Clinical trial NCT01608087
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2012-05-01; Completion date: 2012-11-01
Enrollment: 91 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial will investigate the pharmacokinetics and safety of BI 695502 and to establish pharmacokinetic biosimilarity of BI 695502 compared to bevacizumab.

Detailed description:

Arms: arm 1: Subject to receive one intravenous (i.v.) infusion of BI 695502 arm 2: Subject to receive one i.v. infusion of bevacizumab arm 3: Subject to receive one i.v. infusion of bevacizumab
Interventions: intervention 1: BI 695502 intervention 2: bevacizumab intervention 3: bevacizumab
Intervention descriptions: intervention 1: BI 695502 single i.v. infusion intervention 2: bevacizumab single i.v. infusion intervention 3: bevacizumab single i.v. infusion

Protocol documents:
Prot_000.pdf: 
 
SIGNATURE INFORMATION 
 
Document: 
                               
                           
Document No.:                                                                                                                        
 
Title 
                             
 
 
 
 
 
 
                         
 
SIGNATURES  (ELECTRONICALLY OBTAINED)  
 
Meaning of Signature: 
Signed by: 
Date signed: (GMT) 
                                   
 
 
 
                               
                                                                                     
                                   
 
 
 
                               
                                                                                      
                                   
 
 
 
                               
                                                                                             
                                   
 
 
 
                               
                                                                                      
                                   
 
 
 
                               
                                                                                     
                                  
 
 
 
                               
                                                                                                                     
                                   
 
 
 
                               
                                                                                                                       
1302-0001--protocol-revison-02
U12-1288-03
Pharmacokinetics and safety of BI 695502 in healthy subjects: a
randomized, single-blind, single-dose, parallel-arm, active-comparator
clinical Phase I study
Author-Trial Clinical Monitor
1/11/2013 12:19:33
Author-Team Member Medicine
1/11/2013 12:23:47
Author-Trial Statistician
1/11/2013 13:04:10
Approval-Therapeutic Area 
1/11/2013 14:08:30
Verify Paper Signature Completion
1/13/2013 21:42:23


 
SIGNATURE INFORMATION (continued) 
Document 
                              
                          
Document No.:                                                                                                                        
 
Title 
                             
 
 
 
 
 
 
                         
SIGNATURES  (ELECTRONICALLY OBTAINED)  
(There are no entries on this page if there are up to seven signatures.) 
Meaning of Signature: 
Signed by: 
Date signed: (GMT) 
                                   
 
 
 
                               
                                                                                                                      
                                   
 
 
 
                               
                                                                                                                      
                                   
 
 
 
                               
                                                                                                                      
                                     
 
 
 
                                 
                                                                                                                      
                                     
 
 
                                 
                                                                                                                      
                                     
 
 
                               
                                                                                                                       
                                     
 
 
                                
                                                                                                                       
                                     
 
 
                                 
                                                                                                                     
 
1302-0001--protocol-revison-02
U12-1288-03
Pharmacokinetics and safety of BI 695502 in healthy subjects: a
randomized, single-blind, single-dose, parallel-arm, active-comparator
clinical Phase I study


  
 
Clinical Trial Protocol 
 
Doc. No.: U12-1288-
032
BI Trial No.: 
1302.1 
 
BI Investigational 
Product(s): 
BI 695502 
Title: 
Pharmacokinetics and safety of BI 695502 in healthy subjects: a 
randomized, single-blind, single-dose, parallel-arm, active-comparator 
clinical Phase I study 
Clinical Phase: 
I 
Trial Clinical 
Monitor: 
Phone: 
 
Fax: 
 
Co-ordinating 
Investigator: 
                                                                 
                                                         
                                                             
Phone: 
 
   Fax: 
 
Status: 
Final Protocol (Revised Protocol (based on global amendment 01 and 
02) 
Version and Date: 
Version: 32.0  
         
Date: 11 Jan 201326 Nov 2012 
 
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TITLE PAGE 


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BI Trial No.: BI 695502 
 
Doc. No.: U12-1288-032 
Trial Protocol 
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CLINICAL TRIAL PROTOCOL SYNOPSIS 
Name of company: 
Tabulated 
Trial Protocol 
 
Boehringer Ingelheim 
 
Name of finished product: 
NA 
Name of active ingredient: 
 
BI 695502 
 
Protocol date: 
Trial number: 
 
Revision date:  
11 Jan 201326 Nov 
2012 
27 Mar 2012 
1302.1 
Title of trial: 
Pharmacokinetics and safety of BI 695502 in healthy subjects: a randomized, 
single-blind, single-dose, parallel-arm, active-comparator clinical Phase I study 
Co-ordinating 
Investigator 
Trial sites: 
Multi-center trial in two clinical sites in one country.   
Clinical phase: 
I 
Objective(s): 
The primary objective of this study is to establish pairwise pharmacokinetic similarity 
between BI 695502, Avastin®, US origin and Avastin®, EU origin following one 
intravenous infusion. 
 
The secondary objective of this study is to evaluate safety of BI 695502 and 
bevacizumab (Avastin®) US and EU origin and other pharmacokinetic parameters. 
Methodology: 
This is a randomized, single-blind, parallel-arm, single-dose, active-comparator study. 
The trial will consist of three parallel arms of BI 695502, bevacizumab (US-origin 
Avastin®), and bevacizumab (EU-origin Avastin®) with pairwise comparisons 
between each of the arms. 
No. of subjects:  
Up to approximately 180 subjects will be enrolled (90 subjects in Stage 1; 90 subjects 
in Stage 2, if applicable) 
 
total entered: 
Subjects with evaluable data 
 
each treatment: 
• 
BI 695502/concentrate for solution for infusion - approximately 60 subjects 
(30 subjects in Stage 1 and 30 in Stage 2, if applicable) 
• 
Bevacizumab (Avastin®) / solution for intravenous infusion, US source - 
approximately 60 subjects (30 subjects in Stage 1 and 30 subjects in Stage 2, 
if applicable) 
• 
Bevacizumab (Avastin®) / concentrate for solution for infusion, EU source - 
approximately 60 subjects (30 subjects in Stage 1 and 30 subjects in Stage 2, 
if applicable) 
The first six subjects will be dosed over 6 days (i.e., 1 subject per day) and each 
subject will be required to remain in the trial center for 48 hours after dosing 
(overnight) for safety observations. At least one subject will receive BI 695502. 
Diagnosis : 
Healthy male subjects 


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Doc. No.: U12-1288-032 
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Name of company: 
Tabulated 
Trial Protocol 
 
Boehringer Ingelheim 
 
Name of finished product: 
NA 
Name of active ingredient: 
 
BI 695502 
 
Protocol date: 
Trial number: 
 
Revision date:  
11 Jan 201326 Nov 
2012 
27 Mar 2012 
1302.1 
Main criteria 
for inclusion: 
Healthy male subjects, aged 21 to 50 years, body weight 65 to 95 kg, and BMI 
≤ 30 kg/m2 
Test product(s): 
BI 695502/concentrate for solution for infusion 
 
dose: 
1 mg/kg 
 
mode of admin.: 
Intravenous infusion 
Comparator products: Bevacizumab (Avastin®)/solution for intravenous infusion, US source 
 
dose: 
1 mg/kg 
 
mode of admin.: 
Intravenous infusion 
 
Bevacizumab (Avastin®)/concentrate for solution for infusion, EU source 
 
1 mg/kg 
 
Intravenous infusion 
Duration of treatment: This study will have a screening period of up to 28 days. The subject will check-in to 
the study center on Day -1 and be resident until the Day 3 discharge procedures are 
complete. All patients will remain hospitalized for 48 hours after dosing but can be 
discharged after 24 hours at investigator´s discretion. The subject will then return to 
the clinic for 9 ambulatory visits (Days 5, 8, 15, 22, 36, 50, 64, 78, and 99 End of 
trial).   
 


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Doc. No.: U12-1288-032 
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Name of company: 
Tabulated 
Trial Protocol 
 
Boehringer Ingelheim 
 
Name of finished product: 
NA 
Name of active ingredient: 
 
BI 695502 
 
Protocol date: 
Trial number: 
 
Revision date: 
11 Jan 201326 Nov 
2012 
27 Mar 2012 
1302.1 
Criteria for 
pharmacokinetics:  
The primary pharmacokinetic endpoint for assessment of pharmacokinetic similarity 
is the following: 
• 
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity (AUC0-∞) 
The following secondary pharmacokinetic parameters will be evaluated: 
• 
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the time of the last quantifiable data point (AUC0-tz) 
• 
Maximum measured concentration of the analyte in plasma (Cmax) 
Criteria for safety: 
Physical examination, vital signs (blood pressure and pulse rate), temperature, weight, 
12-lead electrocardiogram, laboratory tests, concomitant medications, and adverse 
events.  
Statistical methods: 
The trial will be performed as a two-stage group sequential design with Pocock 
boundaries. At interim analysis, after approximately 50% of subjects are evaluable, an 
early look for similarity, will be performed. The alpha levels for the interim look and 
the final look are both given as 6.07% (two-sided) based on an overall (two-sided) 
alpha of 10%. This is equivalent to comparing the 93.93% two-sided confidence 
interval for the ratio of the geometric means with the boundaries of 0.80 and 1.25. The 
trial will be stopped at interim analysis for early similarity if the confidence intervals 
for AUC0-∞ are within these boundaries for all three comparisons (BI 695502 versus 
EU-sourced Avastin®, BI 695502 versus US-sourced Avastin®, and EU versus 
US-sourced Avastin®). Stopping after interim of a single arm is possible if both 
comparions for the investigated arm already show early similarity. The trial will be 
considered positive at final analysis if the confidence intervals for AUC0-∞ are within 
these boundaries for all three comparisons (BI 695502 versus EU-sourced Avastin®, 
BI 695502 versus US-sourced Avastin® and EU versus US-sourced Avastin®). 
Descriptive statistics for safety (e.g., vital signs, laboratory values, and adverse 
events) and pharmacokinetic parameters will be calculated. The statistical model for 
the analysis of pharmacokinetics similarity will be an analysis of variance on the 
logarithmic scale, including following sources of variation: ‘treatment’ and ‘weight’. 
All effects will be considered as fixed. Based on the residual error from analysis of 
variance, two-sided confidence intervals for the inter-subject ratio will be calculated. 
 


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FLOW CHART 1.1 SCHEDULE OF ASSESSMENTS  
 
Screening1 
Study period  
End 
of 
study2
Visit 
1 
2 
3 
Day 
-28 to -2 
-1 
1 
2 
 
3 
5 
8 
(±2) 
15 
(±2) 
22 
(±2) 
36 
(±2) 
50 
(±2) 
64 
(±2) 
78 
(±2)
99 
(±2) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of 
eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temperature 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Body height(only at 
screening), weight, and 
calculation of BMI 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug and virus 
screening8 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination10 
X 
X 
X3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LABS/SAFETY ASSESSMENTS  
Laboratory tests (serum 
chemistry, hematology, 
and urinalysis) 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
X 
X5 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
Adverse events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OTHER ASSESSMENTS 
Pharmacokinetics 
 
 
X6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Trial period 
Screening1 
Study period 1 
End 
of 
study2
Visit 
1 
2 
3 
Day 
-28 to -2 
-1 
1 
2 
 
3 
5 
8 
(±2) 
15 
(±2) 
22 
(±2) 
36 
(±2) 
50 
(±2) 
64 
(±2) 
78 
(±2)
99 
(±2) 
TRIAL MEDICATION 
Check-in 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge9 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Randomization 
(predose) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Administration of trial 
medication7 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Ambulatory visit 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
End of participation 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
BMI: body mass index; Con med: concomitant medication; ECG: electrocardiogram. 
Note: Please refer to Appendix 10.2 for specific planned time points for safety and pharmacokinetic assessments 
 
1.  
Screening within 28 days before drug administration and include subject information, signed informed consent, 
assessment of eligibility, demographics, medical and surgical history, drug and virus screening, physical 
examination, ECG, vital signs, body height, weight and calculation of BMI, laboratory/urinalysis, adverse event 
and concomitant medication recording. 
2. 
End-of-study examination will be Day 99 and includes physical examination, temperature, vital signs, laboratory 
tests, ECG, and AEs/concomitant medication recording.  For subjects who discontinue from the trial early, a 
complete end of study visit will be performed. 
3. 
Predose.   
4. 
Predose and at 1, 2, 3, 4, 5, and 6 hours postdose.  
5. 
ECG performed at end of infusion, 2, and 8 hours after start of infusion. 
6. 
Pharmacokinetic samples to be taken predose, just before end of infusion 2, 4, and 8 hours after start of infusion. 
7. 
Infusion for all BI 695502 and comparators will be 30 minutes.  
8.  
Drug screening: cannabis, benzodiazepine, barbiturates, opiates, cocaine, amphetamines, and methadone. Virus 
screening: Hepatitis B, hepatitis C, and HIV. Virus screening only at screening. 
9.  
All patients will remain hospitalized for 48 hours after dosing but can be discharged after 24 hours at investigator´s 
discretion. Patients discharged on Day 2, must return to the site on Day 3. 
10.  
Symptom directed physical examination as clinically indicated on Day 2 to Day 78. 
 
 


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TABLE OF CONTENTS 
TITLE PAGE ..................................................................................................... 1 
CLINICAL TRIAL PROTOCOL SYNOPSIS ............................................... 2 
FLOW CHART 1.1 SCHEDULE OF ASSESSMENTS ................................ 5 
TABLE OF CONTENTS .................................................................................. 7 
ABBREVIATIONS .......................................................................................... 11 
1. 
INTRODUCTION .................................................................................... 13 
1.1 
MEDICAL BACKGROUND ............................................................................13 
1.2 
DRUG PROFILE ...............................................................................................13 
2. 
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 14 
2.1 
RATIONALE FOR PERFORMING THE TRIAL ........................................14 
2.2 
TRIAL OBJECTIVES .......................................................................................14 
2.2.1 Primary objective ..................................................................................14 
2.2.2. Secondary objectives .............................................................................14 
2.3 
BENEFIT - RISK ASSESSMENT ...................................................................14 
3. 
DESCRIPTION OF DESIGN AND TRIAL POPULATION .............. 17 
3.1 
OVERALL TRIAL DESIGN AND PLAN ......................................................17 
3.1.1 Administrative structure of the trial ...................................................17 
3.2 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S) .....................................................................................17 
3.3 
SELECTION OF TRIAL POPULATION ......................................................18 
3.3.1 Main diagnosis for study entry ............................................................19 
3.3.2 Inclusion criteria ...................................................................................19 
3.3.3 Exclusion criteria ..................................................................................20 
3.3.4 Removal of subjects from therapy or assessments .............................21 
3.3.4.1 Removal of individual subjects ................................................ 21 
3.3.4.2 Discontinuation of the trial by the sponsor .............................. 21 
4. 
TREATMENTS ........................................................................................ 23 
4.1 
TREATMENTS TO BE ADMINISTERED ....................................................23 
4.1.1 Identity of Boehringer Ingelheim investigational product and 
comparator product(s)..........................................................................23 
4.1.2 Method of assigning subjects to treatment groups ............................23 
4.1.3 Selection of doses in the trial ................................................................24 
4.1.4 Drug assignment and administration of doses for each subject .......24 
4.1.5 Blinding and procedures for unblinding ............................................25 
4.1.5.1 Blinding.................................................................................... 25 
4.1.5.2 Procedures for emergency unblinding ..................................... 25 
4.1.6 Packaging, labeling, and re-supply......................................................25 


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4.1.7 Storage conditions .................................................................................25 
4.1.8 Drug accountability ..............................................................................25 
4.2 
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT ....................................................................................................26 
4.2.1 Rescue medication, emergency procedures, and additional 
treatment(s) ...........................................................................................26 
4.2.2 Restrictions ............................................................................................26 
4.2.2.1 Restrictions regarding concomitant treatment ......................... 26 
4.2.2.2 Restrictions on diet and life-style ............................................ 26 
4.3 
TREATMENT COMPLIANCE .......................................................................27 
5. 
VARIABLES AND THEIR ASSESSMENT ......................................... 28 
5.1 
EFFICACY - CLINICAL PHARMACOLOGY .............................................28 
5.2 
SAFETY ..............................................................................................................28 
5.2.1 Endpoint(s) of safety .............................................................................28 
5.2.2 Assessment of adverse events ...............................................................28 
5.2.2.1 Definitions of adverse events ................................................... 28 
5.2.2.2 Adverse event and serious adverse event reporting ................. 29 
5.2.3 Vital signs ...............................................................................................30 
5.2.4 ECG (12-lead resting ECG) .................................................................30 
5.2.5 Clinical and laboratory tests ................................................................31 
5.2.6 Medical examination .............................................................................33 
5.4 
APPROPRIATENESS OF MEASUREMENTS .............................................34 
5.5 
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS ..................................................................................34 
5.5.1 Pharmacokinetic endpoints ..................................................................34 
5.5.2 Methods of sample collection ...............................................................35 
5.5.2.1 Urine sampling for pharmacokinetic analysis .......................... 36 
5.5.3 Analytical determinations ....................................................................37 
5.6 
BIOMARKER(S) ...............................................................................................38 
5.7 
PHARMACODYNAMICS ................................................................................38 
5.8 
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP .....38 
6. 
INVESTIGATIONAL PLAN .................................................................. 39 
6.1 
VISIT SCHEDULE ............................................................................................39 
6.2 
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................39 
6.2.1 Screening period (Day -28 to -1) - all subjects ....................................39 
6.2.2 Study period ..........................................................................................39 
6.2.3 End of trial .............................................................................................40 


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7. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE ......................................................................................... 41 
7.1 
STATISTICAL DESIGN - MODEL ................................................................41 
7.1.1 Objectives...............................................................................................41 
7.1.2 Design .....................................................................................................41 
7.1.3 Endpoints ...............................................................................................41 
7.1.4 Model ......................................................................................................41 
7.2 
NULL AND ALTERNATIVE HYPOTHESES ..............................................42 
7.3 
PLANNED ANALYSES ....................................................................................43 
7.3.1 Primary analyses ...................................................................................43 
7.3.2 Secondary analyses ...............................................................................44 
7.3.3 Safety analyses .......................................................................................44 
7.3.4 Interim analyses ....................................................................................45 
7.3.5 Pharmacokinetic analyses ....................................................................45 
7.3.6 Pharmacodynamic analyses .................................................................45 
7.3.7 Pharmacogenomic analyses..................................................................46 
7.4 
HANDLING OF MISSING DATA ..................................................................46 
7.4.1 Safety ......................................................................................................46 
7.4.2 Plasma concentration - time profiles ...................................................46 
7.4.3 Pharmacokinetic parameters ...............................................................46 
7.5 
RANDOMIZATION ..........................................................................................47 
7.6 
DETERMINATION OF SAMPLE SIZE ........................................................47 
8. 
INFORMED CONSENT, DATA PROTECTION, AND 
TRIAL RECORDS ................................................................................... 49 
8.1 
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................49 
8.2 
DATA QUALITY ASSURANCE .....................................................................49 
8.3 
RECORDS ..........................................................................................................50 
8.3.1 Source documents .................................................................................50 
8.3.2 Direct access to source data and documents .......................................51 
8.4 
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS ..............................................................................................................51 
8.4.1 Listedness ...............................................................................................51 
8.4.2 Expedited reporting to health authorities and IECs/IRBs ................51 
8.5 
STATEMENT OF CONFIDENTIALITY .......................................................51 
9. 
REFERENCES ......................................................................................... 52 
9.1 
PUBLISHED REFERENCES ...........................................................................52 
9.2 
UNPUBLISHED REFERENCES .....................................................................52 
10. APPENDICES .......................................................................................... 53 
10.1 CLINICAL EVALUATION OF LIVER INJURY .........................................53 
10.1.1 Introduction ...........................................................................................53 


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10.1.2 Procedures .............................................................................................53 
10.2 PLANNED TIME POINTS FOR SAFETY AND 
PHARMACOKINETICS ASSESSMENTS ....................................................55 
11. DESCRIPTION OF GLOBAL AMENDMENT(S) .............................. 57 


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ABBREVIATIONS   
 
 
AE 
Adverse event 
ANOVA 
Analysis of variance 
 
 
 
 
AUC0-∞ 
Area under the concentration-time curve of the analyte in plasma over 
the time interval from 0 extrapolated to infinity 
AUC0-tz 
Area under the concentration-time curve of the analyte in plasma over 
the time interval from 0 to time of the last quantifiable data point 
BLQ 
Below limit of quantification 
BMI 
Body mass index (weight divided by height squared) 
 
 
Cmax 
Maximum measured concentration of the analyte in plasma 
CRA 
Clinical Research Associate 
CTP 
Clinical Trial Protocol 
CTR 
Clinical Trial Report 
CV 
Coefficient of variation  
δ 
Biosimilarity margin 
DILI 
Drug-induced liver injury  
DMC 
Data monitoring committee 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
EDTA 
Ethylendiaminetetraacetic acid 
ELISA 
Enzyme linked immunosorbent assay  
EU 
European Union 
GCP 
Good Clinical Practice 
Hep B 
Hepatitis B 
Hep C 
Hepatitis C 
HIV 
Human immunodeficiency virus 
ICH 
International Committee on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
iv 
Intravenous  
 
 
mAb 
Monoclonal antibody 
 
 
NOA 
Not analyzed 
NOP 
No peak detectable 
NOR 
No valid result 
NOS 
No sample available 
PK 
Pharmacokinetic(s) 
RDC 
Remote Data Capture 


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SAE 
Serious adverse event 
SOP 
Standard operating procedure 
  
 
 
 
ULN 
Upper limit of normal 
US 
United States 
VEGF 
Vascular endothelial growth factor 
 
 
 
 
 
 


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1. 
INTRODUCTION 
1.1 
MEDICAL BACKGROUND 
Vascular endothelial growth factor (VEGF) is a key angiogenic factor mediating tumor 
angiogenesis. Multiple studies have described increased VEGF levels in a variety of human 
cancers and the VEGF expression levels have been correlated with poor survival (R10-4862, 
R12-0947, R12-0948). 
Bevacizumab (Avastin®) is a therapeutic humanized monoclonal antibody (mAb) specific for 
VEGF exerting its pharmacologic antiangiogenesis effect by binding to and neutralizing 
VEGF, thereby blocking its signal transduction through VEGF receptors (R12-1012). This 
has been demonstrated in vitro through antibody inhibition of several late-phase VEGF-
dependent vascular endothelial cell functions such as proliferation, migration, and survival. 
Bevacizumab (Avastin®) has shown antitumor activity and clinical benefit in combination 
with chemotherapy in metastatic colorectal cancer, metastatic breast cancer, advanced non-
small cell lung cancer, and ovarian cancer (R12-0939, R12-0971). Furthermore, clinical 
benefit was reported with the combination of bevacizumab and interferon in renal cell cancer 
(R12-0939, R12-0971) or as a single agent in glioblastoma (R12-0971). 
BI 695502 is being developed as a proposed biosimilar to bevacizumab. 
1.2 
DRUG PROFILE 
BI 695502 is a genetically engineered humanized mAb directed against human VEGF that 
selectively binds all isoforms of VEGF and neutralizes VEGF’s biologic activity through a 
steric blocking of the binding of VEGF to its receptors on the surface of the endothelial cells, 
on tumor cells and autocrine and paracrine loops. 
 


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2. 
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT 
2.1 
RATIONALE FOR PERFORMING THE TRIAL 
BI 695502 is being developed as a biosimilar to bevacizumab (Avastin®), which is planned to 
meet the need for alternatives to high-priced biologic agents in oncology treatments.  The 
planned clinical development follows the currently understood concepts from published 
guidance documents and statements from regulatory authorities for biosimilar mAb 
development. The general approach is to demonstrate sequentially a high degree of similarity 
(i.e., statistical similarity) between the biosimilar and originator compound, first in PK and 
subsequently for efficacy. While also demonstrating a high degree of similarity (but not 
necessarily powered for statistical similarity) for safety and immunogenicity. 
As such, trial 1302.1 is the stepping stone for successful clinical development of BI 695502 
as it aims to establish PK similarity of BI 695502 to bevacizumab (Avastin®) originator 
compounds and will assess initial safety of BI 695502 in healthy subjects. 
Since the PK of Avastin® is linear for doses ≥ 1 mg, the  dose of 1 mg/kg of BI 695502 and 
bevacizumab (Avastin®) is the lowest dose that can allow PK extrapolation for the standard 
clinical dose.  
This trial will be conducted in compliance with Clinical Trial Protocol (CTP), the 
International Conference of Harmonization (ICH) guidelines, Good Clinical Practice (GCP), 
and with all applicable and current regulatory requirements.   
2.2 
TRIAL OBJECTIVES 
2.2.1 
Primary objective 
The primary objective of this study is to establish pairwise PK similarity between BI 695502, 
Avastin®, US origin and Avastin®, EU origin following one iv infusion.  
2.2.2. 
Secondary objectives 
The secondary objective of this study is to evaluate safety of BI 695502 and bevacizumab 
(Avastin®) US and EU origin and other pharmacokinetic parameters.  
2.3 
BENEFIT - RISK ASSESSMENT 
Participation in this study is without any (therapeutic) benefit for healthy subjects.  Their 
participation in the study, however, is of major importance to the development of this new 
drug. 
Healthy subjects who participate in study 1302.1 may be exposed to:  
• The risks of the study procedures; 


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• The known risks related to the exposure with the study medications (tested drug and 
comparator drugs) ; and 
• The unknown risks that might be related to the exposure with the study medication. 
Procedure-related risks 
The use of an indwelling cannula for the purpose of drug administration and blood sampling 
may be accompanied by mild bruising and in rare cases, by transient inflammation of the wall 
of the vein. After initial irritation, the presence of an indwelling cannula is usually painless 
and hardly noticeable. The same applies to vein puncturing for further blood sampling. In rare 
cases, a nerve might be injured while inserting the cannula. This could be followed by 
paresthesia, reduced sensibility, and/or pain. 
Drug-related risks and safety measures 
Based on safety data from over 3,500 patients with various malignancies, predominantly 
treated with Avastin® in combination with chemotherapy in clinical trials, the most frequently 
reported side effect were hypertension, proteinuria, fatigue, diarrhea, and abdominal pain. 
The serious adverse events (SAEs) were gastrointestinal perforation, hemorrhage, and arterial 
thromboembolism (R12-0939).  
Analyses of the clinical safety data suggest that the occurrence of hypertension and 
proteinuria with Avastin® therapy are likely to be dose-dependent. 
 
The subject’s risk will be minimized in this trial by: 
• Using a low dose of Avastin® or BI 695502; 
• Implementing conservative eligibility criteria; and 
• Close monitoring in a Phase I study center for the first 48 hours after drug 
administration. Subjects will also be followed during out-patient ambulatory visits. 
The ambulatory visits will occur on Days 5, 8, 15, 22, 36, 50, 64, 78, and 99 and will 
allow for collection of safety signs and symptoms that may occur or arise following 
study treatment.   
In addition, the first six subjects will be dosed in a sequential manner (i.e., 1 subject per day). 
At least one subject will receive BI 695502. 
Adverse events and vital sign data will be collected throughout the trial and subjects will be 
monitored for safety outcomes over a prolonged period of time. Physical examinations are 
performed at every visit.  Special attention will be given to assessment of potential drug-
induced liver injury (DILI). 


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Although rare, a potential for DILI is under constant surveillance by sponsors and regulators. 
Therefore, this study will require timely detection, evaluation, and follow-up of laboratory 
alterations of selected liver laboratory parameters to ensure subjects´ safety. 


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3. 
DESCRIPTION OF DESIGN AND TRIAL POPULATION 
3.1 
OVERALL TRIAL DESIGN AND PLAN 
The study will be performed as a randomized, single-blind, single-dose, parallel-arm, 
active-comparator clinical Phase I study. Subjects will be randomly allocated to one of three 
treatment groups.  
The treatments will be single dose of 1-mg/kg BI 695502/concentrate for solution for 
infusion: 1-mg/kg bevacizumab (Avastin®), US source/solution for intravenous infusion; or 
1-mg/kg bevacizumab (Avastin®), EU source/concentrate for solution for intravenous 
infusion. 
The first six subjects will be dosed over 6 days (i.e., 1 subject per day) and each subject will 
be required to remain in the trial center for 48 hours after dosing (overnight) for safety 
observations. At least one subject will receive BI 695502. This study will occur in two stages: 
Stage 1 – 90 subjects (30 per treatment group)  
Stage 2 – 90 subjects (30 per treatment group) 
An interim analysis will be conducted and if the pre-specified criteria for early PK 
biosimilarity are achieved then the study may be stopped. It is also possible that a single arm 
is going to be stopped based on the chosen boundaries and the interim results. This is the case 
if both comparisons for the specific arm show an early similarity. If any comparison does not 
show early similarity then the trial will proceed to Stage 2.  
3.1.1 
Administrative structure of the trial 
A data monitoring committee (DMC) will be appointed to periodically assess the trial data to 
ensure overall safety and integrity of the trial. Details of the DMC responsibilities will be 
described in the DMC charter. 
Inclusion of subjects in the trial may be stopped temporarily after the assigned number of 
subjects for Stage 1 has been randomized. Inclusion might be restarted in case the interim 
analysis fails to show early PK biosimilarity. 
Decisions on trial termination, amendment, or cessation of subject recruitment, based on 
safety or outcome findings, can be made upon agreement after recommendations from the 
DMC. 
3.2 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S) 
This is a randomized, single-blind, single-dose, parallel-arm, two-stage, active-comparator 
study to investigate the PK and safety of BI 695502, and to establish PK similarity of BI 
695502 to bevacizumab (Avastin®), as US and EU source in healthy, male subjects.   


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Subjects will be enrolled in two sites in New Zealand. Each of the three arms (BI 695502 and 
bevacizumab [Avastin®], as US and EU source) will include approximately 60 subjects 
(totaling approximately 180 subjects), which is considered sufficient for PK testing.   
Subjects will be randomized in a 1:1:1 ratio to receive BI 695502, bevacizumab (Avastin®) as 
US source, or bevacizumab (Avastin®) as EU source. Randomization minimizes selection 
bias between the treatment groups. Note that for Stage 2 it might be possible that one of the 
arms will be stopped for early similarity and therefore the ratio might change to 1:1 for the 
remaining arms. The parallel-group, active-comparator design takes into account the safety of 
the healthy subjects. 
The trial bioanalyst as well as the trial pharmacokineticist will be blinded until final database 
lock to the origin of the PK 
 samples to maintain objectivity. 
The investigator and other sponsor representative will not be blinded to be able to follow the 
safety data of the subjects randomized into the trial. 
A DMC will periodically assess the trial data as described in Section 3.1.1. 
3.3 
SELECTION OF TRIAL POPULATION 
It is planned that up to a maximum of 180 healthy, male subjects will be randomized enrolled 
into  theis study (see Section 7.6).    
This study will be performed in healthy subjects since this population is most sensitive to 
product differences. A healthy subject population may provide greater sensitivity to detect 
differences in PK profiles, as there are no underlying factors, e.g., tumor burden, which may 
affect the PK results. 
Bevacizumab is used in the clinic mostly in combination with chemotherapy agents in 
treatment of solid tumors. Avastin® can be used at a low dose of 5 mg/kg every 2 weeks or 
10 mg/kg every 3 weeks (dose intensity of 2.5 mg/kg/week) or at a high dose of 7.5 mg/kg 
every 2 weeks or 15 mg/kg every 3 weeks (dose intensity of 5 mg/kg/week). The most 
frequent side effects reported with bevacizumab given at this dose were hypertension, fatigue, 
diarrhea, and abdominal pain. Proteinuria is also a common laboratory change reported with 
Avastin®.  
Analysis of the safety data suggests that the occurrence of hypertension and proteinuria with 
Avastin® therapy are likely to be dose-dependent (R12-0939). 
 
 
 
 
  


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Based on the safety profile of Avastin® (side effect dose-dependency and cumulative toxicity) 
it is expected that the proposed single and low dose (1 mg/kg) will be well tolerated with no 
or limited and mild side effects.  
A log of all subjects entered into the trial (i.e., having given informed consent) will be 
maintained in the Investigator Site File (ISF) at the investigational site irrespective of 
whether they have been treated with the study medication or not.   
3.3.1 
Main diagnosis for study entry 
The study will be performed in healthy male subjects according to the criteria listed in 
Section 3.3.2 and 3.3.3. 
3.3.2 
Inclusion criteria 
Healthy males according to the following criteria: 
1. Complete medical history, including physical examination, vital signs (blood 
pressure and pulse rate), 12-lead electrocardiogram (ECG), and clinical laboratory 
tests; 


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2. Aged 21 to 50 years; 
3. Body mass index (BMI) ≤ 30; 
4. Body weight of 65 to 95 kg, inclusive;  
5. Signed and dated written informed consent prior to admission to the study in 
accordance with GCP and the local legislation; 
 
3.3.3 
Exclusion criteria 
Healthy males according to the following criteria: 
1. Any finding of the medical examination (including blood pressure, pulse rate, and 
ECG) deviating from normal and of clinical relevance; 
2. Any evidence of a clinically relevant concomitant disease, as judged by the 
investigator, including gastrointestinal, hepatic, renal, respiratory, cardiovascular, 
metabolic, immunological, hormonal disorders, or diseases of the central nervous 
system (such as epilepsy), psychiatric disorders, or neurological disorders; 
3. History of relevant orthostatic hypotension, fainting spells, or blackouts; 
4. Chronic or relevant acute infections. A negative result for human 
immunodeficiency virus (HIV), Hepatitis B (Hep B), and Hepatitis C (Hep C) 
testing is required for participation;   
5. History of relevant allergy/hypersensitivity (including allergy to the study 
medications or its excipients); 
6. Intake of prescribed or over-the-counter drugs within less than six half-lives of the 
respective drug prior to study drug administration or during the trial; 
7. Participation in another trial with a study medication within two months prior to 
administration or during the trial (six half-lives); 
8. Smoker (> 10 cigarettes or > 3 cigars or > 3 pipes/day); 
9. Inability to refrain from smoking during days of confinement at the study center; 
10. Current alcohol abuse as judged by the investigator; 
11. Current drug abuse, as judged by the investigator; 
12. Blood donation (more than 100 mL within four weeks prior to administration or 
during the trial); 
13. Participation in collision sports (e.g. ice hockey, rugby etc.) 
14. Any out-of-range laboratory values considered clinically significant by the 
investigator; 
15. Subject considered unsuitable for inclusion by the investigator (e.g., inability to 
understand and/or comply with study requirements or presence of any condition 
which, in the opinion of the investigator, would not allow safe participation in the 
study); 
 
Exclusion criteria specific for this study include: 
16. Hypertension or relevant family history of hypertension, as judged by the 
investigator;  
17. Major injuries and/or surgery or bone fracture within 4 weeks of trial inclusion, or 
planned surgical procedures during the trial period. Intended participation in 
collision sports during the study; 


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18. Less than 15 weeks from previous dosing of a mAb;  
19. History of  hemorrhagic or thromboembolic event;  
20. Known inherited predisposition to bleeding or to thrombosis. 
21. Pre-existing proteinuria 
 
3.3.4 
Removal of subjects from therapy or assessments 
3.3.4.1 Removal of individual subjects 
An individual subject is to be withdrawn from the trial if: 
• The subject withdraws consent, without the need to justify a decision; 
• The subject has to take any concomitant drugs interfering with the study medication; and 
• The subject is no longer able to participate for other medical reasons (e.g., surgery, AEs, 
or other diseases). 
A subject can be withdrawn after discussion between the sponsor and the investigator if 
eligibility criteria are being violated or if the subject fails to comply with the CTP (e.g., 
non-attendance at study assessments, incomplete, missing or wrong trial drug administration).  
If a subject is withdrawn from the study prior to the randomization, the data of this subject 
will not be entered in the trial database and not be reported. The only exception to this rule is 
when the subject has a serious or significant AE. If a subject discontinues or withdraws from 
the study thereafter, this will be documented and the reason for withdrawal will be recorded 
in the electronic Case Report Forms (eCRFs), the data will be included in the trial database 
and will be reported. At the time of discontinuation, a complete end-of-study evaluation will 
be performed, if possible, and the information will be recorded in the eCRFs. Those 
withdrawals will be discussed in the final Clinical Trial Report (CTR).  
Subjects who are enrolled in the trial and do not fulfill the inclusion / exclusion criteria or 
have inadequate number PK samples performed will be replaced for each stage, separately. 
For Stage 1, in case less than 90 subjects (30 per treatment group) complete the trial, the 
investigator, together with the trial pharmacokineticist and trial statistician, will decide if and 
how many subjects will be replaced. Similarly, subjects might be replaced for Stage 2, if 
applicable. Each subject will have a unique study subject number, including replacing 
subjects. Replacement subjects will be assigned the next available randomization number 
from the randomization list.   
3.3.4.2 Discontinuation of the trial by the sponsor 
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons: 
1. Failure to meet expected enrollment goals overall or at a particular trial site; 
2. Emergence of any efficacy / safety / toxicological information that could 
significantly affect continuation of the trial; 
3. Violation of GCP, the CTP, or the contract by a trial site or investigator, 
disturbing the appropriate conduct of the trial; or  


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4. The recommendation of the DMC that would require discontinuation of the trial 
including stopping for early PK biosimilarity. 
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason). 


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4. 
TREATMENTS 
4.1 
TREATMENTS TO BE ADMINISTERED 
4.1.1 
Identity of Boehringer Ingelheim investigational product and comparator 
product(s) 
Details of the trial medication are provided in Table 4.1.1: 1. 
Table 4.1.1: 1  
Study medications 
Trial medication 
Dosage form (concentration) 
Manufacturer 
BI 695502, clear to slightly 
opalescent, colorless to 
slightly yellow, sterile, 
pH 6.2 concentrate for 
solution for infusion 
Concentrate for solution for 
infusion (25 mg/mL) 
Boehringer Ingelheim 
Pharma GmbH & Co KG, 
Germany 
Bevacizumab (Avastin®), US 
source, clear to slightly 
opalescent, colorless to pale 
brown, sterile, pH 6.2 
solution for intravenous 
infusion 
Solution for intravenous 
infusion (25 mg/mL) 
Genentech, Inc. 
Bevacizumab (Avastin®), EU 
source, clear to slightly 
opalescent, colorless to pale 
brown, sterile, pH 6.2 
concentrate for solution for 
infusion 
Concentrate for solution for 
infusion (25 mg/mL) 
Roche Pharma AG 
 
The pharmacist will use the appropriate aseptic technique. He/she will inspect the drug and 
look for particulate matter and discoloration prior to administration to the subject, if the 
solution and container permit such inspection. The necessary amount of study medication 
will be withdrawn and diluted in 0.9% of sodium chloride. Standard of concentration is 
1.4 mg/ml. The volume to be administered for each subject will be calculated based on the 
subject’s weight respecting the recommended concentration of 1.4 mg/ml. If any solution 
remains in the vial, the vial and solution will be discarded, as the product does not contain 
preservatives (R12-0939, R12-0971). 
4.1.2 
Method of assigning subjects to treatment groups 
The allocation process of subjects to one of the three treatment groups per the randomization 
list (see Section 7.5 for details) is performed on Day 1 prior to administration of the study 
drug.  The list of subject and medication numbers will be provided to the trial site in advance. 
Once a subject number has been assigned, it cannot be reassigned to any other subject. (The 
same applies for randomization numbers). 


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4.1.3 
Selection of doses in the trial 
Bevacizumab (Avastin®) is approved for the below indications (R12-0939, R12-0971): 
• Metastatic colorectal cancer; 
•  Metastatic breast cancer (EU only); 
•  Metastatic or recurrent non-small cell lung cancer; 
• Advanced and/or metastatic renal cell cancer;  
• Epithelial ovarian, fallopian tube, or primary peritoneal cancer (EU only); and  
• Glioblastoma (US only). 
Avastin® can be used at a low dose of 5 mg/kg every 2 weeks or 10 mg/kg every 3 weeks 
(dose intensity of 2.5 mg/kg/week) or at a high dose of 7.5 mg/kg every 2 weeks or 15 mg/kg 
every 3 weeks (dose intensity of 5 mg/kg/week). 
The primary focus of this trial is to demonstrate the similarity of BI 695502 with the 
approved reference products, bevacizumab (Avastin®), as US and EU source.   
During the treatment period, each subject will receive a single 1-mg/kg iv infusion of the 
drug to which they are randomized. It has been observed that the PK of bevacizumab is 
dose-independent, except for doses < 1 mg/kg. The PK of bevacizumab appears to be linear 
over the dose range 1 to 10 mg/kg (R12-1012). As bevacizumab or BI 695502 is to be 
administered to healthy subjects, the lowest possible dose in the linear PK range is the 
appropriate dose for the PK similarity comparison. 
4.1.4 
Drug assignment and administration of doses for each subject 
The treatments to be evaluated are as outlined in Table 4.1.4: 1 below: 
Table 4.1.4: 1  Treatments in single administration 
Treatment Substance 
Formulation 
Total dose  
1 
BI 695502 
Concentrate for  
solution for infusion 
1 mg/kg 
2 
bevacizumab 
(Avastin®), 
US source 
Solution for 
intravenous infusion 
1 mg/kg 
3 
bevacizumab 
(Avastin®), 
EU source 
Concentrate for  
solution for infusion 
1 mg/kg 
 


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On Day 1 of Visit 2, the medication will be administered as a single dose of 1 mg/kg as a 
30-minute iv infusion in the supine position under the supervision of the investigator or 
designee. Subjects will be kept under close medical surveillance until up to 48 hours 
following drug administration. Days 5 to 99 will be performed in an ambulatory fashion. 
This trial is a three parallel-arm study. All subjects will be randomized to BI 695502, 
bevacizumab (US-origin Avastin®), or bevacizumab (EU-origin Avastin®). 
4.1.5 
Blinding and procedures for unblinding 
4.1.5.1 Blinding 
This will be a single-blind study. Additionally, the trial bioanalyst as well as the trial 
pharmacokineticist will be blinded to the origin of PK 
 samples to maintain 
objectivity.  
4.1.5.2 Procedures for emergency unblinding 
Not applicable. 
4.1.6 
Packaging, labeling, and re-supply 
For details of packaging, retention sampling and description of the label, refer to the ISF. 
Resupply is planned once decision of the Stage 2 recruitment is made.  
4.1.7 
Storage conditions 
Drug supplies will be kept in their original packaging under the recommended storage 
conditions (light protected, between +2 and +8°C) and should not be frozen or shaken.   
4.1.8 
Drug accountability 
Drug supplies, which will be provided by the sponsor, must be kept in a secure, 
limited-access storage area under the storage conditions defined by the sponsor. Where 
necessary, a temperature log must be maintained to make certain that the drug supplies are 
stored at the correct temperature. 
The site pharmacist will receive the study medications delivered by the sponsor when the 
following requirements are fulfilled: 
• Approval of the study CTP by the Institutional Review Board (IRB) / ethics 
committee; 
• Availability of a signed and dated clinical trial contract between the sponsor and the 
head of trial center; 
• Approval / notification of the regulatory authority (e.g., competent authority); 
• Availability of the curriculum vitae of the investigator; 
• Availability of a signed and dated CTP or immediately imminent signing of the CTP; 
and  
• Availability of the proof of a medical license for the investigator, as necessary. 


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The investigator and / or delegate must maintain records of the product’s delivery to the trial 
site, the inventory at the site, the use by each subject, and the return to the sponsor or 
alternative disposition of unused product(s).  
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers assigned to the study medication and trial subjects. The investigator 
/ delegate will maintain records that document adequately that the subjects were provided the 
doses specified by the CTP and reconcile all study medication received from the sponsor. At 
the time of return to the sponsor, the investigator / delegate must verify that all unused or 
partially used drug supplies have been returned and that no remaining supplies are in the 
investigator’s possession. 
4.2 
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT 
4.2.1 
Rescue medication, emergency procedures, and additional treatment(s) 
Primarily, no concomitant therapy will be allowed. However, in case of AEs in need of 
treatment, symptomatic therapy according to the judgment of the investigator will be 
permitted. All concomitant and/or rescue therapies will be recorded on the appropriate pages 
of the eCRFs. 
In the case of AEs the subjects will be treated, as necessary and as appropriate kept under 
constant supervision in the clinical unit or transferred to a hospital until such time that all the 
results of the evaluations have returned to a medically-acceptable level. 
4.2.2 
Restrictions 
4.2.2.1 Restrictions regarding concomitant treatment 
Primarily, no concomitant therapy will be allowed (see Section 4.2.1).  
4.2.2.2 Restrictions on diet and life-style 
Subjects should abstain from smoking and alcoholic beverages 48 hours prior to the study 
medication administration until day 8. After that smoking is allowed ( < 10 cigarettes or < 3 
cigars or < 3 pipes/day). No more than 2 units of alcohol and per day are allowed until the 
end of study.   
In addition, subjects should abstain from alcoholic beverages for 24 hours prior to further 
study visits. 
Participation in collision sport (e.g., ice-hockey, rugby etc.) should be avoided during the 
course of the study. 


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4.3 
TREATMENT COMPLIANCE 
Subjects who are non-compliant (e.g., they do not appear for assessments or violate the 
restrictions), may be withdrawn from the trial and the eCRF will be completed accordingly 
(for further procedures see Section 6.2).  
Compliance will be assured by administration of all study medication under supervision of 
the investigating physician or a designee at the investigational sites in New Zealand.  The 
measured plasma concentrations will provide additional information about compliance. 


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5. 
VARIABLES AND THEIR ASSESSMENT 
5.1 
EFFICACY - CLINICAL PHARMACOLOGY  
Efficacy measurements will not be performed. 
5.2 
SAFETY 
5.2.1 
Endpoint(s) of safety 
All safety parameters will be evaluated descriptively and based on the investigations 
described below.  
5.2.2 
Assessment of adverse events 
5.2.2.1 Definitions of adverse events 
Adverse event 
An AE is defined as any untoward medical occurrence, including an exacerbation of a 
pre-existing condition, in a subject in a clinical investigation who received a pharmaceutical 
product. The event does not necessarily have to have a causal relationship with this treatment. 
Serious adverse event 
An SAE is defined as any AE which results in death, is immediately life-threatening, results 
in persistent or significant disability / incapacity, requires or prolongs subject hospitalization, 
is a congenital anomaly / birth defect, or is to be deemed serious for any other reason if it is 
an important medical event when based upon appropriate medical judgment which may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definitions. 
Intensity of adverse event 
The intensity of AEs should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events version 4 in the eCRF. 
Causal relationship of adverse event 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases, and relevant 
history. Assessment of causal relationship should be recorded in the eCRFs.  
Yes: 
There is a reasonable causal relationship between the study medication 
 
administered and the AE.  
No: 
There is no reasonable causal relationship between the study medication 
 
administered and the AE.  


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If an SAE is reported from a still-blinded trial, the causal relationship must be provided by 
the investigator for all potential trial drugs (i.e., BI 695502, bevacizumab US and EU source). 
Worsening of the underlying disease or other pre-existing conditions 
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
(S)AE in the eCRF. 
Changes in vital signs, ECG, physical examination, and laboratory test results 
Changes in vital signs, ECG, physical examination, and laboratory test results will be 
recorded as an (S)AE in the eCRF, if they are judged clinically relevant by the investigator. 
Protocol-specified significant events 
The following are considered as CTP-specified significant events: 
• Gastrointestinal perforation (if the grade is ≥ 3); 
• Wound healing complications (if the grade is ≥ 3); 
• Hemorrhage - severe or fatal hemorrhage, hemoptysis, gastrointestinal bleeding, and 
central nervous system hemorrhage (if the grade is ≥ 3); 
• Hepatic injury defined by the following alterations of liver parameters:  
• For subjects with normal liver function at baseline: an elevation of aspartate 
aminotransferase and/or alanine transaminase > 3 fold upper limit of normal (ULN) 
combined with an elevation of total bilirubin > 2 fold ULN measured in the same 
blood draw sample; and 
• Subjects showing these laboratory abnormalities need to be followed up according to 
Section 10.1.2 of this CTP and the “DILI checklist” provided in remote data capture 
(RDC). 
Protocol-specified significant events are to be reported in an expedited manner similar to 
SAEs, even if they do not meet any of the seriousness criteria – for details see 
Section 5.2.2.2. 
5.2.2.2 Adverse event and serious adverse event reporting 
All AEs, serious and non-serious, occurring during the course of the clinical trial (i.e., from 
signing the informed consent onwards through the observational phase) will be collected, 
documented, and reported to the sponsor by the investigator on the appropriate eCRFs / SAE 
reporting forms. After the end of study evaluation all SAEs related to trial medication and/or 
trial design have to be reported by the investigator. Reporting will be done according to the 
specific definitions and instructions detailed in the ‘Adverse Event Reporting’ section of the 
ISF.  
For each AE, the investigator will provide the onset date, end date, intensity, treatment 
required, outcome, seriousness, and action taken with the investigational drug. The 
investigator will determine the relationship of the investigational drug to all AEs as defined in 
Section 5.2.2.1.  


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If not stipulated differently in the ISF, the investigator must report the following events using 
the paper SAE form via telephone / fax immediately (within 24 hours or the next business 
day whichever is shorter) to the sponsor: SAEs and non-serious AEs occurring at the same 
time as an SAE and/or which are medically related to the SAE(s), and CTP-specified 
significant events.    
Boehringer Ingelheim has set up a list of AEs which are defined to be always serious. In 
order to support the investigator with the identification of these “always serious adverse 
events”, if a non-serious AE is identified to be serious per Boehringer Ingelheim definition, a 
query will be raised. The investigator must verify the description and seriousness of the 
event.  If the event description is correct, the item “serious” needs to be ticked and an SAE 
has to be reported in expedited fashion following the same procedure as above. 
The list of these AEs can be found via the RDC-system. 
The SAE form is to be forwarded to the defined unique entry point (country-specific contact 
details will be provided in the ISF). This immediate report is required irrespective of whether 
the investigational product has been administered or not and irrespective of causal 
relationship. It also applies if new information to existing SAEs or protocol-specified 
significant events becomes available. 
5.2.3 
Vital signs 
Blood pressure and pulse rate will be measured at the time points described in the Flow 
Chart 1.1.  
Systolic and diastolic blood pressure, as well as pulse rate will be measured by means of a 
validated automated blood pressure monitor after subjects have rested for 5 minutes in the 
supine position.  All recordings should be made using the same type of blood pressure 
recording instrument of the same arm, if possible. 
5.2.4 
ECG (12-lead resting ECG) 
The 12-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded for a 10-second 
duration using (
 site will use GE Dash 3000 and 
 
 site will use Marquette MAC3500) a validated ECG machine. Electrode 
placement will be performed according to the American Heart Association guidelines.   
Electrocardiograms will be recorded at the time points indicated in the Flow Chart 1.1 after 
the subjects have rested for at least 5 minutes in a supine position.   
The ECGs will be evaluated by the study investigator or qualified designee.  The automatic 
algorithm analysis (built into the ECG machines) will assist in evaluating the exclusion 
criteria and an immediate safety assessment during the screening and course of the study.  
The ECGs may be repeated for quality reasons.  Additional ECGs may be collected by the 
investigator for safety reasons. Clinically relevant abnormal findings will be reported as AEs. 


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5.2.5 
Clinical and laboratory tests 
A total amount of 125 mL blood will be taken per subject during the whole course of the 
study for laboratory parameters. This amount may be exceeded if unscheduled (additional) 
monitoring of laboratory results is warranted.  
Blood samples for the laboratory parameters will be taken in the fasting state at the time 
points indicated in the Flow Chart 1.1.   
The parameters that will be determined are listed in Tables 5.2:5: 1 and 5.2.5: 2. The 
respective reference ranges will be provided in the ISF, (see Flow Chart 1.1 for time points of 
laboratory blood sampling).  
The laboratory tests listed in Tables 5.2:5: 1 and 5.2.5: 2 will be performed at the site’s local 
laboratory in New Zealand. 
Urine sediment analysis will only be performed if there is a clinically significant positive 
finding on the urinalysis at investigator´s discretion. The tests listed in Table 5.2.5: 2 
constitute exclusionary laboratory safety tests. These tests may be repeated, as required. The 
results will not be included in the CTR. To encourage compliance, a standard breath alcohol 
test (the detailed make and model is documented in the ISF) may be performed at any time 
during the study at the discretion of the investigator or designee. The results will not form 
part of the CTR.   
Laboratory data will be transmitted electronically from the site’s laboratory to the trial sites.   


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Table 5.2.5: 1  
Routine laboratory tests 
Category 
Test name  
Hematology 
Hematocrit  
Hemoglobin  
Red blood cell count / Erythrocytes 
White blood cells / Leucocytes 
Platelet count / Thrombocytes  
Diff automatic 
Neutrophils (absolute count) 
Eosinophils (absolute count) 
Basophils (absolute count) 
Monocytes (absolute count) 
Lymphocytes (absolute count) 
Coagulation (performed at 
screening, baseline (Day -1 to Day 
1 predose), end of study, and at the 
investigator’s discretion) 
Partial thromboplastin time  
Prothrombin time (Quick and international normalized ratio) 
Fibrinogen 
Enzymes 
Aspartate aminotransferase  
Alanine aminotransferase  
Alkaline phosphatase  
Creatine kinase  
Creatine kinase-MB if creatine kinase is elevated 
Gamma-glutamyl transferase  
Lactic dehydrogenase  
Pancreatic amylase 
Substrates1, 
Glucose  
Creatinine  
Bilirubin total  
Bilirubin direct 
Protein, total 
Albumin, total 
C-Reactive protein 
Uric acid  
Cholesterol, total  
Triglycerides 
Electrolytes1 
Calcium 
Sodium 
Potassium 
Urinalysis1 (Stix) 
Urine nitrite 
Urine protein 
Urine glucose 
Urine ketone 
Urobilinogen 
Urine bilirubin 
Urine red blood cells/Erythrocyte 
Urine white blood cells/Leukocytes 


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Table 5.2.5: 1  
Routine laboratory tests (continued)  
Category 
Test name  
Urinalysis1 (Stix) 
Urine pH
Urine sediment1 
(microscopic examination) 
(if urine analysis abnormal) 
 
Urine sediment bacteria  
Urine cast in sediment  
Urine squamous epith cells  
Urine sediment red blood cell /Erythrocytes   
Urine sediment white blood cell/Leucocytes  
ALT: alanine aminotransferase; AST: aspartate aminotransferase.  
 
1  
Substrates, electrolytes, and urine analysis / sediment only at screening and end of study (all portions) and at 
baseline (Day -1 to Day 1 predose). 
 
The following tests will be performed only at the screening examination; the results will not 
be part of the CTR. 
Table 5.2.5: 2  
Exclusionary testing 
Category 
Test name  
Drug screening (Urine) 
Cannabis 
Benzodiazepine 
Barbiturates 
Opiates  
Cocaine  
Amphetamines  
Methadone 
Infectious serology 
Hep B surface antigen (qualitative) 
Hep B HBc antibody (qualitative) 
Hep C antibodies (qualitative) 
HIV-1 and HIV -2 antibody (qualitative) 
 
5.2.6 
Medical examination 
A medical examination will be carried out within 28 days before the study (screening), at 
check-in on Day -1, and on Day 99 for each subject. At the screening visit, the medical 
examination will include documentation of subject information, informed consent, 
demographics, relevant medical and surgical history, review of inclusion / exclusion criteria, 
review of vital signs (blood pressure and pulse rate), temperature, height, weight, and 
calculation of BMI, 12-lead ECG, laboratory assessments, drug and virus screening, and a 
physical examination. On Day -1, the medical examination will include review of inclusion / 
exclusion criteria, drug  screening, physical examination, vital signs (blood pressure and 
pulse rate), laboratory assessments, 12-lead ECG, temperature, body weight,, and calculation 
of BMI. At the end-of-study examination, it will include review of vital signs, 12-lead ECG, 


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laboratory assessment, and a physical examination. Adverse events and concomitant therapies 
will be assessed throughout the study. 
5.4 
APPROPRIATENESS OF MEASUREMENTS 
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor safety aspects and to determine PK parameters in an 
appropriate way. 
5.5 
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS 
The date and exact clock time of administration as well as PK sampling times must be 
recorded.  
Exact time points of plasma sampling will be documented in the eCRFs by the medical 
personnel or sent as electronic files. These actual sampling times will be used for 
determination of PK parameters. 
5.5.1 
Pharmacokinetic endpoints 
PRIMARY ENDPOINT 
The primary PK endpoint for assessment of PK similarity is the following: 
• Area under the concentration-time curve of the analyte in plasma over the time 
interval from 0 extrapolated to infinity (AUC0-∞) 
 
 
 
 


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SECONDARY ENDPOINTS 
The following secondary PK parameters will be evaluated: 
• Area under the concentration-time curve of the analyte in plasma over the time 
interval from 0 to the time of the last quantifiable data point (AUC0-tz) 
• Maximum measured concentration of the analyte in plasma (Cmax) 
 
 
5.5.2 
Methods of sample collection 
A total amount of 125-mL blood will be taken per subject during the whole course of the 
study for PK
 purposes. 
For quantification of BI 695502 and bevacizumab plasma concentrations, 2.7 mL of blood 
will be collected from a forearm vein in a K3-ethylendiaminetetraacetic acid 
(EDTA)-anticoagulant blood drawing tube at time points indicated in Appendix 10.2. For the 
early time points after drug administration, the PK samples should be obtained from the 
forearm not used in the BI 695502 or bevacizumab iv administration. Immediately after blood 
sampling the drawing tubes will be transferred into an ice bath until centrifugation. 
 
The EDTA-anticoagulated blood samples will be centrifuged within 30 minutes after 
collection (intermittent storage in ice water or on ice). Centrifugation will last for 
approximately 10 minutes at 2000 to 4000 x g at 4 to 8°C. Ethylenediaminetetraacetic acid 
plasma will be transferred into two appropriately-labeled cryotubes (2 to 3-mL polypropylene 
cryovials with flat bottom and screw caps; e.g., Nunc #368632), each to contain 0.5 mL of 
plasma. Plasma samples will be stored at approximately -20°C or below until shipped to the 
analytical laboratory. Initially, only one aliquot will be shipped to the analytical laboratory. 


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The second aliquot will be stored at approximately -20°C or below at the investigational site 
and shipped only if requested by the analytical laboratory. 
 
Plasma concentrations of BI 695502 and bevacizumab will be measured using a sandwich 
enzyme linked immunosorbent assay (ELISA) method. 
 
After completion of the study, plasma samples may be used for further methodological 
investigations (e.g., for stability testing). However, only data related to the analyte and/or its 
metabolite(s) will be generated by these additional investigations. The study samples will be 
discarded after completion of the additional investigations but no later than 3 years after the 
final CTR has been signed. 
 
Additional samples for bioanalytical purposes: 
 
In order to assess the stability of BI 695502 in whole blood, one additional blood sample will 
be taken from the first eight subjects of each dose group. 
 
2.7 mL of blood will be taken in a K3-EDTA-anticoagulant blood drawing tube at the time 
point: 24 hours (planned time, immediately after the drawing of a regular blood sample i.e., 
no additional venous puncture will be necessary). The EDTA-anticoagulated blood will be 
split into two aliquots: 
• One aliquot will be centrifuged within 30 minutes after collection. Centrifugation will last 
for about 10 minutes (at approximately 2000 to 4000 x g at 4 to 8°C, and the resulting 
plasma will be transferred into a polypropylene cryotube (e.g., Nunc #368632). 
 
• The second aliquot will be stored for about 4 hours at room temperature and ambient light 
conditions (documentation of storage time necessary) and then centrifuged. 
Centrifugation will last for about 10 minutes (at about 2000 to 4000 x g at 4 to 8°C), and 
the resulting plasma will be transferred into a polypropylene cryotube (e.g., Nunc 
#368632). 
The aliquots should be labelled with the following information: study number, subject 
number, planned time, “BA-sample”. Until transfer to the analytical laboratory, both aliquots 
will be stored at approximately -20°C or below at the clinical site. Both aliquots will be 
provided to the responsible bioanalyst together with the information about sample handling 
(i.e., storage time of “sample” at room temperature).   
The results of the stability investigation will be documented in the corresponding method 
validation project but will not be included in the CTR. 
5.5.2.1 Urine sampling for pharmacokinetic analysis 
This section is not applicable. 


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5.5.3 
Analytical determinations 
Plasma concentrations of bevacizumab of US origin, bevacizumab of EU origin, and 
BI 695502 will be quantitated using a validated sandwich ELISA. 
 
  
 


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5.6 
BIOMARKER(S) 
Not applicable. 
5.7 
PHARMACODYNAMICS 
Not applicable. 
5.8 
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP 
Not applicable. 


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6. 
INVESTIGATIONAL PLAN 
6.1 
VISIT SCHEDULE 
Exact times of measurements outside the permitted time windows will be documented. Time 
windows are permitted as follows: 
• General medical examination: at screening (1 to 28 days prior to the first study day) and 
at the end-of-study evaluation (Day 99); 
• The tolerance for vital signs andECG  will be ± 1 hour; and 
• Study measurements and assessments scheduled to occur on Day 1 prior to drug 
administration have to be performed and completed within 2 hours prior to drug 
administration. 
For planned individual plasma concentration sampling times refer to the Flow Chart 1.1.  
While these nominal times should be adhered to as closely as possible, the actual sampling 
times will be recorded and used for determination of PK parameters. 
If a subject misses an appointment, it will be rescheduled, if possible. 
6.2 
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS 
6.2.1 
Screening period (Day -28 to -1) - all subjects 
After the subjects have been informed on the trial, all subjects will give their written 
informed consent in accordance with GCP and the local legislation prior to admission to the 
study. The subject’s eligibility will be assessed and his demographic information and medical 
and surgical history will be recorded.   
Each subject will have a physical examination, ECG, height, weight, calculation of BMI, 
temperature, and their vital signs will be recorded. 
For the medical and laboratory examination, including drug and virus screening during the 
screening visit, see Sections 5.2.6 and 5.2.5.   
Adverse events and concomitant mediations will start being recorded during this visit.  
6.2.2 
Study period 
The subjects will be kept under close medical surveillance until discharge from the 
investigational site after formal assessment and confirmation of their fitness by the 
investigator or designee.  
Subjects will be randomly allocated to the treatment as described in Section 4.1.2.  
For details on time points for collection of plasma samples for PK analysis and all other trial 
procedures, see Flow Chart 1.1. 
For details on time points for all other trial procedures, see Flow Chart 1.1. 


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Adverse events and concomitant medication will be evaluated continuously from the signing 
of the informed consent until the end-of-study examination. 
6.2.3 
End of trial  
A review of vital signs, 12-lead ECG, laboratory assessments, temperature and a physical 
examination will be performed at the end-of-study evaluation (Day 99). 
All clinically significant abnormal values (including laboratory parameters) will be followed 
up using the appropriate tests until a return to a medically acceptable level is achieved, as 
judged by the investigator and/or sponsor.  
Adverse events and concomitant medication will be evaluated continuously from the signing 
of the informed consent until the end-of-study examination. 
 


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7. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
7.1 
STATISTICAL DESIGN - MODEL 
7.1.1 
Objectives 
The objective of the current study is to establish the PK biosimilarity of BI 695502 compared 
to bevacizumab (Avastin®) US and EU source bevacizumab (Avastin®), US source and 
bevacizumab (Avastin ®), EU source, respectively, following one iv administration. A 
three-fold comparison will be performed (BI 695502 vs bevacizumab (Avastin®), US source, 
BI 695502 vs bevacizumab (Avastin ®), EU source, and bevacizumab (Avastin®), US source 
vs bevacizumab (Avastin ®), EU source). 
7.1.2 
Design 
The study will be conducted according to a randomized, single-blind, single-dose, two-stage, 
parallel-arm, active-comparator design. Pharmacokinetic similarity will be determined by 
comparing BI 695502 and bevacizumab (Avastin®), US source, BI 695502 and bevacizumab 
(Avastin ®), EU source as well as bevacizumab (Avastin®), US source and bevacizumab 
(Avastin ®), EU source between subjects. 
The trial will be performed in a two-stage design with Pocock boundaries for early stopping. 
The interim analysis will be performed when approximately 50% of the subjects are 
evaluable for the primary endpoint. A single treatment may be stopped at interim analysis if 
both comparisons where the treatment is involved in show an early significance. A stop of the 
whole trial based on the interim analysis results for early significance is possible. 
Although a crossover design is viewed favorably for similarity trials, it was not chosen for 
this trial because of the long terminal half-life of the compound. 
7.1.3 
Endpoints 
Pharmacokinetic similarity of BI 695502 and bevacizumab is to be determined on the basis of 
the primary PK parameter as displayed in Section 5.5.1. 
The derivation of the PK parameters is given in Appendix 10.2. 
Safety will be evaluated based on the investigations described in Section 5.2. 
7.1.4 
Model 
The statistical model used for the analysis of the primary PK parameters will be an analysis 
of variance (ANOVA) model on the logarithmic scale. This model will include effects 
accounting for the following sources of variation: 'treatment' and 'weight'. All effects will be 
considered as fixed. The model is described by the following equation: 
yij = μ + τi + ξj+ eij, 


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where 
yij 
logarithm of response measured on subject j receiving treatment i; 
μ
the overall mean; 
τi 
the ith treatment effect, i = 1, 2, 3; 
ξj 
weight of the jth subject; and 
eij 
the random error associated with the jth subject who received treatment i. 
7.2 
NULL AND ALTERNATIVE HYPOTHESES 
Pharmacokinetic similarity is established by using the average biosimilarity method to ensure 
that the ratio for treatments (of the respective PK parameter[s]) is contained within a 
pre-specified acceptance range (see below). This goal is accomplished by testing the below 
hypothesis on the log scale. 
Null hypothesis H0 (Non-similarity): 
δ
≥
µ
−
µ
δ
−
≤
µ
−
µ
R
T
R
T
or
 
(i.e., the difference of the means is either less than or equal to the lower bound or 
greater than or equal to the upper bound of the acceptance range), 
Alternative hypothesis Ha (Similarity): 
δ
<
µ
−
µ
<
δ
−
R
T
 
(i.e., the difference of the means is both greater than the lower bound and less than the 
upper bound of the acceptance range), 
where 
T
µ  and 
R
µ  are the means of the log-transformed measures for the two treatments (Test 
and Reference) under investigation, 
and δ  is the biosimilarity limit that defines the acceptance range for PK parameter(s) 
on the logarithmic scale. 
In this trial, δ is taken to be ln(1.25). This translates to an acceptance range of 80% to 125% 
for the ratio of the geometric means for treatments on the original scale. 
This hypothesis and its alternative can be decomposed into two one-sided null hypotheses, 
H01 and H02, with their accompanying alternatives: 
H01: 
δ
−
≤
µ
−
µ
R
T
 
vs. 
Ha1: 
δ
µ
µ
R
T
−
>
−
 
H02: 
δ
µ
µ
R
T
≥
−
 
vs. 
Ha2: 
δ
µ
µ
R
T
<
−
 


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The test of the null hypothesis at the α = 0.05 level is similar to carrying out two one-sided 
tests of the above null hypotheses each at the α = 0.05 level of significance. The rejection of 
both null hypotheses H01 and H02 at the α = 0.05 level is equivalent to the inclusion of the 
90% confidence interval for 
R
T
µ
−
µ
 in the acceptance range. The α-level for the significance 
testing will be adjusted for considering multiple stages (i.e. looks) based on a Pocock 
boundary. Hence the confidence intervals considered at each analysis (interim and final) are 
the 93.93% confidence intervals. No adjustment for multiple comparisons will be performed 
due to the fact that all three comparisons (BI 695502 vs bevacizumab (Avastin®), US source, 
BI 695502 vs bevacizumab (Avastin ®), EU source, bevacizumab (Avastin®), US source vs 
bevacizumab (Avastin ®), EU source) need to be significant. 
7.3 
PLANNED ANALYSES 
7.3.1 
Primary analyses 
The primary PK parameters (see Section 7.1.3) will be log transformed (natural logarithm) 
prior to fitting the ANOVA model described in Section 7.1.4. The difference between the 
expected means for log(Test)-log(Reference) will be estimated by the difference in the 
corresponding least-squares means (point estimate), and two-sided 93.93% confidence 
intervals based on the t-distribution will be computed. These quantities will then be 
back-transformed to the original scale to give the point estimator and interval estimates for 
the inter-subject ratio of the geometric means for treatments. 
A claim of PK similarity will be made if the 93.93% confidence interval(s) of the ratio of the 
geometric means are contained in the pre-defined acceptance range for all three comparisons.  
All randomized subjects will be included in the analysis of PK similarity, if they 
• Received at least one dose of study drug; 
• Had no important CTP deviation relevant to the evaluation of PK similarity. (Whether 
a CTP deviation is relevant, will be decided no later than the combined report 
planning and database lock meeting, see below.); and  
• Provide at least one evaluable observation of a PK endpoint. (Whether a single PK 
endpoint or the entire treatment period will be classified as a non-evaluable will be 
decided no later than the combined report planning and database lock meeting.) 
Subjects with protocol deviations relevant for PK similarity should generally be excluded 
from PK analysis prior to start of bioanalytical determinations. Classification of a protocol 
deviation as “relevant” will be made by the investigator, together with the trial 
pharmacokineticist. Examples for relevant deviations are: 
• Randomized study drug not administered or wrong trial drug administered. 
• Not observing the pre-defined treatment regimen completely, i.e.: Administered dose 
(amount of drug) is not in compliance with the protocol, i.e. too high or too low. Note 
that adjustment of the infusion rate will not be considered as relevant deviation, 
although potential impact on Cmax as secondary endpoint should be discussed. 


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7.3.2 
Secondary analyses 
The PK parameters AUC0-tz and Cmax will statistically be assessed using the same statistical 
model as described for the primary endpoint. For these endpoints (AUC0-tz and Cmax) the 90% 
confidence intervals will be computed. 
Concentrations will be used for graphs and calculations in the format that is reported in the 
bioanalytical report. 
Plasma concentrations will be plotted graphically versus time for all subjects as listed in the 
drug plasma concentration-time tables. For the presentation of the mean profiles, the 
arithmetic mean and the planned blood sampling times will be used. 
The following descriptive statistics will be calculated for plasma concentrations as well as for 
all primary and secondary PK parameters: N (sample size), arithmetic mean, standard 
deviation, minimum, median, maximum, arithmetic coefficient of variation, geometric mean, 
and geometric coefficient of variation. The data format for descriptive statistics of 
concentrations will be identical with the data format of the respective concentrations. The 
descriptive statistics of PK parameters will be calculated using the individual values with the 
number of decimal places as provided by the evaluation program. The individual values as 
well as the descriptive statistics will be reported with three significant digits in the CTR. 
7.3.3 
Safety analyses 
All subjects who receive at least one dose of study drug will be included in the safety 
evaluation (treated set). Safety analyses will be performed in accordance with Boehringer 
Ingelheim standards. 
Adverse events will be coded using the most recent version of the Medical Dictionary for 
Drug Regulatory Activities. The analysis of AEs will be based on the concept of 
treatment-emergent AEs. All AEs occurring after study medication intake until the 
end-of-study visit will be assigned to treatment. All AEs occurring before drug intake will be 
assigned to ‘screening’ and all AEs occurring after the end-of-study visit will be assigned to 
‘poststudy’. 
Independent of this rule, the relationship of an AE to the study drug treatments will be 
assessed by the investigator. Adverse event information as reported in the eCRFs will be 
aggregated in a two-step process. First, multiple recordings (AE occurrences) of the same AE 
will be combined into one AE episode (collapsing). The second step will combine all of the 
AE episodes of an AE into one AE record as needed for by-subject summaries (condensing). 
The evaluation of AEs will comprise various frequency tabulations. 
Descriptive statistics of laboratory values and vital signs over time and for the change from 
baseline will be provided. Frequency tables of changes with respect to the reference range 
between baseline and last value on treatment will also be presented. 


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7.3.4 
Interim analyses 
After Stage 1 of the trial, an interim analysis will be performed based on the pre-specified 
boundaries for early PK biosimilarity. As described in Section 7.2, the α-level will be 
adjusted for these multiple looks based on a Pocock boundary. This leads to a 93.93% 
confidence interval being relevant for the actual testing of similarity. This interim analysis 
will be performed by a DMC which will provide a recommendation whether to stop the trial 
for early PK biosimilarity. Additionally, in order to get the full data picture, the DMC will 
look at secondary and other PK parameters. If the trial is stopped after the interim analysis a 
full CTR will be written. Note that it is also possible that only a single arm is stopped for 
early similarity at interim if for both comparisons the arm is involved in early similarity can 
be shown. 
Additionally, a continuous monitoring of all safety data will be done by a DMC to ensure an 
acceptable safety profile at any time. The DMC may consider recommending stopping the 
trial in case that emerging data might suggest doing so. 
7.3.5 
Pharmacokinetic analyses 
The PK parameters described in Section 5.5.1 will be determined if feasible. 
The primary PK parameter will be analyzed as described in Section 7.3.1, secondary PK 
parameters will be analyzed using the same statistical model (see Section 7.3.2). 
 
 
Concentrations will be used for graphs and calculations in the format that is reported in the 
bioanalytical report. Only concentrations within the validated concentration range will be 
used for the calculation of PK parameters. 
Plasma concentrations will be plotted graphically versus time for all subjects as listed in the 
drug plasma concentration-time tables, if possible, with the actual sampling times. For the 
presentation of the mean profiles, the arithmetic mean, and the planned blood sampling times 
will be used. 
The following descriptive statistics will be calculated for analyte concentrations as well as for 
all PK parameters: N, arithmetic mean, standard deviation, minimum, median, maximum, 
arithmetic coefficient of variation, geometric mean, and geometric coefficient of variation. 
The data format for descriptive statistics of concentrations will be identical with the data 
format of the respective concentrations. The descriptive statistics of PK parameters will be 
calculated using the individual values with the number of decimal places as provided by the 
evaluation program. The individual values as well as the descriptive statistics will be reported 
with three significant digits in the CTR. 
7.3.6 
Pharmacodynamic analyses 
Not applicable. 


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7.3.7 
Pharmacogenomic analyses 
Not applicable. 
7.4 
HANDLING OF MISSING DATA 
7.4.1 
Safety  
With respect to safety evaluations, it is not planned to impute missing values other than AE 
start dates and times. 
7.4.2 
Plasma concentration - time profiles 
Concentration data identified with no sample (NOS), no valid result (NOR), not analyzed 
(NOA), below the limit of quantification (BLQ), and no peak detectable (NOP) will be 
ignored and not replaced by zero at any time point (applies also to the lag phase including the 
predose value). Descriptive statistics of concentrations at specific time points will be 
calculated only when at least 2/3 of the individuals have concentrations within the validated 
concentration range. The overall sample size to decide whether the “2/3 rule” is fulfilled will 
be based on the total number of samples intended to be drawn for that time point (i.e., BLQ, 
NOR, NOS, NOA, and NOP are included). 
7.4.3 
Pharmacokinetic parameters 
In the noncompartmental analysis, concentration data identified with NOS, NOR, and NOA 
will not be considered. Below the limit of quantification and NOP values in the lag phase will 
be set to zero. The lag phase is defined as the period between time zero and the first time 
point with a concentration above the quantification limit. All other BLQ / NOP values of the 
profile will be ignored. 
Every effort will be made to include all concentration data in an analysis. If not possible, a 
case-by-case decision will be required to decide whether the value should only be excluded 
from half-life estimation or the complete analysis. If a concentration is only excluded from 
half-life determination, it will be used for all other calculations, (e.g., descriptive statistics) 
and for graphical presentations. 
If a concentration value is excluded from all calculations, it will not be presented graphically 
or used for the calculation of descriptive statistics and parameter determination. The excluded 
concentration itself will be listed in the tables in Section 15 of the CTR associated with an 
appropriate flag. 
Descriptive statistics of parameters are calculated only when at least 2/3 of the individual 
parameter estimates of a certain parameter are available. If the actual sampling time will not 
be recorded or will be missing for a certain time point, the planned time will generally be 
used for this time point instead. Pharmacokinetic parameters which cannot be determined will 
be identified by "not calculated". 


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7.5 
RANDOMIZATION 
Subjects will be randomized to one of the three treatment groups in a 1:1:1 ratio. If after the 
interim analysis a single arm is stopped for early similarity the randomization ratio for the 
two continued arms in Stage 2 will be 1:1. 
The sponsor will arrange for the randomization as well as packaging and labeling of study 
medication. The randomization list will be generated using a validated system, which 
involves a pseudo-random number generator and a supplied seed number so that the resulting 
allocation of randomization number of medication numbers to treatment is both reproducible 
and non-predictable. 
7.6 
DETERMINATION OF SAMPLE SIZE 
Different overall power for a two arm comparison based on 2x2x30 subjects in a two-stage 
Pocock design are given in the following tables:  
Table 7.6: 1 
Overall power two stage in a two-stage Pocock-design for early 
stopping after 50% of the subjects for two-arm comparisons with 
2x60 pts and an assumed ratio of 1  
Assumed CV 
Overall power 
P(Stop) Stage 1 
Average 
sample number 
0.35 
89% 
41% 
96 
0.30 
97% 
65% 
81 
0.25 
> 99% 
87% 
68 
0.20 
> 99% 
98% 
61 
CV: coefficient of variation. Simulated with Addplan version.5.0, seed=6851, n=100000.  
 
Table 7.6: 2 
Overall power two stage in a two-stage Pocock-design for early 
stopping after 50% of the subjects for two-arm comparisons with 
2x60 pts and an assumed ratio of 0.95 
Assumed CV 
Overall power 
P(Stop) Stage 1 
Average 
sample number 
0.35 
77% 
32% 
101 
0.30 
88% 
53% 
89 
0.25 
96% 
73% 
76 
0.20 
> 99% 
90% 
66 
Simulated with Addplan version 5.0, seed=6851, n=100000. 
 
Hence for an assumed CV of 30% the overall powers are given as approx. 97% (assumed 
ratio of 1.0) and approximately 88% (assumed ratio of 0.95), respectively. Note that these 
numbers do not take into account the multiple comparisons performed as well as the different 
probabilities for stopping the different treatment arms (hence the average sample number has 


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to be regarded with caution). In a ‘worst-case’ scenario of total independence between the 
comparisons the overall power reduces to approximately 94% and 77%, respectively.  


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8. 
INFORMED CONSENT, DATA PROTECTION, AND TRIAL 
RECORDS 
The trial will be carried out in compliance with the CTP, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline for 
GCP, and relevant Boehringer Ingelheim Standard Operating Procedures (SOPs). Standard 
medical care (prophylactic, diagnostic, and therapeutic procedures) remains in the 
responsibility of the treating physician of the subject. 
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the CTP ICH / GCP. 
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in the investigator contract. As a general rule, no trial results should be 
published prior to finalization of the CTR. 
8.1 
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT 
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB / Independent Ethics Committee (IEC) and competent 
authority according to national and international regulations. The same applies for the 
implementation of changes introduced by amendments. 
Prior to subject participation in the trial, written informed consent must be obtained from 
each subject according to ICH / GCP and to the regulatory and legal requirements of the 
participating country. Each signature must be personally dated by each signatory and the 
informed consent and any additional subject information form retained by the investigator as 
part of the trial records. A signed copy of the informed consent and any additional subject 
information must be given to each subject. 
The subject must be informed that his / her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the subject. 
The subject must be informed that his/her medical records may be examined by authorized 
monitors (Clinical Research Associate [CRA]) or Clinical Quality Assurance auditors 
appointed by Boehringer Ingelheim, by appropriate IRB / IEC members, and by inspectors 
from regulatory authorities. 
8.2 
DATA QUALITY ASSURANCE 
The trial will be carried out in compliance with the CTP, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline for 
GCP, in accordance with applicable regulatory requirements, and in accordance with the 
company’s SOPs. 


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Electronic CRFs for individual subjects are provided by the Department of Clinical Data 
Management of the sponsor via remote data capture. 
The eCRFs will be kept current to reflect the subject’s status at each phase during the course 
of the trial. The subject is not to be identified on the eCRFs by name. Appropriately coded 
information (e.g., subject number) is given. The investigator will make a separate confidential 
record of these details (subject identification code list) to permit identification of all subjects 
enrolled in a clinical trial in case follow-up is required.  
Relevant medical history prior to enrollment will be documented during the baseline visit. 
Thereafter, during the trial narrative statements relative to the subject’s progress during the 
trail have to be maintained. 
The investigator is responsible for retaining all records pertaining to the trial. 
Refer to Section 8.3.1 for the handling of source data. 
Originals or copies of ECG results and other results based on hard copies of medical 
machinery will be kept as source documents at the investigational site.   
The investigator / institution permits trial-related monitoring, audits, IRB / IEC review, and 
regulatory inspection, providing direct access to all related source data / documents. 
Electronic CRFs and all source documents, including progress notes (if applicable) and 
copies of laboratory and medical test results will be available at all times for review by the 
sponsor’s clinical trial monitor and inspection by health authorities. The CRA / on-site 
monitor will review all eCRFs and written informed consents. The accuracy of the data will 
be verified by reviewing the above referenced documents. 
A quality assurance audit / inspection of this trial may be conducted by the sponsor or 
sponsor’s designees or by IRBs / IECs or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial. 
8.3 
RECORDS 
Electronic CRFs for individual subjects will be provided by the sponsor, either on paper or 
via remote data capture. See Section 4.1.5.2 for rules about emergency code breaks. For drug 
accountability, refer to Section 4.1.8. 
8.3.1 
Source documents 
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents will be filed at the investigator’s site. 
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. 


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The investigator may need to request previous medical records or transfer records, depending 
on the trial; also current medical records must be available. 
For eCRFs all data must be derived from source documents. 
8.3.2 
Direct access to source data and documents 
The investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
regulatory inspection, providing direct access to all related source data / documents, eCRFs 
and all source documents, including progress notes and copies of laboratory and medical test 
results must be available at all times for review by the sponsor’s clinical trial monitor, auditor 
and inspection by health authorities (e.g., Food and Drug Administration). The CRA / on-site 
monitor and auditor may review all eCRFs and written informed consents. The accuracy of 
the data will be verified by reviewing the documents described in Section 8.3.1. 
8.4 
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS 
8.4.1 
Listedness 
To fulfill the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular AE is "listed" i.e., is a known side effect of the drug or not. Therefore a 
unique reference document for the evaluation of listedness needs to be provided. For the 
BI 695502 this is the current version of the Investigator’s Brochure (U12-1281-01). For the 
bevacizumab (Avastin®) as US and EU source this is the EU SPC and US-PI respectively. 
The current versions of these reference documents are to be provided in the ISF. No AEs are 
classified as listed for matching placebo, study design, or invasive procedures. 
8.4.2 
Expedited reporting to health authorities and IECs/IRBs 
Expedited reporting of SAEs, e.g., suspected unexpected serious adverse reactions to health 
authorities and IECs / IRBs will be done according to local regulatory requirements. Further 
details regarding this reporting procedure are provided in the ISF. 
8.5 
STATEMENT OF CONFIDENTIALITY 
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers. 
Treatment data may be given to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities. 


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9. 
REFERENCES 
9.1 
PUBLISHED REFERENCES 
R10-4862  
Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of 
bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug 
Discov 2004; 3: 391-400. 
R12-0947  
Zhan P, Wang J, Lv X, Wang Q, Qiu L, Lin X, Yu L, Song Y. Prognostic 
value of vascular endothelial growth factor expression in patients with lung 
cancer: A systematic review with meta-analysis. J Thorac Oncol 2009; 
4:1094-1103. 
R12-0948 
Llovet JM, Pena CEA, Lathia CD, Shan M, Meinhardt G, Bruix J, SHARP 
Investigators Study Group. Plasma biomarkers as predictive of outcome in 
patient with advanced hepatocellular carcinoma. Clin Cancer Res 2012. 
R12-1012 
European Medicines Agency.  Avastin:  EPAR – scientific discussion (first 
published 24-Jan-2006), website: 
ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussio 
n/human/000582/WC500029262.pdf (access date: 30 January 2012). 
R12-0939 
Avastin 25 mg/ml concentrate for solution for infusion (Roche Registration) 
 
 
(summary of product characteristics; manufacturer(s) of the biological active 
 
 
substance and manufacturing authorisation holder(s) responsible for batch 
 
 
release; conditions of the marketing authorisation; labelling and package  
 
 
leaflet, date of latest renewal: 14 January 2010, last updated: 5/02/2012), 
 
 
website: ema.europa.eu/docs/en_GB/document_library/EPAR_-  
 
 
_Product_Information/ human/000582/WC500029271.pdf (access date: 9 
 
 
March 2012)  
R12-0971 
Highlights of Prescribing Information. (21-Dec-2011), website: 
gene.com/gene/products/information/pdf/avastin-prescribing.pdf (access date 
01 March 2012). 
 
9.2 
UNPUBLISHED REFERENCES 
U12-1281-01 Investigator’s Brochure BI 695502 in colorectal cancer, breast cancer, non-
 
 
small cell lung cancer, renal cancer, epithelial ovarian, fallopian tube, or  
 
 
primary peritoneal cancer and glioblastoma, Version 1, 13 March 2012 


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10. 
APPENDICES 
10.1 
CLINICAL EVALUATION OF LIVER INJURY 
10.1.1 
Introduction 
Alterations of liver laboratory parameters, as described in Section 5.2.2.1 (CTP-Specified 
Significant Events), are to be further evaluated using the following procedures:  
10.1.2 
Procedures 
Studies without central laboratory 
Repeat the following laboratory tests: ALT, AST, and bilirubin (total and direct) - within 48 
to 72 hours. If ALT and/or AST > 3-fold ULN combined with an elevation of total bilirubin 
> 2-fold ULN are confirmed, results of the laboratory parameters described below must be 
made available to the investigator and to Boehringer Ingelheim as soon as possible. 
In addition,  
• Obtain a detailed history of current symptoms and concurrent diagnoses and medical 
history according to the “DILI checklist” provided in the ISF; 
• Obtain history of concomitant drug use (including non-prescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets according to the “DILI checklist” provided in the ISF; and  
• Obtain a history of exposure to environmental chemical agents (consider home and 
work place exposure) according to the “DILI checklist” provided in the ISF. 
and report these via the eCRF. 
Clinical chemistry 
Alkaline phosphatase, albumin, PT or INR, CK, CK-MB, coeruloplasmin, α-1 antitrypsin, 
transferin, amylase, lipase, fasting glucose, cholesterol, and triglycerides 
Serology 
Hepatitis A (Anti-IgM, Anti-IgG), Hep B (HbsAg, Anti-HBs, DNA), Hep C (Anti-HCV, 
RNA if Anti-HCV positive), Hepatitis D (Anti-IgM, Anti-IgG), Hepatitis E (Anti-HEV, 
Anti-HEV IgM, RNA if Anti-HEV IgM positive), Anti-Smooth Muscle antibody (titer), 
Anti-nuclear antibody (titer), Anti-LKM (liver-kidney microsomes) antibody, 
Anti-mitochondrial antibody. 
 
Hormones, tumormarker 
TSH 
Hematology 
Thrombocytes, eosinophils 


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• Provide abdominal ultrasound to rule out biliary tract, pancreatic or intrahepatic 
pathology e.g., bile duct stones or neoplasm; and  
• Initiate close observation of subjects by repeat testing of ALT, AST, and total 
bilirubin (with fractionation by total and direct) at least weekly until the laboratory 
ALT and / or AST abnormalities stabilize or return to normal, then according to the 
CTP. Depending on further laboratory changes, additional parameters identified e.g., 
by reflex testing will be followed up based on medical judgment and GCP. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.2 
PLANNED TIME POINTS FOR SAFETY AND PHARMACOKINETICS 
ASSESSMENTS
 
Treatment  period 
Visit 
Day 
Planned time 
[h:min] 
Approximate time (actual 
time) [h:min] 
Event and comment 
Laboratory/ 
Urinalysis 
PKblood 
 
12-lead ECG 
 Temperature 
 Physical examination3 
Vital signs  
(Blood pressure and pulse 
rate) 
Adverse events/Con. med 
 
1 
-28 
to -2 
 
 
screening (-28 to -2) 
X 
 
 
X 
X 
X 
X 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
│ 
││ 
▼ 
-1 
 
 
admission to trial center 
X 
 
 
X 
X 
X 
X 
1 
2 
1 
-1:00 
7:00 
 
 
X 
X 
 
X 
X 
X 
0:00 
8:00 
drug administration 
infusion start 
 
 
 
 
 
 
 
0:30 
8:30 
 PK blood draw taken 
just prior to end of 
infusion 
 
X 
 
X1. 
 
 
 
1:00 
9:00 
 
 
 
 
 
 
 
X 
2:00 
10:00 
 
 
X 
 
X 
 
 
X 
3:00 
11:00 
 
 
 
 
 
 
 
X 
4:00 
12:00 
 
 
X 
 
 
 
 
X 
5:00 
13:00 
 
 
 
 
 
 
 
X 
6:00 
14:00 
 
 
 
 
 
 
 
X 
8:00 
16:00 
 
 
X 
 
X 
 
 
 
2 
24:00 
8:00 
 
X 
X4 
 
X 
 
X 
X 
3 
48:00 
8:00 
discharge from trial site 
2 
X 
X 
 
X 
 
X 
X 
5 
96:00 
8:00 
ambulatory visit 
 
X 
 
 
 
X 
X 
8 
168:00 
8:00 
ambulatory visit 
X 
X 
 
 
 
X 
X 
15 
336:00 
8:00 
ambulatory visit 
X 
X 
X 
X 
 
X 
X 
22 
504:00 
8:00 
ambulatory visit 
X 
X 
X 
 
 
X 
X 
36 
840:00 
8:00 
ambulatory visit 
X 
X 
X 
X 
 
X 
X 
50 
1176:00 
8:00 
ambulatory visit 
X 
X 
X 
 
 
X 
X 
64 
1512:00 
8:00 
ambulatory visit 
X 
X 
 
X 
 
X 
X 
78 
1848:00 
8:00 
ambulatory visit 
X 
X 
 
 
 
X 
X 
 
3 
99 
2352:00 
8:00 
ambulatory visit 
X 
X 
X 
X 
 
X 
X 
1. ECG performed at end of infusion. 
2. All patients will remain hospitalized for 48 hours after dosing but can be discharged after 24 hours at investigator´s 
discretion. If discharged on Day 2, patient must return to the site on Day 3. 
3. Symptom directed physical examination as clinically indicated on Day 2 to Day 78. 
4. One “BA-sample” for first 8 patients to be taken at day 2 on time point 24:00 (section 5.5.2) 


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11. 
DESCRIPTION OF GLOBAL AMENDMENT(S) 
This is the original protocol. 
Number of global amendment 
 
01 
Date of CTP revision 
 
26 November 2012 
EudraCT number 
 
NA 
BI Trial number 
 
1302.1 
BI Investigational Product(s) 
 
BI 695502 
Title of protocol 
 
Pharmacokinetics and safety of BI 695502 in 
healthy subjects: a randomized, single-blind, 
single-dose, parallel-arm, active-comparator 
clinical Phase I study. 
 
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities 
 
 
To be implemented 
immediately in order to 
eliminate hazard –  
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval 
 
 
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only 
 
 
 
Section to be changed 
 
 
 
Description of change 
 
 
 
Rationale for change 
 
 
 
 
 
 
Section to be changed 
 
Title page: Trial Clinical Monitor 
Description of change 
 
The study was handed over from 
 to 
 on 6 September 2012 
Rationale for change 
 
Update to actual Clinical Project 
 
 
 
 
Section to be changed 
 
Flow Chart 1.1 Schedule of assessments  
Description of change 
 
Following note was changed from “Note: Please 
refer to Appendix 10.2 for specific planned time 


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Number of global amendment 
 
01 
points” to “Note: Please refer to Appendix 10.2 
for specific planned time points for safety and 
pharmakokinetic assessments” 
Rationale for change 
 
Clarification to Flow Chart 1.1 which specific 
planned time points are meant in accordance to 
Appendix 10.2. 
 
 
 
Section to be changed 
 
Flow Chart 1.1 Schedule of assessments 
Description of change 
 
Screening range was corrected from “day -28 to -
1”  to  “day -28 to -2” 
Rationale for change 
 
Clarification of Screening range to day -28 to -2 
with admission to trial center on day -1 with 
admission to trial center on day -1 and 
confirmation of certain assessments to be conform 
with Appendix 10.2. 
 
 
 
Section to be changed 
 
1.1 
Description of change 
 
Second paragraph first section: “secreted” was 
deleted 
Rationale for change 
 
 The secreted VEGF is only one of the isoforms, 
therefore it was decided to delete “secreted”.  
 
 
 
Section to be changed 
 
1.2 
Description of change 
 
At the end of the first paragraph it was added: 
“…, on tumor cells and autocrine and paracrine 
loops.” 
Rationale for change 
 
Clarification of VEGF receptor locations. 
 
 
 
Section to be changed 
 
2.1 
Description of change 
 
First paragraph last sentence: Added in the 
apprentices “powered for”. 
Rationale for change 
 
Clarification that demonstrated safety and 
immunogenicity similarity will not be powered 
statistical similarity 
 
 
 
Section to be changed 
 
2.3 Drug related risks and safety measures 
Description of change 
 
1. Added proteinuria as most frequently side 
effect 
2.
 
 
 
 
 
 
 


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Number of global amendment 
 
01 
 
 
 
 
 
  
Rationale for change 
 
1. Clarification on most frequently side 
effects in this section 
2. 
 
 
 
 
Section to be changed 
 
3.3 
Description of change 
 
4th paragraph:  
1. 3rd sentence “Single-dose” replaced by 
“Single therapeutic dose of” 
2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rationale for change 
 
1. Clarification that this single dose was a 
single and therapeutic dose (5mg/kg) 
2. 
 
 
 
 
Section to be changed 
 
3.3 Table 3.3: 1  
Description of change 
 
 
 
 
 


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Number of global amendment 
 
01 
 
 
 
Rationale for change 
 
 
 
 
 
 
Section to be changed 
 
4.1.2, 7.5 
Description of change 
 
At end of paragraph 4.1.2 it was added: (The 
same applies for randomization numbers).” 
In last sentence of 7.5 it was changed:”… so that 
the resulting allocation of medication numbers to 
treatment is both reproducible and non-
predictable.” to “…so that the resulting 
allocation of randomization number to treatment 
is both reproducible and non-predictable. 
Rationale for change 
 
Clarification that randomization numbers and not 
medication numbers were allocated 
 
 
 
Section to be changed 
 
4.2.2.2 
Description of change 
 
Restrictions on diet and life-style: Smoker “(>10 
cigarettes or > 3 cigars or >3 pipes/day)“ was 
corrected to “(<10 cigarettes or <3 cigars or <3 
pipes/day)“ 
Rationale for change 
 
Clarification of Restrictions on diet and life-style 
 
 
 
Section to be changed 
 
5.2.1 
Description of change 
 
“Safety will be evaluated based on the 
investigations described in Section 5.2.” was 
corrected to “All safety parameters will be 
evaluated descriptively and based on the 
investigations described below.”  
Rationale for change 
 
Clarification of safety endpoints and analysis 
 
 
 
Section to be changed 
 
5.5.2.3 
Description of change 
 
First sentence “…5 mL of blood will be 
collected…” was changed to “…3 mL of blood 
will be collected…” 
Rationale for change 
 
There is an administrative error in the protocol 
regarding collection of neutralizing antibody 
samples. The sites were provided with 3 ml tubes 
instead of the 5 ml tubes stated in the protocol, so 
that only 3 ml blood was collected  


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Number of global amendment 
 
01 
 
 
 
Section to be changed 
 
5.5.2.3 
Description of change 
 
 
 
 Rationale for change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section to be changed 
 
5.5.3 
Description of change 
 
The following sentence was updated “Plasma 
concentrations of bevacizumab of US origin, 
bevacizumab of EU origin, and BI 695502 will be 
quantitated using a sandwich ELISA.” To 
“Plasma concentrations of bevacizumab of US 
origin, bevacizumab of EU origin, and BI 695502 
will be quantitated using a validated sandwich 
ELISA.”And the following sentence was added 
 
 
Rationale for change 
 
Clarification that the assays used are certainly 
validated 
 
 
 
Section to be changed 
 
Appendix 10.2 
Description of change 
 
The following note to the table was added to PK 
blood column cell day 2: 4. One “BA-sample” for 
first 8 patients to be taken at day 2 on time point 
24:00 (section 5.5.2) 
Rationale for change 
 
Clarification that at this time point the BA sample 
is taken for first 8 patients. 
 
 
 
Section to be changed 
 
Appendix 10.2 
Description of change 
 
 
 


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Number of global amendment 
 
01 
Rationale for change 
 
 
 
 
 
Number of global amendment 
 
02 
Date of CTP revision 
 
11 January 2013 
EudraCT number 
 
NA 
BI Trial number 
 
1302.1 
BI Investigational Product(s) 
 
BI 695502 
Title of protocol 
 
Pharmacokinetics and safety of BI 695502 in 
healthy subjects: a randomized, single-blind, 
single-dose, parallel-arm, active-comparator 
clinical Phase I study. 
 
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities 
 
 
To be implemented 
immediately in order to 
eliminate hazard –  
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval 
 
 
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only 
 
 
 
 
 
 
Section to be changed 
 
3.3 
Description of change 
 
First paragraph: “enrolled” replaced by 
“randomized”; some typos corrected  
Rationale for change 
 
The definition of “enrolled”  is not always 
distinct, therefore it was replaced with 
“randomized” to avoid confusion 
 
 
 
Section to be changed 
 
3.3.3 
Description of change 
 
The exclusion criteria 21. Pre-existing 
proteinuria was added 
Rationale for change 
 
Exclusion criteria proteinuria was omitted in the 
initial protocol. None of the stage I subjects was 


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Number of global amendment 
 
02 
included with proteinuria. Proteinuria is one of 
the most common adverse reactions incidence 
(>10% and at least twice the control arm rate) of 
Avastin.  
 
 
 
Section to be changed 
 
3.3.4.1 
Description of change 
 
Second paragraph: the brackets “(e.g., 
non-attendance at study assessments). “ have 
been changed to “(e.g., non-attendance at study 
assessments, incomplete, missing or wrong trial 
drug administration). “ 
Rationale for change 
 
In order to provide useful examples of situations 
that should be discussed in a timely manner with 
a view to their relevance for assessment. 
 
 
 
Section to be changed 
 
5.5.1   
Description of change 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section to be changed 
 
7.3.1  
Description of change 
 
1. In second paragraph it was added  in the 
brackets “see below”: (Whether a CTP 
deviation is relevant, will be decided no 


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Number of global amendment 
 
02 
later than the combined report planning 
and database lock meeting, see below.); 
and  
2. Third paragraph was added:“Subjects 
with protocol deviations relevant for PK 
similarity should generally be excluded 
from PK analysis prior to start of 
bioanalytical determinations. 
Classification of a protocol deviation as 
“relevant” will be made by the 
investigator, together with the trial 
pharmacokineticist. Examples for relevant 
deviations are: 
• Randomized study drug not 
administered or wrong trial drug 
administered.  
• Not observing the pre-defined 
treatment regimen completely, i.e.: 
Administered dose (amount of drug) is 
not in compliance with the protocol, 
i.e. too high or too low. Note that 
adjustment of the infusion rate will not 
be considered as relevant deviation, 
although potential impact on Cmax as 
secondary endpoint should be 
discussed.” 
Rationale for change 
 
1. Clarify relationship to other text part in 
protocol 
2. In order to facilitate the examples given in 
chapter 3.3.4.1. Same rationale. 
 
 
 
Section to be changed 
 
7.3.3 
Description of change 
 
 
 
 
Rationale for change 
 
 
 
 
 
 
Section to be changed 
 
7.6 
Description of change 
 
Correction of table numbering from 7.6.1:1 and 
7.6.1:2  to 7.6:1 and 7.6:2 
Rationale for change 
 
Formatting of table number to be more logical 
 
 
 
Section to be changed 
 
Flow Chart 1.1 and 10.2 


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Number of global amendment 
 
02 
Description of change 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
 
SIGNATURE INFORMATION 
 
Document: 
                               
                           
Document No.:                                                                                                                        
 
Title 
                             
 
 
 
 
 
 
                         
 
SIGNATURES  (ELECTRONICALLY OBTAINED)  
 
Meaning of Signature: 
Signed by: 
Date signed: (GMT) 
                                   
 
 
 
                               
                                                                                    
                                   
 
 
 
                               
                                                                                    
                                   
 
 
 
                               
                                                                                    
                                   
 
 
 
                               
                                                                                                                      
                                   
 
 
 
                               
                                                                                                                     
                                  
 
 
 
                               
                                                                                                                     
                                   
 
 
 
                               
                                                                                                                       
1302-0001--tsap
T12-1048-01
Pharmacokinetics and safety of BI 695502 in healthy subjects: a
randomized, single-blind, single-dose, parallel-arm, active-comparator
clinical Phase I study
Author-Trial Statistician
12/13/2012 14:39:37
Author-Trial Clinical Monitor
12/17/2012 10:23:58
Verify Paper Signature Completion
12/18/2012 06:52:39


 
SIGNATURE INFORMATION (continued) 
Document 
                              
                          
Document No.:                                                                                                                        
 
Title 
                             
 
 
 
 
 
 
                         
SIGNATURES  (ELECTRONICALLY OBTAINED)  
(There are no entries on this page if there are up to seven signatures.) 
Meaning of Signature: 
Signed by: 
Date signed: (GMT) 
                                   
 
 
 
                               
                                                                                                                      
                                   
 
 
 
                               
                                                                                                                      
                                   
 
 
 
                               
                                                                                                                      
                                     
 
 
 
                                 
                                                                                                                      
                                     
 
 
                                 
                                                                                                                      
                                     
 
 
                               
                                                                                                                       
                                     
 
 
                                
                                                                                                                       
                                     
 
 
                                 
                                                                                                                     
 
1302-0001--tsap
T12-1048-01
Pharmacokinetics and safety of BI 695502 in healthy subjects: a
randomized, single-blind, single-dose, parallel-arm, active-comparator
clinical Phase I study


 
TITLE PAGE 
Trial Statistical Analysis Plan  
 
T12-1048-01 
BI Trial No.: 
1302.1 
Title: 
Pharmacokinetics and safety of BI 695502 in healthy subjects: a 
randomized, single-blind, single-dose, parallel-arm, active-
comparator clinical Phase I study 
Investigational 
Product: 
BI 695502 
Responsible trial 
statisticians: 
Phone: 
 
Fax: 
 
Phone: 
 
Fax: 
 
Date of statistical 
analysis plan: 
13 DEC 2012 SIGNED 
Version: 
Final 
Page 1 of  24
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1. 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................... 1 
1. 
TABLE OF CONTENTS ...................................................................... 2 
LIST OF TABLES .............................................................................................. 4 
2. 
LIST OF ABBREVIATIONS ............................................................... 5 
3. 
INTRODUCTION .................................................................................. 7 
4. 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ...... 8 
5. 
ENDPOINTS .......................................................................................... 9 
5.1 
PRIMARY ENDPOINT ...................................................................................... 9 
5.2 
SECONDARY ENDPOINTS .............................................................................. 9 
5.2.1 
Key secondary endpoints ................................................................................ 9 
5.2.2 
Other Secondary endpoints ............................................................................ 9 
5.5 
SAFETY ENDPOINTS ........................................................................................ 9 
6. 
GENERAL ANALYSIS DEFINITIONS ........................................... 10 
6.1 
TREATMENTS .................................................................................................. 10 
6.2 
IMPORTANT PROTOCOL VIOLATIONS .................................................. 11 
6.3 
PATIENT SETS ANALYSED .......................................................................... 12 
6.5 
POOLING OF CENTRES ................................................................................ 13 
6.6 
HANDLING OF MISSING DATA AND OUTLIERS ................................... 13 
6.6.1 
Safety data in general .................................................................................... 13 
6.6.2 
AE dates and times ........................................................................................ 14 
6.6.3 
Missing plasma concentrations and pharmacokinetic parameters .......... 14 
6.7 
BASELINE, TIME WINDOWS AND CALCULATED VISITS .................. 14 
7. 
PLANNED ANALYSIS ....................................................................... 16 
7.1 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ........ 17 
7.2 
CONCOMITANT DISEASES AND MEDICATION .................................... 17 
7.3 
TREATMENT COMPLIANCE ....................................................................... 17 
7.4 
PRIMARY ENDPOINT .................................................................................... 17 
7.5 
SECONDARY ENDPOINTS ............................................................................ 19 
7.5.1 
Key secondary endpoints .............................................................................. 19 
7.5.2 
Other Secondary endpoints .......................................................................... 19 
7.7 
EXTENT OF EXPOSURE ................................................................................ 19 
7.8 
SAFETY ANALYSIS ......................................................................................... 19 
7.8.1 
Adverse events ............................................................................................... 20 
7.8.2 
Laboratory data ............................................................................................. 21 
7.8.3 
Vital signs ....................................................................................................... 21 
7.8.4 
ECG ................................................................................................................ 21 
7.8.5 
Others ............................................................................................................. 21 
8. 
REFERENCES ..................................................................................... 22 


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10. 
HISTORY TABLE ............................................................................... 24 


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LIST OF TABLES 
 
Table 6.1: 1 
Labels for treatments for use in the CTR ........................................................ 10 
Table 6.1: 2 
Overview of treatments for inter-individual comparison ................................ 11 
Table 6.2: 1 
Important protocol violations .......................................................................... 12 
Table 6.3: 1 
Subject sets for analyses .................................................................................. 13 
Table 10: 1 
History table .................................................................................................... 24 
 
 


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2. 
LIST OF ABBREVIATIONS 
Include a list of all abbreviations used in the TSAP  
Term 
Definition / description 
AE 
Adverse event 
 
 
ADS 
Analysis dataset 
ANOVA 
Analysis of variance 
AUC0-tz 
Area under the concentration-time curve of the analyte in plasma over 
the time interval from 0 to time of the last quantifiable data point 
AUC0-∞ 
Area under the concentration-time curve of the analyte in plasma from 
time zero to infinity 
BI 
Boehringer Ingelheim 
BLQ 
Below limit of quantification 
BRPM 
Blinded report planning meeting 
BRPM/DBLM 
Combined blinded report planning and database lock meeting 
Cmax 
Maximum measured concentration of the analyte in plasma 
CRF 
Case Report Form 
CTP 
Clinical Trial Protocol 
CTR 
Clinical Trial Report 
DM&SM 
Boehringer Ingelheim Data Management and Statistics Manual 
DMC 
Data monitoring committee 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
ICH 
International Conference on Harmonisation 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
Number of observations included in calculation 
NC 
Not calculated 
NOA 
Not analyzed 
NOP 
No peak detectable 
NOR 
No valid result 
NOS 
No sample available 
O*C 
Oracle Clinical 


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Term 
Definition / description 
PK 
Pharmacokinetic(s) 
PKS 
Pharmacokinetic set 
PV 
Protocol violation 
qd 
Quaque die (once a day) 
R/Ref 
Reference treatment 
RAN 
Randomised set 
SAS® 
Statistical Analysis System 
SD 
Standard deviation 
SDL 
Subject Data Listings 
T 
Test treatment 
TS 
Treated set 
TSAP 
Trial statistical analysis plan 
WHO-DD 
World Health Organization Drug Dictionary 
 


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3. 
INTRODUCTION 
As per ICH E9, the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data. 
This trial statistical plan (TSAP) assumes familiarity with the Clinical Trial Protocol (CTP). 
In particular, the TSAP is based on the planned analysis specification as written in CTP 
Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP readers 
may consult the CTP for more background information on the study, e.g., on study objectives, 
study design and population, treatments, definition of measurements and variables, planning 
of sample size, and randomization. 
Study data will be stored in a trial database within the Oracle ClinicalTM (O*C) system. SAS® 
Version 9.2 will be used for all analyses. 
Pharmacokinetic (PK) parameters will be calculated using WinNonlinTM software 
(professional Network version 5.3, Pharsight Corporation, Mountain View, CA 94041-1530, 
USA). 


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4. 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY 
All analyses outlined in the trial protocol are described in the TSAP. Two minor changes 
compared to the protocol will be made. As one referred internal SOP, namely DCP-102, was 
superseded by a new SOP, 001-MCS-36-472, the new SOP will be used as basis for handling 
PK data. Secondly, the model for the analysis of variance (ANOVA) was slightly adapted 
such that the slope β describing the linear trend between response and regressor was added. 


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5. 
ENDPOINTS 
The PK as well as the safety endpoints are described in this section. 
5.1 
PRIMARY ENDPOINT 
CTP: The primary PK endpoint for assessment of PK similarity is the following: 
• AUC0-∞ 
(area under the concentration-time curve of the analyte in plasma over the time 
interval from 0 extrapolated to infinity) 
 
5.2 
SECONDARY ENDPOINTS 
5.2.1 
Key secondary endpoints  
As no key secondary endpoints have been specified in the protocol, this section is not 
applicable. 
5.2.2 
Other Secondary endpoints 
Secondary PK parameters are: 
• AUC0-tz 
(area under the concentration-time curve of the analyte in plasma over the time 
interval from 0 to the time of the last quantifiable data point) 
• Cmax 
(maximum measured concentration of the analyte in plasma) 
 
The assessment of safety will secondarily be based on adverse events; see CTP Section 5.2.2. 
5.5 
SAFETY ENDPOINTS 
Safety parameters (physical examination, vital signs, temperature, body weight, 12-lead ECG, 
laboratory tests); see CTP Sections 2.2.2 and 5.2. 


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6. 
GENERAL ANALYSIS DEFINITIONS 
6.1 
TREATMENTS 
A two-stage group sequential design was planned for this trial: 
• Stage 1: 90 subjects (30 per treatment group) 
• Stage 2: 90 subjects (30 per treatment group) 
 
CTP: An interim analysis will be conducted and if the pre-specified criteria for early PK 
biosimilarity are achieved then the study may be stopped. It is also possible that a single arm 
is going to be stopped [for proven (pairwise) biosimilarity] based on the chosen boundaries 
and the interim results. This is the case if both comparisons for the specific arm show an 
early similarity. If any comparison does not show early similarity then the trial will proceed 
to Stage 2. 
This interim analysis will be performed by a DMC which will provide a recommendation 
whether to stop the trial for early PK biosimilarity or to continue. 
Subjects are randomised to one of the three treatment arms given below. 
Table 6.1: 1 
Labels for treatments for use in the CTR 
PKTRT 
Treatment 
Short label 
A 
BI 695502, 1.4mg/mL solution for infusion, 
1mg/kg, iv, qd1) 
BI 695502 
B 
Avastin(US source), 1.4mg/mL  
solut. for infusion, 1mg/kg, iv, qd1) 
Avastin US 
C 
Avastin(EU source), 1.4mg/mL  
solut. for infusion, 1mg/kg, iv, qd1) 
Avastin EU 
1) “qd” means here a single drug administration on Day 1 of Visit 2. 
Note that these labels do not necessarily reflect the actual randomised code and the DMC outputs 
For detailed information on the handling of the treatments in the O*C views refer to 
Technical TSAP ADS plan (Chapter 2.2.1, 2.2.2). In particular, AEs and laboratory 
excursions will be assigned to BI 695502 or bevacizumab (Avastin ®) from both US and EU 
sources if they occur up to end-of-study visit. 


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Table 6.1: 2 
Overview of treatments for inter-individual comparison 
Test (T) 
Reference (R) 
A (Test 1, T1) 
B (Ref 1, R1) 
A (Test 1, T1) 
C (Ref 2, R2) 
C (Test 2, T2) 
B (Ref 1, R1) 
 
6.2 
IMPORTANT PROTOCOL VIOLATIONS 
Data discrepancies and deviations from the CTP will be identified for all subjects enrolled 
(i.e. signed informed consent available) who did not fail during screening. A list of protocol 
deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will be 
provided to be discussed at the combined report planning and database lock meeting 
(BRPM/DBLM). At this meeting at the latest, it will be decided whether a discrepant data 
point can be used or whether it must be corrected in the clinical database, and whether any 
identified protocol deviation is an important protocol violation (PV). A PV is in general 
defined as important if it affects the rights or safety of a study subject or if it can potentially 
influence the primary outcome measurement(s) for a subject in a way that is neither 
negligible nor in accordance with the study objectives. This second category of important PV 
forms the basis for the decision of whether a subject belongs to any analysis set. 
PVs that do not influence the subjects’ rights and safety or the evaluability of subject data 
with respect to the main study objectives are identified as non-important PVs. These are only 
considered to assess the overall trial quality. 
Important PVs will be described narratively in the CTR (derived from Appendix 16.2). In the 
study report, protocol violations affecting subjects’ rights will be identified separately from 
those affecting analysis sets. 
If any important PVs have been identified, they are summarised into categories and will be 
captured in the BRPM/DBLM minutes via an accompanying Excel spreadsheet [001-MCS-
50-413_RD-02] (1). Table 6.2: 1 contains the categories in which important PVs are 
classified. If other important PVs are identified at the BRPM/DBLM, this table will be 
supplemented accordingly. 
If substantial numbers of PVs are reported at the BRPM/DBLM, a decision about 
summarizing the PVs in a tabular format will be made. Otherwise, only a PV listing will be 
provided. 
Consistency checks will be prepared for identifying violations of time windows. 


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Table 6.2: 1 
Important protocol violations 
Category
/Code 
Description 
A 
 
Entrance criteria not met 
 
A1 
Inclusion criteria not met 
 
A2 
Exclusion criteria not met 
B 
 
Informed consent 
 
B1 
Informed consent not available/not signed 
 
B2 
Informed consent too late 
C 
 
Trial medication and randomization 
 
C1 
Incorrect trial medication taken
 
C2 
Randomization not followed 
 
C3 
Non-compliance 
D 
 
Concomitant medication 
 
D1 
Improper medication washout 
 
D2 
Prohibited medication use 
 
D3 
Mandatory medication not taken 
E 
 
Missing data (for primary and secondary endpoints)1 
 
E4 
Certain violations of procedures used to measure primary and 
secondary data 
F 
 
Incorrect timing (for primary and secondary endpoints)2 
 
F5 
Certain violations of the time schedule used to measure primary 
and secondary data 
G  
Other trial specific important violations 
 
G1 
Wrong dosing 
1 Missing visits, evaluations, and tests of data will be considered missing data, not protocol violations. 
2 Time deviations will only be flagged as important PV, when leading to exclusion of the entire subject from an analysis set 
Source: BI DM&SM, "Handling of Protocol Violations" [001-MCS-50-413_RD-01]  (2) 
 
6.3 
PATIENT SETS ANALYSED 
• Randomised set (RAN): 
This subject set includes randomised subjects, whether treated or not. 


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• Treated set (TS): 
This subject set includes all randomised subjects who have received one dose of study 
drug. 
This is the full analysis set population in the sense of ICH-E9.  
• Pharmacokinetic set (PKS): 
This subject set includes all subjects in the TS who provide at least one PK endpoint 
and had no important protocol violations relevant to the evaluation of PK 
biosimilarity. 
Table 6.3: 1 
Subject sets for analyses 
 
 
Subject set 
Endpoint 
 
RAN 
TS 
PKS 
Primary PK endpoint 
 
 
 
X 
Secondary PK endpoints 
 
 
 
X 
Secondary endpoints (safety 
evaluation) 
 
 
X 
 
Demographic data/Medical 
history and Concomitant 
diagnosis, Concomitant therapy 
 
 
X 
 
Important PVs 
 
 
X 
 
Analysis sets assignment 
 
X 
 
 
 
6.5 
POOLING OF CENTRES 
This section is not applicable, because centre is not included in the statistical model. 
6.6 
HANDLING OF MISSING DATA AND OUTLIERS 
6.6.1 
Safety data in general 
Data of subjects randomised who were not treated will be listed only. The safety data for 
treated subjects who failed to complete all stages of the study (who withdraw or are removed 
from the trial) will be reported as far as their data are available.  


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It is not planned to impute missing values, with exception of missing AE start dates and 
times. These are imputed according to BI standards (see DM&SM “Handling of missing and 
incomplete AE dates” [001-MCG-156_RD-01]) (3). 
All subject discontinuations will be documented and the reason for discontinuation recorded. 
6.6.2 
AE dates and times 
Refer to TSAP Section 6.6.1 above. 
6.6.3 
Missing plasma concentrations and pharmacokinetic parameters 
Handling of missing PK data will be performed according to the BI standard procedure 
“Noncompartmental Pharmacokinetic / Pharmacodynamic Analyses of Clinical Studies” 
[001-MCS-36-472_RD-01] (4). 
Plasma concentration-time profiles and descriptive statistics of concentration data 
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analyzed), BLQ (below the lower limit of quantification), or NOP (no peak 
detectable) will be displayed as such and not replaced by zero at any time point (this rule also 
applies also to the lag phase, including the pre-dose values). 
Pharmacokinetic parameters and their descriptive statistics 
For the noncompartmental analysis, concentration data identified with NOS, NOR or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ or 
NOP will be set to zero. All other BLQ/NOP values of the profile will be ignored. The lag 
phase is defined as the period between time zero and the first time point with a concentration 
above the quantification limit. During the evaluation of bioanalytical data the software, e.g. 
WinNonlin, will automatically interpolate between the value before and the value after a 
"missing" value. 
6.7 
BASELINE, TIME WINDOWS AND CALCULATED VISITS 
The baseline for all analyses will be the last measurement before trial drug administration. 
CTP: Exact times of measurements outside the permitted time windows will be documented. 
Time windows are permitted as follows: 
• General medical examination: at screening (1 to 28 days prior to the first study day) and 
at the end-of-study evaluation (Day 99); 
• The tolerance for vital signs and ECG will be ± 1 hour; and 
• Study measurements and assessments scheduled to occur on Day 1 prior to drug 
administration have to be performed and completed within 2 hours prior to drug 
administration. 


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For planned individual plasma concentration sampling times refer to the Flow Chart 1.1 of 
the CTP. While these nominal times should be adhered to as closely as possible, the actual 
sampling times will be recorded and used for determination of PK parameters. 
Adherence to time windows will be checked via consistency check listings at the 
BRPM/DBLM. 


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7. 
PLANNED ANALYSIS 
CTP: The trial will be performed in a two-stage design with Pocock boundaries for early 
stopping. The interim analysis will be performed when approximately 50% of the subjects are 
evaluable for the primary endpoint. A single treatment may be stopped at interim analysis if 
both comparisons where the treatment is involved in show an early significance. A stop of the 
whole trial based on the interim analysis results for early significance is possible. 
This interim analysis will be performed by a DMC (data monitoring committee) which will 
provide a recommendation whether to stop the trial for early PK biosimilarity. 
Only the final analysis will be reported in the CTR. 
The format of the listings and tables will follow the standards defined in the BI corporate 
guideline “Reporting of clinical trials and project summaries” [001-MCG-159] (5) with the 
exception of those generated for PK/PD-calculations. 
The individual values of all subjects will be listed, sorted by treatment, subject number and 
visit. The listings will be contained in Appendix 16.2 (SDL) of the CTR. 
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables for non-PK parameters.  
N  
 
number of non-missing observations 
Mean   
arithmetic mean 
SD  
 
standard deviation 
Min  
 
minimum 
Median  
median 
Max   
maximum 
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category, as well as the percentage (%) for each 
treatment. Percentages will be rounded to one decimal place. The category ‘missing’ will be 
displayed only if there are current missing values. Percentages will be based on all subjects in 
the each subject set. 
Units of variables should be given in the titles or column/row descriptors in square brackets 
(e.g. [mg]). 
CTP: The following descriptive statistics will be calculated for plasma concentrations as well 
as for all primary and secondary PK parameters: N (sample size), arithmetic mean, standard 
deviation, minimum, median, maximum, arithmetic coefficient of variation, geometric mean, 
and geometric coefficient of variation. The data format for descriptive statistics of 
concentrations will be identical with the data format of the respective concentrations. The 
descriptive statistics of PK parameters will be calculated using the individual values with the 
number of decimal places as provided by the evaluation program. The individual values as 
well as the descriptive statistics will be reported with three significant digits in the CTR. 


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The format of the listings and tables will follow the standards defined in this TSAP. 
7.1 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Only descriptive statistics are planned for this section of the report, based on the treated set.  
The following variables will be displayed: gender, race, age, height, weight, body mass index, 
smoking status and alcohol status. 
The data will be summarised by treatment and in total.  
7.2 
CONCOMITANT DISEASES AND MEDICATION 
Frequency tables are planned for this section of the report, based on the set. 
Concomitant diseases will be coded using the coding system of the Medical Dictionary for 
Drug Regulatory Activities (MedDRA). Medications will be coded using the World Health 
Organization Drug Dictionary (WHO-DD). The coding version number will be displayed as a 
footnote in the respective output. 
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies should be marked with a "No" in the respective column. 
7.3 
TREATMENT COMPLIANCE 
CTP: Compliance will be assured by administration of all study medication under 
supervision of the investigating physician or a designee at the investigational sites in New 
Zealand. The measured plasma concentrations will provide additional information about 
compliance. 
It is not intended to list the compliance separately. Any deviations from complete intake will 
be addressed in the BRPM/DBLM (cf TSAP Section 6.2) and described in the CTR. 
7.4 
PRIMARY ENDPOINT 
CTP: The objective of the current study is to establish the PK biosimilarity of BI 695502 
compared to bevacizumab (Avastin®) US and EU source […], respectively, following one iv 
administration. A three-fold comparison will be performed (BI 695502 vs bevacizumab 
(Avastin®), US source, BI 695502 vs bevacizumab (Avastin ®), EU source, and bevacizumab 
(Avastin®), US source vs bevacizumab (Avastin ®), EU source). 
Similarity of BI 695502 and bevacizumab (Avastin ®) will be investigated on the primary PK 
parameter (AUC0-∞). 
Statistical model 
CTP: The statistical model used for the analysis of the primary PK parameter (AUC0-∞) will 
be an analysis of variance (ANOVA) model on the logarithmic scale. This model will include 


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effects accounting for the following sources of variation: 'treatment' and 'weight at baseline'. 
All effects will be considered as fixed. The model is described by the following equation: 
 
yij = µ + τi + β·ξj + eij  
where 
 
yij = logarithm of response measured on subject j receiving treatment i; 
 
µ = the overall mean; 
 
τi  = ith treatment effect, i = 1, 2, 3; 
 
ξj = weight of jth subject; 
 
β = regression coefficient; and 
 
eij = the random error associated with the jth subject who received treatment i. 
and eij ~ N(0, σi
2) are independent random variables. 
This analysis will be accomplished by using the repeated measures model (MIXED procedure 
with unstructured covariance structure; for the approximation of the degrees of freedom the 
Kenward and Roger method will be used). The analysis will be based on the PKS and 
performed using the following (dummy) SAS code: 
PROC MIXED DATA=indata; 
 
CLASS treatment; 
 
MODEL logkp = treatment weight / DDFM=KR HTYPE=2; 
 
REPEATED / TYPE=UN(1) GROUP=treatment; 
 
LSMEANS treatment / PDIFF CL ALPHA=0.0607; 
RUN; 
The α-level for the significance testing will be adjusted based on Pocock boundaries due to 
the two stage group sequential design. Hence the confidence intervals considering at each 
analysis (interim and final) are 93.93 % confidence intervals. 
CTP: The primary PK parameter (see Section 7.1.3 of the CTP) will be log transformed 
(natural logarithm) prior to fitting the ANOVA model described in Section 7.1.4 of the CTP. 
The difference between the expected means for log(Test)-log(Reference) will be estimated by 
the difference in the corresponding least-squares means (point estimate), and two-sided 
93.93% confidence intervals based on the t-distribution will be computed. These quantities 
will then be back-transformed to the original scale to give the point estimator and interval 
estimates for the inter-subject ratio of the geometric means for treatments.  
A claim of PK similarity will be made if the 93.93% confidence interval(s) of the ratio of the 
geometric means are contained in the pre-defined acceptance range for all three 
comparisons. 


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As additional sensitivity analysis, the combined data from the two stages will be analysed 
including a term for stage in the ANOVA model. 
7.5 
SECONDARY ENDPOINTS 
7.5.1 
Key secondary endpoints 
This section is not applicable as no key secondary endpoint has been specified in the protocol. 
7.5.2 
Other Secondary endpoints 
CTP: For the final analysis, the PK parameters AUC0-tz and Cmax will be statistically assessed 
using the same statistical model as described for the primary endpoint. For these endpoints 
(AUC0-tz and Cmax) the 90% confidence intervals will be computed.  
For the safety endpoints refer to Section 7.8 for detailed description. 
7.7 
EXTENT OF EXPOSURE 
Descriptive statistics are planned for this section of the report based on the TS. 
7.8 
SAFETY ANALYSIS 
All safety analyses will be performed on the TS. 
If not stated otherwise, the safety results will be sorted by treatment. 


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7.8.1 
Adverse events 
The analyses of AEs will be descriptive in nature and will be based on BI standards as 
presented in the corporate guideline: “Handling and summarisation of adverse event data for 
clinical trial reports and integrated summaries” [001-MCG-156] (7). 
AEs will be coded with the most recent available version number of MedDRA referred to in 
the footnote of tables and listings. 
All analyses of AEs will be based on the number of subjects with AEs (and not on the number 
of AEs). For this purpose, AEs data will be combined in a 2-step procedure into AEs records. 
In a first step, AEs occurrences, i.e. AEs entries on the CRF (case report form), will be 
collapsed into AEs episodes provided that all of the following applies: 
•
the same lowest level term was reported for the occurrences; 
•
the occurrences were time-overlapping or time-adjacent (time-adjacency of 2 
occurrences was given if the second occurrence started on the same day or on the day 
following the end date of the first occurrence); 
•
treatment did not change between the onset of the occurrences or treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence. 
In a second step, AEs episodes will be condensed into AEs records provided that the episodes 
are reported with the same term on the respective MedDRA level and that the episodes are 
assigned to the same treatment. For further details on summarisation of AEs data are available 
in the guideline “Handling and summarization of adverse event data for clinical trial reports 
and integrated summaries” [001-MCG-156] (7). 
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. All adverse events occurring before drug intake will be assigned to ‘screening’. All 
AEs occurring up to end-of-study visit will be assigned to the treatment period and all AEs 
occurring after the end-of-study visit will be assigned to ‘post study’. For more detail see 
TSAP ADS plan (Chapter 2.2.3). 
According to ICH E3 (8), AEs classified as ‘other significant’ will include those non-serious 
and non-significant AEs with  
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or 
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a Report Planning Meeting.  
An overall summary of adverse events will be presented for each part.  
Frequency of subjects with adverse events will be summarised by treatment, primary system 
organ class and preferred term. Separate tables will be provided for subjects with other 
significant adverse events according to ICH E3 (8), for subjects with serious adverse events 


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as well as for subjects with drug related AEs. The system organ classes will be sorted 
according to the standard sort order specified by EMA (European Medicines Agency). 
Preferred terms will be sorted by frequency (within system organ class). 
In addition, frequency of subjects with non-serious adverse events that exceed 5%-threshold 
will be summarised by treatment, primary system organ class and preferred term. 
7.8.2 
Laboratory data 
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (see DM&SM: “Display and Analysis of Laboratory Data” [001-MCG-157]) (9). 
Descriptive statistics will be calculated over time and for the difference from baseline 
including post examination values. Baseline is understood as the last available measurement 
before the start of trial medication ‘Last value on treatment’ is understood as the last 
measurement. 
CTP: Frequency tables of changes with respect to the reference range between baseline and 
last value on treatment will also be presented. 
7.8.3 
Vital signs 
Only descriptive statistics including change from baseline will be performed for vital signs 
(blood pressure and pulse rate). In the listing the difference from baseline will also be 
displayed. Baseline is understood as the last available measurement before start of trial 
medication. 
In addition, descriptive statistics for body weight as well as for body temperature will be 
performed on the TS. 
7.8.4 
ECG 
Clinically relevant abnormal findings for ECG will be listed under “Relevant Medical 
History / Baseline Conditions” (when they occurred during screening) or will be reported as 
adverse events (when they occurred during treatment). 
7.8.5 
Others 
A frequency table of local tolerability will be provided on the TS. 


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8. 
REFERENCES 
1 
001-MCS-50-413_RD-02: Reference Document, "Important Manual Protocol 
Violations Spreadsheet"; IDEA for CON. 
2 
001-MCS-50-413_RD-01: Reference Document, "Handling of Protocol 
Violations", current version; IDEA for CON. 
3 
001-MCG-156_RD-01: Reference Document, "Handling of missing and 
incomplete AE dates", current version; IDEA for CON. 
4 
001-MCS-36-472_RD-01: Reference Document, "Noncompartmental 
Pharmacokinetic / Pharmacodynamic Analyses of Clinical Studies", current 
version; IDEA for CON. 
5 
001-MCG-159: Corp Guideline, “Reporting of clinical trials and project 
summaries”, current version; IDEA for CON. 
6 
001-MCS-36-472: Corp SOP, "Standards and processes for analyses performed 
within Clinical Pharmacokinetics/Pharmacodynamics", current version; IDEA for 
CON. 
7 
001-MCG-156: Corp Guideline, “Handling and summarization of adverse event 
data for clinical trial reports and integrated summaries”, current version; IDEA for 
CON. 
8 
CPMP/ICH/137/95 “Structure and Content of Clinical Study Reports”, ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version. 
9 
001-MCG-157: "Display and Analysis of Laboratory Data", current version, IDEA 
for CON. 
 


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10. 
HISTORY TABLE 
Table 10: 1 
History table 
Version 
Date 
(DD-Mmm-YY) 
Author 
Sections 
changed 
Brief description of change 
Final 
13-Dec-12 
None 
This is the final TSAP without any 
modification