Clinical trial NCT03086356
Conditions: Healthy Volunteers
Sponsor: Boehringer Ingelheim
Start date: 2017-05-10; Completion date: 2017-09-12
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of the trial is to investigate the pharmacokinetics and pharmacodynamics of idarucizumab in Chinese healthy male and female subjects following intravenous administration of idarucizumab followed by idarucizumab with 15 minutes interval when administered at or close to the steady state of dabigatran.

Another objective of this trial is to explore the effect idarucizumab on the PK (pharmacokinetic(s)) and PD (pharmacodynamic) parameters of dabigatran.

Detailed description:

Arms: arm 1: Dabigatran etexilate alone (days 1-4) and (days 8-10) and with Idarucizumab (day 11)
Interventions: intervention 1: Dabigatran etexilate intervention 2: Idarucizumab
Intervention descriptions: intervention 1: Days 1-4 and Day 8-11 intervention 2: Day 11

Protocol documents:
Prot_000.pdf: 







































































































































































































SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c16578188-04
BI Trial No.:
1321.6
Title:
Open label Phase I trial in healthy Chinese male and female 
volunteers to investigate pharmacokinetics and pharmacodynamics
of idarucizumab to reverse dabigatran anticoagulant activity.
Including Protocol Amendment 1 [c02286986-03]
Investigational
Product(s):
Idarucizumab
Responsible trial 
statistician(s):
Phone:
Fax:
Date of statistical 
analysis plan:
14 SEP 2017 SIGNED
Version:
Revised
Page 1 of 19
Proprietary confidential information
2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


Boehringer Ingelheim
TSAP for BI Trial No: 1321.6
Page 2 of 19
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
1.
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
1.
TABLE OF CONTENTS ......................................................................2
LIST OF TABLES ..............................................................................................4
2.
LIST OF ABBREVIATIONS ...............................................................5
3.
INTRODUCTION..................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......8
5.
ENDPOINTS ..........................................................................................9
5.1
PRIMARY ENDPOINT ......................................................................................9
5.2
SECONDARY ENDPOINTS..............................................................................9
5.4
OTHER VARIABLES.........................................................................................9
5.4.1
Demographic data and baseline characteristics ...........................................9
5.4.2
Safety data........................................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS...........................................10
6.1
TREATMENT....................................................................................................10
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................10
6.3
PATIENT SETS ANALYSED..........................................................................11
6.4
SUBGROUPS .....................................................................................................12
6.5
POOLING OF CENTRES ................................................................................12
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................12
6.6.1
Safety data......................................................................................................12
6.6.2
Pharmacokinetic data ...................................................................................12
6.6.3
Pharmacodynamic data ................................................................................12
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................12
7.
PLANNED ANALYSIS.......................................................................13
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........13
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................13
7.3
TREATMENT COMPLIANCE .......................................................................13
7.4
PRIMARY ENDPOINT ....................................................................................13
7.5
SECONDARY ENDPOINTS............................................................................14
...........................................14
...........................................14
...........................................14
...........................................14
7.7
EXTENT OF EXPOSURE................................................................................14
7.8
SAFETY ANALYSIS.........................................................................................15
7.8.1
Adverse events ...............................................................................................15
7.8.2
Laboratory data.............................................................................................15
7.8.3
Vital signs.......................................................................................................16
7.8.4
ECG ................................................................................................................16
7.8.5
Others .............................................................................................................16
8.
REFERENCES.....................................................................................17


Boehringer Ingelheim
TSAP for BI Trial No: 1321.6
Page 3 of 19
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
9.
ADDITIONAL SECTIONS ................................................................18
10.
HISTORY TABLE...............................................................................19


Boehringer Ingelheim
TSAP for BI Trial No: 1321.6
Page 4 of 19
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
LIST OF TABLES
Table 6.2: 1
Important PVs..................................................................................................11
Table 6.7: 1
Upper limit normal values for PD parameters.................................................12
Table 10: 1
History table ....................................................................................................19


Boehringer Ingelheim
TSAP for BI Trial No: 1321.6
Page 5 of 19
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADA
Anti-drug antibodies
ADS
Analysis data set
AE
Adverse event
AESI
Adverse events of special interest
BI
Boehringer Ingelheim
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DE
Dabigatran etexilate
dTT
Diluted thrombin time
ECG
Electrocardiogram
ETP
Endogenouos Thrombin Potential
HR
Heart rate
ICH
International Conference on Harmonisation
MedDRA
Medical Dictionary for Regulatory Activities
O*C
Oracle Clinical
PD
Pharmacodynamics
PDS
Pharmacodynamic set
PK
Pharmacokinetics
PKS
Pharmacokinetic set
PR
Pulse rate
PV
Protocol violation
QT
Time between the start of the Q-wave and the end of the T-wave in an 
ECG
QT(c)
QT interval, any correction
QTcB
QT interval, corrected according to Bazett’s formula
QTcF
QT interval, corrected according to Fridericia’s formula
SD
Standard deviation


Boehringer Ingelheim
TSAP for BI Trial No: 1321.6
Page 6 of 19
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Term
Definition / description
TSAP
Trial statistical analysis plan
WHO-DDE
World Health Organization Drug Dictionary Enhanced/Herbal


Boehringer Ingelheim
TSAP for BI Trial No: 1321.6
Page 7 of 19
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
3.
INTRODUCTION
As per International Conference on Harmonisation (ICH) E9, the purpose of this document is
to provide a more technical and detailed elaboration of the principal features of the analysis
described in the protocol, and to include detailed procedures for executing the statistical
analysis of the primary and secondary variables and other data.
This trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned
analysis specification as written in CTP, Section 7 “Statistical Methods and Determination of
Sample Size”. Therefore, TSAP readers may consult the CTP for more background
information on the study, e.g., on study objectives, study design and population, treatments,
definition of measurements and variables, planning of sample size, randomization.
SAS® Version 9.4 will be used for all analyses.
Pharmacokinetic (PK) and pharmacodynamic (PD) parameters will be calculated using 
WinNonlinTM software (professional Network version 6.3, Pharsight Corporation, Mountain 
View, CA 94041-1530, USA).


Boehringer Ingelheim
TSAP for BI Trial No: 1321.6
Page 8 of 19
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
There has been no change in planned analyses from the statistical methods described in the
CTP.


Boehringer Ingelheim
TSAP for BI Trial No: 1321.6
Page 9 of 19
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoints will be used as defined in the CTP, Section 5.1.1.
5.2
SECONDARY ENDPOINTS
The secondary endpoints will be used as defined in the CTP, Section 5.1.2.
5.4
OTHER VARIABLES
5.4.1
Demographic data and baseline characteristics

Sex (Male, female)

Age [years]

Height [cm]

Body weight [kg]

Body mass index [kg/m2]

Smoking status (Never smoked, Ex-smoker, Currently smokes)

Alcohol status (Non-drinker, Drinks – no interference, Drinks - possibly interference)

Medical history/baseline conditions

Concomitant therapy
5.4.2
Safety data
The data used for safety assessment are specified in the CTP, Section 5.3.


Boehringer Ingelheim
TSAP for BI Trial No: 1321.6
Page 10 of 19
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT
The treatment regimens/study intervals with short label, sort order and start date/time 
included in the treatment set-up in Oracle Clinical (O*C) are described in the analysis data 
set (ADS) plan. Codes, decodes and sort order for treatment regimen included in the 
treatment set-up in O*C are described in the ADS plan. Detailed specifications are described 
in the ADS plan.
For safety analyses, the treatment assignment will be applied as defined in the CTP, Section 
7.3.4. The data recorded prior to first intake of dabigatran will be assigned to 'screening', and 
those between first intake of dabigatran until first idarucizumab intake will be assigned to 
‘dabigatran period’, and those between first intake of idarucizumab until the EOT visit will 
be assigned to ‘dabigatran + treatment’, and those between EOT visit until the end of trial 
(FU2 visit) will be assigned to ‘post- treatment’, and those after the end of trial visit 
examination will be assigned to ‘post-study’. 
6.2
IMPORTANT PROTOCOL VIOLATIONS
The Table 6.2: 1 shows a list of all important protocol violations (PVs) since they may
potentially affect the rights or safety of subjects. PVs are summarised into the following
categories. They will be determined for entered subjects only. Exclusion of patients from 
analyses due to the PVs will be discussed at the final report planning meeting/the database 
lock meeting.


Boehringer Ingelheim
TSAP for BI Trial No: 1321.6
Page 11 of 19
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 6.2: 1
Important PVs
Category/
Code
Description
Example/Comment
Excluded 
from
Program/Manual
A
Entrance criteria not met
A1
Inclusion criteria not met
A1.1
age<18 or age>45 years
IN1 not met.
None
Program + 
Manual
A1.2
Heathy volunteer criteria not met
IN2 not met.
None
Program + 
Manual
A1.3
Weight <50 kg or (BMI<19.0 or BMI 
≥24.0 kg/m2)
IN3 not met.
None
Program + 
Manual
A2
Exclusion criteria violated
Exclusion criteria 
not met as specified 
in the protocol.
None
Program + 
Manual
B
Informed consent
B1
Informed consent not available/not 
done
IN4 not met.
All
Program + 
Manual
B2
Informed consent too late
Informed consent 
date was after Visit 
1 date.
None
Program + 
Manual
C
Trial medication and randomisation
C1
Incorrect trial medication taken
Wrong medication 
None
Manual
D
Concomitant medication
D1
Prohibited medication use
Prohibited 
medication
None
Manual
6.3
PATIENT SETS ANALYSED
All analyses will be based on the treated set.

Treated set (TS):
This subject set includes all subjects who received the idarucizumab.

Pharmacokinetic set (PKS):
This subject set includes all subjects who received the idarucizumab and who had at 
least one PK parameter.

Pharmacodynamic set (PDS):
This subject set includes all subjects in the TS who provide at least one evaluable 
predose and/or one on-treatment PD observation after the start of administration of 
dabigatran. This analysis set is used for all PD analyses. 


Boehringer Ingelheim
TSAP for BI Trial No: 1321.6
Page 12 of 19
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
6.4
SUBGROUPS
No subgroup analysis is planned.
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in one centre only.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
6.6.1
Safety data
With respect to safety, it is not planned to impute any missing values except for missing
dates.
Missing or incomplete adverse event (AE) dates will be imputed according to Boehringer 
Ingelheim (BI) standards “Handling of missing and incomplete AE dates” (001-MCG-
156_RD-01[1]).
6.6.2
Pharmacokinetic data
Missing data and outliers of PK data are handled according to “Noncompartmental 
Pharmacokinetic Analyses of Clinical Studies” (001-MCS-36-472_RD-01 [2]).
6.6.3
Pharmacodynamic data
Missing data and outliers of PD data are handled as PK according to “Noncompartmental 
Pharmacokinetic Analyses of Clinical Studies” (001-MCS-36-472_RD-01 [2]).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For safety evaluation (except for ECG), the baseline will be defined as the last available 
measurement prior to the first dabigatran administration.
For PD parameters of individual subject, the baseline (Ebase) is defined as the arithmetic mean 
values at Day -1and Day 1 [0:00]. The Ebase will be used for individual calculation of the ratio 
of PD parameters [PD value at each timepoint/Ebase].
For all parameters 
, dTT and 
), reversal to baseline is defined as a coagulation 
test value being below the upper limit normal (ULN) as determined based on the pre-dose
values of the coagulation parameter prior to dabigatran drug administration in this study. In 
addition, reversal to baseline will be calculated using the ULN as determined based on the 
pre-dose values in studies of 1321.1and 1321.2 (Table 6.7: 1) as sensitivity analysis.
Table 6.7: 1
Upper limit normal values for PD parameters
dTT [s]
ULN
35.5


Boehringer Ingelheim
TSAP for BI Trial No: 1321.6
Page 13 of 19
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.
PLANNED ANALYSIS
For End-Of-Text tables for non-PK parameters, the set of summary statistics is: N / Mean / 
SD / Min / Median / Max. 
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all subjects in the respective subject
set whether they have non-missing values or not). Percentages will be rounded to one decimal 
place. The category missing will be displayed only if there are actually missing values.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the clinical trial report (CTR).
Demographic variables are described in Section 5.4.1.
7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the CTR. Concomitant diseases will be coded 
using the coding system of the Medical Dictionary for Drug Regulatory Activities 
(MedDRA). Medications will be coded using the World Health Organization Drug Dictionary 
Enhanced/Herbal (WHO-DDE).
7.3
TREATMENT COMPLIANCE
Idarucizumab will be administered and monitored by the investigator, 
 deputy or members 
of
 staff. The measured plasma concentrations of Idarucizumab will provide information 
regarding compliance. It is not intended to list the compliance separately.
7.4
PRIMARY ENDPOINT
The analysis of PK parameters is performed according to “Noncompartmental 
Pharmacokinetic Analyses of Clinical Studies” (001-MCS-36-472_RD-01 [2]).
Comparative figure of PD parameter of dTT (dTT: AUECabove, 2-12 on day 4 without 
Idarucizumab and day 11 with Idarucizumab) will be presented in the presence or absence of 
Idarucizumab.
The following analyses will be performed:

Percent (%) of subjects with dTT values (at least one value) reversed to baseline within 
time frame [completion of first infusion of Idarucizumab, completion of second infusion 
of Idarucizumb].

Percent (%) of subjects with dTT values (all values) reversed to baseline for 2, 4, 6, 12 or 
72 hours after completion of first infusion of Idarucizumab.
AUEC2-12 of individual subject will be calculated from dTT ratio. AUECabove, 2-12 based on 
dTT ratio will be calculated by subtracting the area under the 1 between 2 and 12 hour (1x 


Boehringer Ingelheim
TSAP for BI Trial No: 1321.6
Page 14 of 19
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
10[hrs]) after administration of Dabigatran from AUEC2-12 based on dTT ratio (see also, 
“Noncompartmental Pharmacokinetic Analyses of Clinical Studies” (001-MCS-36-472_RD-
01 [2])).
The percent (%) reduction in dTT of AUEC above, 2-12 based on dTT ratio from day 11
compared to day 4 will be explored.
7.5
SECONDARY ENDPOINTS
The analysis of PK parameters for secondary endpoints is performed according to
“Noncompartmental Pharmacokinetic Analyses of Clinical Studies” (001-MCS-36-472_RD-
01 [2]).
7.7
EXTENT OF EXPOSURE
Frequency and percentage of patients will be summarized by Idarucizumab doses used.


Boehringer Ingelheim
TSAP for BI Trial No: 1321.6
Page 15 of 19
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set.
7.8.1
Adverse events
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on BI 
standards as described in the BI guideline “Handling and summarisation of adverse event 
data for clinical trial reports and integrated summaries (001-MCG-156 [3]).
All reported AEs for enrolled subjects will be coded with the most recent version of the 
MedDRA.
For analysis of AE, occurrence data on CRF will be collapsed into one AE as described in the 
AE guideline. Please refer (1) (3).
The analysis of AEs will be based on the concept of treatment emergent AEs. The assignment 
of treatment regimen will be based on those defined in the CTP, Section 7.3.4.
Protocol specified adverse events of special interest (AESI) will be used as defined in the 
CTP, Section 5.3.6.1
According to ICH E3 (4), AEs classified as ‘other significant’ will include those non-serious 
and non-significant AEs with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a Report Planning Meeting.
An overall summary of AEs will be presented.
The frequency of subjects with AEs will be summarised by treatment, primary system organ 
class and preferred term. Separate tables will be provided for subjects with drug related AEs,
for subjects with serious AEs, for subjects with drug related serious AEs, for subjects with 
AESI and for subjects with other significant AEs according to ICH E3 (4).
The system organ classes will be sorted according to the standard sort order specified by
European Medicines Agency, preferred terms will be sorted by frequency (within system 
organ class).
Subjects with serious AEs, AESI or other significant AEs will be listed in Section 15.4.2 of 
the CTR.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (5). Descriptive statistics will be calculated for original and normalized (if 
applicable) values over the time and for the difference from baseline including post 
examination values. Changes from baseline to last value on treatment in categorization with 


Boehringer Ingelheim
TSAP for BI Trial No: 1321.6
Page 16 of 19
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
respect to the reference range will also be presented by frequency tables.
Anti-drug antibodies (ADA)
The analysis of anti-idarucizumab antibodies will be presented in Section 15.8 of the CTR. 
Only descriptive statistics are planned for this section of the report based on the treated set.
7.8.3
Vital signs
Only descriptive statistics of vital signs (blood pressure, PR, and body temperature) over the
time (original value and change from baseline) are planned for this section of the CTR.
7.8.4
ECG
No ECG data are collected in this study.
7.8.5
Others
A frequency table will be provided for local tolerability.


Boehringer Ingelheim
TSAP for BI Trial No: 1321.6
Page 17 of 19
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
8.
REFERENCES
1
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
2
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic Analyses of
Clinical Studies", current version; IDEA for CON.
3
001-MCG-156: "Handling and summarisation of adverse event data for clinical 
trial reports and integrated summaries", version 5; IDEA for CON.
4
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version.
5
001-MCG-157: "Display and Analysis of Laboratory Data", current version, IDEA 
for CON.


Boehringer Ingelheim
TSAP for BI Trial No: 1321.6
Page 18 of 19
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
9.
ADDITIONAL SECTIONS
Not applicable as no additional information is needed.


Boehringer Ingelheim
TSAP for BI Trial No: 1321.6
Page 19 of 19
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
10.
HISTORY TABLE
This is a revised TSAP including the following modifications to the final TSAP.
Table 10: 1
History table
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
Initial
30-Mar-17
None
This is the initial TSAP without any 
change.
Initial 
06-Apr-17
None
No change in the content, but redo the 
process due to some error in system 
process.
Final
17-Aug-17
Sections 
5, 6 & 7
This is the final TSAP. Some revisions 
are made upon the initial TSAP in 
sections 5, 6 and 7.
Revised
14-Sep-17
Section 
6.7 & 
7.4
Revise the calculation rules for reversal 
to baseline in section 6.7. Minor change 
in section 7.4 from “within 2, 4, 6, 12” 
to “for 2, 4, 6, 12” to be consistent in 
wording with other studies.