statistical analysis plan addendum 1t p- e p. b s- w w-008-04 effective date: 29 jul 15 related to:...

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 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 nt er n ati o n al

St atisti c al A n al ysi s Pl a n A d d e n d u m

B o e hri n g er I n g el h ei m Fi n al 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 Eff e cti v e d at e: 2 9 J ul 1 5 R el at e d t o: S O P- E P. B S- W W- 0 0 2 P a g e 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

V e r si o n V e rsi o n D at e A ut h o r S u m m a r y of C h a n g es M a d e

Dr aft 1. 0 2 0 O ct 2 0 1 7 N e w d o c u m e nt

Dr aft 2. 0 0 7 N o v 2 0 1 7 C o m pl et el y r e vi s e d a n d pr o vi d e d a n o v er vi e w T a bl e 2

Dr aft 3. 0 2 1 N o v 2 0 1 7 I m pl e m e nt ati o n of c o m m e nt s a n d si m plifi c ati o n of T a bl e 1 a n d T a bl e 2

Fi n al 1. 0 2 2 N o v 2 0 1 7 Mi n or r e vi si o n




1 3 5 8. 2 2 2/ N o v/ 2 0 1 7


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 h a n g es i n str u ct ur e a n d c o nt e nt of t a bl es a n d listi n gs ........................................ 8

2. 2 Cl arifi c ati o n a n d A d diti o n al P K P ar a m et ers ........................................................ 8

2. 3 A d diti o n al A n al ys es ............................................................................................. 9

2. 4 S u p p orti v e a n d S e c o n d ar 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

T a bl e 1: P K p ar a m et ers f or d os e i nt er v al 0- 1 2 o n D a y 7 ................................................................ 9

T a bl e 2: O v er vi e w of a n al ys es of P K p ar a m et ers o n D a y 7 ......................................................... 1 0

T a bl e 3: T a bl es a n d listi n gs r ef err e d i n t h e t e xt ............................................................................ 1 1




1 3 5 8. 2 2 2/ N o v/ 2 0 1 7


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 b r e vi ati o n / A c r o n y m D efi niti o n / E x p a nsi o n

A U C Ar e a u n d er t h e c o n c e ntr ati o n-ti m e c ur v e

A U C 0- τ, s s A U C o v er t h e d osi n g i nt er v al at st e a d y st at e

A U C 0- τ, s s, n or m b y g el A U C o v er t h e d osi n g i nt er v al at st e a d y st at e n or m ali z e d t o w ei g ht of a d mi ni st er e d g el

BI D Bi s i n di e, t wi c e d ail y

C S P Cli ni c al St u d y Pr ot o c ol

C m a x, s s M a xi m u m o bs er v e d c o n c e ntr ati o n at st e a d y st at e d uri n g t h e d osi n g i nt er v al

C m a x, s s, n or m b y g el M a xi m u m o bs er v e d c o n c e ntr ati o n at st e a d y st at e d uri n g t h e d osi n g i nt er v al n or m ali z e d t o w ei g ht of a d mi ni st er e d g el

I M P I n v esti g ati o n al M e di ci n al Pr o d u ct

P K P h ar m a c o ki n eti c

S A P St ati sti c al A n al ysis Pl a n




1 3 5 8. 2 2 2/ N o v/ 2 0 1 7


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 h e St ati sti c al A n al ysi s Pl a n ( S A P) A d d e n d u m d et ails t h e c h a n g es a n d/ or a d diti o n al a n al ys e s r e q uir e d t h at ar e

n ot c urr e ntl y d es cri b e d i n t h e fi n al S A P V er si o n Fi n al 1. 0 d at e d 0 8/ S e p/ 2 0 1 7. T h e S A P A d d e n d u m d es cri b es a n y

d e vi ati o ns fr o m t h e pl a n n e d a n al ys es, a d diti o n al a n al ys e s a n d if a p pli c a bl e, n e w t a bl e s, listi n gs a n d fi g ur es t h at

ar e t o b e pr o d u c e d.




1 3 5 8. 2 2 2/ N o v/ 2 0 1 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 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 g e s i n st r u ct u r e a n d c o nt e nt of t a bl es a n d li sti n gs

I n a p p e n di x 1 6. 1. 9. 3 t h e t a bl es will b e r estr u ct ur e d t o s h o w o n e t a bl e p er t y p e of a n al ysis, i n cl u di n g all a n al yt es

i n o n e t a bl e, as s h o w n i n T a bl e 3 b el o w.

I n Li sti n g 1 6. 2. 7: 1 “ A d v ers e E v e nts ”, f or cl arifi c ati o n, t h e f o ot n ot e “ N ot e: A n e v e nt wit h o ut c o m e 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 dir e ctl y f oll o w e d b y a s u bs e q u e nt e v e nt wit h o ut c o m e

“ R E C O V E R E D/ R E S O L V E D ”.’ will b e a d d e d.

I n Li sti n g 1 6. 2. 5: 1 “ E x p os ur e t o St u d y Dr u g ” a c ol u m n f or t h e t u b e w ei g ht diff er e n c e ( g) us e d f or n or m ali z ati o n

of P K p ar a m et ers will b e a d d e d.

I n T a bl e 1 5. 1. 5: 1 “ E xt e nt of E x p os ur e ” t h e c ol u m n l a b el f or tr e at m e nt s A a n d R will b e s u p pl e m e nt e d wit h t h e

s u bst a n c e n a m e “ Di cl of e n a c ”. A n e w c h ar a ct eri sti c “ A d mi ni st er e d G el ( g) o n D a y 7 ” s u m m ari zi n g t h e t u b e

w ei g ht diff er e n c es o n D a y 7 will b e a d d e d. T h e s u m m ar y st ati sti cs f or “ O v er all St u d y ” c ol u m n will n ot b e

di s pl a y e d.

I n Li sti n g 1 6. 2. 3: 1 “ Pr ot o c ol D e vi ati o ns ” t h e c ol u m ns “ St u d y D a y of D e vi ati o n ”, “ P eri o d ”, a n d “ Ti m e P oi nt of

D e vi ati o n ” will b e c h a n g e d f or cl arifi c ati o n t o “ P eri o d ”, “ St u d y D a y R el at e d t o St art of P eri o d ”, a n d “ S c h e d ul e d

Ti m e P oi nt ”, r es p e cti v el y.

2. 2 Cl a rifi c ati o n a n d A d diti o n al P K P a r a m et e rs

T h e S A P d efi n e s C m a x, s s as t h e m a xi m u m o bs er v e d c o n c e ntr ati o n at st e a d y st at e ( D a y 7) a n d t m a x, s s as t h e ti m e

c orr e s p o n di n g t o o c c urr e n c e of C m a x, s s at st e a d y st at e. As t his dr u g w as a d mi ni st er e d BI D P K p ar a m et ers n e e d t o

b e c al c ul at e d d uri n g t h e d osi n g i nt er v al t a u ( τ), 0- 1 2 h, o n D a y 7.

T h e f oll o wi n g P K p ar a m et er s will b e d eri v e d f or t h e d os e i nt er v al 0- 1 2 h o ur s o n D a y 7 ( T a bl e 1):




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.




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 AnalysisMain Without Extreme Value

Final SAPAUC0-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.




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 Eff e cti v e d at e: 2 9 J ul 1 5 R el at e d t o: S O P- E P. B S- W W- 0 0 2 P a g e 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 bl e 3: T a bl e s a n d li sti n g s r ef e r r e d i n t h e t e xt

T y p e Titl e n u m b e r Titl e P o p ul ati o n

L 1 6. 2. 3: 1 Pr ot o c ol D e vi ati o ns S af et y P o p ul ati o n

L 1 6. 2. 5: 1 E x p o s ur e t o St u d y Dr u g S af et y P o p ul ati o n

L 1 6. 2. 6: 1 P h ar m a c o ki n eti c P ar a m et er s of Di cl of e n a c S af et y P o p ul ati o n

L 1 6. 2. 6: 2 P h ar m a c o ki n eti c P ar a m et er s of C a p s ai ci n S af et y P o p ul ati o n

L 1 6. 2. 7: 1 A d v er s e E v e nts S af et y P o p ul ati o n

T 1 5. 1. 5: 1 E xt e nt of E x p o s ur e S af et y P o p ul ati o n

T 1 5. 5: 1 St atisti c al A n al ysis of Pri m ar y P h ar m a c o ki n eti c E n d p oi nt s i n Pl as m a b y A n al yt e

P h ar m a c o ki n eti c P o p ul ati o n

T 1 5. 5: 2 S u p p orti v e A n al ysis of Pri m ar y P h ar m a c o ki n eti c E n d p oi nts i n Pl as m a b y A n al yt e a n d R a c e


T 1 5. 5: 3 S e c o n d ar y A n al ysis of Pri m ar y P h ar m a c o ki n eti c E n d p oi nts i n Pl as m a b y A n al yt e


T 1 5. 5: 4 N ot a p pli c a bl e o ut p ut f or s e nsiti vit y a n al ysis (r a n d o m eff e ct) c a n b e f o u n d i n T a bl e 1 5. 5: 1 a n d T a bl e 1 6. 1. 9. 3: 2

T 1 5. 6. 3: 1 S u m m ar y of P h ar m a c o ki n eti c P ar a m et er s b y Pr o d u ct a n d A n al yt e P h ar m a c o ki n eti c P o p ul ati o n

T 1 5. 6. 3: 2 S u m m ar y of P h ar m a c o ki n eti c P ar a m et er s b y Pr o d u ct a n d A n al yt e a n d R a c e P h ar m a c o ki n eti c P o p ul ati o n

T 1 6. 1. 9. 3: 1 St atisti c al A n al ysis of Pri m ar y P h ar m a c o ki n eti c E n d p oi nt s i n Pl as m a b y A n al yt e


T 1 6. 1. 9. 3: 2 S e nsiti vit y A n al ysis of Pri m ar y P h ar m a c o ki n eti c E n d p oi nts i n Pl as m a b y A n al yt e


T 1 6. 1. 9. 3: 3 S u p p orti v e A n al ysis of Pri m ar y P h ar m a c o ki n eti c E n d p oi nts i n Pl as m a b y A n al yt e a n d R a c e


T 1 6. 1. 9. 3: 4 S e c o n d ar y A n al ysis of Pri m ar y P h ar m a c o ki n eti c E n d p oi nts i n Pl as m a b y A n al yt e


L: Li sti n g; T: T a bl e




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 Eff e cti v e d at e: 2 9 J ul 1 5 R el at e d t o: S O P- E P. B S- W W- 0 0 2 P a g e 1 2 of 1 2

4. LI S TI N G S 4. LI S TI N G S

N o n e w listi n gs t h at ar e t o b e pr o d u c e d.

STATISTICAL ANALYSIS PLAN

Version: Final 1.0 Date: 08/Sep/2017

REVISION HISTORY

Version Version Date Author Summary of Changes Made

TABLE OF CONTENTS

LIST OF TABLES

ABBREVIATION AND ACRONYM LIST

Abbreviation / Acronym Definition / Expansion

Abbreviation / Acronym Definition / Expansion

STATISTICAL ANALYSIS PLAN

1. STUDY OBJECTIVES

1.1 Primary Objective

1.2 Secondary Objective

2. STUDY DESIGN

o

o

o

o

3. STUDY POPULATION

4. STATISTICAL BASIS FOR SAMPLE SIZE

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 Precisionupper CL/lower CL

5. RANDOMIZATION

6. STATISTICAL ANALYSIS CONVENTIONS

6.1 Analysis Variables

6.1.1 Demographic and Background Variables

6.1.2 Safety Variables

6.1.2.1 Adverse Events

6.1.2.2 Clinical Laboratory Tests

Clinical chemistry:

Hematology:

Urinalysis:

Serology:

Drugs of abuse:

6.1.2.3 Vital Signs

6.1.2.4 Electrocardiograms

6.1.2.5 Physical Examination

6 6 D e

6.1.2.7 Overall Assessment of Tolerability

6.1.2.8 Inspection of IMP application sites

6.1.2.9 Concomitant Medication

6.1.3 Pharmacokinetics Variables

6.1.3.1 Pharmacokinetic Parameters

Table 4 PK Parameters after Multiple Dose Administration for Diclofenac

Parameter Definition

6.1.3.2 Pharmacokinetic Parameter Calculation Methods

6.2 Analysis Populations

6.2.1 Safety Population

6.2.2 Pharmacokinetic Population

6.3 Statistical Analysis Methods

6.3.1 Listings and Descriptive Statistics

6.3.2 Rounding and Decimal Places

o

o

o

o

o

o

o

o

6.3.3 Statistical Significance Level

6.3.4 Software

6.3.5 Missing Data

6.3.6 Interim Analysis

6.3.7 Protocol Deviations

Table 6 Protocol Deviations Categories

Code Category

6.3.8 Demographic Data

6.3.9 Concomitant Medication

6.3.10 Exposure to the Investigational Medicinal Product

6.3.11 Pharmacokinetic Concentrations and Variables

6.3.11.1 Handling of Values Below the Limit of Quantification (BLQ) in Concentration Summaries,Listings and Graphical Presentations

Handling of values below the limit of quantification (BLQ) in listings and for the calculation of descriptive statistics at each time point:

Graphical presentation:

6.3.12 Assessment of Relative Bioavailability

6.3.12.1 Main Analysis

o

o

6 2 S s

6 3 S s

6 4 S s

6.3.13 Safety Analysis

6.3.13.1 Adverse Events

Hepatic Injury

6.3.13.2 Clinical Safety Laboratory Tests (hematology, clinical chemistry and urinalysis)

6.3.13.3 Vital Signs

6.3.13.4 12-Lead Electrocardiogram

6.3.13.6 Overall Tolerability

6.3.13.7 Inspection of IMP Application Site

6.3.13.8 Physical Examination

7. REFERENCES

8. CLINICAL STUDY REPORT

15.1 TRIAL SUBJECTS

15.1.1 Disposition of subjects

Table 15.1.1: 1

15.1.2 Definition of analysis sets

15.1.3 Important protocol violations #

15.1.4 Demographic data and baseline characteristics - including diagnoses and therapies

Table 15.1.4:1

15.1.5 Extent of exposure

Table 15.1.5:1

15.1.6 Compliance data

Table 15.1.6:1

15.2 EFFICACY EVALUATION #

15.3 SAFETY EVALUATION

15.3.1 Adverse Events

Table 15.3.1:1

Table 15.3.1:2

Table 15.3.1:3

Table 15.3.1:4

Table 15.3.1:5

Table 15.3.1:6

Table 15.3.1:7

Table 15.3.1:8

15.3.2 Clinical Laboratory Evaluation

Table 15.3.2:1

Table 15.3.2:2

15.3.3 Vital Signs – Physical Findings and Other Relevant Observations Related to Safety

Table 15.3.3:1

Table 15.3.3:2

Table 15.3.3:5

15.4 STANDARD SAFETY TABLES

15.4.1 Possible clinically significant abnormal laboratory value listing

Table 15.4.1:1

Table 15.4.1:2

15.4.2 Listings of deaths - other serious adverse events - adverse events of special interest and other significant adverse events

Table 15.4.2:1

Table 15.4.2:2

Table 15.4.2:3

Table 15.4.2: 4

15.5 STATISTICAL EVALUATION OF CLINICAL PHARMACOLOGY ENDPOINTS

Table 15.5:1

15.6 CLINICAL PHARMACOLOGY EVALUATION

15.6.1 Drug concentration-time data

Table 15.6.1:1

Table 15.6.1:2

15.6.2 Pharmacokinetic parameters

15.6.3 Overall Summary of Pharmacokinetic parameters

Table 15.6.3:1

Table 15.6.3:2

15.6.4 Demographic data #

15.6.5 Pharmacokinetic Figures

Figure 15.6.5:1

Figure 15.6.5:2

Figure 15.6.5:3

Figure 15.6.5:4

Figure 15.6.5:5

Figure 15.6.5:6

Figure 15.6.5:7

Figure 15.6.5:8

Figure 15.6.5:9

Figure 15.6.5:10

Figure 15.6.5:11

Figure 15.6.5:12

Figure 15.6.5:13

Figure 15.6.5:14

Figure 15.6.5:15

Figure 15.6.5:16

Figure 15.6.5:17

Figure 15.6.5:18

Figure 15.6.5:19

Figure 15.6.5:20

Figure 15.6.5:21

Figure 15.6.5:22

Figure 15.6.5:23

Figure 15.6.5:24

9. APPENDICES TO BE INCLUDED IN SECTION 16 OF THE CLINICAL STUDY REPORT

Appendix 16.1.9.1

Appendix 16.1.9.2

Appendix 16.1.9.3

Table 16.1.9.3:1

Appendix 16.1.9.4

Appendix 16.1.9.5

10. LISTINGS TO BE INCLUDED IN SECTION 16 OF THE CSR

16.2 SUBJECT DATA LISTINGS

16.2.1 Disposition of subjects - discontinued subjects

Listing 16.2.1:1

Listing 16.2.1:2

Listing 16.2.1:3

16.2.2 Subjects excluded from the efficacy analysis

Listing 16.2.2:1

16.2.3 Protocol Deviations

Listing 16.2.3:1

16.2.4 Demographic data

Listing 16.2.4:1

Listing 16.2.4:2

Listing 16.2.4:3

Listing 16.2.4:4

16.2.5 Exposure - compliance and - or drug concentration data

Listing 16.2.5:1

Listing 16.2.5:2

16.2.6 Pharmacokinetic Data

Listing 16.2.6:1

Listing 16.2.6:2

16.2.7 Adverse Event listings

Listing 16.2.7:1

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

Listing 16.2.8.1:2

Listing 16.2.8.1:3

Listing 16.2.8.1:4

16.2.8.2 Other relevant observations related to safety

Listing 16.2.8.2:1

Listing 16.2.8.2:2

Listing 16.2.8.2:4

Listing 16.2.8.2:5

Listing 16.2.8.2:6

11. SCHEDULE OF STUDY ASSESSMENTS

AssessmentScreening (Day -21

to -1)

Admission Treatment Period 1 Admission Treatment Period 2

Admission Treatment Period 3 Follow-up

Visit1

AssessmentScreening (Day -21

to -1)

Admission Treatment Period 1 Admission Treatment Period 2

Admission Treatment Period 3 Follow-up

Visit1

statistical analysis plan addendum 1t p- e p. b s- w w-008-04 effective date: 29 jul 15 related to:...

Documents