Clinical trial NCT03074162
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2017-04-20; Completion date: 2017-06-29
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main objective of this study is to assess the relative systemic bioavailability of diclofenac in the presence and absence of capsaicin by comparing the systemic bioavailability of diclofenac from a combination product (Diclofenac 2% + Capsaicin 0.075% Topical Gel) with two diclofenac only products, Diclofenac Mono Gel 2% and Voltarol® 12 Hour Emulgel 2.32% Gel, following topical administration.

In order to examine potential racial differences in pharmacokinetics (PK), the study population will be stratified 50:50, Caucasian versus Black people. With respect to the main objective, additionally a supportive analysis will be performed to investigate the influence of race on the intra-individual bioavailability ratios.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Diclofenac Sodium intervention 2: Diclofenac & Capsaicin intervention 3: Diclofenac Sodium Topical Gel
Intervention descriptions: intervention 1: twice daily intervention 2: twice daily intervention 3: twice daily

Protocol documents:
Prot_000.pdf: 
c09839764-02
Clinical Study Protocol Revised 
According to Amendment No. 1
Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
TITLE PAGE
Clinical Study Protocol  
A SINGLE CENTER, MULTIPLE-DOSE, OPEN-LABEL, 
RANDOMIZED, THREE-PERIOD CROSSOVER STUDY TO 
DETERMINE THE RELATIVE BIOAVAILABILITY OF 
DICLOFENAC IN THE TOPICAL GEL COMBINATION 
PRODUCT (DICLOFENAC 2% + CAPSAICIN 0.075%) 
COMPARED TO DICLOFENAC MONO GEL 2% AND
VOLTAROL® 12 HOUR EMULGEL 2.32% GEL IN AT LEAST 
42 HEALTHY MALES AND FEMALES  
 STUDY NUMBER:
229554
SPONSOR STUDY NUMBER:
1358.2
DOCUMENT NUMBER:
c09839764-02
TEST PRODUCTS:
Diclofenac Mono Gel 2% (Test 1)
Combination of Diclofenac 2% + Capsaicin 0.075% 
Topical Gel (Test 2)
REFERENCE PRODUCT:
Voltarol® Emulgel 2.32%
DEVELOPMENT PHASE:
Phase I Relative Bioavailability Study
SPONSOR:
Boehringer Ingelheim Pharma GmbH & Co. KG
STUDY CENTER:
REGION OF SUBMISSION:
Europe
ORIGINAL PROTOCOL:
Final 1.0, 17 October 2016
REVISED
PROTOCOL ACCORDING 
TO AMENDMENT NO. 1:
Final 1.0, 13 February 2017
Confidentiality Statement
This confidential document is the property of Boehringer Ingelheim Pharma GmbH & Co. KG.  No 
unpublished information contained herein may be disclosed without prior written approval from
Boehringer Ingelheim Pharma GmbH & Co. KG.  Access to this document must be restricted to 
relevant parties.
Document prepared in Microsoft Word® 2010.
Page 1 of 83


c09839764-02
Clinical Study Protocol Revised 
According to Amendment No. 1
Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
SYNOPSIS
Title of the Study
A SINGLE CENTER, MULTIPLE-DOSE, OPEN-LABEL, RANDOMIZED, THREE-PERIOD CROSSOVER 
STUDY TO DETERMINE THE RELATIVE BIOAVAILABILITY OF DICLOFENAC IN THE TOPICAL 
GEL COMBINATION PRODUCT (DICLOFENAC 2% + CAPSAICIN 0.075%) COMPARED TO 
DICLOFENAC MONO GEL 2% AND VOLTAROL® 12 HOUR EMULGEL 2.32% GEL IN AT LEAST 
42 HEALTHY MALES AND FEMALES
Study Objectives 
The main objective of this study is to assess the relative systemic bioavailability of diclofenac in the presence 
and absence of capsaicin by comparing the systemic bioavailability of diclofenac from a combination product 
(Diclofenac 2% + Capsaicin 0.075% Topical Gel) with two diclofenac only products, Diclofenac Mono Gel 2% 
and Voltarol® 12 Hour Emulgel 2.32% Gel, following topical administration.  
In order to examine potential racial differences in pharmacokinetics (PK), the study population will be stratified 
50:50, Caucasian versus Black people. With respect to the main objective, additionally a supportive analysis 
will be performed to investigate the influence of race on the intra-individual bioavailability ratios.
Study Design
The study will comprise:
x
Screening period of maximum 21 days; 
x
Three-treatment periods (each of which will include a multiple dose period of 7 days [twice daily and 
only in the morning on Day 7] and two PK profile periods of 12 hours [Day 1] and 24 hours [Day 7])
separated by a wash-out period of at least 7 calendar days between the last administration of the 
investigational medicinal product (IMP) in a treatment period and the first administration of IMP in the 
next treatment period.  Clinic stay/visits will be as follows:
x
Subjects will be admitted to the study center on Day -1 and leave the center after the morning dose 
on Day 2 at least 24 hours after the initial dosing on Day 1 
x
Subjects will visit the study center on Days 3 and 4 for the morning dose
x
On Day 5, they will visit the center for PK blood sampling prior to morning and evening doses and 
will be re-admitted to the study center on the evening of Day 5 
x
Subjects will leave the center at least 24 hours after the morning dose on Day 7 
x
A follow-up visit will occur within 72 hours after completion of the last treatment period of the study. 
Before the first administration of IMPs subjects will be randomized to one of 6 treatment sequences stratified by 
race (Black, Caucasian), i.e., 4 Black and 4 Caucasian subjects will be assigned to each treatment sequence. 
The duration of this study is expected to be approximately 38 days per subject (excluding the screening period). 
Clinic Stay
Subjects will be admitted to the study center on Day -1 and on the evening of Day 5 and are allowed to leave at 
least 24 hours after first dosing on Day 1 and at least 24 hours after the morning dose on Day 7. 
Pharmacokinetic Sampling Times
For the determination of diclofenac and diclofenac + capsaicin PK, blood samples will be collected on Day 1 at 
the following time points: 0 hours (prior to morning dose) and at 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose 
(prior to evening dose) (total: 10 samples per treatment period) and on Day 7 pre-dose at 0 hours and at 0.5, 1, 2, 
3, 4, 6, 8, 10, 12, 14, 16, 18, 20 and 24 hours post-dose (15 samples per treatment period).  Additional blood 
samples to establish attainment of steady state will be collected on Days 5 and 6 (prior to morning dose and 
evening dose).
Page 2 of 83


c09839764-02
Clinical Study Protocol Revised 
According to Amendment No. 1
Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
Blood Volume
The total blood volume to be collected from each subject during the study should not exceed 308 mL (repeat 
laboratory investigations not included).
Study Population
The study population for this study will be stratified 50:50 (Caucasians versus Black People) and subjects who 
meet the inclusion criteria will be considered eligible to participate in the study.
Inclusion Criteria:
1.
Healthy males and females, 18 to 50 years (inclusive) at time of screening.
2.
Body mass index between 18.5 and 29.9 kg/m2 (inclusive).
3.
Body mass not less than 50 kg for males and females.
4.
Findings for medical history, vital signs, physical examination, standard 12-lead electrocardiogram (ECG) 
and laboratory investigations must be normal or within laboratory reference ranges for the relevant 
laboratory tests, unless the Principal Investigator (PI) considers the deviation to be not clinically significant
for the purpose of the study.
5.
Non-smokers. 
6.
Females, if:
x
Not of childbearing potential, e.g., has been surgically sterilized, undergone a hysterectomy, 
DPHQRUUKHDIRU months and considered post-menopausal,
Note: In post-menopausal women, the value of the serum pregnancy test may be slightly increased.  
This test will be repeated to confirm the results.  If there is no increase indicative of pregnancy, the 
female will be included in the study.
x
Of childbearing potential, the following conditions are to be met:

Negative pregnancy test

If this test is positive, the subject will be excluded from the study.  In the rare circumstance 
that a pregnancy is discovered after the subject received the IMP; every attempt must be made 
to follow her to term

Not lactating

Abstaining from sexual activity (if this is the usual lifestyle of the subject) or must agree to 
use an accepted method of contraception, and agree to continue with the same method 
throughout the study

In this study the concomitant use of hormonal contraceptives is allowed

Examples of reliable methods of contraception include oral (documented that the dose has 
been stable for at least one month before the first intake of the IMP), injectable or implantable 
contraceptives, non-hormonal/hormonal intrauterine device, and barrier methods combined 
with an additional contraceptive method

Other methods, if considered by the PI as reliable, will be accepted
7.
Written informed consent given for participation in the study.
Investigational Medicinal Products
Test Product 1(A) 
Generic name
: 
Diclofenac sodium
Trade name
: 
Diclofenac mono gel 2%
Dosage form
: 
Immediate release topical gel
Dose
: 
Multiple doses (2 g, bid) of Diclofenac 2%
Route of administration
: 
Topical
Manufacturer
: 
Boehringer Ingelheim Pharma GmbH & Co. KG
Country of origin
: 
Germany
Test Product 2 (B)
Generic name
: 
Diclofenac + Capsaicin
Page 3 of 83


c09839764-02
Clinical Study Protocol Revised 
According to Amendment No. 1
Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
Product name
: 
Combination of Diclofenac 2% + Capsaicin 0.075% formulation
Dosage form
: 
Immediate release topical gel
Dose
: 
Multiple doses (2 g, bid) of Diclofenac 2% + Capsaicin 0.075%
Route of administration
: 
Topical
Manufacturer
Boehringer Ingelheim Pharma GmbH & Co. KG
Country of origin
: 
Germany
Reference Product (C) 
Generic name
: 
Diclofenac sodium topical gel
Trade name
: 
Voltarol® 12 Hour Emulgel 2.32% Gel
Dosage form
: 
Immediate release topical gel
Dose
: 
Multiple doses (2 g, bid) of Voltarol (Diclofenac sodium 2.32%) 
Route of administration
: 
Topical
Manufacturer
: 
Novartis Consumer Health UK Ltd.
Country of origin
: 
United Kingdom
Analytes
Diclofenac and capsaicin
Sample Size
Up to 48 eligible subjects (stratified 50:50 Caucasian versus Black people) will be enrolled into the study, to 
complete the study with at least 42 evaluable subjects. 
Pharmacokinetic Endpoints
Primary and secondary endpoints are only calculated for diclofenac.
Primary Pharmacokinetic Endpoints: 
 
x
Area under the plasma concentration-time curve (AUC) over one GRVLQJLQWHUYDOĲ = 12 hours) (AUC0-Ĳ,ss)
(Day 7) 
x
Maximum plasma drug concentration during a dosage interval (Cmax,ss) obtained directly from the 
concentration-time data (Day 7) 
Secondary Pharmacokinetic Endpoints: 
x
Time to maximum observed plasma concentration at steady state (tmax,ss) (Day 7)
x
Average plasma concentration (Cav,ss) calculated as AUC0-Ĳ,ss/Ĳ, Ĳ is one dosing interval (12 hours)
x
Percentage peak-trough fluctuation (%PTF), calculated as [100*(Cmax,ss – Cpre,ss)/Cav,ss] 
 
 
 
 
 
 
 
 
Page 4 of 83


c09839764-02
Clinical Study Protocol Revised 
According to Amendment No. 1
Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
Safety Variables (other endpoints)
Safety variables will include vital signs, 12-lead ECG, hematology, clinical chemistry, pregnancy test results,
overall assessment of tolerability
  Adverse events (AEs) and concomitant medication 
will also be reported.
Statistical Analysis
Pharmacokinetic population:  
The PK population will consist of all subjects in the safety population for whom at least one of AUC0-Ĳ,ss or
Cmax,ss can be calculated for one treatment and who have no major protocol deviations thought to impact on the 
analysis of the PK data.
Relative bioavailability will be estimated for diclofenac by the ratios of the geometric means for the steady-state 
AUC0-Ĳ and Cmax,ss.  Additionally, their two-sided 90% confidence intervals (CIs) will be provided.  The 
statistical model will be an analysis of variance (ANOVA) on the logarithmic scale including fixed effects for 
sequence, subject nested within sequence, period and treatment.  For each endpoint, the difference between the 
expected means for log(Test)-log(Reference) will be estimated by the difference in the corresponding adjusted 
means (Least Squares Means).  CIs will be calculated based on the residual error from ANOVA.  The 
differences between the test and reference product and the CIs will be back-transformed to the original scale, 
resulting in point estimates of the Test/Reference gMean ratios and 90% CIs.
The following comparisons will apply:
x
Test Product 2 vs Reference
x
Test Product 2 vs Test Product 1
Only the data for the comparison under investigation will be included in the statistical analysis i.e., when 
comparing Test Product 2 and Reference, the data for the Test Product 1 will be removed from the dataset.   
Only subjects with observations for both treatments will be included in each comparison.  
  
  
The effect of race on relative bioavailability will be analyzed separately as supportive analysis,, supportive 
because race is not expected to influence intra-individual bioavailability ratios. The statistical model of the 
supportive analysis will be an ANOVA on the logarithmic scale including fixed effects for sequence, period, 
race, treatment, treatment and race interaction and subject nested within sequence and race interaction.  The 
effect of race will be checked and for each endpoint, least squares means by treatment and race will be 
tabulated.  Point estimates of the T/R gMean ratios and 90% CIs will be presented by race in the same way as 
for the main analysis.
Capsaicin concentrations will be analyzed descriptively.
Safety population:
All subjects who received at least one dose of IMP will be included in the safety analysis of the study.
Safety data will be listed as applicable.
Hematology and clinical chemistry values will be listed and summarized.  Abnormal hematology and clinical 
chemistry values will be flagged in the listings.
Electrocardiograms will be classified as “Normal”, “Abnormal not clinically significant”, “Abnormal clinically 
significant”, and listed and summarized.  Vital signs will be flagged for measurements that are outside the 
reference range and listed, including changes from baseline.  Summary statistics will be provided.
Prior and concomitant medication will be coded and listed separately.
and data from inspection of IMP application site will be listed. Overall assessment of 
Page 5 of 83


c09839764-02
Clinical Study Protocol Revised 
According to Amendment No. 1
Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
tolerability will be listed.
Additional listings will be presented for physical examination, urinalysis, pregnancy testing, serology and drugs 
of abuse and tobacco use.
Page 6 of 83




c09839764-02
Clinical Study Protocol Revised 
According to Amendment No. 1
Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
STATEMENT AND SIGNATURE: PRINCIPAL INVESTIGATOR
A SINGLE CENTER, MULTIPLE-DOSE, OPEN-LABEL, 
RANDOMIZED, THREE-PERIOD CROSSOVER STUDY TO 
DETERMINE THE RELATIVE BIOAVAILABILITY OF 
DICLOFENAC IN THE TOPICAL GEL COMBINATION 
PRODUCT (DICLOFENAC 2% + CAPSAICIN 0.075%) 
COMPARED TO DICLOFENAC MONO GEL 2% AND 
VOLTAROL® 12 HOUR EMULGEL 2.32% GEL IN AT LEAST 
42 HEALTHY MALES AND FEMALES  
 STUDY NUMBER:
229554 
SPONSOR STUDY NUMBER:
1358.2
I, the undersigned, verify that, to the best of my abilities and knowledge: 
1.
I have reviewed this clinical study protocol and approve its contents. 
2.
I am familiar with the properties of the investigational medicinal product as described 
in the References.  I am qualified by scientific training and experience to conduct the 
clinical investigational study identified above.  My medical education and experience 
is stated in the curriculum vitae provided. 
3.
The study center has adequate study staff and appropriate facilities (including
laboratories) that will be available for the duration of the study to be conducted in 
conformance with this clinical study protocol and Good Clinical Practices ([GCP] 
including the South African Clinical Trials guidelines), as assured by an in-house 
quality assurance program.
4.
I agree to obtain permission from the Sponsor in writing should any changes be 
required to the clinical study protocol.  Should the safety of the subjects necessitate 
immediate action, which represents a deviation from the clinical study protocol, the 
Sponsor will be informed as soon as possible. 
5.
I shall obtain in writing the necessary approval from the independent ethics committee
(IEC) and the Medicines Control Council (MCC).  I shall ensure communication of 
any modification, amendment or deviation of the clinical study protocol, and also 
Page 8 of 83




c09839764-02
Clinical Study Protocol Revised 
According to Amendment No. 1
Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
1.
TABLE OF CONTENTS
TITLE PAGE .................................................................................................................................. 1 
SYNOPSIS ...................................................................................................................................... 2 
SIGNATURE: SPONSOR SIGNATORY ...................................................................................... 7 
STATEMENT AND SIGNATURE: PRINCIPAL INVESTIGATOR .......................................... 8 
1. 
TABLE OF CONTENTS ................................................................................................ 10 
1.1. 
List of Tables ...................................................................................................... 12 
2. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................. 13 
3. 
ETHICS ........................................................................................................................... 17 
3.1. 
Mandatory Approvals and Protocol Amendments ............................................. 17 
3.2. 
Ethical Conduct of the Study .............................................................................. 17 
3.3. 
Subject Information and Informed Consent ....................................................... 18 
3.3.1. 
Confidentiality ................................................................................................ 18 
3.3.2. 
Remuneration of Subjects ............................................................................... 18 
3.3.3. 
Indemnity ........................................................................................................ 19 
4. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ...................... 20 
5. 
INTRODUCTION ........................................................................................................... 23 
5.1. 
Background Information .................................................................................... 23 
5.2. 
Clinical Pharmacokinetics .................................................................................. 24 
5.3. 
Adverse Events, Contraindications and Warnings ............................................. 25 
5.4. 
Study Rationale .................................................................................................. 26 
5.5. 
Risks and Benefits .............................................................................................. 26 
6. 
STUDY OBJECTIVES ................................................................................................... 27 
7. 
INVESTIGATIONAL PLAN .......................................................................................... 28 
7.1. 
Overall Study Design and Plan: Description ...................................................... 28 
7.1.1. 
Study Design ................................................................................................... 28 
7.2. 
Discussion of Study Design................................................................................ 29 
7.2.1. 
Treatment Periods and Schedule of Study Assessments ................................. 29 
7.2.2. 
Safety and Data Monitoring Committees ....................................................... 34 
7.2.3. 
Interim Analyses ............................................................................................. 34 
7.2.4. 
Expected Duration of Study ............................................................................34 
7.2.5. 
Screening ........................................................................................................ 34 
7.2.6. 
Treatment Periods ........................................................................................... 34 
7.2.7. 
Follow-up Evaluations .................................................................................... 35 
7.2.8. 
Sampling, Interim Handling and Storage........................................................ 36 
7.2.8.1. Safety Blood and Urine Samples ..................................................... 36 
7.2.8.2. Pharmacokinetic Blood Samples ..................................................... 37 
7.2.9. 
Blood Volume ................................................................................................. 37 
7.2.10. 
General and Dietary Restrictions .................................................................... 38 
7.2.10.1. Posture ............................................................................................. 38 
7.2.10.2. Diet .................................................................................................. 38 
Page 10 of 83


c09839764-02
Clinical Study Protocol Revised 
According to Amendment No. 1
Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
7.2.10.3. Physical Activity ............................................................................. 39 
7.2.10.4. Special Precautions .......................................................................... 39 
7.3. 
Selection of Study Population ............................................................................ 39 
7.3.1. 
Inclusion Criteria ............................................................................................ 39 
7.3.2. 
Exclusion Criteria ........................................................................................... 40 
7.3.3. 
Withdrawal Criteria ........................................................................................ 42 
7.3.4. 
Replacement of Subjects ................................................................................. 43 
7.3.5. 
Premature Termination of the Study ............................................................... 43 
8. 
TREATMENTS ............................................................................................................... 45 
8.1. 
Products to Be Administered .............................................................................. 45 
8.2. 
Identity of Investigational Medicinal Products .................................................. 45 
8.2.1. 
Identification of Investigational Medicinal Products ...................................... 46 
8.2.2. 
Supply and Storage ......................................................................................... 46 
8.2.3. 
Investigational Medicinal Product Accountability ......................................... 46 
8.2.4. 
Retention Samples .......................................................................................... 46 
8.2.5. 
Labelling and Packaging ................................................................................. 46 
8.3. 
Method of Assigning Subjects to Treatment Groups ......................................... 47 
8.4. 
Selection of Doses in the Study .......................................................................... 47 
8.5. 
Selection and Timing of Dose for Each Subject ................................................ 47 
8.6. 
Blinding .............................................................................................................. 47 
8.7. 
Prior and Concomitant Medication .................................................................... 48 
8.8. 
Treatment Compliance ....................................................................................... 48 
9. 
PHARMACOKINETIC ENDPOINTS AND SAFETY VARIABLES .......................... 49 
9.1. 
Pharmacokinetic and Safety Measurements ....................................................... 49 
 
 
9.1.2. 
Overall Assessment of Tolerability ................................................................ 49 
9.2. 
Appropriateness of Measurements ..................................................................... 49 
9.3. 
Drug Concentration (Pharmacokinetic) Measurements ..................................... 50 
9.3.1. 
Pharmacokinetic Endpoints ............................................................................ 50 
9.3.2. 
Pharmacokinetic Sample Collection, Sample Handing and Storage .............. 50 
9.3.3. 
Pharmacokinetic Drug Assays ........................................................................ 50 
10. 
DATA QUALITY ASSURANCE AND DATA MANAGEMENT ............................... 51 
10.1. 
Quality Control and Source Data Verification ................................................... 51 
10.2. 
Audit/Inspections ................................................................................................ 51 
10.3. 
Study Monitoring................................................................................................ 51 
10.4. 
Data Collection ................................................................................................... 51 
10.5. 
Data Management ............................................................................................... 52 
11. 
STATISTICAL METHODS ............................................................................................ 54 
11.1. 
Statistical Methodology ...................................................................................... 54 
11.1.1. 
Pharmacokinetic Population ........................................................................... 54 
11.1.2. 
Safety Population ............................................................................................ 54 
11.2. 
Determination of Sample Size ............................................................................ 54 
11.3. 
Protocol Deviations and Changes to Planned Analyses ..................................... 55 
Page 11 of 83


c09839764-02
Clinical Study Protocol Revised 
According to Amendment No. 1
Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
11.4. 
Pharmacokinetic Endpoints ................................................................................ 55 
11.4.1. 
Primary Pharmacokinetic Endpoints .............................................................. 56 
11.4.2. 
Secondary Pharmacokinetic Endpoints........................................................... 56 
 
 
11.5. 
Safety Variables.................................................................................................. 57 
11.6. 
Presentation of PK Data, Descriptive Statistics and PK Assessment ................. 57 
11.7. 
Analysis of Relative Bioavailability ................................................................... 58 
11.8. 
Presentation of Baseline Characteristics and Safety Data .................................. 60 
12.
ADVERSE EVENTS ...................................................................................................... 62
12.1. 
Definitions .......................................................................................................... 62 
12.1.1. 
Adverse Events ............................................................................................... 62 
12.1.2. 
Serious Adverse Events .................................................................................. 62 
12.1.3. 
Adverse Events of special interest .................................................................. 63 
12.2. 
Classification of Adverse Events ........................................................................ 64 
12.3. 
Causal Relationship of Adverse Events ............................................................. 64 
12.4. 
Reporting Procedures of Adverse Events/Serious Adverse Events ................... 65 
12.5. 
Allocation of Adverse Events to Treatment Groups .......................................... 67 
12.6. 
Expedited Reporting of Adverse Events ............................................................ 67 
13.
LEGAL AND ADMINISTRATIVE ASPECTS ............................................................. 68
13.1. 
Documentation ................................................................................................... 68 
13.2. 
Publication of Results ......................................................................................... 68 
13.3. 
Sponsor’s Obligation .......................................................................................... 68 
13.4. 
Clinical Study Report ......................................................................................... 68 
14.
REFERENCES ................................................................................................................ 69
15.
APPENDICES ................................................................................................................. 71
15.1. 
Product Information – Reference Product .......................................................... 71 
 
 
1.1.
List of Tables
Table 7-1 
Schedule of Study Assessments ........................................................................... 30 
Table 7-2 
Total Blood Volume to be Collected During the Study ....................................... 38 
Table 11-1 
Expected Two-sided 90% Confidence Intervals for Different Ratios T/R 
and gCVs for a Sample Size of 42, Coverage Probability = 95% ........................ 55 
 
 
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c09839764-02
Clinical Study Protocol Revised 
According to Amendment No. 1
Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.:
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
2.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
%PTF
Percentage peak-trough fluctuation 
E-HCG
Beta human chorionic gonadotropin
Adverse event reporting 
Adverse events will be documented from the time that the 
informed consent document (ICD) has been signed 
AE
Adverse event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase 
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
AUC(0-Ĳ,ss)
Area under the plasma concentration-time curve over one dosing 
LQWHUYDOĲ= 12 hours) at steady state
BASD
 Bioanalytical Services Division
BI
Boehringer Ingelheim Pharma GmbH & Co. KG
BLQ
Below the limit of quantification
BMI
Body mass index 
Cav,ss
Average plasma concentration at steady state
CI
Confidence interval
Citrus fruits
Any of numerous fruits of the genus Citrus e.g., orange, lemon, 
lime, grapefruit and tangerine
Clinic day
Time ranging from the start of the profile period until discharge 
from the clinic
Cmax,ss
Maximum steady-state plasma drug concentration during a 
dosage interval 
Completer
Enrolled subject who completes the entire study 
Concomitant medication
Any medication given in addition to the IMP 
CRF
Case report form
CS
Clinically significant (abnormalities)
CSR
Clinical Study Report
CV
Coefficient of variation
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Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
Cpre
Observed plasma concentration at the end of a dosing interval, 
immediately preceding the next dose
DCF
Data clarification form
DEDP
Drug exposure during pregnancy 
DILI
Drug-induced liver injury
DMP
Data management plan
DRM
Data review meeting
DVS
Data validation specification
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
EMA
European Medicines Agency (established 1995)
Enrolled subject 
Person allocated a subject number which confirms formal entry 
into the study 
EU
European Union/European Community 
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GGT
Gamma glutamyl transferase (transpeptidase)
GLP
Good Laboratory Practice
gMean
Geometric mean
GMP
Good Manufacturing Practice
HIV 
Human immunodeficiency virus 
IB
Investigator’s Brochure
ICD
Informed consent document 
ICH
International Council for Harmonisation
IEC
Independent ethics committee
IMP
Investigational medicinal product
ISF
Investigator site file
K2-EDTA
Potassium-ethylenediaminetetraacetic
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LLOQ
Lower limit of quantification
MCC
Medicines Control Council (of South Africa) 
Medication number
Number of tube with medication used to track the tubes
n
Number of subjects 
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Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
NCS
Not clinically significant (abnormalities)
NOA
Not analyzed
Non-smoker 
Subject who has not smoked previously and/or has not used 
nicotine or nicotine-containing products for at least 3 months; 
subjects who have discontinued smoking or the use of 
nicotine/nicotine-containing products (including snuff and 
similar products) at least 3 months before the first administration 
of the IMP 
NOR
No valid result 
NSAID
Nonsteroidal anti-inflammatory drug
NSAID
Non-steroidal anti-inflammatory drug
PI
Principal Investigator
PK
Pharmacokinetic(s)
Profile period
Pharmacokinetic blood sampling period, including clinic stay 
REP
Residual effect period
Replacement
Eligible subject who enters the study to replace a subject who 
withdrew or was withdrawn from the study 
SAE
Serious adverse event
SAP
Statistical Analysis Plan
Screening period
Time window during which potential subjects are evaluated to 
establish eligibility for enrollment into the study
SD
Standard deviation
SOC
System organ class
SOP
Standard operating procedure 
SPC
Summary of Product Characteristics
Standby 
A subject (screened within the required time period before the 
first administration of the IMP, considered eligible but not 
enrolled as the required number of subjects for enrollment has 
been met) available as a replacement
Study start
Study start is defined as administering or giving directions for 
the administration of the IMP to a subject for the purposes of 
this study
tmax,ss
Time to maximum observed plasma concentration at steady state
Treatment period
Time between the first and last study-related procedures of a 
period of IMP administration
TRPV1
Transient receptor potential vanilloid 1 
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Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
ULN
Upper limit of normal
Wash-out period 
Period between consecutive administrations of IMP 
Withdrawal
Enrolled subject who is withdrawn by the Investigator before the 
clinical phase of the study has been completed
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Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
3.
ETHICS
3.1.
Mandatory Approvals and Protocol Amendments 
Written approval for the final version of the clinical study protocol and any amendments (if 
applicable), as well as other applicable documents will be obtained from an IEC and the 
MCC of South Africa before performance of any study-related procedures.
Independent Ethics Committee
Ethics Committee of the Faculty of Health Sciences
Research Division
Internal Post Box G40 
Campus of the University of the Free State
9301 Bloemfontein 
South Africa 
Tel:
+27 51 405 2812 
Fax:
+27 51 444 4359 
This protocol is to be followed exactly.  Amendments must be written to alter the protocol.  
However, in the event of any medical emergency, the PI is free to institute any medical 
procedure he/she deems appropriate.  Such events and procedures must be reported promptly 
to the Sponsor (Boehringer Ingelheim Pharma GmbH & Co. KG). 
Amendments will be made available to study protocol recipients. 
3.2.
Ethical Conduct of the Study
The study will be conducted in compliance with this clinical study protocol and ethical 
principles that have their origins in the Declaration of Helsinki, including the following 
guidelines: 
x
Department of Health, South Africa (Guidelines for Good Practice, 2006) 
x
International Council for Harmonisation (ICH) Guideline for GCP (2002) which meets 
the ethical requirements of the European Union (EU) Clinical Trials Directive 
2001/20/EC, 04 April 2001 and Directive 2005/28/EC, 08 April 2005 
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Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
3.3.
Subject Information and Informed Consent
Before commencement of the screening procedures, the potential subjects will be informed 
verbally by the Investigator and in writing by way of the informed consent document (ICD) 
concerning the nature, purpose and risks involved in the screening procedures, as well as the
procedures, restrictions, obligations, remuneration, insurance coverage and possible adverse 
drug reactions relevant to the study. 
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the potential subjects in non-technical terms.  Potential subjects will be required 
to read, sign and date the ICD before enrollment.  They will be assured that they may 
withdraw from the study at any time without jeopardizing their medical care.  Each potential 
subject will be given a signed copy of the ICD. 
The original, as well as any revision of the ICD provided to the subjects, will be submitted 
for ethics approval. 
Representative written information for the subjects and sample consent forms will be kept in 
the investigator site file (ISF).
3.3.1.
Confidentiality
Study data will be stored in accordance with local and global data protection laws.  
Information on confidentiality is also contained in the ICD. 
Potential subjects will be informed that representatives of the Sponsor, IEC, regulatory 
authorities or auditors may inspect their medical records to verify the information collected, 
and that all personal information made available for inspection will be handled in strictest 
confidence and in accordance with local data protection laws.
The Investigator will maintain a subject identification list (subject numbers with the 
corresponding subject names) to enable records to be identified.  All communications and 
documents relevant to subjects in the study will identify each person only by the subject’s 
study number. 
3.3.2.
Remuneration of Subjects
Compensation will be reasonable and related to the nature and degree of inconvenience and 
discomfort as a result of participation in the study.  Information on how subjects will be 
compensated is contained in the ICD. 
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Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
3.3.3.
Indemnity
Insurance coverage has been arranged to indemnify the subjects in the event of death or any 
deterioration in health or well-being caused by participation in the study. 
The certificate of insurance will be kept in the ISF.
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Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
4.
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
Principal Investigator and Study Staff
Information on the Investigators and other persons whose participation will materially affect 
the conduct of the study is contained in the ISF. 
Study Center
h
Physical address:
Postal address:
Tel:
 (Reception) 
Fax:
Routine Safety and Analytical Laboratory 
Physical address:
Postal address:
Tel:
Fax:
Statistical Analysis 
Physical address:
Tel:
Email: 
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Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
Pharmacokinetics
Physical address:
Postal address:
Tel:
Email:
Sponsor
Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173 
55216 Ingelheim
Germany
Tel:
Fax:
Sponsor Contact Person 
Senior Medical Advisor 
Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173 
55216 Ingelheim
Germany
Tel:
Fax:
Email:
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Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
Sponsor Statistical Analysis Contact Person 
Study statistician
Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173 
55216 Ingelheim
Germany
Tel:
Email:
Monitor 
Information on the monitor to the study is contained in the ISF. 
h  The 
 will
be referred to as 
 in this document, as well as in the ICDs for this 
study.
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Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
5.
INTRODUCTION
5.1.
Background Information 
Diclofenac
Diclofenac is a non-steroidal drug with anti-inflammatory and analgesic activity.  It inhibits 
the enzyme cyclooxygenase, and so directly inhibits the biosynthesis of prostaglandins and 
thromboxanes from arachidonic acid.  The topical usage of diclofenac in acute pain 
conditions is considered well established and is associated with an improved safety profile 
due the low systemic plasma concentrations [2, 3]. 
Voltarol 
Voltarol® 12 Hour Emulgel 2.32% (diclofenac) Gel is indicated for the local symptomatic
relief of pain and inflammation in:
x
Trauma of the tendons, ligaments, muscles and joints, e.g., due to sprains, strains and 
bruises 
x
Localized forms of soft tissue rheumatism
The marketed reference product
Voltarol® 12 Hour Emulgel 2.32% Gel is an 
anti-inflammatory and analgesic preparation designed for topical application.  In 
inflammation and pain of traumatic or rheumatic origin, Voltarol® 12 Hour Emulgel 2.32% 
Gel relieves pain, decreases swelling and shortens the time to return to normal function.  In 
one ankle sprain study (VOPO-P-307), Voltarol® 12 Hour Emulgel 2.32% Gel significantly 
decreased pain on movement scores versus placebo treated subjects within 3 days of starting 
treatment, including a subgroup of patients with severe pain. In addition treatment with 
Voltarol® 12 Hour Emulgel 2.32% Gel also significantly improved ankle joint function 
within 3 days of beginning treatment [1]. 
Capsaicin 
Capsaicin is a highly selective and potent exogenous agonist for the transient receptor 
potential vanilloid 1 (TRPV1) receptor.  When activated TRPV1 opens transiently and 
initiates a depolarization mediated by influx of sodium and calcium ions. In the nociceptive 
(mostly C- DQGVRPH$į-fibers) nerve endings which selectively express TRPV1, capsaicin
mediated depolarization results in action potentials, which are transmitted to the spinal cord 
and brain and are usually reported as warming, burning, stinging or itching sensations.  
Capsaicin causes an initial excitation of the neurons and a short period of hypersensitivity.  
This is followed by a refractory period with reduced sensitivity and, after repeated 
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Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
applications, persistent desensitization and decreased sensitivity to pain.  There is also 
evidence that capsaicin treatment may interfere with substance P synthesis [4]. 
5.2.
Clinical Pharmacokinetics
Capsaicin
In the current Investigator’s Brochure (IB), studies examining higher strengths of capsaicin 
have found that, for a small proportion of patients, low, transient levels of capsaicin can be 
detected in the systemic circulation [5]. 
Voltarol 
The information provided below is based on the approved product information as per the 
Summary of Product Characteristic (SPC) of Voltarol® 12 Hour Emulgel 2.32% Gel [1].
Absorption: 
The quantity of diclofenac absorbed through the skin is proportional to the size of the treated 
area, and depends on both the total dose applied and the degree of skin hydration.  After 
topical application to approximately 400 cm2 of skin, the extent of systemic exposure as 
determined by plasma concentration of Voltarol® 12 Hour Emulgel 2.32% Gel 
(2 applications/day) was equivalent to diclofenac 1.16% gel (4 applications/day).  The 
relative bioavailability of diclofenac (area under the plasma concentration-time curve [AUC] 
ratio) for Voltarol® 12 Hour Emulgel 2.32% Gel versus tablet was 4.5% on Day 7 (for 
equivalent diclofenac sodium dose).  Absorption was not modified by a moisture and vapor 
permeable bandage.
Distribution:
Diclofenac concentrations have been measured from plasma, synovial tissue and synovial 
fluid after application of topical diclofenac to hand and knee joints.  Maximum plasma 
concentrations were approximately 100 times lower than after oral administration of the same 
quantity of diclofenac, 99.7% of diclofenac is bound to serum proteins, mainly albumin 
(99.4%).  Diclofenac penetrates inflamed areas, preferentially distributing to and persisting in 
deep inflamed tissues such as joints, where it is found in concentrations up to 20 times higher 
than in plasma. 
Biotransformation: 
Biotransformation of diclofenac involves partly glucuronidation of the intact molecule, but 
mainly single and multiple hydroxylation resulting in several phenolic metabolites, most of 
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Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
which are converted to glucuronide conjugates.  Two of the phenolic metabolites are 
biologically active, however, to a much smaller extent than diclofenac.
Elimination:
The total systemic clearance of diclofenac from plasma is 263 ± 56 mL/min.  The terminal 
plasma half-life is 1 to 2 hours. Four of the metabolites, including the 2 active ones, also 
have short plasma half-lives of 1 to 3 hours. 
One metabolite, 3'-hydroxy-
4'-methoxy-diclofenac, has a longer half-life, but is virtually inactive.  Diclofenac and its 
metabolites are excreted mainly in the urine.
Characteristics in Patients: 
No accumulation of diclofenac and its metabolites is to be expected in patients suffering from 
renal impairment.  In patients with chronic hepatitis or non-decompensated cirrhosis, the 
kinetics and metabolism of diclofenac are the same as in patients without liver disease.
5.3.
Adverse Events, Contraindications and Warnings 
As with any medication, the list of adverse events (AEs) will never be exhaustive, and 
unexpected or very rare AEs not listed in the Product Information could potentially occur. 
Diclofenac
x
Should be applied only to intact, non-diseased skin and not to skin wounds or open 
injuries.
x
It should not be used with occlusion.  
x
It should not be allowed to come into contact with the eyes or mucous membranes, and 
should never be taken by mouth. 
Capsaicin 
x
Should not be applied near the eyes or to mucous membranes. 
x
The application site should not be scratched to avoid damage to the skin. 
x
Additional heat (e.g., sunlight, infrared treatment, heating pads or warm water) should not 
be applied while using the cream. The heat effect can be intensified through physical 
activity (sweating). If the heat effect is too intense, use should be discontinued, and
cream residue should be removed with cold water or another skin cream. 
x
Using the cream on a large area of skin should be avoided. 
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Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
x
It should be noted that the heat effect does not occur immediately after the cream has 
been applied. 
Refer to the product information presented in Appendix 15.1. 
5.4.
Study Rationale 
The purpose of this study is to assess the systemic bioavailability of diclofenac in the 
presence and absence of capsaicin. 
Capsaicin has been shown to act as a penetration enhancer (e.g., for indomethacin [6], 
naproxen [7]) and thus, might improve the penetration rate and absorption of diclofenac.  In 
addition, both substances have different pharmacodynamics properties and complementary 
mechanisms of action. By combining both substances in a topical formulation, the new 
combination product will lead to an increased pain relief compared to the respective mono 
products. 
For a more detailed description of the drug profile refer to the current IB [5], which is 
included in the ISF. 
The proposed study in healthy males and females is designed to establish a PK profile for the 
topically applied test and reference products to evaluate relative bioavailability. 
There is some evidence of racial differences in the transcutaneous penetration of chemicals 
and drug absorption: decreased transcutaneous penetration has been reported in Black people
[13].  To take this into account the study population will be stratified 50:50, Caucasian versus 
Black people.  This will allow estimating and comparing PK endpoints by treatment and race.  
However, bioavailability ratios as intra-individual comparisons are not expected to be 
influenced by race.  To confirm this, a supportive analysis is planned including the 
stratification factor race in the model.
5.5.
Risks and Benefits
Safety measures are instituted to closely monitor subject safety during this clinical study and
to assess known risks of the investigational medicinal products (IMPs). 
As healthy male and female subjects will be included in this clinical study, they will not 
directly benefit from participation.
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Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
6.
STUDY OBJECTIVES
The main objective of this study is to assess the relative systemic bioavailability of diclofenac 
in the presence and absence of capsaicin by comparing the systemic bioavailability of 
diclofenac from a combination product (Diclofenac 2% + Capsaicin 0.075% Topical Gel)
with two diclofenac only products, Diclofenac Mono Gel 2% and Voltarol® 12 Hour 
Emulgel 2.32% Gel, following topical administration. A
In order to examine potential racial differences in pharmacokinetics (PK), the study 
population will be stratified 50:50, Caucasian versus Black people.  With respect to the main 
objective, additionally a supportive analysis will be performed to investigate the influence of 
race on the intra-individual bioavailability ratios.
Refer to Section 11.4 and Section 9 for primary and secondary endpoints/variables.
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Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
7.
INVESTIGATIONAL PLAN
Bias is limited by strict adherence to the inclusion and exclusion criteria, the use of a 
randomization schedule and application of the particular study design.  All measurement 
procedures are clearly defined in advance, and consistently and precisely applied. 
7.1.
Overall Study Design and Plan: Description
7.1.1.
Study Design
This will be a multiple-dose, open-label, randomized, 3-period, 3-treatment, 6 sequence 
(3x3x6) crossover study with topically administered diclofenac 2% (2 g) in the presence and 
absence of capsaicin 0.075%, in at least 42 healthy male and female subjects (stratified 50:50 
Caucasian versus Black people) in a single study center.
The study will comprise: 
x
Screening period of maximum 21 days. 
x
Three-treatment periods (each of which will include a multiple-dose period of 7 days
[twice daily and only in the morning on Day 7] and two PK profile periods of 12 hours 
[Day 1] and 24 hours [Day 7]) separated by a wash out period of at least 7 calendar days 
between the last administration of the IMP in a treatment period and the first 
administration of IMP in the next treatment period. Clinic stay/visits will be as follows:
x
Subjects will be admitted to the study center on Day -1 and leave the center after 
the morning dose on Day 2, at least 24 hours after the initial dosing on Day 1 
x
Subjects will visit the study center on Days 3 and 4 for the morning dose  
x
On Day 5, they will visit the center for PK blood sampling prior to morning and
evening dose and will be re-admitted to the study center on the evening of Day 5  
x
Subjects will leave the center at least 24 hours after the morning dose on Day 7 
x
A follow-up visit will occur within 72 hours after completion of the last treatment period 
of the study. 
Before the first administration of IMPs subjects will be randomized to one of 6 treatment 
sequences stratified by race (Black, Caucasian), i.e., 4 Black and 4 Caucasian subjects will be 
assigned to each treatment sequence. 
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Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
7.2.
Discussion of Study Design
7.2.1.
Treatment Periods and Schedule of Study Assessments
The timing of assessments is displayed in Table 7-1.
The time of dosing commencement may vary for logistical reasons.  Actual clock times will 
vary between subjects, in relation to actual dosing times.
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Amendment No. 1
Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.:
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
Table 7-1 
Schedule of Study Assessments
Assessment
Screening 
(Day -21
to -1)
Admission 
Treatment Period 1 
Admission Treatment Period 2 
Admission
Treatment Period 3 
Follow-up
Visit1
Days
-1 & 5
Days 
2 - 4 
Day 
5, 6 
Days 
1 & 7
Days
-1 & 5
Days
2 - 4
Day 
5, 6
Days 
1 & 7
Days
-1 & 5
Days
2 - 4
Day 
5, 6
Days 
1 & 7
Informed consent
X
In-house stay2
X
X
X
X
X
X
Demographic and anthropometric 
data3
X
Review of inclusion/exclusion 
criteria
X
Alcohol and tobacco consumption 
patterns
X
Medical and medications history4
X
X
Adverse events and concomitant 
medication5 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination6
X
Vital signs7
X
X
X
X
X
12-Lead ECG8
X
X
Hematology9
X
X
Clinical chemistry10
X
X
Serology tests11
X
Urinalysis12
X
Pregnancy test13
(female subjects only)
X
X
X
X
X
Urine screen for drugs of abuse14
X
X
X
X
Urine screen for tobacco use15
X
Alcohol breath test16
X
X
X
X
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Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
Assessment
Screening 
(Day -21
to -1)
Admission 
Treatment period 1 
Admission Treatment period 2 
Admission
Treatment period 3 
Follow-up
Visit1
Days
-1 & 5
Days 
2 - 4 
Day 
5, 6
Days 
1 & 7
Days
-1 & 5
Days
2 - 4
Day 
5, 6
Days 
1 & 7
Days
-1 & 5
Days
2 - 4
Day 
5, 6
Days 
1 & 7
Randomization
X
(Day 1)
Weighing of the IMP tube17
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IMP administration19
X18
X
X18
X
X18
X
PK profile20
X
X
X
Additional PK sampling21
X
X
X
X
X
X
Inspection of IMP application sites
by PI22
X
X
X
X
X
X
X
X
X
X
X
X
X
Overall assessment of tolerability23
X
(Day 8)
X
(Day 8)
X
(Day 8)
ECG = electrocardiogram; IMP = investigational medicinal product; PK = pharmacokinetic
1.
Within 72 hours of completion of the last period of the study or, in the case of a subject who took the IMP and was withdrawn or withdrew, within 72 hours of 
withdrawal/withdrawing from the study.
2.
Subjects will be admitted to the study center on Day -1 and the evening of Day 5 and will be discharged after the morning dose on Day 2 and at least 24 hours after
last dosing on Day 7.
3.
Sex, race, date of birth, age, height and body weight.
4.
The recorded medical history will be updated if necessary on admission to treatment period 1.
5.
Medication taken before dosing will be entered as history in the screening CRF of the subject.
6.
A full physical examination will include the following: Evaluation for jaundice, pallor (anemia), cyanosis, clubbing, edema and lymphadenopathy; skin evaluation; 
external ophthalmological evaluation, including fundoscopy; ear, nose and throat; cardiovascular assessment; respiratory assessment; abdominal evaluation; 
musculoskeletal assessment and neurological assessment; other evaluations may be performed as deemed necessary by the Investigator.  This will be commented 
upon in the clinical study report, if applicable. Refer to Section 7.2.7 for follow-up physical examination.
7.
Supine and standing systolic and diastolic blood pressure and pulse will be recorded at screening and at the follow-up visit. Supine blood pressure and pulse will be 
recorded before administration of IMP; in addition, supine blood pressure and pulse will be recorded at 2, 4 and 6 hours post-dose (Days 1 and 7). Body temperature 
will be recorded at screening and before administration of IMP (morning dose).
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Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
8.
Standard 12-lead ECG will be performed at screening and at the follow-up visit.
9.
Hematology (ethylenediaminetetraacetic acid [EDTA tubes]): white blood cell count, red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, 
mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, absolute differential count (neutrophils, lymphocytes, monocytes, eosinophils and 
basophils) and platelets.
10.
Clinical chemistry (Serum separator tubes [SST]): Potassium, sodium, urea, creatinine, uric acid, calcium, protein, albumin, total bilirubin, alkaline phosphatase 
(ALP), gamma glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and glucose.
11.
Tests for human immunodeficiency virus (HIV), Hepatitis B and Hepatitis C, performed using commercially available test kits.  Pre- and post-test counseling will 
be provided as appropriate.
12.
Urinalysis (dipstick): Glucose, bilirubin, ketone, specific gravity, blood, pH, protein, urobilinogen, nitrite and leucocytes. Abnormal urinalysis results may be 
repeated at the discretion of the Investigator.  All results will be reported.
13.
Serum SUHJQDQF\WHVWTXDQWLWDWLYHȕ-HCG [beta human chorionic gonadotropin] method) at screening.  On admission to each treatment period (Day -1 each period)
urine pregnancy testing will be performed.  If any of these tests are positive, subjects will not be allowed further participation in the study. Urine pregnancy test at 
the follow-up visit. 
14.
Using a rapid, one-step screening test for simultaneous, qualitative detection of multiple drugs and drug metabolites, such as amphetamines, barbiturates, 
benzodiazepines, cocaine, opiates, phencyclidine (phenylcyclohexalpiperidine), tetrahydrocannabinol, methadone, methamphetamine, tricyclic antidepressants, 
oxycodone and propoxyphene.  Subjects with alleged false positive test results will be excluded from the study.  However, a positive test may be repeated once at the 
discretion of the Investigator.
15.
Cotinine testing using commercially available testing procedures.
16.
Alcohol breath test using a portable breath alcohol measuring device.  The test will be performed at screening, on admission to each treatment period and at 
random.  If any of these tests are positive, subjects will not be allowed further participation in the study.
17.
The tubes will be weighed before and after dosing, whenever the subject is at the study center. 
19.
IMP will be self-administered in the morning and evening (12 hours apart) on Days 1 to 6 and only in the morning on Day 7.  Refer to Section 7.2.6 for window 
allowance.
20.
Blood for PK analysis will be collected on Day 1 at the following time points: 0 hours (prior to morning dose) and at 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose 
(prior to evening dose) (total: 10 samples per treatment period) and on Day 7 pre-dose at 0 hours and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20 and 24 hours 
post-dose (15 samples per treatment period). PK sampling should take preference over other assessments.
21.
Additional blood samples to establish attainment of steady state will be collected on Days 5 and 6 (prior to morning dose and evening dose).
22.
Inspection of IMP application sites will be done at screening, before every IMP administration and post-dose at 1 and 6 (± 9) hours on Day 1 and Day 7, 
respectively. On Days 2 to 5 inspections will be done before IMP administration during the morning visit to the clinic (subjects will still be in the clinic the morning 
of Day 2) and on Day 6 inspection will be done before IMP administration, in the morning and evening, respectively.
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Clinical Study Protocol Revised According to 
Amendment No. 1
Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
23.
Assessment will be done before discharge on the morning of Day 8.  Refer to Section 9.1.2 and Appendix 15.2.
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Clinical Study Protocol Revised 
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Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
7.2.2.
Safety and Data Monitoring Committees 
No safety and data monitoring committee has been established for this study.
7.2.3.
Interim Analyses
No interim analyses will be performed in this study. 
7.2.4.
Expected Duration of Study
The duration of this study is expected to be approximately 38 days per subject (excluding the 
screening period).  The actual overall study duration and study recruitment time may vary.
7.2.5.
Screening
Within 21 days before the first administration of IMP and after written informed consent is
obtained, screening procedures will be performed on each potential subject (see Table 7-1).  
Subjects who meet the inclusion criteria (Section 7.3.1) will be considered eligible to 
participate in the study.  Subjects who meet one or more of the exclusion criteria 
(Section 7.3.2) will not be considered eligible to participate in the study.
At the discretion of the PI, vital signs and laboratory investigations of variables outside the 
reference ranges may be repeated up to 3 times.  Should the variables return to within the 
reference range, or should the PI consider the variable to be at an acceptable level in relation 
to the reference range, the persons will be considered eligible to participate in the study.
7.2.6.
Treatment Periods
Each treatment period will include a profile period of 12 hours on Day 1 and 24 hours on 
Day 7 and dosing twice daily on Days 1, 2, 3, 4, 5 and 6 and only in the morning on Day 7. 
Subjects will be admitted to the study center on Day -1 and on the evening of Day 5. 
Details on the requirements for storage of IMP at home, instructions on administration of 
IMP and completing of the diary card will be communicated to the subjects in an information 
leaflet. 
Training of Self-administration 
IMP will be self-administered.  Subjects will be trained by the study staff on Day -1 of each 
treatment period to administer the IMP on one of the upper thighs.  An area of about 20 cm2 
will be marked with a black skin marker pen. 
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c09839764-02
Clinical Study Protocol Revised 
According to Amendment No. 1
Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
One thigh should be used during the study.  During one treatment period (out of 3) one thigh 
MUST be used.  If this is not possible for safety reasons, then the patient will be 
discontinued. 
If, after one period the subject suffers from skin irritation or non-intact skin (e.g., due to 
injury) the other thigh may be used for the following period.  
The IMP will be administered twice (morning and evening) on Days 1 and 6 (12 hours 
± 10 min), twice on Days 2 to 5 (12 hours ± 120 min) and in the morning only on Day 7.
Each IMP administration will be recorded on a diary card.
Patients will be equipped with disposable gloves and instructed to wear them whenever 
applying the IMP.  An area of approximately 20 cm x 20 cm (corresponding to approximately
2 hand sizes) will be treated.  A gel drop of approximately the size of a hazelnut will be 
applied to the subject’s gloved hand and quickly massaged into the skin until the whole 
amount of gel is absorbed.  Each subject will have a new tube assigned per treatment period.  
The tubes will be weighed before and after dosing, whenever the subject is at the study center
and the application site will be inspected by the Investigator at these time points as well.
Refer to Schedule of Study Assessments in Table 7-1.
Showering/bathing should be avoided for at least 1 hour before and after the application.  
External heat and/or occlusive dressings should not be applied to treated area.  Wearing of 
clothing or covering the application area with clothes and/or blankets should be avoided for at 
least 10 minutes after applying the gel.  Also refer to Section 5.3 and Section 7.2.10.1.
Before dosing on Day 1 and Day 7, an indwelling venous cannula will be inserted.  The 
medical staff will decide when to remove or replace the venous cannula based on the time 
(since insertion of the cannula) or if clotting occurs.  If the cannula is removed, the 
subsequent blood samples will be collected by venipuncture or the cannula will be replaced.
The cannula will be removed before discharge on Day 1 and Day 8 or as needed when not 
functioning properly any more as stated above. 
Food and beverages restrictions are described in Section 7.2.10.2.
Subjects will be allowed to leave the study center at least 24 hours after administration of the 
first dosing of IMP on Day 1 and at least 24 hours after the last dosing on Day 7. 
7.2.7.
Follow-up Evaluations 
See Table 7-1. 
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Clinical Study Protocol Revised 
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Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
At the discretion of the PI, a follow-up physical examination will be performed on subjects
withdrawn from the study due to an AE. 
Follow-up laboratory investigations with variables outside the reference ranges will not
necessarily be repeated to establish if and when those variables returned to within the 
reference ranges.  The variables will be reviewed against the clinical background, other 
relevant investigations and their relevance to the administered IMP, before a decision will be 
made to repeat the investigations in question.  At the discretion of the PI, the investigations of 
certain variables outside the reference ranges may be repeated until the variables return to 
within the reference range for the particular laboratory test, or until the PI considers the 
repeated variable to be at an acceptable level in relation to the reference range.  If the 
Investigator has made every effort to contact the subject, but he/she remains unavailable to 
attend the clinic for repeat of applicable laboratory investigations, the Investigator may 
declare him/her lost to follow-up. 
In cases where results of follow-up evaluations are reported after the database has been 
locked, the applicable clinical laboratory reports will be presented in the appendices to the 
clinical study report (CSR).
7.2.8.
Sampling, Interim Handling and Storage 
7.2.8.1.
Safety Blood and Urine Samples
Refer to Table 7-1. 
Before starting the study, the Investigator (or designee) will supply the Sponsor with the 
reference ranges and units of measurement for the laboratory safety variables to be used 
during the study.  If the reference ranges change during the course of the study, the 
Investigator (or designee) must provide the Sponsor with a list of the new reference ranges 
and the effective dates.
All safety blood and urine sampling will be performed by the study center, according to 
 standard operating procedures (SOPs). 
The PI or designee will ensure that all biological fluids collected during the study will not be 
used for purposes other than as directed by the clinical study protocol.  All collected 
biological fluids used for safety investigations will be destroyed within 3 months after the 
clinical execution of the study has been completed. 
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Clinical Study Protocol Revised 
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Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
7.2.8.2.
Pharmacokinetic Blood Samples 
Pharmacokinetic blood samples will be collected as indicated in the Schedule of Assessments 
(Table 7-1). The actual blood sampling times will be recorded on source data/ClinBase™ 
and attached to the case report forms (CRFs). 
Venous blood samples, 2 mL for the determination of diclofenac and 4 mL for the 
determination 
of 
capsaicin 
concentrations,
will 
be 
collected 
into 
labeled
potassium-ethylenediaminetetraacetic acid plastic (K2-EDTA) tubes. 
If not processed immediately, blood samples are to be placed on ice between sample 
collection and centrifuging.  Within one hour of collection, centrifuging of blood samples 
will commence at approximately 2700 g within a range of 0qC to 8qC for 10 minutes.  
Thereafter, the supernatant of each sample will be divided into 2 aliquots (of at least 0.8 mL 
plasma each for capsaicin and 0.4 mL each for diclofenac) and transferred to labeled, plastic 
tubes and frozen immediately. 
All sample tube labels will contain at least the following information: study number, analyte, 
time (protocol time and/or relative sampling time), subject number, blood sample number and 
treatment period.  Plasma samples will be stored at -20ºC in a temperature mapped freezer 
until transfer to 
 Bioanalytical Services Division (BASD). The labels of sample 
plasma tubes for capsaicin will be labeled similarly, but will not reflect the treatment period 
in order to keep the blind in the bioanalytical laboratory.  Pooled samples for concentration 
range estimation will be prepared according to 
 SOPs.  These specificity samples 
originate from some of the blood samples collected for drug assays and may be used by the 
analytical laboratory to determine suitable quantification ranges.
Unused duplicate plasma PK samples will be stored at BASD for 6 months after completion 
of the bioanalysis phase of the study.  The Sponsor will be required to indicate whether 
additional storage is needed or whether the samples may be discarded. 
7.2.9.
Blood Volume 
The total blood volume to be collected from each subject during the study is indicated in 
Table 7-2. 
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c09839764-02
Clinical Study Protocol Revised 
According to Amendment No. 1
Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
Table 7-2 
Total Blood Volume to be Collected During the Study
Assay
Volume per 
sample (mL) 
Total number of 
samples
Number of 
treatment 
periods
Total blood 
volume
(mL)
Diclofenac (Day 1)
2
10
3
60
Capsaicin (Day 1)
4
10
1
40
Diclofenac (Days 5,6 and 7)
2
15 + 2(2)
3
114
Capsaicin (Days 5, 6 and 7)
4
15 + 2(2)
1
76
Hematology
4
2
8
Clinical chemistry*
5
2
10
Total blood volume (entire 
study)**
308
*
Serum pregnancy tests (females only) and serology tests at screening will be performed on the sample 
collected for clinical chemistry
**
Excluding repeat laboratory investigations
7.2.10.
General and Dietary Restrictions
7.2.10.1.
Posture
The IMP will be self-administered as described Section 7.2.6. On Days 1 and 7, after dosing 
the subjects will remain in the supine position for 10 minutes before covering the dosing area 
with either clothing or blankets.  Except for bladder voiding and ingestion of meals (where 
applicable), subjects will remain recumbent until 2 hours after administration of study 
medication, after which no restrictions concerning posture or movement will apply.  Posture 
control procedures will be documented (see Source Data Agreement).  For the application of 
the IMP at home and at the clinic on the other days the subjects will wait 10 minutes before 
covering the dosing area with either clothing or blankets, with no restrictions on posture or 
movement. 
7.2.10.2.
Diet
The ingestion of food and beverages containing citrus fruits and/or apple or pineapple will 
not be allowed for 72 hours before the administration of IMP and until the last PK blood
sample is collected per treatment period.
The ingestion of food and beverages containing alcohol and/or methylxanthines e.g., caffeine 
(coffee, tea and cola) will not be allowed for 24 hours before the administration of IMP and 
until the last PK blood sample is collected per treatment period.
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Clinical Study Protocol Revised 
According to Amendment No. 1
Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
Food and beverage intake during the clinic stay will be standardized per treatment period.  
Meals taken during the clinic stay will be standardized in regard to composition and time of 
administration (see Source Document Agreement).
Water is allowed as desired.  Food and beverage intake will be allowed ad libitum, unless 
restrictions apply, after the subjects have been discharged from the clinic.
7.2.10.3.
Physical Activity
Strenuous physical activity will not be allowed for 24 hours before the administration of 
study medication and until the last PK blood sample was collected per PK profile period. 
7.2.10.4.
Special Precautions
Subjects will be informed verbally by the Investigator and in writing by way of the ICD of 
the AEs that they may experience after taking the IMP.
7.3.
Selection of Study Population 
The criteria are set to ensure a homogeneous subject population without accompanying 
diseases interfering with the conduct and scientific evaluation of the study.  The study 
population will be stratified 50:50 Caucasian versus Black people.  Additionally, the criteria 
have been selected to minimize risk to the subject’s well-being.
7.3.1.
Inclusion Criteria
1.
Healthy males and females, 18 to 50 years (inclusive) at time of screening. 
2.
Body mass index (BMI) between 18.5 and 29.9 kg/m2 (inclusive). 
3.
Body mass not less than 50 kg for males and females.
4.
Findings for medical history, vital signs, physical examination, standard 12-lead 
electrocardiogram (ECG) and laboratory investigations must be normal or within 
laboratory reference ranges for the relevant laboratory tests, unless the PI considers 
the deviation to be not clinically significant for the purpose of the study. 
5.
Non-smokers. 
6.
Females, if:
x
Not of childbearing potential, e.g., has been surgically sterilized, undergone a 
hysterectomy, amenorrhea for  12 months and considered post-menopausal,  
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Clinical Study Protocol Revised 
According to Amendment No. 1
Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
Note: In post-menopausal women, the value of the serum pregnancy test may be 
slightly increased.  This test will be repeated to confirm the results.  If there is no 
increase indicative of pregnancy, the female will be included in the study.
x
Of childbearing potential, the following conditions are to be met: 

Negative pregnancy test.
If this test is positive, the subject will be excluded from the study.  In the rare 
circumstance that a pregnancy is discovered after the subject received IMP, 
every attempt must be made to follow her to term.

Not lactating. 

Abstaining from sexual activity (if this is the usual lifestyle of the subject) or 
must agree to use an accepted method of contraception, and agree to continue 
with the same method throughout the study. 

In this study the concomitant use of hormonal contraceptives is allowed. 

Examples of reliable methods of contraception include oral (documented that 
the dose has been stable for at least one month before the first intake of the 
IMP), injectable or implantable contraceptives, non-hormonal/hormonal 
intrauterine device, and barrier methods combined with an additional 
contraceptive method. 

Other methods, if considered by the PI as reliable, will be accepted.
7.
Written informed consent given for participation in the study. 
7.3.2.
Exclusion Criteria
1.
Evidence of psychiatric disorder, antagonistic personality, poor motivation, emotional 
or intellectual problems likely to limit the validity of consent to participate in the 
study or limit the ability to comply with protocol requirements. 
2.
Current alcohol use > 21 units of alcohol per week for males and > 14 units of alcohol 
per week for females.
One unit (10 g alcohol) is equal to beer (330 mL), wine 
(200 mL), or distilled spirits (25 mL) per day.
3.
Regular exposure to substances of abuse (other than alcohol) within the past year. 
4.
Use of any medication, prescribed or over-the-counter (especially products containing 
diclofenac or use of other oral nonsteroidal anti-inflammatory drugs [NSAIDS]) or 
herbal remedies, within 2 weeks before the first administration of IMP except if this 
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Clinical Study Protocol Revised 
According to Amendment No. 1
Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
will not affect the outcome of the study in the opinion of the PI (in collaboration with 
the Sponsor).  In this study the concomitant use of hormonal contraceptives is
allowed. 
5.
Participation in another study with an experimental drug, where the last 
administration of the previous IMP was within 8 weeks (or within 5 elimination 
half-lives for chemical entities or 2 elimination half-lives for anti-bodies or insulin), 
whichever is the longer before administration of IMP in this study, at the discretion of 
the PI. 
6.
Treatment within the previous 3 months before the first administration of IMP with 
any drug with a well-defined potential for adversely affecting a major organ or 
system.
7.
A major illness during the 3 months before commencement of the screening period. 
8.
History of hypersensitivity or allergy (acute rhinitis, angioedema, urticaria or 
bronchial asthma) to the IMP or its excipients or any related medication (Aspirin or 
any other NSAID). 
9.
History of hypersensitivity or allergy to cayenne pepper or other capsaicinoids 
(paprika plants). 
10.
History of bronchospasm or bronchial asthma, arterial hypertension, myocardial 
infarction, thrombotic events, stroke, congestive heart failure, impaired renal function 
or liver disease.
11.
History or current diagnosis of gastrointestinal bleeding or peptic ulcer disease. 
12.
Elevated transaminases (ALT and AST) at screening.
13.
History of convulsions. 
14.
History of porphyria.
15.
Relevant history or laboratory or clinical findings indicative of acute or chronic 
disease, likely to influence study outcome. 
16.
Donation or loss of blood equal to or exceeding 500 mL during the 8 weeks before the 
first administration of IMP.
17.
Diagnosis of arterial hypotension made during the screening period. 
18.
Diagnosis of hypertension made during the screening period or current diagnosis of 
hypertension. 
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Clinical Study Protocol Revised 
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Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.:
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
19.
Resting pulse of > 100 beats per minute or < 40 beats per minute during the screening 
period, either supine or standing. 
20.
Positive testing for HIV, Hepatitis B and/or Hepatitis C. 
21.
Positive urine screen for drugs of abuse. In case of a positive result, the urine screen 
for drugs of abuse may be repeated once at the discretion of the PI. 
22.
Positive cotinine test.
23.
Positive pregnancy test.
24.
History of any bleeding or blood clotting disorders. 
25.
History or active severe skin diseases.
26.
Immunization using a live organism vaccine within 4 weeks before the first dosing of 
IMP.
27.
Any specific investigational product safety concern.
28.
Vulnerable subjects, e.g. persons in detention. 
29.
Bruises, damaged skin, eczema or wounds on the application site, or the application 
site inappropriate for applying the IMP in the opinion of the PI. 
7.3.3.
Withdrawal Criteria
Subjects have the right to withdraw from the study at any time, irrespective of the reason, 
without detriment to their medical care.
The following are pre-defined incidents that may lead to withdrawal from further 
participation at the discretion of the PI, and are optional withdrawal criteria: 
1.
AEs at the discretion of the PI. 
2.
Intercurrent illness requiring medication.  The decision whether or not to withdraw the 
subject will be at the discretion of the PI and will depend on the nature of the illness 
and medication used. 
3.
Protocol violation by subjects, at the discretion of the PI.  Protocol violation is defined 
as the willful disobeying of protocol instructions which have been communicated to 
the subjects verbally and in writing. 
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Clinical Study Protocol Revised 
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Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
The following are pre-defined incidents that will lead to withdrawal from further participation 
and are mandatory withdrawal criteria:
4.
Pathologically raised oral body temperature, above 38.0ºC, before morning dose of 
IMP administration on profile days. 
5.
Positive testing for pregnancy during the study. 
6.
Positive testing for drugs of abuse during the study. 
7.
Positive alcohol breath test during the study. 
8.
Skin irritation of such magnitude that dosing is not possible at IMP application site of 
the marked thigh during a specific period (the other thigh may be used in another 
period if needed).
9.
If the subject withdraws consent. 
The primary reason for treatment discontinuation will be documented (see Source Document 
Agreement). 
If the PI withdraws a subject from treatment or if a subject declines further participation, a 
follow-up visit will be completed for those who were exposed to IMP, within 72 hours of 
withdrawal/withdrawing from the study.
If a subject's reason for discontinuation is an AE, this must be reported in accordance with the 
procedures detailed in Section 12.
The Investigator must make every effort to contact a 
subject before he/she can be regarded as lost to follow-up. 
7.3.4.
Replacement of Subjects 
Subjects who withdraw or are withdrawn from the study will not be replaced, unless fewer 
complete the study than the estimated required number of evaluable subjects (see 
Section 11.2).
If a subject is replaced, the replacement will be allocated the subject number of 500 plus the 
subject number being replaced (e.g., Subject 
 will be replaced by 
). The subject 
numbers being replaced will be selected such that the replacement subjects receive the same 
treatment sequence as the withdrawn subjects and the sequence balance is maintained.
7.3.5.
Premature Termination of the Study
The Sponsor or the PI has the right to terminate the study at any time for medical and/or 
administrative reasons.  As far as possible, this should occur after mutual consultation. 
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Clinical Study Protocol Revised 
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Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.:
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
If the study is prematurely terminated for any reason, the Investigator will promptly inform 
the subjects and will ensure appropriate therapy and follow-up for them.  The IEC and the 
MCC will be informed as soon as possible after the decision has been made to terminate the 
study and the reasons for termination. 
Should the study be prematurely terminated, the completed and partially completed CRFs and 
remaining IMP must be destroyed locally in agreement with the Sponsor. 
A list of 
 SOPs governing these actions will be contained in the ISF.
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Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
8.
TREATMENTS
8.1.
Products to Be Administered
Subjects will receive either the test or reference products, according to the randomization 
schedule. Subjects will receive multiple doses of the test or reference products in 3 different 
treatment periods. 
8.2.
Identity of Investigational Medicinal Products
Test Product 1 (A): 
Generic name
:
Diclofenac sodium
Trade name
:
Diclofenac mono gel 2%
Dosage form
:
Immediate release topical gel
Dose
:
Multiple doses (2 g, bid) of Diclofenac 2%
Route of administration
:
Topical
Manufacturer
:
Boehringer Ingelheim Pharma GmbH & Co. KG
Country of origin 
: Germany
Test Product 2 (B): 
Generic name
:
Diclofenac + Capsaicin 
Product name 
: Combination of Diclofenac 2%  + Capsaicin 0.075% 
formulation 
Dosage form
:
Immediate release topical gel
Dose
: Multiple doses (2 g, bid) of Diclofenac 2%  + Capsaicin 
0.075%
Route of administration
:
Topical
Manufacturer
:
Boehringer Ingelheim Pharma GmbH & Co. KG
Country of origin
:
Germany
Reference Product (C):
Generic name
:
Diclofenac sodium topical gel
Trade name
:
Voltarol® Emulgel 2.32% Gel
Dosage form
:
Immediate release topical gel
Dose
:
Multiple doses (2 g, bid) of Voltarol (Diclofenac sodium 

The sample used in this study is from a validation batch.
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Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
2.32%)
Route of administration
:
Topical
Manufacturer
:
Novartis Consumer Health UK Ltd.
Country of origin
United Kingdom
8.2.1.
Identification of Investigational Medicinal Products
The Sponsor will conduct drug identification and content assay for the test products and, if 
possible, for the reference product.  Certificates of analysis will be provided in the CSR. 
8.2.2.
Supply and Storage 
The Sponsor will supply sufficient quantities of all products suitably packed for random 
choice of IMP for dosing.  The PI or designee will ensure that the IMPs are stored in a limited 
access area according to the storage instructions supplied by the Sponsor which is; store 
between 2-25ºC, excursions permitted to 26-33ºC for not more than 14 days.  The PI or 
designee will report any relevant deviations from the storage conditions to the Sponsor 
immediately.
8.2.3.
Investigational Medicinal Product Accountability 
The PI or designee will ensure that records of the receipt and administration of the IMP are 
kept and that the IMP will not be used for purposes other than as directed by the clinical 
study protocol.  Once the clinical phase of the study has been completed or prematurely 
terminated, and after drug accountability has been performed, unused IMPs will be destroyed 
locally in accordance with Sponsor requirements.  If incinerated, the certificate of 
incineration will be filed in the ISF. 
8.2.4.
Retention Samples
The Sponsor will retain IMP samples in accordance with the EU Guidelines to Good 
Manufacturing Practice
(GMP), Annex 13 – Investigational Medicinal Products, 
03 February 2010. 
8.2.5.
Labelling and Packaging 
The IMPs will be supplied by the Sponsor packaged in 50 g tubes. 
Each tube will be labeled, by the Sponsor, with a medication number.  Test Product 1 will 
have numbers 101 to 184.  Test Product 2 will have numbers 201 to 284.  The Reference 
Product will have numbers 301 to 384. 
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Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
Each subject will use a new tube per treatment period.
8.3.
Method of Assigning Subjects to Treatment Groups
A randomization schedule will be provided by 
 Biostatistics.  The randomization 
schedule will be generated utilizing the PROC PLAN procedure of SAS® software. 
Forty-eight subjects will be randomized to a 6 sequence Williams square design for 3 periods 
and 3 treatments:  ABC, BCA, CAB, CBA, ACB, BAC.  Subjects will be randomized to 1 of 
6 treatment sequences balanced over race. Thus, of each race, 4 subjects will be allocated to 
a particular sequence.
Subjects will be assigned randomization numbers 001 – 048. 
The tubes (and thus medication numbers) will be randomly selected during dosing. 
Possible replacements will be handled according to Section 7.3.4.
Blinding is described in Section 8.6.
8.4.
Selection of Doses in the Study
In compliance with bioavailability guidelines, the dosage in this study will include multiple 
topical doses of 2 g (as diclofenac) in 3 treatment periods. 
See Section 5 and Appendix 15.1.
8.5.
Selection and Timing of Dose for Each Subject
Subjects will receive Test Product 1, Test Product 2 or the Reference Product (according to 
the randomization schedule). 
See Section 7.2.6.
8.6.
Blinding
This is an open-label, laboratory-blind study.  Access to the randomization schedule will be 
restricted to assigned study staff members of 
 Biostatistics and 
 
Pharmaceutical Services, as well as the PI and designee.  Study staff members of BASD are 
not allowed access to the randomization schedule until after statistical analysis of the study 
results. Refer to Section 7.2.8.2 for the handling of capsaicin samples for the protection of 
the blind.  The final statistical analysis will be done according to the Statistical Analysis Plan
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Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
(SAP) that will be finalized before database lock and will be based on data following 
database lock.
8.7.
Prior and Concomitant Medication 
Subjects must refrain from using any medication, prescribed or over-the-counter (especially 
products containing diclofenac or use of other oral NSAIDs) or herbal remedies (including 
St. John's wort [Hypericum perforatum]), for 2 weeks before the first administration of IMP 
and for the duration of the study. 
In this study, the concomitant use of hormonal contraceptives is allowed. 
Concomitant use of other topical products, including sunscreens, cosmetics, lotions, 
moisturizers, insect repellants or other topical medications is not allowed anywhere on the 
body, except on the face.
Concomitant use with oral NSAIDs or Aspirin is also not 
allowed. 
The administration of concomitant medication will be handled on a case-by-case basis at the 
discretion of the PI.  If any medication is required during the course of the study, it must 
immediately be reported to the PI.  Where medication is taken or needs to be taken, a 
decision whether to continue or discontinue the subject’s participation in the study will be 
based on safety concerns, the time of medication administration and the possible influence of 
the ingested medication on the PK of the IMP and interference with the assay method.
8.8.
Treatment Compliance
To ensure treatment compliance, the IMP will be administered by the subject himself/herself,
for all doses on the same marked area on the same thigh each time as far as possible. Refer to 
Section 7.2.6 and Section 7.3.3.
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Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
9.
PHARMACOKINETIC ENDPOINTS AND SAFETY VARIABLES
9.1.
Pharmacokinetic and Safety Measurements
Refer to Section 7.2.1 for Schedule of Assessments.

9.1.2.
Overall Assessment of Tolerability
Refer to Table 7-1 for timing of assessments.
The subject will assess the overall tolerability of the trial treatment on a 4-point verbal rating 
scale, see Appendix 15.2. The PI will make the corresponding assessment at about the same 
time as the subject.  Assessments will be made independently from each other, i.e., without 
knowing the other’s assessment result when making the assessment. 
9.2.
Appropriateness of Measurements
Standard measures to assess PK and safety apply during the study.  As this is a bioavailability
study, the planned safety measurements are considered to be adequate because the safety of 
the IMP has been proven by the innovator. 
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Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
9.3.
Drug Concentration (Pharmacokinetic) Measurements
9.3.1.
Pharmacokinetic Endpoints
Refer to Section 11.4. 
9.3.2.
Pharmacokinetic Sample Collection, Sample Handing and Storage
Refer to Section 7.2.8.2. 
9.3.3.
Pharmacokinetic Drug Assays
The Clinical Laboratory of 
 BASD is accredited according to the International 
Organization for Standardization/the International Electrotechnical Commission 17025 
Standard.  The analytical laboratories of BASD have been inspected for their compliance 
with Good Laboratory Practice (GLP), based on the Organization for Economic Cooperation 
and Development guidelines ENV/MC/CHEM (98)17 revised in 1997.  These inspections 
have confirmed that the laboratory is able to successfully apply GLP principles in studies that 
are performed at BASD.  Analytical methods are validated according to internationally 
accepted standards (as per European Medicines Agency [EMA] guideline for Bioanalytical 
Method Validation).  The quality and integrity of the analytical work generated in this study 
are evaluated according to the acceptance criteria, as described in the SOPs of 
 
BASD.
Quantitative analysis of diclofenac and capsaicin in the collected plasma samples will be 
performed by BASD using liquid chromatography with tandem mass spectrometry 
(LC-MS/MS).
The pure substances with a certificate of analysis of diclofenac and capsaicin will be supplied 
by the Sponsor.  Alternatively,
 BASD will purchase the pure substances from 
trustworthy suppliers on behalf of the Sponsor.  These pure substances will be used as 
analytical standards for the preparation of calibration standards that are required for the 
quantitative analysis of diclofenac and capsaicin. 
All the samples received at BASD, including samples of subjects who withdrew/were
withdrawn, will be analyzed.  Bioanalytical data will be processed according to the relevant 
SOPs of BASD.
Complete method validation and bioanalytical reports will be provided. 
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Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
10.
DATA QUALITY ASSURANCE AND DATA MANAGEMENT
A study initiation meeting chaired by the PI or designee will be held before study 
commencement.
10.1.
Quality Control and Source Data Verification 
Source data verification will be conducted with due regard to subject confidentiality.
The site will allow the study monitor and Sponsor representatives’ direct access to all study 
documents, medical files, and source documents to enable verification of the study data, 
whilst maintaining the anonymity of the subject and confidentiality of the data.
Internal quality control will be performed at all stages of the study by the study center. 
10.2.
Audit/Inspections
The Investigator site, facilities and all data and documentation may be audited/inspected by 
independent auditor/inspector/any representatives of regulatory authorities.  The Investigator 
must allow the auditor/inspector/any representatives of regulatory authorities access to all 
relevant documents and be available to discuss any findings/issues.  An audit certificate will 
be included in the CSR if an audit was performed.
10.3.
Study Monitoring
The conduct of the study will be monitored by a representative of the Sponsor to ensure 
compliance with applicable regulatory requirements and GCP.  The summary of the 
documentation of the monitoring visits will form part of the study documentation and will be 
archived as such.
10.4.
Data Collection 
 Data Management will provide a CRF to be completed for each subject.  The 
entries will be checked by trained personnel.  Errors or inconsistencies will be corrected.  
Any changes or corrections to a CRF will be dated, initialed and explained (if necessary) and 
will not obscure the original entry (e.g. correction fluid or covering labels must not be used).  
An explanation for the omission of any required data will appear on the appropriate page.  
The Investigator will sign the completed CRF, thereby taking responsibility for the accuracy 
of the data in the entire CRF.
The Investigator will retain records of the changes and 
corrections. 
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Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
Source data will be defined as such in the Source Document Agreement.  The study center's 
electronic data capture and process control system may be used, as indicated in the Source 
Document Agreement.
The responsible study monitor will check data at the monitoring visits to the study center (see 
Section 10.3).  The Investigator will ensure that the data collected are accurate, complete and 
legible.
All clinical work conducted under the clinical study protocol is subjected to GCP regulations.  
These include an inspection by the Sponsor and Regulatory Authority representatives at any 
time.  The Investigator will agree to the inspection of study-related records by Regulatory 
Authority representatives and to audits of the Sponsor or third parties named by the Sponsor 
(also see Section 10.2).
10.5.
Data Management 
 will utilize standardized and validated procedures and systems to collect, process 
and file the clinical data of this study.  Any system used will be compliant with FDA 21 CFR 
Part 11 requirements. 
A data management plan (DMP) may be prepared to describe the work- and data-flow within 
the clinical study.  If applicable, Sponsor-specific requests, timelines, versions for the 
computer systems and the coding will be defined in the DMP.  The DMP must be finalized 
before data entry.
Appropriate data validation checks may be developed based on the data sources.  A data 
validation specification (DVS) may be created if existing standard checks alone are not 
adequate.  In such case, study-specific DVS will be created incorporating standard and 
custom checks that are already available.  If applicable, the DVS must be finalized before 
data validation. 
After the data had been monitored, they will be transferred to 
Data Management, 
and all CRFs received will be logged and filed. 
Data will be entered from completed paper CRFs into the clinical database by double data 
entry.  Electronic source data will be utilized directly without data entry.  Only trained study 
staff will have access to the clinical database and every change in data will have a full audit 
trail.
The raw data intended for further processing will be checked by standard routines or 
according to the study DVS and queries will be generated and sent on the data clarification 
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Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
forms (DCFs) to the Investigator for response.  Appropriate corrections to the data will be 
made based on the responses on the signed DCFs.  This process will be repeated until no 
further discrepancies are found.  The data will be then be declared as clean.  Applicable 
documentation will be stored in the study files.
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Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
11.
STATISTICAL METHODS
11.1.
Statistical Methodology 
The statistical methodology below describes the statistical analysis as it is foreseen when the 
study is being planned.  A SAP will be prepared with more details on the planned statistical 
methodology and will be finalized prior to database lock. 
If applicable, deviations from the original SAP and reasons for the deviations, as well as any 
alternative or additional statistical analysis that may be performed, will be documented in the 
CSR. 
The tables, figures and listings that will be provided are detailed in the SAP. 
11.1.1.
Pharmacokinetic Population
The PK population will consist of all subjects in the safety population for whom at least one 
of area under the plasma concentration-time curve over one dosing interval (AUC0-Ĳ,ss
>Ĳ = 12 hours]) or maximum steady-state plasma drug concentration during a dosage interval 
(Cmax,ss) can be calculated for one treatment and who have no major protocol deviations 
thought to impact on the analysis of the PK data. 
11.1.2.
Safety Population 
All subjects who received at least one dose of IMP will be included in the safety analysis for 
the study. 
11.2.
Determination of Sample Size
Up to 48 eligible subjects will be entered into the study to complete the study with at least 
42 evaluable subjects.
The sample size determination is not based on a power calculation, but to assure a precise 
estimation of relative bioavailability ratios with respect to AUCss and Cmax,ss.  Precision is 
defined as the ratio of upper to lower confidence interval (CI) limit and can also be shown in 
terms of the width of CIs (note that the precision is independent of the actual ratio of 
geometric means [gMeans] but CIs are not as can be seen in the table below).
Different estimates of the geometric coefficient of variation (gCV) for AUC and Cmax values 
of topical diclofenac were found in literature [9] regarding AUCss and Cmax,ss of PENNSAID 
topical solution and [10] regarding Cmax and AUC0-24 of Voltaren topical gel.  There, 
variability was very high, gCVs were calculated from CIs of ratios which ranged from 21 to 
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Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
41 % and even 57% in one case.  Based on this data, a gCV of 40% was used for estimation 
of precision for different scenarios.
Assuming an intra-individual variability of 40% for both AUCss and Cmax,ss, the trial will need 
N=42 analyzable subjects in order to achieve two-sided 90% CIs meeting a precision of 1.42 
with a probability of 95%. 
Table 11-1 
Expected Two-sided 90% Confidence Intervals for Different Ratios T/R 
and gCVs for a Sample Size of 42, Coverage Probability = 95% 
gCV [%] 
T/R 
90% CI
Precision
upper CL/lower CL
40
0.95
80 - 113
1.41
1.00
84 - 119
1.42
1.05
88 - 125
1.42
45
0.95
78 - 115
1.47
1.00
83 - 121
1.46
1.05
87 - 127
1.46
The calculation was performed as described by Julious [11, Section 7.2] and Elashoff [12].
11.3.
Protocol Deviations and Changes to Planned Analyses 
Permission from the Sponsor in writing will be obtained should any changes be required to 
the clinical study protocol and a protocol amendment will then be drawn up to be submitted 
to the regulatory authorities.  No waivers will be accepted.  Should the safety of the subjects 
necessitate immediate action, which represents a deviation from the clinical study protocol, 
the Sponsor will be informed as soon as possible. 
All protocol deviations will be discussed at the data review meeting prior to database hard 
lock in order to define the analysis populations for the study. 
Protocol deviations and changes to planned analyses will be described in the CSR. 
For protocol amendments, see Section 3.1. 
11.4.
Pharmacokinetic Endpoints
Calculation of the PK endpoints will be made with Phoenix® WinNonlin® 6.2 (or higher) 
(Certara, L.P., 1699 South Hanley Road, St Louis, Missouri 63144, USA).
The PK endpoints will be calculated for each subject and treatment using non-compartmental 
analysis and using the actual sampling time points (relative to IMP administration).
Steady state will be confirmed by visual inspection of a graph of the pre-dose samples on 
Days 5, 6, and 7. 
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Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
  
Additionally, samples with relevant time deviations may be excluded from statistical 
analysis. Such deviations which may impact accurate calculations of PK parameters will be 
reviewed at the data review meeting (DRM).  In all cases, the data will be reported in the 
CSR listing.
11.4.1.
Primary Pharmacokinetic Endpoints
Primary and secondary endpoints are only calculated for diclofenac.
x
Area under the plasma concentration-time over one GRVLQJ LQWHUYDO Ĳ = 12 hours) 
(AUC0-Ĳ,ss) (Day 7) 
x
Cmax,ss obtained directly from the concentration-time data (Day 7) 
11.4.2.
Secondary Pharmacokinetic Endpoints
x
Time to maximum observed plasma concentration at steady state (tmax,ss) (Day 7)
x
Average plasma concentration (Cav,ss) calculated as AUC0-Ĳ,ssĲĲLVRQHGRVLQJLQWHUYDO
(12 hours) 
x
Percentage peak-trough fluctuation (%PTF), calculated as [100*(Cmax,ss – Cpre,ss)/Cav,ss] 
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Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
 
11.5.
Safety Variables
See Section 11.8.
11.6.
Presentation of PK Data, Descriptive Statistics and PK Assessment
The actual blood sampling times and time deviations will be listed for each subject dosed, by 
treatment and scheduled sampling time.  Plasma concentrations of diclofenac and capsaicin
will be listed and summary statistics (number of subjects [n], arithmetic mean, gMean
(geometric mean), median, gCV, coefficient of variation (CV), standard deviation [SD], 
minimum and maximum) per treatment will be provided.  These same summary statistics by 
treatment and race will be provided.
Concentrations below the lower limit of quantification (LLOQ) will be indicated as below the 
limit of quantification (BLQ).  These BLQ concentrations will be handled as follows: 
x
For descriptive statistics, BLQ concentrations will not be substituted by zero before the 
calculation of the summary statistics. Values reported as ‘NS’ (no sample) will be set to 
“missing”.
x
For PK calculations, missing concentrations will be deleted, resulting in an interpolation
between the nearest 2 concentration values.
x
For PK assessment, all BLQ values at pre-dose and in the absorption phase, before the 
first reported concentration, will be substituted by zeros.  The BLQ values between 
evaluable concentrations and during the terminal phase will be set to missing, before the 
calculation of the PK endpoints. 
x
Concentration data identified with no valid result (NOR) or not analyzed (NOA) are not 
considered in the evaluation (graphs and calculations). However, they are listed in the
respective tables of the CSR.
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Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
The PK endpoints of diclofenac and capsaicin will be listed and summary statistics (n, 
arithmetic mean, gMean, median, gCV, CV, SD, minimum, 10th percentile [P10], 25th
percentile [Q1], 75th percentile [Q3], 90th percentile [P90] and maximum) per treatment will 
be provided.  These same summary statistics per treatment and race will be provided.
Descriptive statistics of concentrations at specific time points and PK parameters are 
calculated by default 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 is based on the total number of samples that were drawn at the specific time point 
(i.e., BLQ, NOR, and NOA are included). 
The individual plasma diclofenac 
 concentration versus actual time profiles for 
each subject and treatment, as well as the mean (arithmetic and geometric) plasma diclofenac 
 concentration versus scheduled time profiles for each treatment, will be 
presented graphically on a linear-linear and log-linear scale.  Mean (arithmetic and 
geometric) plasma diclofenac 
concentration versus scheduled time profiles for 
each treatment, will be presented graphically on a linear-linear and log-linear scale by race.
Individual plasma concentrations will be presented using actual, rather than planned, 
sampling times.  Combined individual concentration versus time graphs per treatment will 
also be presented on a linear-linear scale, together with the gMean values.  The individual 
log-linear graphs reflecting the WinNonlin modeling results will also be provided. 
The data listings, descriptive statistics, statistical analysis and graphs of this study will be 
generated using SAS® software*.
11.7.
Analysis of Relative Bioavailability
Relative bioavailability will be estimated for diclofenac by the ratios of the gMeans
(test/reference [T/R]) for AUC and Cmax at steady state (refer to Section 11.4.1). 
Additionally, their two-sided 90% CIs will be provided. 
The statistical model will be an analysis of variance (ANOVA) on the logarithmic scale 
including fixed effects for sequence, subject nested within sequence, period and treatment.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means).  CIs 
*
SAS® Version 9.2 or higher of the SAS System.  Copyright 2002-2003.  SAS Institute Inc.  SAS and all 
other SAS Institute Inc. product or service names are registered trademarks or trademarks of SAS Institute 
Inc., Cary, North Carolina, USA.
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CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
will be calculated based on the residual error from ANOVA. The differences between the
test and reference product and the CIs will be back-transformed to the original scale, resulting 
in point estimates of the T/R gMean ratios and 90% CIs. 
The following comparisons will apply: 
x
Test Product 2 vs Reference
x
Test Product 2 vs Test Product 1 
Only the data for the comparison under investigation will be included in the statistical 
analysis (i.e., when comparing Test Product 2 and Reference, the data for the Test Product 1 
will be removed from the dataset), only subjects with data for both products will be retained 
in the analysis.
The effect of race on relative bioavailability will be analyzed as supportive analysis,
supportive because race is not expected to influence intra-individual bioavailability ratios
[14]. 
The statistical model of the supportive analysis will be an ANOVA on the logarithmic scale 
including fixed effects for sequence, period, race, treatment, treatment and race interaction 
and subject nested within sequence and race interaction.  The effect of race will be checked 
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CONFIDENTIAL
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Date: 13 February 2017
and for each endpoint, least squares means by treatment and race will be tabulated.  Point 
estimates of the T/R gMean ratios and 90% CIs will be presented by race in the same way as 
for the main analysis.
11.8.
Presentation of Baseline Characteristics and Safety Data
Baseline characteristics and safety data will be presented as indicated below.
Demographic and anthropometric data will be listed for all subjects in the safety population.  
Demographic characteristics will be summarized (n, mean, SD, minimum and maximum for 
age and BMI; and frequency counts and percentages for race, and sex).
Subject disposition will be listed and summarized including the number and percentage of 
discontinued subjects and primary reason for discontinuation. 
AEs will be coded, listed and summarized by treatment.
The coded AEs will also be 
summarized by System Organ Class (SOC) and preferred term and product; SOC, preferred 
term, causality and product; and SOC, preferred term, intensity and product.  For the 
tabulations, the AEs will be grouped into 2 categories, namely “Reasonably Related” and 
“Not Related”.
Hematology and clinical chemistry values will be listed and summarized (n, mean, SD,
median, minimum, maximum), and urinalysis data will be listed for all subjects in the safety 
population.  Abnormal hematology and clinical chemistry values will be flagged as “L” (for 
values lower than the lower limit of the reference range) and “H” (for values higher than the 
upper limit of the reference range).  The assessment of the clinical significance will be 
indicated as “NCS” (abnormal, not clinically significant) or “CS” (abnormal, clinically 
significant) or “Rep” (whether the test was repeated).
ECGs will be classified as “Normal”, “Abnormal NCS”, “Abnormal CS” and listed, 
including changes from baseline. Summary statistics will be provided. 
Vital signs will be flagged for measurements that are outside the reference range (low [L] or 
high [H]) and listed, including changes from baseline. Summary statistics will be provided.
and data from inspection of IMP application site will be listed.  
Inspection results will be reported as normal or abnormal as indicated in the CRF.  Based on 
the DRS, skin reactions will EHFDWHJRUL]HGDVSRVLWLYHIRUVFRUHV 3 and negative for scores 
< 3.  Overall tolerability scores will be listed.  
Prior and concomitant medication will be coded and listed separately.
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Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
Additional listings will be presented for physical examination, urinalysis, pregnancy testing, 
serology and drugs of abuse and tobacco use. 
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Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
12.
ADVERSE EVENTS
Each subject will be carefully monitored by the Investigator for AEs.  In addition, 
information on AEs will be obtained from the subjects by study staff regularly questioning 
them, although no leading questions will be asked.  When an AE occurs, the PI will decide 
whether to withdraw the subject from the study and/or initiate appropriate treatment.  After 
withdrawal from the study, it will be ensured that the subject is given appropriate medical 
care, if needed, which may take the form of referral to a physician.
In the case of any event requiring medical intervention occurring during the clinic stay, the 
Investigator will institute general supportive measures including, where necessary, 
respiratory assistance and cardiopulmonary resuscitation.
12.1.
Definitions
12.1.1.
Adverse Events
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
Adverse Reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and
unintended.  Response in this context means that a causal relationship between a medicinal
product and an AE is at least a reasonable possibility.  Adverse reactions may arise from use 
of the product within or outside the terms of the marketing authorization or from occupational 
exposure.  Conditions of use outside the marketing authorization include off label use, 
overdose, misuse, abuse and medication errors. 
12.1.2.
Serious Adverse Events
A serious AE (SAE) is defined as any AE which: 
x
Results in death; 
x
Is life-threatening;
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CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
Life-threatening in this context refers to an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have caused 
death if more severe.
x
Requires in-patient hospitalization or prolongation of existing hospitalization;
x
Results in persistent or significant disability or incapacity;
x
Is a congenital anomaly or birth defect; 
x
,s 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. 
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
AE regardless of the duration between discontinuation of the IMP and the occurrence of 
cancer, if the site becomes aware of such an occurrence. 
In accordance with the EMA initiative on Important Medical Events, the Sponsor has set up a 
list of further AEs, which by their nature, can always be considered to be “serious” even 
though they may not have met the criteria of a SAE as given above.  A copy of the latest list 
of “Always Serious AEs” will be provided for reference and filing in the ISF.  These events 
should always be reported as SAEs as described in Section 12.4.
12.1.3.
Adverse Events of special interest
The term AEs of special interest (AESIs) relates to any specific AE that has been identified at 
the project level as being of particular concern for prospective safety monitoring and safety 
assessment within this trial, e.g., the potential for AEs based on knowledge from other 
compounds in the same class. AESI need to be reported to the Sponsor’s Pharmacovigilance
Department within the same time frame that applies to SAE, please see Section 12.4.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
x
An elevation of aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
 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/or 
x
MDUNHGSHDNDPLQRWUDQVIHUDVH$/7DQGRU$67HOHYDWLRQV 10 fold ULN 
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Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
These laboratory findings constitute a hepatic injury alert and the patients showing these 
laboratory abnormalities will be followed up according to the drug-induced liver injury 
(DILI) checklist provided in the ISF.  In case of clinical symptoms of hepatic injury (icterus, 
unexplained encephalopathy, unexplained coagulopathy, right upper quadrant abdominal 
pain, etc.) without laboratory results (ALT, AST, total bilirubin) available, the PI will make 
sure these parameters are analyzed, if necessary in an unscheduled blood test. Should the 
results meet the criteria of hepatic injury alert, the procedures described in the DILI checklist 
will be followed.  
12.2.
Classification of Adverse Events
AEs have to be recorded on an AE form in the subject's CRF and graded as mild, moderate, 
or severe according to the following definitions:
x
Mild: Awareness of sign(s) or symptom(s) that is/are easily tolerated. 
x
Moderate: Enough discomfort to cause interference with usual activity. 
x
Severe: Incapacitating or causing inability to work or to perform usual activities.
12.3.
Causal Relationship of Adverse Events
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an AE.  An adverse reaction, in 
contrast to an AE, is characterized by the fact that a causal relationship between a medicinal 
product and an occurrence is suspected. 
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. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be: 
x
The event is consistent with the known pharmacology of the drug 
x
The event is known to be caused by or attributed to the drug class 
x
A plausible time to onset of the event relative to the time of drug exposure 
x
Evidence that the event is reproducible when the drug is re-introduced 
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Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
x
No medically sound alternative etiologies that could explain the event (e.g., pre-existing 
or concomitant diseases, or co-medications)
x
The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome) 
x
An indication of dose-response (i.e., greater effect size if the dose is increased, smaller 
effect size if dose is diminished)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be: 
x
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g., pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
x
Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g., after 5 half-lives). Of note, this 
criterion may not be applicable to events whose time course is prolonged despite 
removing the original trigger
x
Additional arguments amongst those stated before, like alternative explanation (e.g., 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned) 
x
Disappearance of the event even though the study drug treatment continues or remains 
unchanged
12.4.
Reporting Procedures of Adverse Events/Serious Adverse Events
The PI or designee is responsible for recording in the CRF all AEs which have occurred from 
signed informed consent until individual subject’s end of study, regardless of their 
relationship to the IMP.  After the individual subject’s end of study the Investigator does not 
need to actively monitor the subject for AEs but should only report relevant SAEs and 
relevant AESI of which the Investigator may become aware of.
The Investigator must report SAEs, AESIs and non-serious AEs which are relevant for the 
reported SAE or AESI on the Sponsor’s SAE form via fax immediately (within 24 hours) to 
the Sponsor’s unique entry point 
The same timeline applies 
if follow-up information becomes available. In specific occasions the Investigator could 
inform the Sponsor upfront via telephone. This does not replace the requirement to complete 
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Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
and fax the BI SAE form. With receipt of any further information to these events, a 
follow-up SAE form has to be provided. For follow-up information the same rules and 
timeline apply as for initial information.
The residual effect period (REP) for each treatment period in this study is defined as 1 day 
(24 hours) after trial medication application of the corresponding treatment period. 
Information Required
For each AE, the Investigator should provide the information requested on the appropriate
CRF pages and the BI SAE form.  The Investigator should determine the causal relationship 
to the trial medication.
The following should also be recorded as an AE/SAE in the CRF and SAE form (if 
applicable): 
x
Worsening of pre-existing conditions
x
Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically significant by the Investigator 
x
Dermal reactions, if they are judged clinically significant by the Investigator
x
Abnormal reporting of IMP application site, if judged clinically significant by the 
Investigator 
If such abnormalities already pre-exist prior trial inclusion they will be considered as baseline 
conditions. 
All AEs and SAEs including those persisting after individual subjects end of trial must 
be followed up until they have been resolved, have been sufficiently characterized, or no 
further information can be obtained. In the event of an SAE, the outcome has to be 
reported in the CSR, as well as to the PI, Sponsor, monitor, the IEC and the MCC. 
Pregnancy
In rare cases, pregnancy may occur in a clinical trial.  Once a subject has been enrolled into 
this clinical trial, and has taken trial medication the Investigator must report immediately 
(within 24 hours of awareness) a potential drug exposure during pregnancy (DEDP) to the 
Sponsor’s unique entry point (fax number: 
The Pregnancy Monitoring Form for Clinical Trials (Part A) should be used. 
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Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
The outcome of the pregnancy associated with the DEDP must be followed up and reported 
to the Sponsor’s unique entry point on the Pregnancy Monitoring Form for Clinical Trials 
(Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition. The ISF will contain the Pregnancy Monitoring Form 
for Clinical Trials (Part A and B). 
12.5.
Allocation of Adverse Events to Treatment Groups
AEs are allocated to treatment groups based on start date/time of the AE in relation to dosing 
in each period. 
x
All AEs with start date/time prior to dosing in period 1 are pre-treatment AEs and are 
assigned to screening. 
x
All AEs with start date/time after the date/time of first dosing in period 1, but before 
dosing in period 2, would be assessed against the treatment received in period 1. 
x
AEs with start date/time after the date/time of first dosing in period 2, but before dosing 
in period 3 would be assessed against the treatment received in period 2. 
x
AEs with start date/time after the date/time of first dosing in period 3 would be assessed 
against the treatment received in period 3. 
With this definition AEs occurring in wash-out are assessed against the treatment received in 
the preceding period.  AEs up to the follow-up visit would be assessed against the treatment 
received in period 3 if the start date/time of the AE was after dosing in period 3. 
12.6.
Expedited Reporting of Adverse Events
The Sponsor is responsible for fulfilling their legal regulatory reporting obligation and in 
accordance to the regulatory requirements.
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Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
13.
LEGAL AND ADMINISTRATIVE ASPECTS
13.1.
Documentation 
All source documents generated in connection with the study will be retained in the limited 
access file storage area, respecting the privacy and confidentiality of all records that could 
identify the subjects.  Direct access is allowed only for authorized people for monitoring and 
auditing purposes.  Source documents will be handled, stored and archived according to 
in-house procedures. 
Investigator-specific essential documents will be retained until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.  These 
documents could be retained for a longer period however, if required by the regulatory 
requirements or by an agreement with the Sponsor.  It is the responsibility of the Sponsor to 
inform the Investigator as to when these documents no longer need to be retained. 
Study documentation will be archived by 
 for 15 years.
13.2.
Publication of Results
If a publication (e.g., in a scientific journal) based on the results of this study is envisaged, 
approval from the Sponsor will be obtained and a draft manuscript will be submitted to the 
Sponsor for scrutiny and comment.  The choice of conduit will be mutually agreed on by the 
PI and the Sponsor. 
13.3.
Sponsor’s Obligation 
The onus rests with the Sponsor to ensure that the clinical study protocol complies with all 
their requirements.
13.4.
Clinical Study Report
An integrated CSR will be prepared in accordance with the standards of the ICH Guideline 
for Structure and Content of CSRs (ICH E3).  Copies of the CSR will be provided to the IEC 
and the MCC in accordance with regulatory requirements and 
 SOPs.  In the event 
of premature termination of the study or other conditions specified in ICH E3, an abbreviated 
CSR may be prepared.
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Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
14.
REFERENCES
1.
Summary of Product Characteristics. Voltarol 12 hour Emulgel 2.32 % Gel or 
Voltarol Extra Strength Emulgel 2.32% Gel, revised 20 March 2013. 
2.
Derry S, Moore RA. Topical capsaicin (low concentration) for chronic neuropathic 
pain in adults (review). Cochrane Database Syst Rev (9), CD010111 (2012) 
3.
Zacher J, Altman R, Bellamy N, Bruehlmann P, Silva J da, Huskisson E, Taylor RS. 
Topical diclofenac and its role in pain and inflammation: an evidence-based review. 
Curr Med Res Opin 24 (4), 925 - 950 (2008) 
4.
O'Neill J, Brock C, Olesen AE, Andresen T, Nilsson M, Dickenson AH. Unravelling 
the mystery of capsaicin: a tool to understand and treat pain. Pharmacol Rev 64 (4), 
939 - 971 (2012) 
5.
Investigator’s 
Brochure, 
diclofenac 
and 
capsaicin, 
Version 1, 
dated 
19 December 2015 
6.
Fang JY, Fang CL, Hong CT, Chen HY, Lin TY, Wei HM. Capsaicin and nonivamide 
as novel skin permeation enhancers for indomethacin. Eur J Pharm Sci 12, 195 - 203 
(2001) 
7.
Degim IT, Uslu A, Hadgraft J, Atay T, Akay C, Cevheroglu S. The effects of Azone 
and capsaicin on the permeation of naproxen through human skin. Int J Pharm 179, 
21 - 25 (1999) 
8.
European Medicines Agency.  Committee for Medicinal Products for Human Use 
(CHMP): guideline on the pharmacokinetic and clinical evaluation of modified 
release dosage forms (EMA/CPMP/EWP/280/96 corr1) (draft XXIII) (London, 21 
February 2013, EMA/CHMP/EWP/280/96 rev1). 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/0 
3/WC500140482.pdf (access date: 18 March 2015); London: European Medicines 
Agency (EMA) (2013) 
9.
Center for Drug Evaluation and Research, application number 204623Orig1s00.
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204623Orig1s000ClinPhar
mR.pdf. Accessed on May 2016. 
10.
Center 
for 
Drug 
Evaluation 
and 
Research, 
application 
number 
21-22. 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022122_sumr.pdf. 
Accessed on May 2016. 
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Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
11.
Julious SA. Sample sizes for clinical trials with Normal data. Statist Med 2004; 
23:1921–1986. 
12.
Elashoff JD. nQuery Advisor version 7.0 user's guide.  Cork: Statistical Solutions 
2007.
13.
Alexa B. Kimball. Skin Differences, Needs, and Disorders across Global Populations.
J Investig Dermatol Symp Proc (1):2-5 (2008).
14.
European Medicines Agency. International Council for Harmonisation Topic E 9. 
Note for guidance on Statistical Principles for Clinical Trials (CPMP/ICH/363/96), 
September 1998 
Guidance documentation referred to within the clinical study protocol include, but are not 
limited to the following: 
x
Declaration of Helsinki, Fortaleza 2013 
x
Department of Health, South Africa.  Guidelines for Good Practice, 2006 
x
International Council for Harmonisation Guideline for Good Clinical Practice, 2002 
x
European Union Directive 2001/20/EC, 04 April 2001 
x
European Union Directive 2005/28/EC, 08 April 2005 
x
European Union Directive 2001/83/EC, 06 November 2001 
x
EudraLex Volume 4 – European Union Guidelines to Good Manufacturing Practice 
Medicinal Products for Human and Veterinary Use, Annex 13 – Investigational Medicinal 
Products, ENTR/F/2/AM/an D (2010) 3374, 03 February 2010 
x
Medicines Control Council of South Africa, Biostudies Guideline 
x
Maintenance of the ICH guideline on clinical safety data management: Data elements for 
transmission of individual case safety reports, E2B (R2), February 2001 
x
International Council for Harmonisation Guideline for Structure and Content of Clinical 
Study Reports (ICH E3), 1996 
x
European Medicines Agency Guideline on the Investigation of Bioequivalence 
CPMP/QWP/EWP/1401/98 Rev. 1, 2010 
x
European Medicines Agency Guideline on the pharmacokinetic and clinical evaluation of 
modified release dosage forms EMA/CPMP/EWP/280/96 Corr1, 2014 
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Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
15.
APPENDICES
15.1.
Product Information – Reference Product
Summary of Product Characteristics. Voltarol 12 hour Emulgel 2.32 % Gel or Voltarol Extra 
Strength Emulgel 2.32% Gel, revised 20 March 2013. 
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SUMMARY OF PRODUCT CHARACTERISTICS 
1 
NAME OF THE MEDICINAL PRODUCT 
Voltarol 12 Hour Emulgel 2.32% Gel 
or
Voltarol Extra Strength Emulgel 2.32% Gel 
2 
QUALITATIVE AND QUANTITATIVE COMPOSITION 
Diethylammonium-{-o-[2,6-dichlorophenyl)-amino]-phenyl}-acetate. 
100g of Voltarol® 12 Hour Emulgel 2.32% Gel contains 2.32g of the active 
substance diclofenac diethylammonium, which corresponds to 2g diclofenac sodium. 
Excipients: 
Propylene glycol (50 mg/g gel) 
Buthylhydroxytoluene (0.2 mg/g gel). 
For the full list of excipients, see section 6.1 
3 
PHARMACEUTICAL FORM 
Gel 
White to practically white, soft, homogeneous, cream-like gel. 
4 
CLINICAL PARTICULARS 
4.1 
Therapeutic indications 
 
  For the local symptomatic relief of pain and inflammation in: 
 
- 
trauma of the tendons, ligaments, muscles and joints,  
 
 
e.g. due to sprains, strains and bruises 
 
- 
localised forms of soft tissue rheumatism 
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Clinical Study Protocol Revised
According to Amendment No. 1
Relative Bioavailability Study
CONFIDENTIAL
__________________________________________________________________________________
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Final 1.0
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4.2 
Posology and method of administration 
Adults and children aged 14 years and over:  Voltarol® 12 Hour Emulgel 
2.32% Gel should be rubbed gently into the skin.  Depending on the size of the 
affected site to be treated 2-4g (a circular shaped mass approximately 2.0-2.5cm 
in diameter) should be applied 2 times daily (preferably morning and evening).
The maximum daily dose is 8g. Therefore the maximum weekly dose is 56g. 
After application, the hands should be washed unless they are the site being 
treated.
If symptoms persist after 7 days or get worse at any time, medical advice should 
be sought. 
 
Not to be used for more than 7 days unless recommended by a doctor. 
 
Use in the elderly:  The usual adult dosage may be used. 
Children and adolescents: There are insufficient data on efficacy and safety available 
for the children and adolescents below 14 years of age (see also contraindications 
section 4.3). In children aged 14 years and over, if this product is required for more 
than 7 days for pain relief or if the symptoms worsen the patient/parents of the 
adolescent is/are advised to consult a doctor. 
4.3 
Contraindications 
Patients with or without chronic asthma in whom attacks of asthma, urticaria or acute 
rhinitis are precipitated by aspirin or other non-steroidal anti-inflammatory agents.   
Hypersensitivity to diclofenac, acetylsalicylic acid or other non-steroidal anti-
inflammatory drugs.
Hypersensitivity to any other ingredient of the gel. 
Concomitant use of oral NSAID's.
Voltarol® 12 Hour Emulgel 2.32% Gel should not be co-administered with other 
products containing diclofenac. 
During the last trimester of pregnancy.
4.4 
Special warnings and precautions for use 
The possibility of systemic adverse events from application of Voltarol® 12 Hour 
Emulgel 2.32% Gel cannot be excluded if the preparation is used on large areas of skin 
and over a prolonged period (see the product information on systemic forms of 
diclofenac). 
Voltarol® 12 Hour Emulgel 2.32% Gel should be applied only to intact, non-diseased 
skin and not to skin wounds or open injuries.  It should not be used with occlusion.  It 
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Boehringer Ingelheim Pharma GmbH & Co. KG  
Combination of Diclofenac 2% + Capsaicin 0.075%
__________________________________________________________________________________
Clinical Study Protocol Revised
According to Amendment No. 1
Relative Bioavailability Study
CONFIDENTIAL
__________________________________________________________________________________
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229554 
SPONSOR STUDY No.: 1358.2 
Final 1.0
Date: 13 February 2017
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should not be allowed to come into contact with the eyes or mucous membranes, and 
should never be taken by mouth. 
Patients with a history of, or active, peptic ulceration.
Some possibility of 
gastro-intestinal bleeding in those with a significant history of this condition 
has been reported in isolated cases. 
Like other drugs that inhibit prostaglandin synthetase activity, diclofenac and other 
NSAIDs can precipitate bronchospasm if administered to patients suffering from or 
with a previous history of asthma or allergic disease. 
Discontinue if rash develops. 
Information concerning excipients 
Voltarol® 12 Hour Emulgel 2.32% Gel contains propylene glycol, which may cause 
mild, localised skin irritation in some people. It also contains butylhydroxytoluene 
which may cause local skin reactions (e.g. contact dermatitis) or irritation to the eyes 
and mucous membranes. 
4.5 
Interaction with other medicinal products and other forms of interaction 
Systemic absorption of diclofenac from topical application is very low and no 
drug interactions during treatment with Voltarol Emulgel have been reported, 
but the following have been observed with oral forms of diclofenac or other 
NSAIDs. 
Lithium and digoxin:  Voltarol may increase plasma concentrations of lithium 
and digoxin. 
Anticoagulants:  Although clinical investigations do not appear to indicate that 
Voltarol has an influence on the effect of anticoagulants, there are isolated 
reports of an increased risk of haemorrhage with the combined use of 
diclofenac and anticoagulant therapy.  Therefore, to be certain that no change in 
anticoagulant dosage is required, close monitoring of such patients is required.  
As with other non-steroidal anti-inflammatory agents, diclofenac in a high dose 
can reversibly inhibit platelet aggregation. 
Antidiabetic agents:  Clinical studies have shown that Voltarol can be given 
together with oral antidiabetic agents without influencing their clinical effect.  
However there have been isolated reports of hypoglycaemic and 
hyperglycaemic effects which have required adjustment to the dosage of 
hypoglycaemic agents. 
Ciclosporin:  Cases of nephrotoxicity have been reported in patients receiving 
concomitant cyclosporin and NSAIDs, including diclofenac.  This might be 
mediated through combined renal antiprostaglandin effects of both the NSAID 
and cyclosporin. 
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Methotrexate:  Cases of serious toxicity have been reported when methotrexate 
and NSAIDs are given within 24 hours of each other.  This interaction is 
mediated through accumulation of methotrexate resulting from impairment of 
renal excretion in the presence of the NSAID. 
Quinolone antimicrobials:  Convulsions may occur due to an interaction 
between quinolones and NSAIDs.  This may occur in patients with or without a 
previous history of epilepsy or convulsions.  Therefore, caution should be 
exercised when considering the use of a quinolone in patients who are already 
receiving an NSAID. 
Other NSAIDs and steroids:  Co-administration of Voltarol with other systemic 
NSAIDs and steroids may increase the frequency of unwanted effects.  
Concomitant therapy with aspirin lowers the plasma levels of each, although no 
clinical significance is known. 
Diuretics:  Various NSAIDs are liable to inhibit the activity of diuretics.  
Concomitant treatment with potassium-sparing diuretics may be associated with 
increased serum potassium levels, hence serum potassium should be monitored. 
Mifepristone:  NSAIDs should not be used for 8-12 days after mifepristone 
administration as NSAIDs can reduce the effects of mifepristone. 
Anti-hypertensives:  Concomitant use of NSAIDs with antihypertensive drugs 
(i.e. beta-blockers, angiotensin converting enzyme (ACE) inhibitors, diuretics) 
may cause a decrease in their antihypertensive effect via inhibition of 
vasodilatory prostaglandin synthesis. 
4.6 
Fertility, pregnancy and lactation 
Fertility 
Treatment with Voltarol® 12 Hour Emulgel 2.32% Gel is unlikely to have an 
adverse effect on fertility because the systemic exposure to diclofenac after 
application of Voltarol® 12 Hour Emulgel 2.32% Gel is low. 
Pregnancy 
The systemic concentration of diclofenac is lower after topical administration, 
compared to oral formulations. With reference to experience from treatment with 
NSAIDs with systemic uptake, the following is recommended: 
Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the 
embryo/fetal development. Data from epidemiological studies suggest an increased 
risk of miscarriage and of cardiac malformation and gastroschisis after use of a 
prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for 
cardiovascular malformation was increased from less than 1%, up to approximately 1.5 
%. The risk is believed to increase with dose and duration of therapy. In animals, 
administration of a prostaglandin synthesis inhibitor has been shown to result in 
increased pre- and post-implantation loss and embryo-fetal lethality. In addition, 
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Date: 13 February 2017
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increased incidences of various malformations, including cardiovascular, have been 
reported in animals given a prostaglandin synthesis inhibitor during the organogenetic 
period. During the first and second trimester of pregnancy, diclofenac should not be 
given unless clearly necessary. If diclofenac is used by a woman attempting to 
conceive, or during the first and second trimester of pregnancy, the dose should be 
kept as low and duration of treatment as short as possible. 
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may 
expose the fetus to:  
-
cardiopulmonary toxicity (with premature closure of the ductus arteriosus and 
pulmonary hypertension); 
-
renal dysfunction, which may progress to renal failure with oligo-
hydroamniosis; 
The mother and the neonate, at the end of pregnancy, to:  
-
possible prolongation of bleeding time, an anti-aggregating effect which may 
occur even at very low doses. 
-
inhibition of uterine contractions resulting in delayed or prolonged labour.  
Consequently, diclofenac is contraindicated during the third trimester of pregnancy. 
Lactation 
Like other NSAIDs, diclofenac passes into breast milk in small amounts. However, at 
therapeutic doses of Voltarol® 12 Hour Emulgel 2.32% Gel no effects on the suckling 
child are anticipated. Because of a lack of controlled studies in lactating women, the 
product should only be used during lactation under advice from a healthcare 
professional. Under this circumstance, Voltarol® 12 Hour Emulgel 2.32% Gel should 
not be applied on the breasts of nursing mothers, nor elsewhere on large areas of skin 
or for a prolonged period of time (see section 4.4). 
4.7 
Effects on ability to drive and use machines 
Voltarol® 12 Hour Emulgel 2.32% Gel has no or negligible influence on the 
ability to drive and use machines.   
4.8 
Undesirable effects 
Undesirable effects include mild and passing skin reactions at the site of application.  
In very rare instances, allergic reactions may occur. 
Adverse reactions are listed below, by system organ class and frequency. Frequencies 
are defined as: very common (≥ 1/10) common (≥ 1/100 to < 1/10); uncommon (≥
1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within 
each frequency grouping, undesirable effects are presented in order of decreasing 
seriousness. 
Infections and infestations
Very rare: Rash pustular 
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Immune system disorders
Very rare: Hypersensitivity (including urticaria), angioedema  
Respiratory, thoracic and mediastinal disorders
Very rare: Asthma 
Skin and subcutaneous tissue disorders
Common: Dermatitis (including contact dermatitis), rash, erythema, 
eczema, pruritus. 
Rare: Dermatitis bullous. 
Very rare: Photosensitivity reaction
The following additional side-effects have been observed with oral forms of 
diclofenac.
Gastro-intestinal tract
Occasional:  Epigastric pain, other gastro-intestinal disorders (e.g. nausea, 
vomiting, diarrhoea, abdominal cramps, dyspepsia, flatulence, anorexia). 
Rare:  Gastro-intestinal bleeding, peptic ulcer (with or without bleeding or 
perforation), bloody diarrhoea.   
In isolated cases:  Lower gut disorders (e.g. non-specific haemorrhagic colitis 
and exacerbations of ulcerative colitis or Crohn's proctocolitis, colonic damage 
and stricture formation), pancreatitis, aphthous stomatitis, glossitis, 
oesophageal lesions, constipation. 
Central Nervous System:
Occasional:  Headache, dizziness, or vertigo.   
Rare:  Drowsiness, tiredness. 
In isolated cases:  Disturbances of sensation, paraesthesia, memory 
disturbance, disorientation, disturbance of vision (blurred vision, diplopia), 
impaired hearing.  Tinnitus, insomnia, irritability, convulsions, depression, 
anxiety, nightmares, tremor, psychotic reactions.  Taste alteration disorders.   
Skin:
Occasional:  Rashes or skin eruptions.   
Rare:  Urticaria.
In isolated cases:  Eczema, erythema multiforme, Stevens-Johnson syndrome, 
Lyell's syndrome, (acute toxic epidermolysis), photosensitivity reactions, 
erythroderma (exfoliative dermatitis), loss of hair, purpura including allergic 
purpura.
Kidney:
In isolated cases:  Acute renal failure, urinary abnormalities (e.g. haematuria, 
proteinuria), interstitial nephritis, nephrotic syndrome, papillary necrosis. 
Liver:
Occasional:  Elevation of serum aminotransferase enzymes (ALT, AST). 
Rare:  Liver function disorders including hepatitis (in isolated cases fulminant) 
with or without jaundice. 
Blood:
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In isolated cases:  Thrombocytopenia, leucopenia, agranulocytosis, haemolytic 
anaemia, aplastic anaemia. 
Hypersensitivity:
Hypersensitivity reactions have been reported following treatment with 
NSAIDs.  These may consist of rare cases of anaphylactic/anaphylactoid 
systemic reactions including hypotension, and respiratory tract reactivity 
comprising  
asthma, aggravated asthma, bronchospasm or dyspnoea.  (See also “Skin”). 
Other organ systems:
Rare:  Oedema 
Isolated cases:  Impotence (association with diclofenac is doubtful), 
palpitation, chest pain, hypertension. 
4.9 
Overdose 
The low systemic absorption of topical diclofenac renders overdose very 
unlikely.  
However undesirable effects, similar to those observed following an overdose 
of Voltarol tablets, can be expected if Voltarol® 12 Hour Emulgel 2.32% Gel 
is inadvertently ingested (e.g. 1 tube of 50 g contains the equivalent of 1 g 
diclofenac sodium.)
In the event of accidental ingestion, resulting in significant systemic adverse 
effects, general therapeutic measures normally adopted to treat poisoning with 
non-steroidal anti-inflammatory medicines should be used.  Gastric lavage and 
the use of activated charcoal should be considered, especially within a short 
time of ingestion. 
5 
PHARMACOLOGICAL PROPERTIES 
5.1 
Pharmacodynamic properties 
Pharmacotherapeutic group: Topical products for joint and muscular pain. Anti-
inflammatory preparations, non-steroids for topical use, ATC code: M02A A15  
Mechanism of action and pharmacodynamic effects:
Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) with pronounced 
analgesic, anti-inflammatory and antipyretic properties.  Inhibition of 
prostaglandin synthesis is the primary mechanism of action of diclofenac.   
Voltarol® 12 Hour Emulgel 2.32% Gel is an anti-inflammatory and analgesic 
preparation designed for topical application.  In inflammation and pain of 
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Clinical Study Protocol Revised
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traumatic or rheumatic origin, Voltarol® 12 Hour Emulgel 2.32% Gel relieves 
pain, decreases swelling, and shortens the time to return to normal function.   
In one ankle sprain study (VOPO-P-307), Voltarol® 12 Hour Emulgel 2.32% 
Gel significantly decreased pain on movement scores versus placebo treated 
subjects within three days of starting treatment, including a subgroup of patients 
with severe pain. In addition treatment with Voltarol® 12 Hour Emulgel 2.32% 
Gel also significantly improved ankle joint function within 3 days of beginning 
treatment.
Due to an aqueous-alcoholic base the gel also exerts a cooling effect. 
5.2 
Pharmacokinetic properties 
Absorption
The quantity of diclofenac absorbed through the skin is proportional to the size 
of the treated area, and depends on both the total dose applied and the degree of 
skin hydration.  After topical application to approximately 400 cm2 of skin, the 
extent of systemic exposure as determined by plasma concentration of 
Voltarol® 12 Hour Emulgel 2.32% Gel (2 applications/day) was equivalent to 
diclofenac 1.16% gel (4 applications/day).  The relative bioavailability of 
diclofenac (AUC ratio) for Voltarol® 12 Hour Emulgel 2.32% Gel versus tablet 
was 4.5% on day 7 (for equivalent diclofenac sodium dose).  Absorption was 
not modified by a moisture and vapour permeable bandage.   
Distribution 
Diclofenac concentrations have been measured from plasma, synovial tissue 
and synovial fluid after application of topical diclofenac to hand and knee 
joints.  Maximum plasma concentrations were approximately 100 times lower 
than after oral administration of the same quantity of diclofenac.  99.7 % of 
diclofenac is bound to serum proteins, mainly albumin (99.4 %). 
Diclofenac penetrates inflamed areas, preferentially distributing to and 
persisting in deep inflamed tissues such as joints, where it is found in 
concentrations up to 20 times higher than in plasma. 
Biotransformation 
Biotransformation of diclofenac involves partly glucuronidation of the intact 
molecule, but mainly single and multiple hydroxylation resulting in several 
phenolic metabolites, most of which are converted to glucuronide conjugates.  
Two of the phenolic metabolites are biologically active, however, to a much 
smaller extent than diclofenac. 
Elimination 
The total systemic clearance of diclofenac from plasma is 263 ± 56 ml/min.  
The terminal plasma half-life is 1-2 hours.  Four of the metabolites, including 
the two active ones, also have short plasma half-lives of 1-3 hours.  One 
metabolite, 3'-hydroxy-4'-methoxy-diclofenac, has a longer half-life but is 
virtually inactive.  Diclofenac and its metabolites are excreted mainly in the 
urine.
Characteristics in patients 
No accumulation of diclofenac and its metabolites is to be expected in patients 
suffering from renal impairment.  In patients with chronic hepatitis or non-
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CONFIDENTIAL
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Final 1.0
Date: 13 February 2017
Page 79 of 83


decompensated cirrhosis, the kinetics and metabolism of diclofenac are the 
same as in patients without liver disease.
5.3 
Preclinical safety data 
Voltarol® 12 Hour Emulgel 2.32% Gel was well tolerated in a variety of studies. 
There was no potential for phototoxicity and diclofenac-containing gel caused no skin 
sensitisation or irritation.  
6 
PHARMACEUTICAL PARTICULARS 
6.1 
List of excipients 
Butylhydroxytoluene 
Carbomers
Cocoyl caprylocaprate 
Diethylamine 
Isopropyl alcohol 
Liquid paraffin 
Macrogol cetostearyl ether 
Oleyl alcohol 
Propylene glycol 
Perfume eucalyptus sting 
Purified water 
6.2 
Incompatibilities 
None Stated 
6.3 
Shelf life 
Three years 
6.4 
Special precautions for storage 
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Do not store above 30°C. 
Voltarol® 12 Hour Emulgel 2.32% Gel should be kept out of reach and sight of 
children. 
6.5 
Nature and contents of container 
Aluminium laminated tube [low density polyethylene / aluminium / high 
density polyethylene (internal layer)] fitted with a high density polyethylene 
shoulder and closed by a moulded seal. The tube is closed with a 
polypropylene screw cap, incorporating a moulded feature used to insert, twist 
and remove the seal before first use. 
Pack sizes: 20g, 30g, and 50g  
Not all pack sizes may be marketed. 
6.6 
Special precautions for disposal 
None
7 
MARKETING AUTHORISATION HOLDER 
Novartis Consumer Health UK Ltd. 
Trading as Novartis Consumer Health 
 
Watchmoor Park, Camberley Surrey 
GU15 3YL  
UK
8 
MARKETING AUTHORISATION NUMBER(S) 
PL 00030/0447 
9 
DATE OF FIRST AUTHORISATION/RENEWAL OF THE     
AUTHORISATION 
     
20/03/2013 
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CONFIDENTIAL
__________________________________________________________________________________
 STUDY No.:
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Final 1.0
Date: 13 February 2017
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10 
DATE OF REVISION OF THE TEXT 
20/03/2013
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CONFIDENTIAL
__________________________________________________________________________________
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Final 1.0
Date: 13 February 2017
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c09839764-02
Clinical Study Protocol Revised 
According to Amendment No. 1
Boehringer Ingelheim Pharma GmbH & Co. KG
Relative Bioavailability Study
Combination of Diclofenac 2% + Capsaicin 0.075%
CONFIDENTIAL
 STUDY No.: 
229554
Final 1.0
SPONSOR STUDY No.: 1358.2
Date: 13 February 2017
Page 83 of 83

SAP_001.pdf: 
 International 
Statistical Analysis Plan Addendum 
Boehringer Ingelheim 
Final 1.0 
1358.2 
22/Nov/2017 
TP-EP.BS-WW-008-04 
Effective date: 29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
Page 1 of 12
STATISTICAL ANALYSIS PLAN ADDENDUM 1 
Sponsor Study Number: 1358.2 
A SINGLE CENTER, MULTIPLE-DOSE, OPEN-LABEL, RANDOMIZED, THREE-PERIOD 
CROSSOVER STUDY TO DETERMINE THE RELATIVE BIOAVAILABILITY OF 
DICLOFENAC IN THE TOPICAL GEL COMBINATION PRODUCT (DICLOFENAC 2% + 
CAPSAICIN 0.075%) COMPARED TO DICLOFENAC MONO GEL 2% AND VOLTAROL® 12 
HOUREMULGEL 2.32% GEL IN AT LEAST 42 HEALTHY MALES AND FEMALES 
Version:  Final 1.0 
Date: 22/Nov/2017 


 I nter nati o nal 
Statistical A nal ysis Pla n A d de n d u m 
B oe hri n ger I n gel hei m 
Fi nal 1. 0 
1 3 5 8. 2 
2 2/ N o v/ 2 0 1 7 
T P- E P. B S- W W- 0 0 8- 0 4 
Effecti ve date: 2 9 J ul 1 5 
Relate d t o:  S O P- E P. B S- W W- 0 0 2 
P a ge 2 of 1 2
R E VI SI O N HI S T O R Y 
R E VI SI O N HI S T O R Y 
Versi o n  
Versi o n D ate  
A ut h or 
S u m m ar y of C h a n ges M a de 
Draft 1. 0  
2 0 Oct 2 0 1 7 
Ne w d oc u me nt 
Draft 2. 0  
0 7 N o v 2 0 1 7 
C o m pletel y re vise d a n d pr o vi de d a n o ver vie w 
T a ble 2  
Draft 3. 0  
2 1 N o v 2 0 1 7 
I m ple me ntati o n of c o m me nts a n d si m plificati o n 
of T a ble 1 a n d T a ble 2 
Fi nal 1. 0  
2 2 N o v 2 0 1 7 
Mi n or re visi o n 






 I nter nati o nal 
Statistical A nal ysis Pla n A d de n d u m 
B oe hri n ger I n gel hei m 
Fi nal 1. 0 
1 3 5 8. 2 
2 2/ N o v/ 2 0 1 7 
T P- E P. B S- W W- 0 0 8- 0 4 
Effecti ve date: 2 9 J ul 1 5 
Relate d t o:  S O P- E P. B S- W W- 0 0 2 
P a ge 5 of 1 2
T A B L E O F C O N T E N T S 
T A B L E O F C O N T E N T S 
R E VI SI O N HI S T O R Y .................................................................................................................... 2
SI G N A T U R E P A G E - B O E H RI N G E R I N G E L H EI M .................................................................. 3
SI G N A T U R E P A G E -  
 ................................................................................................. 4
T A B L E O F C O N T E N T S ................................................................................................................ 5
LI S T O F T A B L E S .......................................................................................................................... 5
A B B R E VI A TI O N A N D A C R O N Y M LI S T .................................................................................. 6
1. 
S T A TI S TI C A L A N A L Y SI S P L A N A D D E N D U M.......................................................... 7
2.  
O V E R VI E W O F C H A N G E S R E Q UI R E D ....................................................................... 8
2. 1 
C ha n ges i n str u ct ure a n d c o nte nt of ta bles a n d listi n gs ........................................ 8
2. 2 
Clarificati o n a n d A d diti o nal P K Para meters ........................................................ 8
2. 3  
A d diti o nal A nal yses ............................................................................................. 9
2. 4 
S u p p orti ve a n d Sec o n dar y A n al ys es .................................................................... 9
3. 
T A B L E S/ FI G U R E S......................................................................................................... 1 1
4. 
LI S TI N G S ........................................................................................................................ 1 2
LI S T O F T A B L E S 
LI S T O F T A B L E S 
Ta ble 1: P K para m eters f or d ose i nter val 0- 1 2 o n Da y 7 ................................................................ 9
Ta ble 2: O ver vi e w of a n al yses of P K p ara met ers o n Da y 7 ......................................................... 1 0
Ta ble 3: Ta bles a n d listi n gs r eferre d i n t he te xt ............................................................................ 1 1


I nter nati o nal 
Statistical A nal ysis Pla n A d de n d u m 
B oe hri n ger I n gel hei m 
Fi nal 1. 0 
1 3 5 8. 2 
2 2/ N o v/ 2 0 1 7 
T P- E P. B S- W W- 0 0 8- 0 4 
Effecti ve date: 2 9 J ul 1 5 
Relate d t o:  S O P- E P. B S- W W- 0 0 2 
P a ge 6 of 1 2
A B B R E VI A TI O N A N D A C R O N Y M LI S T  
A B B R E VI A TI O N A N D A C R O N Y M LI S T  
A b bre vi ati o n / Acr o n y m 
Defi niti o n / E x p a nsi o n 
A U C 
Area u n der t he c o nce ntrati o n-ti me c ur ve 
A U C 0-τ, ss
A U C o ver t he d osi n g i nter val at stea d y state 
A U C 0-τ, ss, n or m b y gel
A U C o ver t he d osi n g i nter val at stea d y state n or malize d t o wei g ht of a d mi nistere d gel 
BI D 
Bis i n die, t wice dail y 
C S P 
Cli nical St u d y Pr ot oc ol 
C ma x, ss
Ma xi m u m o bser ve d c o nce ntrati o n at stea d y state d uri n g t he d osi n g i nter val 
C ma x, ss, n or m b y gel
Ma xi m u m o bser ve d c o nce ntrati o n at stea d y state d uri n g t he d osi n g i nter val 
n or malize d t o wei g ht of a d mi nistere d gel 
I M P 
I n vesti gati o nal Me dici nal Pr o d uct 
P K 
P har mac o ki netic 
S A P 
Statistical A nal ysis Pla n 


 I nter nati o nal 
Statistical A nal ysis Pla n A d de n d u m 
B oe hri n ger I n gel hei m 
Fi nal 1. 0 
1 3 5 8. 2 
2 2/ N o v/ 2 0 1 7 
T P- E P. B S- W W- 0 0 8- 0 4 
Effecti ve date: 2 9 J ul 1 5 
Relate d t o:  S O P- E P. B S- W W- 0 0 2 
P a ge 7 of 1 2
1. 
S T A TI S TI C A L A N A L Y SI S P L A N A D D E N D U M 
1. 
S T A TI S TI C A L A N A L Y SI S P L A N A D D E N D U M 
T he Statistical A nal ysis Pla n ( S A P) A d de n d u m details t he c ha n ges a n d/ or a d diti o nal a nal yses re q uire d t hat are 
n ot c urre ntl y descri be d i n t he fi nal S A P Versi o n Fi nal 1. 0 date d 0 8/ Se p/ 2 0 1 7. T he S A P A d de n d u m descri bes a n y 
de viati o ns fr o m t he pla n ne d a nal yses, a d diti o nal a nal yses a n d if a p plica ble, ne w ta bles, listi n gs a n d fi g ures t hat 
are t o be pr o d uce d.


 I nter nati o nal 
Statistical A nal ysis Pla n A d de n d u m 
B oe hri n ger I n gel hei m 
Fi nal 1. 0 
1 3 5 8. 2 
2 2/ N o v/ 2 0 1 7 
T P- E P. B S- W W- 0 0 8- 0 4 
Effecti ve date: 2 9 J ul 1 5 
Relate d t o:  S O P- E P. B S- W W- 0 0 2 
P a ge 8 of 1 2
2.  
O V E R VI E W O F C H A N G E S R E Q UI R E D 
2.  
O V E R VI E W O F C H A N G E S R E Q UI R E D 
2. 1  
C h a n ges i n str uct ure a n d c o nte nt of t a bles a n d listi n gs 
I n a p pe n di x 1 6. 1. 9. 3 t he ta bles will be restr uct ure d t o s h o w o ne ta ble per t y pe of a nal ysis, i ncl u di n g all a nal ytes 
i n o ne ta ble, as s h o w n i n Ta ble 3  bel o w. 
I n Listi n g 1 6. 2. 7: 1 “ A d verse E ve nts”, f or clarificati o n, t he f o ot n ote “ N ote: A n e ve nt wit h o utc o me of " N O T 
R E C O V E R E D/ N O T 
R E S O L V E D" 
is 
directl y 
f oll o we d 
b y 
a 
s u bse q ue nt 
e ve nt 
wit h 
o utc o me 
“ R E C O V E R E D/ R E S O L V E D”.’ will be a d de d. 
I n Listi n g 1 6. 2. 5: 1 “ E x p os ure t o St u d y Dr u g” a c ol u m n f or t he t u be wei g ht differe nce ( g) use d f or n or malizati o n 
of P K para meters will be a d de d. 
I n T a ble 1 5. 1. 5: 1 “ E xte nt of E x p os ure” t he c ol u m n la bel f or treat me nts A a n d R will be s u p ple me nt e d wit h t he 
s u bsta nce na me “ Dicl ofe nac”. A ne w c haracteristic “ A d mi nistere d Gel ( g) o n Da y 7” s u m marizi n g t he t u be 
wei g ht differe nces o n Da y 7 will be a d de d. T he s u m mar y statistics f or “ O verall St u d y” c ol u m n will n ot be 
dis pla ye d. 
I n Listi n g 1 6. 2. 3: 1 “ Pr ot oc ol De viati o ns” t he c ol u m ns “ St u d y Da y of De viati o n”, “ Peri o d”, a n d “ Ti me P oi nt of 
De viati o n” will be c ha n ge d f or clarificati o n t o “ Peri o d”, “ St u d y Da y Relate d t o Start of Peri o d”, a n d “ Sc he d ule d 
Ti me P oi nt”, res pecti vel y. 
2. 2  
Cl arific ati o n a n d A d diti o n al P K P ar a meters 
T he S A P defi nes C ma x, ss as t he ma xi m u m o bser ve d c o nce ntrati o n at stea d y state ( Da y 7) a n d t ma x, ss  as t he ti me 
c orres p o n di n g t o occ urre nce of C ma x, ss  at stea d y state.  As t his dr u g was a d mi nistere d BI D P K para meters nee d t o 
be calc ulate d d uri n g t he d osi n g i nter val ta u (τ), 0- 1 2 h, o n Da y 7. 
T he f oll o wi n g P K para meters will be deri ve d f or t he d ose i nter val 0- 1 2 h o urs o n Da y 7 ( Ta ble 1): 


 International 
Statistical Analysis Plan Addendum 
Boehringer Ingelheim 
Final 1.0 
1358.2 
22/Nov/2017 
TP-EP.BS-WW-008-04 
Effective date: 29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
Page 9 of 12
Table 1: PK parameters for dose interval 0-12 on Day 7 
Primary PK 
parameters 
Normalized by weight 
of administered gel 
Normalized by weight of 
administered gel 
Without extreme value [1] 
AUC0-τ, ss [2] 
AUC0-τ, ss, norm by gel 
AUC0-τ, ss, norm by gel
Cmax, ss
Cmax, ss, norm by gel
Cmax, ss, norm by gel
tmax, ss
- 
- 
[1]: Calculated only for subject 008 Period 1 Day 7; [2]: Already defined in 
Final SAP 1.0; -: Parameter will not be calculated 
The PK parameters will be listed in Listing 16.2.6:1 and Listing 16.2.6:2 and summarized in Table 15.6.3:1 and 
Table 15.6.3:2. Original and weight normalized parameters will be sorted in listings and summary tables directly 
in turn. 
2.3
Additional Analyses 
During the conduct of the study, a range of actual tube weight differences of 1 g to 5.1 g was observed in 
contrast to a planned weight of administered gel of 2 g. In order to investigate a possible bias on the study results 
it was decided to add analyses (Table 2): These will be performed for the primary PK endpoints (AUC0-τ, ss and 
Cmax, ss) normalized by the weight of the administered gel on Day 7. Only the weight of Day 7 is used because 
steady state can be assumed. The analysis will also be done for the extreme value rectified PK parameters. 
Please note that normalization by the actual administered dose is not intended. The diclofenac content is 
different in the investigated products (Diclofenac 2% versus 2.32% topical gel) and the ratio of administered 
doses can only be maintained by normalizing by the weight of the administered gel. 
The final SAP Section 6.3.12.2 “Sensitivity Analysis” will be amended by an extra sensitivity analysis of the 
main analysis. There will be no changes to the structure/format of the tables, figures and listings based on this 
change. 
Same statistical model and SAS code as per relative bioavailability will be used for additional analyses. 
2.4
Supportive and Secondary Analyses 
The analysis of the primary PK parameters, with and without extreme value and normalized by weight of 
administered gel, will also be added to the statistical analyses shown in Table 2. Primary PK endpoints in plasma 
will be calculated for diclofenac and capsaicin, however, the secondary analysis is not applicable for capsaicin. 
The statistical analyses will be added to the shells indicated in the following Table 2. 


 International 
Statistical Analysis Plan Addendum 
Boehringer Ingelheim 
Final 1.0 
1358.2 
22/Nov/2017 
TP-EP.BS-WW-008-04 
Effective date: 29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
Page 10 of 12
Table 2: Overview of analyses of PK parameters on Day 7 
PK Parameters 
Main 
Analysis 
Fixed Effects 
Sensitivity 
Analysis 
Random Effect 
Supportive 
Analysis 
Race 
Secondary Analysis
Main Without 
Extreme Value 
Final SAP
AUC0-τ,ss
x 
x 
x 
x 
SAP Addendum 
Cmax, ss
x 
x 
x 
x 
AUC0-τ, ss, norm by gel
x 
x 
x 
x 
Cmax, ss, norm by gel
x 
x 
x 
x 
Used shells 
T 15.5:1 
T 16.1.9.3:1 
T 16.1.9.3:2 
T 15.5:2 
T 16.1.9.3:3 
T 15.5:3 
T 16.1.9.3:4 
Norm by gel: normalized by the weight of administered gel; τ: dosing interval 0-12 hours; 
ss: steady state; x: requested analysis. 
The first two rows in Table 2 display the planned statistical analyses described in the SAP final version 1.0. The 
clarified PK parameter Cmax, ss and the additional PK parameters normalized by weight of the administered gel 
will be added to the statistical analyses as requested above. 


 I nter nati o nal 
Statistical A nal ysis Pla n A d de n d u m 
B oe hri n ger I n gel hei m 
Fi nal 1. 0 
1 3 5 8. 2 
2 2/ N o v/ 2 0 1 7 
T P- E P. B S- W W- 0 0 8- 0 4 
Effecti ve date: 2 9 J ul 1 5 
Relate d t o:  S O P- E P. B S- W W- 0 0 2 
P a ge 1 1 of 1 2
3. 
T A B L E S/ FI G U R E S 
3. 
T A B L E S/ FI G U R E S 
T a ble 3: T a bles a n d listi n gs referre d i n t he te xt 
T y pe 
Title n u m ber  
Title 
P o p ul ati o n 
L  
1 6. 2. 3: 1  
Pr ot oc ol De viati o ns 
Safet y 
P o p ulati o n 
L  
1 6. 2. 5: 1  
E x p os ure t o St u d y Dr u g 
Safet y 
P o p ulati o n 
L  
1 6. 2. 6: 1  
P har mac o ki netic P ar a meters of Dicl ofe nac 
Safet y 
P o p ulati o n 
L  
1 6. 2. 6: 2  
P har mac o ki netic P ar a meters of Ca psaici n 
Safet y 
P o p ulati o n 
L  
1 6. 2. 7: 1  
A d verse E ve nts 
Safet y 
P o p ulati o n 
T  
1 5. 1. 5: 1  
E xte nt of E x p os ure 
Safet y 
P o p ulati o n 
T  
1 5. 5: 1 
Statistical A nal ysis of Pri mar y P har mac o ki netic E n d p oi nts i n Plas ma b y 
A nal yte 
P har mac o ki netic 
P o p ulati o n 
T  
1 5. 5: 2 
S u p p orti ve A nal ysis of Pri mar y P har mac o ki netic E n d p oi nts i n Plas ma b y 
A nal yte a n d Race 
P har mac o ki netic 
P o p ulati o n 
T  
1 5. 5: 3 
Sec o n dar y A nal ysis of Pri mar y P har mac o ki netic E n d p oi nts i n Plas ma b y 
A nal yte 
P har mac o ki netic 
P o p ulati o n 
T  
1 5. 5: 4 
N ot a p plica ble o ut p ut f or se nsiti vit y a nal ysis (ra n d o m effect) ca n be f o u n d i n 
T a ble 1 5. 5: 1 a n d T a ble 1 6. 1. 9. 3: 2 
T  
1 5. 6. 3: 1  
S u m mar y of P har mac o ki netic P ara meters b y Pr o d uct a n d A nal yte 
P har mac o ki netic 
P o p ulati o n 
T  
1 5. 6. 3: 2  
S u m mar y of P har mac o ki netic P ara meters b y Pr o d uct a n d A nal yte a n d Race  
P har mac o ki netic 
P o p ulati o n 
T  
1 6. 1. 9. 3: 1  
Statistical A nal ysis of Pri mar y P har mac o ki netic E n d p oi nts i n Plas ma b y 
A nal yte 
P har mac o ki netic 
P o p ulati o n 
T  
1 6. 1. 9. 3: 2  
Se nsiti vit y A nal ysis of Pri mar y P har mac o ki netic E n d p oi nts i n Plas ma b y 
A nal yte 
P har mac o ki netic 
P o p ulati o n 
T  
1 6. 1. 9. 3: 3  
S u p p orti ve A nal ysis of Pri mar y P har mac o ki netic E n d p oi nts i n Plas ma b y 
A nal yte a n d Race 
P har mac o ki netic 
P o p ulati o n 
T  
1 6. 1. 9. 3: 4  
Sec o n dar y A nal ysis of Pri mar y P har mac o ki netic E n d p oi nts i n Plas ma b y 
A nal yte 
P har mac o ki netic 
P o p ulati o n 
L: Listi n g; T: T a ble


 I nter nati o nal 
Statistical A nal ysis Pla n A d de n d u m 
B oe hri n ger I n gel hei m 
Fi nal 1. 0 
1 3 5 8. 2 
2 2/ N o v/ 2 0 1 7 
T P- E P. B S- W W- 0 0 8- 0 4 
Effecti ve date: 2 9 J ul 1 5 
Relate d t o:  S O P- E P. B S- W W- 0 0 2 
P a ge 1 2 of 1 2
4. 
LI S TI N G S 
4. 
LI S TI N G S 
N o ne w listi n gs t hat are t o be pr o d uce d. 


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STATISTICAL ANALYSIS PLAN
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Version:  Final 1.0 
Date: 08/Sep/2017
REVISION HISTORY
Version
Version Date
Author
Summary of Changes Made
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TABLE OF CONTENTS
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STUDY POPULATION
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STATISTICAL BASIS FOR SAMPLE SIZE
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Table 1
Expected Two-sided 90% Confidence Intervals for Different Ratios T/R and gCVs 
for a Sample Size of 42, Coverage Probability = 95% 
gCV [%]
T/R1
90% CI
Precision
upper CL/lower CL
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6.
STATISTICAL ANALYSIS CONVENTIONS
6.1
Analysis Variables 
6.1.1
Demographic and Background Variables 
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6.1.2
Safety Variables 
6.1.2.1
Adverse Events
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6.1.2.2
Clinical Laboratory Tests 
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6.1.2.3
Vital Signs 
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Physical Examination
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Overall Assessment of Tolerability
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6.1.3
Pharmacokinetics Variables
6.1.3.1
Pharmacokinetic Parameters
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Table 4
PK Parameters after Multiple Dose Administration for Diclofenac
Parameter
Definition
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6.1.3.2
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6.2
Analysis Populations
6.2.1
Safety Population 
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6.2.2
Pharmacokinetic Population
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6.3
Statistical Analysis Methods
6.3.1
Listings and Descriptive Statistics
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6.3.2
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6.3.3
Statistical Significance Level
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6.3.4
Software 
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6.3.5
Missing Data 
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6.3.6
Interim Analysis
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6.3.7
Protocol Deviations 
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Table 6 
Protocol Deviations Categories 
Code
Category
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6.3.8
Demographic Data 
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6.3.9
Concomitant Medication
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6.3.10
Exposure to the Investigational Medicinal Product
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6.3.11
Pharmacokinetic Concentrations and Variables
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Handling of Values Below the Limit of Quantification (BLQ) in Concentration Summaries,
Listings and Graphical Presentations
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Assessment of Relative Bioavailability  
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Safety Analysis 
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Clinical Safety Laboratory Tests (hematology, clinical chemistry and urinalysis)
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Vital Signs 
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12-Lead Electrocardiogram 
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6.3.13.6
Overall Tolerability
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6.3.13.7
Inspection of IMP Application Site
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6.3.13.8
Physical Examination
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7.
REFERENCES
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8.
CLINICAL STUDY REPORT
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15.1 TRIAL SUBJECTS 
15.1.1
Disposition of subjects
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6XEMHFW'LVSRVLWLRQE\7UHDWPHQW6HTXHQFHDQG2YHUDOO6DIHW\3RSXODWLRQ
15.1.2
Definition of analysis sets
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15.1.3
Important protocol violations # 
15.1.4
Demographic data and baseline characteristics - including diagnoses and 
therapies
Table 15.1.4:1 
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15.1.5
Extent of exposure 
Table 15.1.5:1 
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15.1.6
Compliance data
Table 15.1.6:1 
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15.2 EFFICACY EVALUATION # 
15.3 SAFETY EVALUATION
15.3.1
Adverse Events
Table 15.3.1:1
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Table 15.3.1:3 
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Table 15.3.1:7  
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Table 15.3.1:8 
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15.3.2
Clinical Laboratory Evaluation 
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15.3.3
Vital Signs – Physical Findings and Other Relevant Observations Related 
to Safety
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Table 15.3.3:2
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Table 15.3.3:5 
6XPPDU\RI2YHUDOO7ROHUDELOLW\6DIHW\3RSXODWLRQ
15.4 STANDARD SAFETY TABLES
15.4.1
Possible clinically significant abnormal laboratory value listing
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Table 15.4.1:2
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15.4.2
Listings of deaths - other serious adverse events - adverse events of special 
interest and other significant adverse events
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Table 15.4.2: 4 
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15.5 STATISTICAL EVALUATION OF CLINICAL PHARMACOLOGY ENDPOINTS
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15.6 CLINICAL PHARMACOLOGY EVALUATION
15.6.1
Drug concentration-time data
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3URGXFWDQG$QDO\WH3KDUPDFRNLQHWLF3RSXODWLRQ
Table 15.6.1:2 
6XPPDU\RI3ODVPD&RQFHQWUDWLRQVYHUVXV1RPLQDO6DPSOLQJ7LPHVE\5DFH
3URGXFWDQG$QDO\WH3KDUPDFRNLQHWLF3RSXODWLRQ
15.6.2
Pharmacokinetic parameters
15.6.3
Overall Summary of Pharmacokinetic parameters
Table 15.6.3:1 
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Table 15.6.3:2 
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15.6.4
Demographic data # 
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15.6.5
Pharmacokinetic Figures
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9.
APPENDICES TO BE INCLUDED IN SECTION 16 OF THE CLINICAL 
STUDY REPORT
2XWSXWVPDUNHGZLWKKDVKDUHQRWDSSOLFDEOHWRWKHVWXG\
Appendix 16.1.9.1 
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Appendix16.1.9.2
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Appendix16.1.9.3
6WDWLVWLFDO$QDO\VLVRI&OLQLFDO3KDUPDFRORJ\
Table 16.1.9.3:1 
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Appendix16.1.9.4
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Appendix16.1.9.5
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10.
LISTINGS TO BE INCLUDED IN SECTION 16 OF THE CSR
16.2
SUBJECT DATA LISTINGS
16.2.1
Disposition of subjects - discontinued subjects
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16.2.2
Subjects excluded from the efficacy analysis
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16.2.3
Protocol Deviations 
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16.2.4
Demographic data 
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16.2.5
Exposure - compliance and - or drug concentration data
Listing 16.2.5:1
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16.2.6
Pharmacokinetic Data  
Listing 16.2.6:1 
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16.2.7
Adverse Event listings
Listing 16.2.7:1
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16.2.8
Listing of individual laboratory measurements by subject and other 
relevant observations related to safety
16.2.8.1
Clinical laboratory 
Listing 16.2.8.1:1 
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16.2.8.2
Other relevant observations related to safety
Listing 16.2.8.2:1 
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