAION 
assessment (2 of 3 experts confirmed the diagnosis). Subjects fulfilling all the criteria for 
NAION at Visit 1 who are subsequently lost to follow-up (no follow-up information available 
on visual status after 3 months) will be interpreted as definite NAION cases. Subjects not 
returning after 3 months for Visit 2 will be contacted by telephone and questioned about their 
visual status. This information can be used for analysis instead of Visit 2 if deemed 
appropriate by the expert panel.
Safety analysis set
All subjects who signed informed consent and who have any of the following collected at 
Visit 1 will be valid for safety: laboratory values, physical exam, any eye exams, or adverse 
events.
6.
Statistical Methodology
Vardenafil project standards were used as appropriate (ie, Relative day, etc). 
In the interview questionnaire, if there are any inconsistencies between the “Yes/no” questions 
(ie, Did you take a <PDE5 Inhibitor> on the day of or on the day before you noticed your eye 
problem; Did you take a PDE5-Inhibitor 7 or 8 days, 14 or 15 days or 21 or 22 before the day 
your eye problem started) and the subsequent dates associated with these question, then the 
dates will be used as the deciding factor as to whether the value falls within a certain risk or 
control period. If the patient says he doesn’t remember we will not impute a date of exposure 
for that risk or control period.
In the interview questionnaire for PDE5 inhibitor used PRN, if a yes was given to question 
did you take a PDE5 Inhibitor 7 or 8 days, 14 or 15 days or 21 or 22 before the day your eye 
problem started, respectively but the only a partial date is given and the subject stated they 
took the PDE5 Inhibitor in the 28-day period before the eye problem started, then we impute
the exposure partial dates as follows: the date of Day 0 during risk period  and the date 7,14 
and 21 days before the day NAION was started for the control periods.  
In the interview questionnaire, if the concomitant medication page suggest PDE5 inhibitor use 
overlapped NAION onset but the interviewer failed to ask questions related to PRN use of the 


Statistical Analysis Plan
Protocol No.: BAY 38-9456/12912
Page: 8 of 8
PDE5 Inhibitor no assumptions about PDE5 Inhibitor exposure during the risk or any of the 
three control periods will be made. In this case PDE5 inhibitor exposure will be considered 
“Missing”.
Due to the limited number of patients valid for analysis (safety n=10 and Valid for NAION
n=7) in this study an abbreviated set of tables and listing will be prepared. No analysis will be
done.
Demographics, subject disposition (overall, screening and end of study), subject validity and 
primary reason for exclusion and medical history will be tabulated. Continuous variables will 
be summarized by mean, SD, Median, Min and Max.  Frequencies and percentages will be 
reported for categorical variables. 
6.1
Population characteristics
Due to the limited number of patients valid for analysis (safety n=10 and Valid for NAION
n=7) no subset analysis will be performed.
6.2
Efficacy
As this is a safety study, no assessment of efficacy will be made. 
6.3
Pharmacokinetics/pharmacodynamics
N/A
6.4
Safety
Overall summary of number of subjects with adverse events, number of subjects with adverse 
events by primary SOC and PT after Visit 1, and frequency of exposure to PDE5 inhibitors at 
risk and control periods will be tabulated. A listing of serious AEs will also be provided.
Laboratories (collected at baseline (Visit 1)) will be listed. Vital signs will also be listed.
Frequencies and percentages will be reported for categorical variables. 
Adverse conditions starting prior to informed consent will be captured as part of the medical 
history; adverse conditions reported after informed consent will be recorded as adverse events 
on the CRF. Accordingly, NAION starting before informed consent will be reported by the 
investigator and processed as a solicited postmarketing serious adverse event. Worsening of 
NAION after signing of informed consent will be recorded on the Adverse Event page of the 
CRF as a serious adverse event and reported. Concomitant diseases, pre-existing diseases, and 
laboratory data reported as medical history or reported as an adverse event will be classified 
according to the Medical Dictionary for Regulatory Activities (MedDRA) Version 20.1. 
Conditions that worsen or occur between Visit 1 and Visit 2, after the subjects had signed the 
informed consent form, will be recorded as adverse events on the CRF.
7.
Document history and changes in the planned statistical analysis
No signed off SAPs before this SAP.
8.
References
None