An Open-label Trial, Enrolling Subjects Aged 6 Years to Less Than 18 Years Suffering From Pain Requiring Prolonged Release Opioid Treatment, to Evaluate the Safety and Efficacy of Tapentadol PR Versus Morphine PR, Followed by an Open-label Extension
Phase: PHASE2
Conditions: Pain
Sponsor: Grünenthal GmbH

NCT02151682

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Version
Date
DMS Version:
Valid for
Original:
28 Apr 2014
DMS version 4.0
All countries
Amendment 01
26 Jun 2014
DMS version 5.0
All countries
Amendment 02
23 Jun 2015
DMS version 6.0
All countries
Amendment 03
07 Dec 2016
DMS version 7.0
United States (US)
Amendment 04
23 May 2017
DMS version 8.0
All countries
Amendment 05
27 Jul 2017
DMS version 9.0
All countries
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1
PROTOCOL SYNOPSIS
Trial objectives:
The trial objectives for Part 1 of the trial are:
•
To assess the 14-day safety and efficacy of tapentadol PR in comparison to morphine PR in 
subjects aged from 6 years to less than 18 years suffering from long-term pain requiring 
prolonged release opioid treatment.
•
To evaluate the pharmacokinetic profile of tapentadol and its major metabolite 
tapentadol-O-glucuronide after multiple doses of tapentadol PR tablets. 
The trial objective for Part 2 of the trial is:
•
To describe the long-term safety profile covering up to a 12-month period with treatment of 
tapentadol PR taken twice daily (Tapentadol Period) in subjects aged 6 years or older 
suffering from long-term pain requiring prolonged release opioid treatment, or in subjects 
without tapentadol treatment (Observation Period) aged 6 years or older who have received 
at least 1 dose of investigational medicinal product (IMP).
Trial design:
This is a 2-part trial: 
Part 1 is a 14-day (Treatment Period) Phase II/III, randomized, multi-site, open-label, 
active-controlled, parallel group trial in subjects aged 6 years to less than 18 years, suffering from 
long-term pain requiring prolonged release opioid treatment. The target is to allocate 69 subjects in 
a ratio of 2:1 to treatment with tapentadol PR or morphine PR twice daily.
Blood samples for pharmacokinetic evaluations will only be drawn from subjects on tapentadol PR.
Part 2 is an open-label Extension Period with tapentadol treatment (Tapentadol Period) or an 
observation period without tapentadol treatment (Observation Period) lasting for up to 12 months.
Definition of the primary endpoint
Part 1 (primary analysis of the trial)
The primary endpoint is a binary variable “responder”. A subject is defined as “responder” if both 
of the following criteria are met:
•
Completion of the 14-day Treatment Period (Part 1).
•
One of the following calculated from the scheduled pain assessments (“pain right now”) 
documented during the last 3 days of the Treatment Period:
−
Average pain <50 on a visual analog scale (VAS) for subjects aged 12 years to less 
than 18 years; or <5 on the Faces Pain Scale–revised (FPS-R) for subjects aged 6 years 
to less than 12 years.
−
Average reduction from baseline of pain ≥20 on a VAS for subjects aged 12 years to 
less than 18 years; or ≥2 on the FPS-R for subjects aged 6 years to less than 12 years.
The proportion of subjects classified as responders will be assessed and compared between the 
treatment groups.
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Age groups are determined at Visit V2. Baseline pain is defined as “pain right now” at Visit V2, 
and will be assessed before any painful or unpleasant procedure, and before the first intake of IMP. 
Definition of the secondary endpoints
The main secondary endpoints are:
Part 1
•
Constipation as assessed by changes from baseline (Visit V2) of total scores for the 
modified constipation assessment scale (CAS).
Part 1 and Part 2
•
Tolerability as assessed by the number and type of adverse events and adverse drug 
reactions by treatment group during the different trial periods, on a subject and event level.
Definition of other endpoints
Other endpoints compared between treatment groups at each measurement time point are: 
Part 1 - Treatment Period, other endpoints (baseline is the value at Visit V2):
•
Pain as assessed by changes from baseline using the VAS.
•
Pain as assessed by changes from baseline using the FPS-R.
•
Use of rescue medication as assessed by number of doses of rescue medication taken at 
different dose levels of IMP.
•
Description of population pharmacokinetics of tapentadol and tapentadol-O-glucuronide. 
•
Palatability and acceptability as assessed by differences within treatment groups of the 5-
point hedonic faces scale with the verbal rating score at Visit V3 and Visit VE (the End of 
Treatment Visit).
Part 2 - Tapentadol Period, other endpoints (baseline is the value at Visit VE):
•
Pain as assessed by changes from baseline using the VAS.
•
Pain as assessed by changes from baseline using the FPS-R.
•
Constipation as assessed by changes from baseline of total scores for the modified CAS.
Part 2 - Observation Period, other endpoints (baseline is the value at Visit VE or Visit ET [Early 
Termination Visit]):
•
Constipation as assessed by changes from baseline of total scores for the modified CAS.
Part 1 or Part 2 - other endpoints:
•
Opiate withdrawal symptoms as assessed by the scale score of the subjective opiate 
withdrawal scale (SOWS) questionnaire at individual time points and changes to baseline.
•
Time to discontinuation of IMP assessed by a survival analysis.
Trial population
Subjects will be enrolled who are aged 6 years to less than 18 years (for the duration of Part 1 of the 
trial) and suffer from long-term pain requiring prolonged release opioid treatment for at least 
14 days after Visit V2 (Allocation Visit; Day 1), and who comply with the inclusion/exclusion 
criteria given in Section 1.3. Long-term pain is defined as any pain condition that requires a 
minimum of 14 days of treatment with a strong oral opioid. Subjects that could be considered for 
the trial include, but not exclusively, those with expected long-term post-surgical pain (e.g., spinal
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surgery), cancer-related pain (including pain caused by treatment) as well as chronic indications 
with moderate to severe pain.
The age groups of 6 years to less than 12 years and 12 years to less than 18 years are predefined. 
At least 25% of the subjects will be allocated to IMP at Visit V2 in the age group of 6 years to less 
than 12 years. At least 15 subjects must be treated with tapentadol PR for a minimum of 12 weeks.
Trial treatments
The 2 IMPs are:
•
Tapentadol PR tablets containing 25 mg or 100 mg tapentadol (Part 1 and Tapentadol
Period of Part 2).
•
Morphine PR tablets containing 10 mg or 30 mg morphine sulfate (Part 1 only).
The IMP will be taken for 14 days in Part 1. 
Regardless of the treatment received during the treatment period, subjects who are still in need of a 
prolonged release opioid will be given the possibility to enter the Tapentadol Period (Part 2) for up 
to 12 months. Dosing will be twice daily with a dosing interval of ~12 hours (but not less than 
6 hours). 
The initial dose administered will be adjusted to the weight of the subject and then titrated to the 
subject’s optimal dose (see Section 10.2.3 of the body of the protocol). Subjects will be titrated to 
the therapeutic effect, defined as a balance between self-reported analgesia and side effects based 
on the judgment of the investigator and within the given limits as defined per weight group (see 
Table 2 for tapentadol PR and Table 3 for morphine PR in the body of the protocol) after consulting 
the investigator at visits or by using telephone contacts throughout the period of treatment with 
IMP, in Part 1 and Part 2.
Doses may only be increased after a minimum of 2 days (4 scheduled intakes of IMP) on a dose.
The dose can be reduced at any time, but the investigator must be informed as soon as possible.
Rescue medication
During Part 1 only, morphine oral solution will be supplied by the sponsor as rescue medication for 
both treatment groups.
Concomitant medications/therapies
All medications/therapies that are not explicitly mentioned under allowed or forbidden treatments 
are also considered to be allowed.
Subjects will be allowed to participate in trials of marketed therapeutic medications and therapies
(including trials of antibody therapies) at the same time as participating in this trial.
Allowed concomitant medications/therapies with timely or dose restrictions are:
On the day of allocation to IMP (Visit V2):
•
Weak and strong opioids up to a morphine-equivalent dose of <3.5 mg/kg per day.
During the Treatment Period (from Visit V2 to Visit VE):
•
Rescue medication (morphine oral solution) provided by the sponsor.
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During the Treatment Period (from Visit V2 to Visit VE) and Tapentadol Period (from Visit VE 
until Visit ET/Visit F12M):
•
Intravenous opioids during surgery.
During the Tapentadol Period (from Visit VE until Visit ET/Visit F12M):
•
Immediate release strong opioids for treatment of breakthrough pain and incidental pain. 
Forbidden prior and concomitant medication/therapies are:
Before allocation to IMP (Visit V2) and during the Treatment Period (from Visit V2 to Visit VE) 
and Tapentadol Period (from Visit VE until Visit ET/Visit F12M):
•
From 14 days prior to Visit V2 until the last intake of IMP: Monoamine oxidase inhibitors. 
•
From 30 days prior to Visit V2 until the last intake of IMP: Any medication or medical 
devices without a marketing authorization for human use.
Subjects may not undergo a washout of the above for the purposes of the trial.
During the Treatment Period (from Visit V2 to Visit VE) and Tapentadol Period (from Visit VE 
until Visit ET/Visit F12M):
•
Non-trial supplied opioids (unless covered by allowed concomitant treatments).
Caution should be exercised with concomitant medication that:
•
May enhance the risk of central nervous or respiratory depression.
•
Is a serotoninergic medicinal product (e.g., selective serotonin re-uptake inhibitors). 
•
Is a strong enzyme inducer (e.g., rifampicin, phenobarbital, St John’s Wort) that is started 
or stopped during the intake of IMP.
Trial period
Estimated date of first subject in: Oct 2014.
Part 1, estimated date of last subject out: Sep 2018.
Part 2, estimated date of last subject out: Sep 2019.
Each subject is expected to be treated with IMP for 14 days in Part 1. Subjects will be in Part 2 for 
up to 12-months. In total, for each subject, the trial duration will be ~13 months.
Course of the trial
The trial will comprise 2 parts.
Part 1: After the Enrollment Visit, all subjects complying with the inclusion/exclusion criteria will 
enter Part 1. Part 1 of the trial will be completed after the last subject has attended Visit VE. Data of 
Part 1 will comprise the primary analysis of the trial.
Blood samples for pharmacokinetic evaluations will only be drawn from subjects on tapentadol PR.
Part 2 comprises a 12-month Extension Period with tapentadol treatment (Tapentadol Period) or 
without treatment (Observation Period).
Tapentadol Period (12 months): Subjects completing the Treatment Period (Part 1) with 
tapentadol PR or morphine PR and who have need for continued opioid treatment can enter the 
Tapentadol Period. They will be treated with tapentadol PR for up to 12 months until Visit F12M (a 
12-month visit relative to Visit VE). As withdrawal symptoms may occur in subjects transferring 
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from morphine PR to tapentadol PR, because they start tapentadol PR at 70% of the equivalent 
morphine dose, these subjects will have 2 additional visits at the beginning of the Part 2 Tapentadol 
Period (Visit M1 and Visit M2). 
Observation Period (12 months): Subjects not completing the Treatment Period (Part 1), but who 
have taken at least 1 dose of IMP, and those who complete the Treatment Period but do not want to 
continue with tapentadol PR, will enter the Observation Period (12 months). Subjects will be 
followed until Visit F12M. Subjects in the Tapentadol Period of Part 2 may stop treatment early 
(before Visit F12M) and switch to Observation period for the remainder of Part 2.
Part 2 of the trial will be completed after the last subject has completed or discontinued from the 
trial.
See Section 1.1 for a summary of the trial as a flow diagram and Section 1.2 for tabular schedules 
of events for each period.
Blood sampling volumes
The volumes of blood taken for each assessment may vary due to trial site requirements; however, 
the expected total blood volume drawn per subject during the trial (Part 1: 12 mL and Part 2: 
25 mL) should not generally exceed 37 mL (excluding any blood that is discarded). Additional 
blood may be drawn if a (serious) adverse event occurs or if the investigator considers it necessary. 
Key data collected
Subject characteristics data:
•
Demographic data (date of signing the informed consent/assent form, sex, age, and 
race/ethnicity).
•
Medical history including pain history.
•
Prior and concomitant medication and therapies.
Other data:
•
Acceptability and palatability of IMP.
Pharmacokinetic data:
•
Serum pharmacokinetics (serum concentrations of tapentadol and
tapentadol-O-glucuronide). Blood samples for pharmacokinetic evaluations will only be 
drawn from subjects on tapentadol PR.
Safety data:
•
Adverse events.
•
Vital signs (respiratory rate, systolic and diastolic blood pressure, and pulse rate).
•
Twelve-lead electrocardiogram (ECG).
•
Safety laboratory (hematology, clinical chemistry, and urinalysis).
•
Urine test for drugs of abuse outcome.
•
Urine pregnancy test outcome.
•
Physical examination.
•
Height and body weight.
•
SOWS questionnaire.
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•
Modified CAS questionnaire.
Efficacy data:
•
Pain intensities assessed using a VAS and the FPS-R.
•
Rescue medication use.
Population pharmacokinetic and pharmacokinetic/pharmacodynamic methods
Pharmacokinetic data collected in this trial will be used to validate exposure predictions obtained 
with a pediatric tapentadol PR population-pharmacokinetic model developed previously by the 
sponsor. The validation process will enable assessment of tapentadol accumulation in this pediatric 
population during administration of tapentadol PR. The model will be subsequently updated with 
the pharmacokinetic data collected in this trial.
Sample size rationale
The sample size was estimated to reject the null hypothesis of the inferiority of tapentadol PR to 
morphine PR when comparing responders evaluated at the end of the 14-day Treatment Period 
(Part 1, i.e., the primary endpoint). The percentage of responders in both treatment groups is 
estimated to be 80% based on data from previous trials and extrapolation to the trial population 
under investigation. The non-inferiority margin is set to a difference of 20% for the primary 
endpoint.
To show the non-inferiority of tapentadol PR compared to morphine PR using a Farrington-
Manning test by a non-inferiority margin of 20% with at least 80% power and a 1-sided 
significance level of alpha = 0.1, 69 subjects are required in the Full Analysis Set (FAS), assuming 
a 2:1 randomization of tapentadol PR:morphine PR.
Statistical methods
Separate analyses will be performed for Part 1 and Part 2. The analysis for Part 1 will take into 
consideration the Treatment Period of Part 1. The analysis for Part 2 will take into consideration the 
Tapentadol Period and Observation Period of Part 2.
Part 1
For the Treatment Period, baseline measurements are defined as the last evaluation performed 
before starting IMP (i.e., Visit V1, Visit V2, or an unscheduled visit).
For pain assessments, the baseline pain is defined as “pain right now” at Visit V2, and will be 
assessed before any painful or unpleasant procedure, and before the first intake of IMP.
Part 2
For the Tapentadol Period, baseline measurements are defined as the last evaluation performed 
before or at Visit VE.
For the Observation Period, baseline measurements are defined as the last evaluation performed 
before or at:
•
Visit VE for subjects entering the Observation Period directly after Part 1.
•
Visit ET for subjects switching from the Tapentadol Period to the Observation Period.
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General
For continuous variables, descriptive statistics will include the number of observations, arithmetic 
mean, standard deviation, minimum, first quartile (Q1), median, third quartile (Q3), and maximum. 
For categorical variables, frequency counts and percentages will be used to summarize the results. If 
applicable, changes from the baseline or predefined time points will be presented descriptively.
Data will also be listed and summarized using graphical displays, as appropriate.
Main analysis of the trial
The main analysis of the trial will be performed after all subjects have completed the first 12 weeks
(Visit TP3 or Visit OP3) of Part 2.
Primary efficacy endpoint
The analysis of the primary endpoint will be performed on the data collected during the Treatment 
Period (Part 1). The FAS will be the primary analysis set and the Per Protocol Set will be used as a 
sensitivity analysis set. The primary analysis will assess the null-hypothesis of inferiority of the 
responder rate of tapentadol PR compared to the responder rate of morphine PR versus the 
alternative, that the responder rate of tapentadol PR is non–inferior to the responder rate of 
morphine PR by a non-inferiority margin of a difference of 20%. 
As this endpoint is a binomial event rate, it will be summarized by descriptive statistics grouped by 
treatment group. The standard maximum likelihood estimators for the proportion of subjects 
classified as responders in each group will be the estimated proportions adjusted for the baseline 
pain intensity, age group, and underlying pain condition. To obtain these estimators, a logistic 
regression model will be fitted to the response using the baseline pain intensity, age group, 
treatment, and underlying pain condition as explanatory variables. The Farrington-Manning test will 
then be applied and an 80% confidence interval calculated.
In addition, a Bayesian logistic regression model will be fitted as a sensitivity analysis.
Analysis of safety data
Adverse events will be categorized by seriousness, intensity, outcome, countermeasures, and 
relationship to IMP and will be tabulated by system organ class and preferred term. Adverse events 
will be tabulated separately for the treatment periods.
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1.1
Flow diagram summary of the trial (Part 1 and Part 2)
1.1.1
Flow diagram for subjects completing Part 1 and Part 2
Vx = visit number x; VE = End of Treatment Visit for the Treatment Period; F12M = visit 12 months after Visit VE; 
F7D = final post treatment visit; OPx = an unscheduled visit in the Observation Period when the subject stops further 
participation in the trial; Visit OPn = visit at n months in the Observation Period; PR = prolonged release.
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1.1.2
Flow diagram for subjects discontinuing investigational medicinal 
product or the trial during Part 1 or Part 2
Subjects transferring before Visit F12M from the Tapentadol Period to the Observation Period will continue in the 
Observation Period starting from the same trial day number.
Vx = visit number x; VE = End of Treatment Visit for the Treatment Period; ET = early termination Visit after stopping 
investigational medicinal product during the Tapentadol Period; F12M = visit 12 months after Visit VE; F7D = final 
post treatment visit; OPx = an unscheduled visit in the Observation Period when the subject stops further participation 
in the trial; Visit OPn = visit at n months in the Observation Period; PR = prolonged release.
1.2
Schedule of events
The visit time windows are not cumulative, and visits should be performed at the times specified 
within the given time window.
Phone contacts can be made at any time, e.g., if the subject wants to report adverse events, or has 
questions regarding concomitant medication intake/therapies. If no trial site visit takes place, phone 
contacts are mandatory if the subject would like to up or down titrate the IMP. A trial site visit may 
be performed as a home visit after prior approval by the sponsor.
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1.2.1
Part 1: Enrollment Visit and Treatment Period (Visit V1 to Visit VE)
Period
Enrollment
Treatment Period
Visit
V1
V2
V3
VEa
F7Db
Day (range)
-14 to 1
1
8 (±1)
15 (±1)
Obtain informed consent/assent s
X
Record demographic data
X
Record age
X
Xc
X
Record medical history
X
Record pain history
X
Record prior medication intake/therapies
X
Record concomitant medication intake/therapies
X
Xc
X
X
X
Perform physical examination 
X
Xc,d
Xd
Xd
Record height
X
X
Record body weight
X
Xc
X
X
Record vital signs
X
Xc
X
X
X
Record 12-lead ECG t
X
X
Take blood for central laboratory
X
X
Take blood for local laboratory e
X
Perform urine pregnancy test f
X
X
Collect urine/perform dip stick urinalysis (safety laboratory)
X
X
Perform urine test for drugs of abuse
X
Evaluate subject suitability for trial participation: Check 
inclusion/exclusion criteria g
X
X
Diary set up
X
Dispense diary
X
Train/instruct subjects, parents, or legal guardian how:
1. To use the diary to record pain assessments twice daily 
(VAS and FPS-R) k until Visit VE.
2. To record intake of IMP and rescue medication, including
time of administration.
X
X
Xh
Check diary compliance
X
X
Collect diary
Xi
Record pain assessment in diary (VAS, FPS-R)
Xj
Record “pain right now” in CRF (VAS, FPS-R)
Xh
Complete questionnaires l
- Modified constipation assessment scale
X
X
X
- Subjective opiate withdrawal scale
Xm,b
Xm
- Acceptability and palatability of IMP
X
X
Allocate subjects 
X
Collect returned IMP and rescue medication
X
X
Perform drug accountability n
X
X
Dispense IMP (the first dose of IMP will be taken during 
Visit V2, within 24 hours after randomization. Day 1 is the 
X
X
Xh
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Period
Enrollment
Treatment Period
Visit
V1
V2
V3
VEa
F7Db
Day (range)
-14 to 1
1
8 (±1)
15 (±1)
day of first IMP intake)
Dispense rescue medication
X
X
Discuss IMP titration/dose adjustment 
X
X
Xh
Train/instruct subject, parent(s), guardian(s), or caregiver on 
IMP/rescue medication use. Exchange instruction sheet if 
necessary (e.g., due to weight change).
X
X
Xh,o
Take blood sample for serum pharmacokinetics p
X
X
X
Dispense subject trial card
X
Assess/record adverse events
X
Xc
X
X
X
Document changes of each ongoing adverse event
X
Check discontinuation criteria for IMP intake
X
X
Check subject eligibility for the Tapentadol Period or 
Observation Period and assign subject to Tapentadol Period 
or Observation Period
Xq,r
Instruct the subject, parent(s), legal guardian(s), or caregiver 
about the Tapentadol and Observation Periods
X
Complete end of trial tasks, e.g., collect subject trial cards (if
the subject is discontinuing from the trial)
X
Non-invasive procedures, e.g., recording of pain assessment, should be performed before invasive procedures.
a) Visit VE must also be performed within 3 days after last intake of IMP if IMP is stopped during the Treatment 
Period.
b) Only for subjects going in to the Observation Period. This visit is performed 7 (±2) days after the last intake of IMP.
c) If Visit V1 and Visit V2 are on the same day, assessments scheduled for both visits will not be repeated at Visit V2.
d) Document that a physical examination was performed and record the changes from the previous assessment.
e) Local laboratory parameters needed are: total serum bilirubin, serum albumin, aspartate transaminase, alanine 
transaminase, and serum creatinine (the creatinine clearance will be calculated in the electronic CRF). The local 
laboratory sample does not need to be taken at the Enrollment Visit if suitable results from the same local laboratory are 
available from a blood sample obtained in the 14 days prior to Visit 2 for other reasons.
f) In female subjects who are post-menarchal or older than 12 years at the time of the scheduled visit.
g) Compliance with the exclusion criteria will be checked based on local laboratory values. 
h) Only for subjects going into the Tapentadol Period (except for recording rescue medication).
i) Not for subjects entering the Tapentadol Period (Part 2). 
j) “Pain right now” will be documented in the diary at Visit V2 using the VAS and FPS-R before any painful or 
unpleasant procedure, and before the first intake of IMP as a baseline value. 
k) “Pain right now” will be documented in the diary twice daily (preferably before dosing).
l) The caregiver, parent, or legal guardian may assist the subject completing the questionnaires.
m) Complete once daily until the seventh day after the last intake of IMP. At Visit VE, or earlier if applicable, dispense 
the questionnaires. At Visit F7D, collect the completed questionnaires. 
n) Comprises:
•
Confirm and document compliance with IMP intake.
•
Confirm whether returned amount of rescue medication matches expected amount to be returned. 
•
Verify discrepancies with subject, or parent(s), legal guardian(s), or caregiver.
o) Train subject, parent(s), or guardian(s) on tapentadol PR use for subjects entering the Tapentadol Period of Part 2.
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p) Samples will only be drawn from subjects on tapentadol PR for the determination of serum concentrations of 
tapentadol and tapentadol-O-glucuronide: 1 sample at Visit V2 (1 hour to 6 hours after IMP intake for out-patients and 
3 hours to 6 hours after IMP intake for hospitalized subjects), 1 sample at Visit V3, and 1 sample at Visit VE (at any 
time during the visit, but after pain assessments). 
q) Subjects completing the Treatment Period (Part 1) with tapentadol PR or morphine PR and who have need for 
continued opioid treatment can enter the Tapentadol Period. Subjects not completing the Treatment Period (Part 1), but 
who have taken at least 1 dose of IMP, and those who complete the Treatment Period but do not want to continue with 
tapentadol PR, will enter the Observation Period (12 months). Subjects will be followed until Visit F12M. Subjects in 
the Tapentadol Period of Part 2 may stop treatment early (before Visit F12M) and switch to Observation period for the 
remainder of Part 2.
r) Assignment needs to be documented in the case report form and the interactive response technology system. 
s) The informed consent/assent may be obtained earlier than Day -14.
t) The inclusion as well as discontinuation of a subject will be based on the judgment of the investigator. If the subject
has been included but fulfills any of the discontinuation criteria based on the ECG analysis report of the central ECG 
laboratory, the ECG must be repeated within 1 week of receiving the central ECG report and the subject must be 
discontinued if any of the discontinuation criteria is confirmed by the investigator.
Demographic data = date of signing the informed consent/assent form, sex, age, and race/ethnicity; Safety
laboratory = hematology, clinical chemistry, and urinalysis; Serum pharmacokinetics = serum concentrations of 
tapentadol and tapentadol-O-glucuronide; Vital signs = respiratory rate, systolic and diastolic blood pressure, and pulse 
rate.
VE = End of Treatment Visit after stopping IMP during the Treatment Period; Vx = visit number x; F7D = final post 
treatment visit; F12M = visit 12 months after Visit VE.
CRF = case report form; ECG = electrocardiogram; IMP = investigational medicinal product; FPS-R = Faces Pain 
Scale-revised; VAS = visual analog scale; PR = prolonged release.
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1.2.2
Part 2: Tapentadol Period
Period
Tapentadol Period 
Visit 
M1 a
M2 a
TP1
TP2
TP3
TP4
TP5
TP6
TP7
TP8
TP9
TP10
TP11
TP12
ETbc
F12Mb
F7Dd
Day (range)
7 (±2)
14 (±2)
28 (±5)
56 (±5)
84 (±5)
112 (±5)
140 (±5)
168 (±5)
196 (±5)
224 (±5)
252 (±5)
280 (±5)
308 (±5)
336 (±5)
Early
Termin-
ation
365 
(±14)
Record concomitant medication 
intake/therapies
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Perform physical examination
Xe
Xe
Xe
Record height
X
X
X
X
X
X
Record body weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete questionnaires f
- Modified constipation 
assessment scale
X
X
- Subjective opiate withdrawal 
scale
Xg
Xg
Xg
Record “pain right now” in CRF 
(VAS, FPS-R)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Take blood for central laboratory
X
X
X
X
X
X
Collect urine/perform dip stick 
urinalysis (safety laboratory)
X
X
X
X
X
X
Perform urine pregnancy test h
X
X
X
X
X
X
Train/instruct subject how to use 
diary to record intake of IMP, 
including time of administration.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Period
Tapentadol Period 
Visit 
M1 a
M2 a
TP1
TP2
TP3
TP4
TP5
TP6
TP7
TP8
TP9
TP10
TP11
TP12
ETbc
F12Mb
F7Dd
Day (range)
7 (±2)
14 (±2)
28 (±5)
56 (±5)
84 (±5)
112 (±5)
140 (±5)
168 (±5)
196 (±5)
224 (±5)
252 (±5)
280 (±5)
308 (±5)
336 (±5)
Early
Termin-
ation
365 
(±14)
Check diary compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect diary
X
X
Collect returned IMP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Perform drug accountability i
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense IMP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Discuss IMP titration/dose 
adjustment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Train/instruct subject, parent(s), 
guardian(s), or caregiver on IMP 
use. Exchange instruction sheet 
if necessary (e.g., due to weight 
change)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess/record adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Check discontinuation criteria
for IMP intake
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete end of trial tasks, e.g., 
collect subject trial cards
X
Days are referenced by last intake of IMP in Part 1. 
a) Visit M1 and Visit M2 are only for subjects who were allocated to morphine PR in the Treatment Period.
b) If Visit F12M and Visit ET are performed on the same day, assessments scheduled for both visits will not be repeated at Visit F12M.
c) Visit ET must be performed within 3 days after last intake of IMP if IMP is stopped before Visit F12M in Part 2.
d) Visit F7D is performed 7 (±2) days after the last intake of IMP.
e) Document that a physical examination was performed and record the changes from the previous assessment.
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f) The caregiver, parent, or legal guardian may assist the subject completing the questionnaires.
g) Once daily until the seventh day after the last intake of IMP (normally Visit F12M or at Visit ET in case of early termination). At Visit F12M, or as applicable, dispense the 
questionnaires. At Visit F7D, collect the completed questionnaires.
h) In female subjects who are post-menarchal or older than 12 years at the time of the scheduled visit.
i) Comprises:
•
Confirm and document compliance with IMP intake.
•
Verify discrepancies with subject, or parent(s), legal guardian(s), or caregiver.
Safety laboratory = hematology, clinical chemistry, and urinalysis; Vital signs = respiratory rate, systolic and diastolic blood pressure, and pulse rate.
VE = End of Treatment Visit after stopping IMP during the Treatment Period; ET = Early termination Visit after stopping IMP during the Tapentadol Period; F12M = visit 
12 months after Visit VE; F7D = final post treatment visit; Visit TPx = visit at n months during the Tapentadol Period.
FPS-R = Faces Pain Scale-revised; Modified CAS = modified constipation assessment scale; SOWS = subjective opiate withdrawal scale; VAS = visual analog scale; CRF = case 
report form; IMP = investigational medicinal product.
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1.2.3
Part 2: Observation Period
Period
Observation Period
Visit
OP3
OP6
OP9
OPx
F12M a
Month (range: ±14 days)
3
6
9
(unscheduled)
12
Record concomitant medication intake/therapies
X
X
X
X
X
Perform physical examination
Xa,b
Xb
Record height
Xa
X
Record body weight
Xa
X
Record vital signs (respiratory rate, systolic and diastolic 
blood pressure, and pulse rate)
Xa
X
Complete modified constipation assessment scale 
questionnaire c
Xa
X
Take blood for central laboratory (hematology, clinical 
chemistry)
Xa
X
Collect urine/perform dip stick urinalysis
Xa
X
Assess/record adverse events
X
X
X
X
X
Complete end of trial tasks, e.g., collect subject trial 
cards
X
X
Months are referenced by last intake of IMP in Part 1.
a) Assessments are performed for all subjects who discontinue from the Observation Period, unless informed consent is 
withdrawn. 
b) Document that a physical examination was performed and record the changes from the previous assessment.
c) The questionnaire will be filled in by the subject, caregiver, parent or legal guardian.
Visit OPx = an unscheduled visit in the Observation Period when the subject stops further participation in the trial; 
F12M = visit 12 months after Visit VE; Visit OPn = visit at n months in the Observation Period.
IMP = investigational medicinal product.
1.2.4
Phone contacts
Phone contacts can be made at any time, e.g., if the subject wants to report adverse events, or has 
questions regarding concomitant medication intake/therapies. If no trial site visit takes place, phone 
contacts are mandatory if the subject would like to up or down titrate the IMP. A trial site visit may 
be performed as a home visit after prior approval by the sponsor.
Phone contact
Record concomitant medication intake/therapies
X
Discuss titration/dose adjustment
X
Record reason for dose adjustment and new dose, if applicable
X
Assess/record adverse events
X
Check discontinuation criteria
X
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1.3
Inclusion/exclusion criteria
1.3.1
Inclusion criteria
Subjects are eligible for the trial at Visit V1 if all the following apply:
Inclusion criteria
Rationale for criterion
1.
Informed consent/(if applicable) assent obtained.
Legal requirement.
2.
Male or female subject at least 6 years of age at the Enrollment 
Visit and less than 18 years of age on the predicted day of 
Visit VE.
Standardization of trial 
population.
3.
Subject has an underlying long-term pain condition (e.g., cancer, 
chronic disease, planned or performed surgery) that is, according 
to the judgment of the investigator, expected to require a twice-
daily prolonged release opioid treatment until at least the end of 
the 14-day Treatment Period (Visit VE).
Standardization of trial 
population.
4.
Subject can swallow tablets of appropriate size.
Logistical requirement.
5.
Subject is able to participate in the trial as planned and willing to 
comply with the requirements of the protocol including refraining
from drinking beverages containing alcohol and recreational intake 
of drugs while on IMP.
Safety, standardization 
of trial population, and 
practical consideration.
Subjects must satisfy the following criteria at Visit V2 to be allocated to IMP:
Inclusion criteria
Rationale for criterion
6.
Less than 18 years of age on the planned day of Visit VE.
Standardization of trial 
population.
7.
No opioid intake or last calculated morphine equivalent dose at day 
of allocation of <3.5 mg/kg per day.
Standardization of trial 
population.
8.
Subject has a body weight of 17.5 kg.
Standardization of trial 
population.
9.
If a female of childbearing potential (post-menarchal and not 
surgically incapable of childbearing) and sexually active, must 
practice an effective method of birth control (e.g., prescription oral 
contraceptives, contraceptive injections, intrauterine device, 
double-barrier method, contraceptive patch) before allocation to 
IMP until the end of intake of IMP.
Safety.
10. If a female and post-menarchal or older than 12 years, has a 
negative urine pregnancy test on the day before or on the day of 
allocation to IMP. 
Safety.
Note: Subjects will only receive IMP if documentation is available showing that they comply with all inclusion criteria. 
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1.3.2
Exclusion criteria
Subjects are not eligible for the trial if any of the following apply:
The following will be checked at Visit V1:
Exclusion criteria 
Rationale for 
criterion
1.
Has been previously enrolled in this trial or a previous trial with 
tapentadol.
Ethics and interference 
with trial assessments.
2.
Has a clinically relevant history of hypersensitivity, allergy, or 
contraindication to morphine or tapentadol or any ingredient, 
including galactose intolerance (see investigator’s brochure for 
tapentadol PR and summary of product characteristics for 
morphine PR), or naloxone.
Safety.
3.
History or current condition of any one of the following: 
•
Seizure disorder or epilepsy.
•
Serotonin syndrome.
•
Traumatic or hypoxic brain injury, brain contusion, stroke, 
transient ischemic attack, intracranial hematoma, posttraumatic 
amnesia, brain neoplasm, or episode(s) of more than 24 hours 
duration of unconsciousness.
Safety and interference 
with trial assessments.
4.
History or current condition of any one of the following:
•
Moderate to severe renal or hepatic impairment.
•
Abnormal pulmonary function or clinically relevant respiratory 
disease (e.g., acute or severe bronchial asthma, hypercapnia).
•
Complex regional pain syndrome.
•
A pain indication with a strong psycho-somatic component that,
in the judgment of the investigator, is unlikely to respond to 
opioids.
Safety and interference 
with trial assessments.
5.
History of alcohol or drug abuse in the investigator’s judgment, 
based on history and physical examination. Drugs of abuse detected 
in urine screen unless explained by allowed concomitant medication 
(see synopsis section Concomitant medications/therapies).
Safety.
6.
Subject has:
•
A clinically relevant abnormal ECG.
•
Signs of pre-excitation syndrome.
•
Brugada’s syndrome.
•
QT or QTcF (Fridericia) interval >470 ms.
Safety.
7.
Any surgery scheduled during Part 1 of the trial that is expected to 
require post-surgical intensive care unit (ICU) treatment, or that 
Safety.
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Exclusion criteria 
Rationale for 
criterion
requires post–surgical parenteral pain-treatment, or may, in the 
opinion of the investigator, affect the safety of the subject.
8.
Subject is not able to understand and comply with the protocol as 
appropriate for the age of the subject or subject is cognitively 
impaired in the investigator’s judgment such that they cannot 
comply with the protocol.
Ethical requirement
and interference with 
trial assessments.
9.
Subject, parent or the legal representative is an employee of the 
investigator or trial site, with direct involvement in the proposed 
trial or other studies under the direction of that investigator or trial 
site, or family member of the employees or the investigator.
Good Clinical Practice.
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The following will be checked at Visit V1 and Visit V2:
Exclusion criteria 
Rationale for 
criterion
10. Has a concomitant disease or disorder (e.g., endocrine, metabolic, 
neurological, psychiatric, infection) that in the opinion of the 
investigator may affect or compromise subject safety during the trial 
participation.
Safety.
11. Pancreatic/biliary tract disease (e.g., pancreatitis) or paralytic ileus.
Safety.
12. Intake of forbidden concomitant medication/use of forbidden 
therapies (see synopsis section Concomitant medications/therapies).
Safety and 
standardization of trial 
population.
13. Female subject breast-feeding a child.
Safety.
The following will be checked at Visit V2:
Exclusion criteria 
Rationale for 
criterion
14. Has received a drug or used a medical device not approved for 
human use within 30 days prior to Visit V2. 
Safety and 
standardization of trial 
population.
15. Based on data from the local laboratory, one or more of:
•
Total serum bilirubin >2.0 mg/dL.
•
Serum albumin <2.8 g/dL.
•
Aspartate transaminase or alanine transaminase >5-times upper 
limit of normal.
Safety.
16. Based on data from the local laboratory, creatinine clearance 
<30 mL/min per 1.73 m2 (calculated according to a formula that is 
appropriate for the respective age group).
Safety.
17. [criteria deleted]
Ethics and interference 
with trial assessments. 
Note: Subjects will only receive IMP if documentation is available showing that they do not meet any of the exclusion 
criteria.
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1.3.3
Inclusion criteria for the Tapentadol Period (Part 2)
Inclusion criteria
Rationale for 
criterion
18. Subject has completed the 14-day Treatment Period. 
Standardization of trial 
population.
19. Subject is still in need of prolonged release opioid treatment. 
Ethics and 
standardization of trial 
population.
20. Subject does not meet any of the compulsory discontinuation criteria 
(described in Section 9.3.1 of the body of the protocol). 
Safety. 
Note: Subjects will only receive tapentadol PR in the Tapentadol Period if documentation is available showing that they 
comply with these inclusion criteria. 
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2
TABLE OF CONTENTS
1
PROTOCOL SYNOPSIS
3
1.1
Flow diagram summary of the trial (Part 1 and Part 2)
10
1.1.1
Flow diagram for subjects completing Part 1 and Part 2
10
1.1.2
Flow diagram for subjects discontinuing investigational medicinal 
product or the trial during Part 1 or Part 2
11
1.2
Schedule of events
11
1.2.1
Part 1: Enrollment Visit and Treatment Period (Visit V1 to Visit VE)
12
1.2.2
Part 2: Tapentadol Period
15
1.2.3
Part 2: Observation Period
18
1.2.4
Phone contacts
18
1.3
Inclusion/exclusion criteria
19
1.3.1
Inclusion criteria
19
1.3.2
Exclusion criteria
20
1.3.3
Inclusion criteria for the Tapentadol Period (Part 2)
23
2
TABLE OF CONTENTS
24
3
ABBREVIATIONS AND DEFINITION OF TERMS
29
4
ETHICS
30
4.1
Independent ethics committee(s) or institutional review board(s)
31
4.2
Subject information and informed consent
31
4.3
Informing the subject’s healthcare provider
31
5
INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE
32
5.1
Investigators and trial site personnel
32
5.1.1
Investigators
32
5.1.2
Trial site personnel assigned trial-related duties
32
5.2
Contract research organizations
33
5.3
The sponsor and sponsor’s personnel
33
5.4
Data monitoring committee
33
6
INTRODUCTION AND TRIAL BACKGROUND
33
6.1
Background to the investigational medicinal product
33
6.2
Relevant non-clinical and clinical data
33
7
TRIAL OBJECTIVES
37
8
TRIAL DESIGN
37
8.1
Definition of endpoints
38
8.1.1
Primary endpoint definition
38
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8.1.2
Secondary endpoint definitions
39
8.1.3
Other endpoints
39
8.2
Trial rationale
39
8.3
Special agreements with regulatory authorities
40
8.4
Discussion of the trial design
40
8.5
Benefit/risk analysis
45
9
SUBJECT ENROLLMENT AND TRIAL DISCONTINUATION
46
9.1
Subject enrollment procedure
46
9.2
Inclusion/exclusion criteria
47
9.2.1
Inclusion criteria
47
9.2.2
Exclusion criteria
47
9.2.3
Inclusion criteria for the Tapentadol Period (Part 2)
47
9.2.4
Criteria for entry into the Tapentadol Period or Observation Period
47
9.3
Trial discontinuation and treatment not completed
47
9.3.1
Reasons for discontinuation of a subject from IMP (treatment not 
completed)
47
9.3.2
Reasons for discontinuation of a subject from the trial
49
9.3.3
Procedure for the handling of prematurely discontinued subjects
49
9.3.4
Premature termination or suspension of the trial
50
10
TREATMENTS
50
10.1
Investigational medicinal product
50
10.1.1
Identity and composition – tapentadol PR (test)
50
10.1.2
Identity and composition – morphine PR (comparator)
50
10.1.3
Packaging and labeling
51
10.1.4
Delivery, storage and disposal
51
10.2
Administration of trial treatments
51
10.2.1
Administration
51
10.2.2
Total number of doses and dosing interval
51
10.2.3
Dose
51
10.2.4
Titration and dosing tables
54
10.3
Method of assigning subjects to treatment (allocation)
55
10.3.1
Part 1
55
10.3.2
Part 2
56
10.4
Blinding and unblinding
56
10.5
Allowed and forbidden and prior/concomitant medications/therapies
56
10.5.1
Allowed prior and concomitant medications/therapies
57
10.5.2
Forbidden prior and concomitant medication/therapies
57
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10.5.3
Cautionary use
57
10.6
Rescue medication
58
10.6.1
Dose
58
10.6.2
Reasons for administration
58
10.6.3
Documentation
58
10.7
Documentation of drug accountability
59
11
TRIAL PROCEDURES
59
11.1
Course of the trial
59
11.1.1
Part 1
59
11.1.2
Part 2 – Tapentadol Period
63
11.1.3
Visit F7D (Final post treatment visit, at 7 days after stopping IMP, range 
±2 days)
66
11.1.4
Part 2 – Observation Period
67
11.1.5
Phone contacts
68
11.1.6
Additional trial site attendance
68
11.2
Examination hierarchy and time windows
68
11.3
Conditions during the trial
69
11.3.1
Medical care
69
11.3.2
General restrictions
69
11.3.3
Counseling of female subjects of reproductive age
69
11.4
Subject trial cards
69
11.5
Provisions of any additional care of subject after trial termination
70
11.6
Low enrollment
70
12
DATA COLLECTION
70
12.1
Overview of blood sampling in this trial
70
12.2
Collection of subject characteristics data
71
12.2.1
Demographic data
71
12.2.2
Medical history
71
12.2.3
Pain history
71
12.2.4
Prior and concomitant medications and therapies
71
12.3
Collection of pharmacokinetic data
72
12.3.1
Blood sampling for serum pharmacokinetics
72
12.3.2
Bioanalytical assays
72
12.4
Collection of efficacy data
72
12.4.1
Pain intensity
72
12.5
Questionnaires
73
12.5.1
Modified constipation assessment scale
73
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12.5.2
Acceptability and palatability of investigational medicinal product
73
12.5.3
Subjective opiate withdrawal scale
73
12.6
Collection of safety data
74
12.6.1
Adverse events
74
12.6.2
Vital signs
80
12.6.3
Height and body weight
80
12.6.4
Twelve-lead electrocardiogram
80
12.6.5
Safety laboratory
80
12.6.6
Urine test for drugs of abuse
82
12.6.7
Physical examination
82
12.6.8
Pregnancy test
82
12.7
Appropriateness of measurements
83
12.8
Compliance
83
13
DOCUMENTATION OF TRIAL DATA
84
13.1
Case report forms
84
13.2
Subject reported outcomes
84
13.3
Data management
85
13.4
Source data
85
13.5
Investigator’s site file and the trial master file
86
14
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION
87
14.1
Sample size rationale
87
14.2
Analysis of the trial – statistical analysis
87
14.2.1
Analysis populations (analysis sets)
87
14.2.2
General descriptive and graphical methods
88
14.2.3
Analysis of subject characteristics data
89
14.2.4
Analysis of subject disposition
89
14.2.5
Analysis of pharmacokinetic data
89
14.2.6
Analysis of efficacy data
89
14.2.7
Analysis of safety data
91
14.2.8
Acceptability and palatability
93
14.2.9
Final analysis
93
14.3
Population pharmacokinetic modeling and simulation
93
15
QUALITY SYSTEM, AUDIT AND INSPECTION
93
15.1
Quality system
93
15.2
Data quality assurance
93
15.2.1
Clinical research organization/investigator selection
93
15.2.2
Trial site monitoring
94
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15.2.3
Audits
94
15.3
Inspections
94
16
GENERAL CONDITIONS AND AGREEMENTS
94
16.1
Insurance
94
16.2
Legal regulations
94
16.3
Contracts
95
16.4
Subject data and data protection
95
16.5
Publication policy
95
16.6
Final report and reporting of the trial
96
16.7
Approval
97
16.7.1
Sponsor
97
16.7.2
International coordinating investigator
97
17
REFERENCES
97
18
PROTOCOL AMENDMENTS
100
18.1
Protocol amendment 01
100
18.2
Protocol amendment 02
101
18.3
Protocol amendment 03
111
18.4
Protocol amendment 04
112
18.5
Protocol amendment 05
125
19
APPENDIX
127
19.1
List of medical concepts for consideration of seriousness stratified by 
system organ class
127
19.2
Visual analog scale
130
19.3
Faces Pain Scale – Revised
131
19.4
Modified constipation assessment scale
132
19.5
Subjective opiate withdrawal scale
133
19.6
Palatability and acceptability
134
19.7
Algorithm to detect potential severe cases of drug-induced liver injury
135
19.8
Collecting, handling, and shipment of pharmacokinetic serum samples
137
19.8.1
Labeling
137
19.8.2
Devices
137
19.8.3
Procedure
137
19.8.4
Shipment
137
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LIST OF TABLES
Table 1:
Reasons for compulsory and optional discontinuation of subjects from 
investigational medicinal product (treatment not completed)
47
Table 2:
Tapentadol PR dosing table
54
Table 3:
Morphine PR dosing table
55
Table 4:
Approximate volume of blood to be collected from each subject during 
Part 1
70
Table 5:
Approximate volume of blood to be collected from each subject during 
the Tapentadol Period of Part 2
71
Table 6:
Laboratory tests to be performed for the evaluation of alternative causes 
of drug-induced liver injury
136
3
ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviations
Abbreviation
Explanation
CAS
Constipation assessment scale
CP
Conditional power
CRF(s)
Case report form(s)
DMC
Data monitoring committee 
ECG
Electrocardiogram
FAS
Full Analysis Set
FPS-R
Faces Pain Scale–revised
GCP
Good clinical practice
ICU
Intensive care unit
IEC
Independent ethics committee
IMP(s)
Investigational medicinal product(s)
IR
Immediate release
IRB
Institutional review board
PR
Prolonged release
SpO2
Oxygen saturation
SAP
Statistical analysis plan
SOP
Standard operating procedure(s). A synonym for all standard procedural documents.
SOWS
Subjective opiate withdrawal scale (questionnaire)
TEAE
Treatment emergent adverse event
VAS
Visual analog scale
WHO
World Health Organization
Note: Système International d’Unités units and standard hematological and biochemical abbreviations are not listed.
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Definition of terms
Term
Definition
Allocated subjects
Enrolled subjects who are allocated to IMP.
Applicable regulatory 
requirement(s)
Any law(s) and regulation(s) addressing the conduct of clinical trials of investigational 
products of the jurisdiction where the trial is conducted.
Discontinuation (of 
trial)
The act of concluding the participation of an enrolled subject in a trial prior to completion 
of all activities required by the protocol.
Treatment not 
completed
IMP discontinued before scheduled end of the Treatment Period of Part 1 or the Tapentadol 
Period of Part 2.
End of the trial
The trial-related end of the trial is defined as the date of last subject out. 
The subject-related end of trial is defined as date of last contact with the subject according 
to the protocol.
Enrolled subjects
Informed consent form signed. If required by local law and assent form signed.
Enrollment failures
Enrolled subjects who were not allocated to IMP.
First subject allocated
First subject that was allocated to IMP, a synonym for “first subject entered”.
First subject in
Date of first enrolled subject.
Investigational 
medicinal product
A generic term describing the preparations under investigation in this trial, i.e., 
tapentadol PR tablets and morphine PR tablets.
Last subject out
Date of last contact with the last subject according to the protocol. 
Modified CAS
Modified constipation assessment scale (questionnaire).
Opioid naïve
No intake of opioids within the 4 weeks prior to enrollment.
Screened subjects
Screened subjects are subjects undergoing screening. Screening is any activity concerning 
subjects who could potentially be enrolled into the trial before the informed consent form is 
signed.
Treated subjects
Subjects with at least 1 administration of IMP.
Treatment completers 
Part 1
Subjects who have completed the 14-day Treatment Period.
Treatment completers 
Part 2
Subjects who have completed the 12-month Tapentadol Period.
Trial completers Part 1
Subjects who have completed the 14-day Treatment Period and Visit F7D or who entered 
the Tapentadol Period of Part 2.
Trial completers Part 2
Subjects who fully completed the extension period, i.e., either subjects completing the 
Tapentadol Period and the follow-up visit (F7D) or subjects completing the Observation 
Period (F12M) not earlier than 351 days after Visit VE).
4
ETHICS
This trial will be conducted according to the ethical principles that have their origin in the 
Declaration of Helsinki and that are consistent with the protocol, good clinical practice (GCP) and 
applicable regulatory requirements.
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4.1
Independent ethics committee(s) or institutional review board(s)
The relevant independent ethics committee(s) (IEC) or institutional review board(s) (IRB) for this 
trial will be provided with all documents relating to this trial that are required to fulfill its 
responsibilities. Any updates thereof will be provided according to GCP and applicable regulatory 
requirements.
Trial activities will only start after approval from the relevant IEC or IRB is available.
Documentation of all involved IECs and IRBs will be maintained according to GCP and applicable 
regulatory requirements.
4.2
Subject information and informed consent
Before any trial-related procedure is performed, freely given informed consent/assent covering all 
parts of the trial must be obtained. 
The informed consent/assent discussion, the information sheet (if used) and the informed 
consent/assent form provided to the parent(s) or legal guardian(s) or, if applicable the subject, must 
adhere to GCP and applicable regulatory requirements. Unless agreed otherwise, the sponsor’s 
information sheet (if used) and informed consent/assent form must be used. Prior to use, these 
documents must be approved by the relevant IEC or IRB.
The parent(s) or legal guardian(s) of the subject, if applicable, and/or the subject, will be informed 
as soon as possible if new information becomes available that may be relevant to their willingness 
to continue participation in the trial. The communication of this information will be documented.
If subjects, or parent(s) or legal guardian(s), withdraw their consent for participation in the trial, the 
investigator must inform the sponsor in writing.
Subjects (if old enough according to local laws), or parent(s) or legal guardian(s) of the subject 
defined according to local laws, must sign an informed consent form indicating that the signatory 
understands the purpose of the trial, the risks and benefits of the procedures required for the trial, 
and for a parent or legal guardian, give permission for their child’s participation in the trial. 
As the inclusion of exclusively minors at the Enrollment Visit (Visit V1) is foreseen for this trial, 
the subject has to be informed about the trial taking into consideration the age of the subject using 
an appropriate information sheet for the age of the subject and thorough explanation by qualified 
staff. The opinion of the minor has to be taken into account when deciding about participation in the 
trial. An assent form should be signed by the child in adherence to local regulations.
All communication with the child or adolescent must be done by staff having experience dealing 
with minors.
During Part 2 of the trial, subjects may reach the age of majority (e.g., 18 years old, depending on 
local laws). They must sign an informed consent as soon as they reach this age to continue in the 
trial.
4.3
Informing the subject’s healthcare provider
The subject’s healthcare provider will be informed about the subject’s participation in the trial at 
trial enrollment in applicable countries if the subject is treated by a healthcare provider, e.g., general 
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practitioner, and if the subject, parent, or legal guardian, as applicable, agrees in writing in the 
informed consent form. This is to be documented in the case report form (CRF). The subject must 
also be informed and the subject’s opinion taken into consideration. This must be documented on 
the informed consent form/assent form as applicable for the age of the subject.
The healthcare provider will be informed about the trial code, the investigator’s name, and a contact 
(telephone) number at the trial site. Any communication with the healthcare provider will be 
documented in the subject’s medical records.
5
INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE
5.1
Investigators and trial site personnel
5.1.1
Investigators
The investigator, in general, is the person responsible for the conduct of the trial at the trial site and 
the safety of the trial subjects. 
If the trial is conducted by a team of individuals at the trial site, the investigator leading and 
responsible for the team is called the principal investigator. 
All persons assigned responsibility as an investigator will be required to sign a declaration of their 
responsibilities (the “investigator confirmation sheet”) before any trial-related procedure is 
performed. 
An international coordinating investigator will be defined who is responsible for the coordination of 
multiple trial sites in multiple countries.
Curriculum vitae and/or other relevant documents confirming the qualifications of the investigator 
are required by the sponsor. This should include any previous training in the principles of GCP, 
experience obtained from work with clinical trials, and experience with subject care in the target 
population. 
Documentation of all involved investigators will be maintained according to GCP and applicable 
regulatory requirements.
5.1.2
Trial site personnel assigned trial-related duties
The principal investigator may define personnel at a trial site to perform significant trial-related 
procedures and/or to make trial-related decisions under his/her supervision. 
The principal investigator must maintain a signed list of appropriately qualified persons to whom he 
or she delegates significant trial-related duties/responsibilities; the delegated trial-related 
duties/responsibilities must be specified in the list. The delegation of tasks has to comply with 
international and local regulations.
When personnel or responsibility changes are made, the relevant documentation must be updated 
before any trial-related activities are performed.
Documentation of all involved trial site personnel performing significant trial-related procedures 
and/or making trial-related decisions will be maintained according to GCP and applicable 
regulatory requirements.
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5.2
Contract research organizations
Contract research organizations (commercial, academic or other, e.g., central laboratory facilities, 
trial supply management provider, diary provider) may be contracted by the sponsor to perform 
trial-related duties and functions. The extent of the delegation will be documented. All involved 
contract research organizations will be required to have implemented quality control and quality 
assurance processes, and to support the sponsor’s quality control and quality assurance measures. 
Documentation of all involved contract research organizations will be maintained according to GCP 
and applicable regulatory requirements.
5.3
The sponsor and sponsor’s personnel
Grünenthal accepts the responsibilities of the sponsor.
The sponsor will designate appropriately qualified personnel to give advice on trial-related topics. 
The trial site will be provided with contact details for these personnel before any trial-related
procedure is performed. 
A list of key sponsor personnel involved in the preparation of this protocol and the conduct of the 
trial, including their full names, titles, roles, and responsibilities, will be maintained.
5.4
Data monitoring committee
An independent data monitoring committee (DMC) will be established to oversee and evaluate data 
from selected pediatric trials with tapentadol administration performed by Grünenthal. Operational 
aspects of the DMC will be given in a charter which will be issued before the first subject-in in this 
trial. For more details about the planned evaluations of the DMC, see Section 8.5.
6
INTRODUCTION AND TRIAL BACKGROUND
6.1
Background to the investigational medicinal product
Tapentadol is a centrally acting analgesic agent. Tapentadol has been pharmacologically 
characterized as both a mu-opioid receptor agonist and an inhibitor of noradrenaline reuptake. Non-
clinical data suggest that both mechanisms contribute to its analgesic effects. Tapentadol is a pure 
enantiomer that acts directly on the central nervous system and metabolites were shown not to 
contribute to the analgesic activity.
6.2
Relevant non-clinical and clinical data 
For a detailed summary of relevant non-clinical and clinical experience, see the current edition of 
the investigator’s brochure.
Non-clinical pharmacology
Tapentadol is a centrally acting analgesic combining opioid- and non-opioid activities. It has 
agonistic activity at the mu-opioid receptor and it inhibits noradrenaline reuptake as a non-opioid 
activity. Both actions act synergistically in analgesia. In various animal models of acute, chronic, 
inflammatory, and neuropathic pain, tapentadol exerted potent antinociceptive effects. This broad 
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antinociceptive profile reflects its combined mode of action. Both opioid and non-opioid properties 
are relevant for the management of clinical pain. 
The non-clinical safety pharmacology data indicate a low potential for side effects upon the vital 
functions like respiratory depression and gastrointestinal inhibition in humans. Tapentadol has no 
adverse cardiovascular effects in the antinociceptive dose range. 
Clinical experience
In the clinical program to date, tapentadol (as the hydrochloride salt) has been mostly administered 
to adults. It has been given intravenously or orally as an oral solution, as immediate-release (IR) 
tablets or capsules, and as prolonged release tablets (including a tamper resistant formulation). 
More recently, 2 trials have been performed (or are ongoing) in children and adolescents to evaluate 
the pharmacokinetics of a single dose of tapentadol oral solution 1 mg/kg after scheduled surgical 
procedures that routinely produce acute postsurgical pain
 
. No safety issues have so far been identified. 
Pharmacodynamics
Tapentadol showed dose-dependent effects in a model for mu-opioid receptor agonist activity (pupil 
diameter) and in an experimental pain model (pain somatosensory evoked potentials following CO2
[carbon dioxide] laser stimulation) in doses ranging from tapentadol immediate release (IR) 50 mg 
to 200 mg.
Tapentadol IR prolonged the orocecal transit time in a dose-dependent manner, but the effect with 
tapentadol IR 43 mg was less pronounced than with morphine IR 30 mg.
Pharmacokinetics
Tapentadol was rapidly and completely absorbed after oral administration of tapentadol IR. Mean 
absolute bioavailability after single-dose administration (fasting) was ~32%, most probably due to 
an extensive first-pass metabolism. Peak serum concentrations of tapentadol were observed at 
~1.25 hours (tapentadol IR) and ~3 hours to 6 hours (tapentadol PR or tapentadol tamper resistant 
formulation) post-dose. The tapentadol terminal half-life was ~4 hours (tapentadol IR) and ~5 hours 
to 6 hours (tapentadol PR). The serum protein binding of tapentadol was ~20%.
After oral administration, ~70% (comprising 55% as a glucuronide and 15% as a sulfate of 
tapentadol) of the dose is excreted in urine in the conjugated form. A total of 3% of the drug was 
excreted in urine as unchanged drug.
In humans, tapentadol is mainly metabolized via phase 2 conjugation, and only a small amount is 
metabolized via phase 1 oxidative pathways. No metabolite contributes to the analgesic activity. As 
glucuronidation is a high capacity/low affinity system, clinically relevant interactions at the level of 
phase 2 metabolism are unlikely. Since in-vitro investigations showed that tapentadol does not 
inhibit or induce cytochrome P450 enzymes, clinically relevant interactions mediated by the 
cytochrome P450 system are also considered unlikely.
After intravenous administration, tapentadol was widely distributed throughout the body with a 
volume of distribution (Vz) of 540 L. The terminal half-life was ~4.1 hours and total clearance was 
1530 ± 177 mL/min. Systemic exposure to tapentadol (area under the concentration-time curve; 
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AUC) and accumulation factors following multiple dosing were found to be consistent with 
single-dose data. Steady-state was attained ~16 hours to 20 hours after the first administration.
Systemic exposure (maximum concentration of analyte [Cmax] and AUC) to tapentadol showed 
dose-proportional increases over the therapeutic dose range. Consistent with linear 
pharmacokinetics, the accumulation ratio of tapentadol based on the maximum serum 
concentrations at steady-state (Cmax,ss) was close to the theoretically expected value. 
After oral dosing, AUC and Cmax of tapentadol were higher in subjects with mild and moderate 
hepatic impairment compared to healthy subjects. The rate of formation of 
tapentadol-O-glucuronide decreased with increasing liver impairment.
After oral dosing, AUC and Cmax of tapentadol were comparable in subjects with varying degrees of 
renal function (from normal function to severely impaired function). In contrast, increasing 
exposure (i.e., AUC) to tapentadol-O-glucuronide was observed with increasing degrees of renal 
impairment.
In drug-drug interaction trials studying the possible influence of paracetamol, naproxen, 
acetylsalicylic acid, and probenecid on tapentadol glucuronidation, there were no clinically relevant 
effects on tapentadol serum concentrations. Also, there were no clinically relevant effects on the 
absorption of tapentadol in interaction trials of tapentadol with metoclopramide and omeprazole.
Safety in Phase I trials (tapentadol intravenous, tapentadol oral solution, tapentadol IR, and 
tapentadol prolonged release [PR] including tamper resistant formulation)
As studied in single- and multiple-dose Phase I trials, tapentadol IR (single-dose: 200 mg and 
multiple-dose: 175 mg orally every 6 hours) and tapentadol PR (single-dose: 300 mg and 
multiple-dose: 250 mg orally twice daily) were safe; no maximum tolerated dose was reached. The 
adverse event profile was consistent with that of centrally-acting analgesics. The most frequent 
treatment emergent adverse events (TEAEs) were dizziness, headache, somnolence, nausea, fatigue, 
vomiting, and dry mouth. Most TEAEs were mild or moderate in intensity. Overall, there were no 
clinically relevant treatment-related or dose-related effects on laboratory parameters, vital signs, or 
ECG parameters. 
No effects on the QT interval and other ECG parameters were shown after multiple therapeutic 
(100 mg) and supra-therapeutic (150 mg) doses of tapentadol IR in a thorough QT trial. Similarly, 
tapentadol had no relevant effect on heart rate, PR interval, QRS duration, and T-wave or U-wave 
morphology. In a second thorough QT trial, multiple oral administration of 86 mg or 172 mg 
tapentadol PR did not cause QTc prolongation.
A dedicated abuse liability trial conducted in non-dependent healthy recreational users of opioids 
showed a similar abuse liability profile to that of hydromorphone at estimated equianalgesic doses.
Safety Phase II and Phase III (tapentadol PR) in clinical trials
Adverse drug reactions, the most common (10% subjects) being nausea, dizziness, somnolence, 
headache, and constipation observed with tapentadol PR treatment in the dose range of 50 mg to 
250 mg twice daily, are as expected for a centrally-acting analgesic.
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7
TRIAL OBJECTIVES
The trial objectives for Part 1 are:
•
To assess the 14-day safety and efficacy of tapentadol PR in comparison to morphine PR in 
subjects aged from 6 years to less than 18 years suffering from long-term pain requiring 
prolonged release opioid treatment.
•
To evaluate the pharmacokinetic profile of tapentadol and its major metabolite 
tapentadol-O-glucuronide after multiple doses of tapentadol PR tablets. 
The trial objective for Part 2 is:
•
To describe the long-term safety profile covering up to a 12-month period with treatment of 
tapentadol PR taken twice daily (Tapentadol Period) in subjects aged 6 years or older 
suffering from long-term pain requiring prolonged release opioid treatment, or in subjects 
without tapentadol treatment (Observation Period) aged 6 years or older who have received 
at least 1 dose of IMP. 
8
TRIAL DESIGN
This is a 2-part trial: 
Part 1 is a 14-day (Treatment Period) Phase II/III, randomized, multi-site, open-label, 
active-controlled, parallel group trial in subjects aged 6 years to less than 18 years, suffering from 
long-term pain requiring prolonged release opioid treatment. The target is to allocate 69 subjects in 
a ratio of 2:1 to treatment with tapentadol PR or morphine PR twice daily.
After the Enrollment Visit, subjects complying with the inclusion/exclusion criteria will enter 
Part 1. 
Blood samples for pharmacokinetic evaluations will only be drawn from subjects on tapentadol PR.
Part 1 of the trial will be completed after the last subject has attended Visit VE. Data of Part 1 will 
comprise the primary analysis of the trial.
Part 2 is an open-label Extension Period with tapentadol treatment (Tapentadol Period) or an 
observation period without tapentadol treatment (Observation Period) lasting for up to 12 months.
Tapentadol Period (12 months): Subjects completing the Treatment Period (Part 1) and who are 
still in need of treatment with a prolonged release opioid can enter the Tapentadol Period. They will 
be treated with tapentadol PR for up to 12 months until Visit F12M (a 12-month visit relative to 
Visit VE). 
Observation Period (12 months): Subjects not completing the Treatment Period (Part 1), but who 
have taken at least 1 dose of IMP, and those who complete the Treatment Period but do not want to 
continue with tapentadol PR, will enter the Observation Period (12 months). Subjects will be 
followed up until Visit F12M to assess any long-term effects after discontinuing treatment with the 
IMP. Subjects in the Tapentadol Period of Part 2 may stop treatment early (before Visit F12M) and 
switch to the Observation Period for the remainder of Part 2.
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Part 2 of the trial will be completed after the last subject has completed or discontinued from the 
trial.
Trial population
Subjects will be enrolled who are aged 6 years to less than 18 years (for the duration of Part 1 of the 
trial) and suffer from severe long-term pain requiring prolonged release opioid treatment for at least 
14 days after Visit V2 (Allocation Visit; Day 1), and who comply with the inclusion/exclusion 
criteria given in Section 1.3. Long-term pain is defined as any pain condition that requires a 
minimum of 14 days of treatment with a strong oral opioid. Subjects that could be considered for 
the trial include, but not exclusively, those with expected long-term post-surgical pain (e.g., spinal
surgery), cancer-related pain (including pain caused by treatment) as well as chronic indications 
with moderate to severe pain.
The age groups of 6 years to less than 12 years and 12 years to less than 18 years are predefined. 
At least 25% of the subjects will be allocated to IMP at Visit V2 in the age group of 6 years to less 
than 12 years. At least 15 subjects must be treated with tapentadol PR for a minimum of 12 weeks.
Trial period
Estimated date of first subject in: Oct 2014. 
Part 1, estimated date of last subject out: Sep 2018.
Part 2, estimated date of last subject out: Sep 2019.
Each subject is expected to be treated with IMP for 14 days in Part 1, followed by a 12-month 
Extension Period (Part 2). In total, for each subject, the trial duration will be ~13 months.
8.1
Definition of endpoints
For details of the analysis sets, see Section 14.2.1.
8.1.1
Primary endpoint definition
Part 1 (primary analysis of the trial)
The primary endpoint is a binary variable “responder”. A subject is defined as “responder” if both 
of the following criteria are met:
•
Completion of the 14-day Treatment Period (Part 1).
•
One of the following calculated from the scheduled pain assessments (“pain right now”) 
documented during the last 3 days of the Treatment Period:
−
Average pain <50 on a VAS for subjects aged 12 years to less than 18 years; or <5 on 
the FPS-R for subjects aged 6 years to less than 12 years.
−
Average reduction from baseline of pain ≥20 on a VAS for subjects aged 12 years to 
less than 18 years; or ≥2 on the FPS-R for subjects aged 6 years to less than 12 years.
The proportion of subjects classified as responders will be assessed and compared between the 
treatment groups.
Age groups are determined at Visit V2. Baseline pain is defined as “pain right now” at Visit V2, 
and will be assessed before any painful or unpleasant procedure, and before the first intake of IMP.
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8.1.2
Secondary endpoint definitions
The main secondary endpoints are:
Part 1
•
Constipation as assessed by changes from baseline (Visit V2) of total scores for the 
modified CAS.
Part 1 and Part 2
•
Tolerability as assessed by the number and type of adverse events and adverse drug 
reactions by treatment group during the different trial periods, on a subject and event level.
8.1.3
Other endpoints
Other endpoints compared between treatment groups at each measurement time point are:
Part 1 - Treatment Period, other endpoints (baseline is the value at Visit V2):
•
Pain as assessed by changes from baseline using the VAS.
•
Pain as assessed by changes from baseline using the FPS-R.
•
Use of rescue medication as assessed by number of doses of rescue medication taken at
different dose levels of IMP.
•
Description of population pharmacokinetics of tapentadol and tapentadol-O-glucuronide. 
•
Palatability and acceptability as assessed by differences within treatment groups of the 5-
point hedonic faces scale with the verbal rating score at Visit V3 and Visit VE.
Part 2 - Tapentadol Period, other endpoints (baseline is the value at Visit VE):
•
Pain as assessed by changes from baseline using the VAS.
•
Pain as assessed by changes from baseline using the FPS-R.
•
Constipation as assessed by changes from baseline of total scores for the modified CAS.
Part 2 - Observation Period, other endpoints (baseline is the value at Visit VE or Visit ET):
•
Constipation as assessed by changes from baseline of total scores for the modified CAS.
Part 1 or Part 2 - other endpoints:
•
Opiate withdrawal symptoms as assessed by the scale score of the SOWS questionnaire at 
individual time points and changes to baseline.
•
Time to discontinuation of IMP assessed by a survival analysis.
8.2
Trial rationale 
Pain in children is a public health concern of major significance in most parts of the world. 
Although the means and knowledge to relieve pain exists, children’s pain is often not recognized, is 
ignored or even denied (WHO 2012). This might also be due the fact that only few trials have been 
conducted in children with opioids to provide evidence of their safety and efficacy (Finkel et al. 
2005). There is a need for comparative trials of opioids in terms of effectiveness, side-effects and 
feasibility of use in children with persisting pain due to medical illnesses (WHO 2012).
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Choice of population and trial sites
The trial includes children with different indications requiring treatment with an oral strong opioid 
for at least 14 days. Subjects that could be considered for the trial include, but not exclusively, those 
with expected long-term post-surgical pain (e.g., orthopedic surgery), cancer-related pain (including 
pain caused by treatment), as well as chronic indications with moderate to severe pain.
Tapentadol PR has shown to be an efficacious and safe drug for the treatment of different chronic 
pain indications that are common in the adult population, such as low back pain, osteoarthritis and 
cancer-related pain. The data from pivotal clinical trials have been confirmed by post-marketing 
data in further clinical trials as well as in non-clinical trial settings.
The data gained for tapentadol suggest that also children may benefit from treatment with 
tapentadol PR (Section 6.2). 
Chronic daily pain can occur in children in the context of chronic daily headaches, 
neurodegenerative disorders, inflammatory disorders, post-traumatic neuropathic pain conditions, 
and in children with advanced cancer and other life-limiting diseases. Overall, however, chronic 
daily pain is much less prevalent in children than in adults (Berde et al. 2012). This is even more the 
case for painful conditions requiring long-term opioid treatment.
In children with progressive malignant disease, two thirds experience pain requiring opioid 
analgesia (Goldman and Bowman 1990). However, cancer in children is rare. In the United States, 
cancer has been found to occur most frequently in the first year of life with incidence rates of 
~250 cases per million per year. The incidence then drops to only ~100 cases per million per year 
by the age of 10 years, after which the incidence increases again to approach 250 per million cases 
per year at the age of 18 years (Kadan-Lottick 2007). Furthermore, Berde et al. (2012) reported that 
within a single year, only 386 children with cancer pain received oral round-the-clock opioid 
treatment for the duration of 1 month or more in the United States.
Other conditions that often require treatment with prolonged release opioids for at least 2 weeks 
include severe burns and major or complicated surgery. A mail-in survey of pediatric pain control 
practices in North American Burn Centers (Martin-Herz et al. 2003) showed that although 
intravenous morphine was the most frequently used analgesic for the treatment of background pain 
from burns, 21% of the responders used prolonged release opioids for school-age children, and 39% 
for adolescents.
Surgical correction for scoliosis is associated with high levels of pain that extend beyond the initial 
inpatient hospital stay. These patients, as well as others undergoing major surgery with expected 
extended pain duration, may benefit more from early transition to prolonged release formulations 
than from continuous PCA, because prolonged release formulations are associated with lower pain 
levels on average, and present a more convenient route of administration (Czarnecki et al. 2004). 
This is in line with the results shown in clinical trials in adults undergoing major surgery, e.g., hip 
and knee replacement: patients treated with prolonged release opioids 48 hours after surgery had 
improved pain scores compared to those who received continuous treatment with immediate release 
formulations and patient controlled analgesia (PCA), and they had a shorter duration of their 
hospital stay (de Beer et al. 2005).
In conclusion, opioids, especially in a prolonged release formulation, are not only used in children 
suffering from classical chronic pain conditions (e.g., cancer-related pain), but also frequently in a 
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patient population with other long-term pain conditions (e.g., due to major surgery or burns). 
Therefore, it is appropriate to investigate tapentadol PR in the conditions reflective of those that 
will be treated with tapentadol PR when commercially available.
Furthermore, the inclusion of subjects suffering from cancer-related pain participating in other trials 
investigating drugs with marketing authorization is considered to be appropriate, when they 
constitute the standard treatment for particular patient population. As it is known that most drugs 
are administered to children off-label, but represent the current standard of care, it is considered that 
allowing the participation of subjects in trials with marketed drugs does not impose further 
uncertainties or safety risks to the subjects compared to their standard treatment.
Multiple trial sites, e.g., specialized in pediatric oncology and hematology, burns and orthopedics, 
in multiple countries will be required for the recruitment of 69 subjects in the specified time. See 
Section 14.1 for the sample size rationale. 
Morphine as active control
Since its discovery, morphine has been widely accepted as a gold standard in the analgesic 
management of severe pain (De Conno and Kress 2006) and its analgesic efficacy in cancer pain 
has been proven (Broomhead et al. 1997). Morphine is among the top 10 medications given to 
children in the inpatient setting (Lasky et al. 2012). It is one of the few pain medications, and
notably one of the few WHO Step III pain medications, that are authorized for use in children.
Blinding
An open-label trial was selected because it is not appropriate to over-encapsulate tapentadol PR and 
morphine PR tablets as the size of capsules would become too big for children and adolescents to 
swallow. 
A double dummy method is also not feasible due to the large number of tablets that would be 
required to be taken by each subject.
Randomization
Subjects will be allocated in the ratio of 2:1 to treatment with tapentadol PR or morphine PR twice 
daily. A ratio of 2:1 was selected to gain more experience of tapentadol PR in a long-term pain 
requiring prolonged release opioid treatment setting within a pediatric population.
Stratification
Stratification by age and underlying pain condition (cancer/non-cancer-related pain) is planned. 
Stratification by underlying pain condition is foreseen because of the different progression of the 
underlying diseases and thus different progression of pain scores over time. The predefined age 
groups are 6 years to less than 12 years, and 12 years to less than 18 years, and subjects will be 
stratified so that at least 25% of the subjects will be allocated to IMP at Visit V2 in the age group of 
6 years to less than 12 years.
Sample size
See Section 14.1 for the sample size rationale.
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Pain evaluations
During the trial, exploratory subject-reported pain assessments and supplemental analgesic rescue 
dosing information will be collected. To measure pain intensity, 2 pain intensity scales will be used: 
a VAS and the FPS–R. The appropriateness of these assessments is discussed in Section 12.7.
Dosing
The selection of the tapentadol PR dose (see Section 10.2.3 for dosing in this trial) to be evaluated 
in pediatric subjects was based largely upon pharmacokinetic considerations. 
The main metabolic pathway for tapentadol in adults is glucuronidation, which is a system known 
to be immature for the first 2 years of life (Benedetti et al. 2007, Edginton et al. 2006). However, 
the clearance of morphine and paracetamol, both of which undergo glucuronidation, is expected to 
be near the level of adults by the age of 3 years (Anderson and Holford 2009). Thus, it is not 
expected that there will be major differences in the pharmacokinetic profile of tapentadol in subjects
aged above 3 years compared with adults, particularly in the adolescent group of 12 years to less 
than 18 years old. Since Phase 1 oxidative routes only make a minor contribution to the overall 
elimination of tapentadol, ontogeny of the cytochrome P450 family of enzymes is not expected to 
have any effect on the overall pharmacokinetic profile of tapentadol in adolescents.
Tapentadol and its metabolites are excreted almost exclusively (99%) via the kidneys. A total of 3% 
of the drug is excreted in urine as unchanged drug. Renal function has been predicted to reach 90% 
of adult function between the ages of 1 year and 2 years (Rhodin et al. 2009, Hayton 2002) such 
that again no major differences in excretion characteristics of tapentadol are anticipated in the 
children and adolescent age groups. 
Data from a multiple dose trial in healthy adult subjects 
 using tapentadol film-coated 
tablets indicated that the pharmacokinetics of tapentadol at steady-state can be predicted from single 
dose pharmacokinetics. An accumulation factor for AUC in the range of 1.4 to 1.7 was observed 
which agreed well with the theoretical ratio of ~1.7 based on the dosing interval and terminal 
half-life. This provides evidence for time-independent pharmacokinetics for tapentadol. By analogy 
to adults, it is expected that the pharmacokinetics of tapentadol in children and adolescents will be 
predictable and time independent after single and multiple dosing.
Based on the pharmacokinetic evidence described above for tapentadol, the sponsor considers it 
justified to move into an adolescent safety and efficacy trial without a prior pharmacokinetic trial in 
this age group using the prolonged release formulation. An advisory committee meeting (in March 
2012) initiated by the FDA to discuss “clinical pharmacology aspects of pediatric clinical trial 
design and dosing to optimize pediatric drug development” recommended, based on an FDA review 
of 22 products recently approved for adolescent use, that for dose confirmation in adolescents 
(12 years to less than 18 years), no pharmacokinetic trials are needed, but that doses can be derived 
using adult data. 
Non-linear mixed effects modeling was performed to develop a population pharmacokinetic model 
in the pediatric population for the tapentadol oral solution and in the adult population for the 
tapentadol PR formulation. The adult tapentadol PR and pediatric tapentadol oral solution models 
were integrated to obtain a combined pediatric tapentadol PR model. This integrated model served 
as a basis for dose selection in the current trial.
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collected (adverse events, vital signs, 12-lead ECG, safety laboratory, physical examinations, height 
and body weight, SOWS, and modified CAS questionnaire).
To allow early signal detection and to ensure the safety of the trial subjects, an independent DMC 
(see Section 5.4) will be established to oversee and evaluate data from selected pediatric trials with 
tapentadol administration performed by Grünenthal.
8.5
Benefit/risk analysis
Benefits
Tapentadol has been shown to be effective for the treatment of moderate to severe pain in adults 
(Section 6.2). Although data on the specific efficacy of opioids in children and adolescents is 
limited, it is not expected that these will deviate notably from those observed in adults. A single 
dose pharmacokinetic trial 
 in the same age group as the population in this trial has 
been recently performed by the sponsor, the data of which confirmed the dosing of tapentadol PR 
used in this trial.
The comparator in this trial, morphine PR, is a well-known opioid analgesic with proven efficacy in 
adults.
In addition, subjects enrolled in this trial will be intensively monitored during the treatment period, 
more closely than in routine clinical practice.
Risks
Lack of efficacy
Tapentadol may not be as efficacious in children and adolescents as it is in adults, even if the 
exposure is comparable. However, this is considered to be unlikely.
During the Treatment Period, rescue medication, in the form of morphine oral solution, will be 
available for use as rescue medication if pain relief is insufficient. Thereafter, subjects may receive 
immediate release strong opioids for treatment of breakthrough pain and incidental pain.
Safety
The potential risks to subjects in this trial include exposure to tapentadol and morphine, with a 
potential for side effects. Since most of these side effects are related to the use of opioids, i.e., class 
related, and the subjects would anyway require opioid treatment, the added safety risk is considered 
acceptable.
Data on the specific risks of opioids in children and adolescents is limited. However, it is not 
expected that the specific risks of opioids in children and adolescents will deviate from those 
observed in adults. 
Subjects will be monitored for adverse events throughout the trial, and experts in pediatric pain will 
conduct the trial. 
Safety – tapentadol
The assessment of risk for the tapentadol PR is mainly based on experience in adults with the solid 
oral formulations tapentadol IR and tapentadol PR (and a related tamper resistant formulation).
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The safety profile of tapentadol has been well characterized through a completed clinical program 
in adults and post-marketing experience is now available. The safety of tapentadol PR has been 
demonstrated in a 1 year safety trial in adults.
The potential risks to subjects in this trial include long-term exposure to tapentadol PR, with a 
potential for side effects not discovered during single dose treatment in children and long-term 
treatment in adults. However, it is not expected that the safety profile of tapentadol will deviate 
notably from that in adults based on the pharmacodynamic and pharmacokinetic properties of 
tapentadol.
Safety – general and blood sampling
This trial has been designed to protect the interests of the subjects, minimizing the risk to them, and 
ensuring compliance with recommendations (EMEA ad hoc working party 2008) for the amount of 
blood drawn (see Section 12.1). Blood sampling for pharmacokinetic assessments and safety 
monitoring will be performed. These are the only invasive procedures associated with the trial. 
Risks to subjects include stress and discomfort, and the risks associated with the blood sampling 
process (venipuncture) and the volume of blood drawn. 
To reduce the subject stress and discomfort, only staff with experience working with children or 
adolescents will draw blood and the application of a local anesthetic before venipuncture is 
recommended. Also, no more than 2 attempts to collect blood for pharmacokinetic evaluations will
be done at any visit.
To keep the volume of blood drawn to a minimum, only laboratories will be used with expertise in 
handling and analyzing biological samples using small volumes. The number of venipunctures will 
also be kept to a minimum. 
Data monitoring committee
To allow early signal detection and to ensure the safety of the trial subjects, an independent DMC 
(see Section 5.4) will be established to oversee and evaluate data from selected pediatric trials with 
tapentadol administration performed by Grünenthal. The DMC will review and evaluate the data
provided, as defined in a DMC charter, on an ongoing basis. The DMC will provide 
recommendations to the sponsor’s steering committee as described in the DMC Charter.
Conclusion
The efficacy of tapentadol is expected to be similar in children and adolescents to that seen in 
adults. The risks associated with the trial, and the risks associated with the administration of 
tapentadol and morphine, are adequately addressed by the mitigation procedures. As the trial 
generates data that will support the prescribing of tapentadol for control of pain in the pediatric 
population, the overall risk-benefit assessment is considered to be such that the trial can be ethically 
performed.
9
SUBJECT ENROLLMENT AND TRIAL DISCONTINUATION
9.1
Subject enrollment procedure
Before the informed consent form and, if applicable, the assent form, is signed, the subjects will be 
screened to identify subjects who could potentially be enrolled into the trial.
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If a subject is identified to be potentially eligible, the subject, parent(s), or legal guardian(s) will be
requested by the investigator to give consent/(if applicable) assent for the subject’s enrollment in 
the trial as described in Section 4.2. 
The investigator will keep a subject screening log and a subject identification and enrollment log.
9.2
Inclusion/exclusion criteria
9.2.1
Inclusion criteria
See Section 1.3.1.
9.2.2
Exclusion criteria
See Section 1.3.2.
9.2.3
Inclusion criteria for the Tapentadol Period (Part 2)
See Section 1.3.3.
9.2.4
Criteria for entry into the Tapentadol Period or Observation Period
Subjects completing the Treatment Period (Part 1) with tapentadol PR or morphine PR and who 
have need for continued opioid treatment can enter the Tapentadol Period (see Section 1.2.2). 
Subjects not completing the Treatment Period (Part 1), but who have taken at least 1 dose of IMP, 
and those who complete the Treatment Period, but who do not want to continue with tapentadol PR 
treatment, will enter the Observation Period (12 months) (see Section 1.2.3). 
9.3
Trial discontinuation and treatment not completed
Subjects may stop taking IMP (treatment not completed) during the trial, but continue in the 
Observation Period. Subjects may, however, also discontinue participation in the trial completely
(trial not completed).
9.3.1
Reasons for discontinuation of a subject from IMP (treatment not 
completed)
The investigator must discontinue subjects from treatment with IMP (i.e., treatment not completed) 
for the compulsory reasons (stopping criteria) given in Table 1. For reasons marked as optional, the 
investigator may decide to stop IMP administration if the benefit/risk ratio for continued 
administration of IMP is considered not to be favorable.
Table 1:
Reasons for compulsory and optional discontinuation of subjects from investigational 
medicinal product (treatment not completed)
Discontinuation from IMP
Main reason
Compulsory
Optional
Adverse event
-
There is any relevant deterioration in the health of the subject that could alter 
the benefit/risk assessment for the subject, including adverse events, laboratory 
parameters, vital signs, or other safety parameters (e.g., ECG).
X
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Discontinuation from IMP
Main reason
Compulsory
Optional
-
A confirmed QT or QTc interval of >470 ms.
X
-
Based on data from the central laboratory, clinically relevant change in liver 
parameters after dosing if the result is confirmed by 1 additional laboratory 
assessment (see Section 19.7), for 1 or more of: 
•
Alanine transaminase or aspartate transaminase is >5 times above the 
upper limit of normal. 
•
Alanine transaminase or aspartate transaminase is >3 times above upper 
limit of normal and total serum bilirubin >2 times above upper limit of 
normal or international normalized ratio (INR) >1.5 times above the upper 
limit of normal (without documented pathological screening value or 
without pharmacological anticoagulation with vitamin K antagonists).
X
Death (trial discontinuation)
X
Lack of efficacy
-
The subject requires more than 4 doses per day of rescue medication on 
2 consecutive days for persistent intolerable pain while taking the highest dose 
of IMP twice daily. 
X
Pregnancy
X
Enrollment failure (trial discontinuation)
X
Protocol deviation
-
The subject is non-compliant with requirements of the trial.
X
-
Subject is using drugs or medical devices that have no marketing authorization 
for human use.
X
-
The subject continues to take more than the maximum allowed dose of IMP 
after being reminded not to do so.
X
-
Subject continues to take less than the minimum allowed dose of IMP 
according to weight group (see Table 2 and Table 3) after being reminded not 
to do so.
X
-
A female subject becomes post-menarchal or turns 12 years of age and is not 
abstinent, or, if sexually active, is not practicing an effective method of birth 
control (e.g., prescription oral contraceptives, contraceptive injections, 
intrauterine device, double-barrier method, contraceptive patch).
X
-
The subject is taking forbidden medication (see Section 10.5.2).
X
-
Surgery during Part 1 (Treatment Period) of the trial that requires post-surgical 
ICU treatment, or that requires post–surgical parenteral pain-treatment, or, in 
the opinion of the investigator, affects the safety of the subject.
X
Lost to follow-up (trial discontinuation)
X
Technical reasons
-
Technical or logistical grounds (e.g., important technical equipment fails).
X
-
Subject no longer requires opioid analgesia.
X
-
Subject requires a change of route of analgesic administration, e.g., because 
they can no longer swallow the tablets.
X
Withdrawal of informed consent (trial discontinuation)
X
Trial terminated by the sponsor (trial discontinuation)
X
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ECG = electrocardiogram; ICU = intensive care unit; IMP = investigational medicinal product.
9.3.2
Reasons for discontinuation of a subject from the trial
Following discontinuation of a subject from IMP, in certain cases (e.g., withdrawal of consent), the 
subject may also need to be discontinued from trial participation (see items marked trial 
discontinuation in Table 1).
9.3.3
Procedure for the handling of prematurely discontinued subjects
The investigator must inform the sponsor in writing about any discontinuation of a subject from the 
trial or from IMP (treatment not completed) and must document any such discontinuation of a 
subject. The investigator must update the interactive response technology system and CRF within 
48 hours of a subject discontinuing. In case of death or any other serious adverse event, the sponsor 
or the sponsor’s authorized delegate must be informed according to the requirements defined in the 
corresponding protocol section about notification of serious adverse events. Where applicable, the 
relevant IEC or IRB must be informed with a detailed written explanation. Also, any technical 
devices provided to the subjects, e.g., electronic diaries, must be collected. 
For all subjects discontinuing the trial or discontinuing IMP (treatment not completed; these 
subjects may continue the trial in the Observation Period), the following information must be 
documented:
•
Reason for discontinuation.
•
If the parent/legal guardian/subject agrees, perform all assessments for Visit VE or Visit ET 
as appropriate, and Visit F7D (Section 1.2).
For subjects discontinued from the trial, the following information must be documented:
•
Status of all new and ongoing (serious) adverse events.
•
All data captured until discontinuation as required at all attended visits, including the 
recording of concomitant medication taken until the day of discontinuation from the trial.
•
Ensure the return of partially used and unused medication kits.
•
Perform a final IMP and, if applicable, rescue drug accountability. 
•
Collect the diary and any other devices provided to the subject.
•
If the subject agrees, perform all assessments/visits as given in Section 1.2.
For subjects discontinued from IMP (treatment not completed), all efforts should be made to:
•
Ensure the return of partially used and unused medication kits.
•
Perform a final IMP and, if applicable, rescue drug accountability. 
•
Collect the diary and any other devices provided to the subject.
•
If the subject agrees, perform all assessments/visits as given in Section 1.2.
Subjects turning 18 years old before Visit VE may continue in the trial. However, an additional 
subject will then be enrolled and allocated to IMP. Otherwise treated subjects will not be replaced. 
See Section 3 for a definition of allocated and treated subjects. Replacement subjects will receive 
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the same sequence of treatments and undergo the same procedures and assessments up to Visit VE 
as the initially entered subjects.
9.3.4
Premature termination or suspension of the trial
The relevant IEC or IRB, the regulatory authorities, or the sponsor or the sponsor’s authorized 
delegate alone or in conjunction have the power to make a binding decision to prematurely 
terminate or suspend the trial at any or all trial sites. In addition, for an individual trial site, this 
decision can be made by the principal investigator. 
The party prematurely terminating or suspending the trial must promptly inform all other parties 
(i.e., the principal investigator(s), the relevant IEC or IRB, the regulatory authorities, or the 
sponsor/the sponsor’s authorized delegate, as applicable). 
In addition, the investigator must promptly inform the subjects, ensure appropriate follow-up for 
any enrolled subjects, and provide the relevant IEC or IRB and the sponsor or the sponsor’s 
authorized delegate, as applicable, with a detailed written explanation of the termination or 
suspension.
The international coordinating investigator has to be informed immediately if the trial is 
prematurely terminated or suspended.
10
TREATMENTS
10.1
Investigational medicinal product
10.1.1
Identity and composition – tapentadol PR (test)
Name:
Tapentadol prolonged release tablets
Substance code:
CG5503
Substance name:
Tapentadol hydrochloride
Active component(s):
Tapentadol
Dose (strength): 
25 mg, 100 mg tablets (tapentadol)
Manufacturer:
Grünenthal GmbH, Aachen, Germany
For further information about the identity and composition of tapentadol PR, see the current 
investigator’s brochure and the clinical supply specification.
10.1.2
Identity and composition – morphine PR (comparator)
Name:
Morphine prolonged release tablets
Substance name:
Morphine sulfate
Active component(s):
Morphine
Dose (strength): 
10 mg, 30 mg tablets (morphine sulfate)
Final release of the 
re-packaged product:
Grünenthal GmbH, Aachen, Germany
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10.1.3
Packaging and labeling
The IMPs will be manufactured as single oral dosage forms and packed in blister packs. For 
detailed information about the packaging and labeling, see the clinical supply specification.
10.1.4
Delivery, storage and disposal
The sponsor is responsible for supplying the investigator with IMP. These will not be delivered 
until all required documentation (EC/IRB approval, authority approval, signed contract and 
protocol, curriculum vitae) is present at the sponsor.
Storage conditions will be specified on the labels of the IMPs. 
For countries in which tapentadol and morphine have been classified as a controlled/scheduled 
substance, all local requirements for handling, storage, and distribution of narcotics will be 
followed. Controls will be implemented at the trial site to ensure documented compliance with these 
requirements.
10.2
Administration of trial treatments
10.2.1
Administration
The route of administration is oral. Tablets should be taken with at least 50 mL of water or other 
suitable fluid. Tablets can be taken irrespective of food intake.
Subjects taking tapentadol PR 100 mg or more can decide if they prefer to take the smaller 
tapentadol PR 25 mg tablets or a combination of tapentadol PR 25 mg and tapentadol 100 mg 
tablets.
The time of IMP administration and the number of tablets per dose will be captured in the diary
during Part 1 (Treatment Period).
All restrictions and precautions listed in the investigator’s brochure for tapentadol PR and in the 
summary of product characteristics for morphine PR must be followed.
The first dose of IMP will be taken during Visit V2 (Allocation Visit).
A dose must not be repeated if a subject vomits or regurgitates part or all of a dose. Vomiting 
and/or regurgitation of a dose must be recorded as an adverse event.
10.2.2
Total number of doses and dosing interval
The IMP will be taken for 14 (±1) days in Part 1 (Treatment Period) and, thereafter (tapentadol PR 
only), for up to ~12 months in the Tapentadol Period of Part 2. Dosing will be twice daily with a 
dosing interval of ~12 hours (but not less than 6 hours). 
10.2.3
Dose
10.2.3.1
Starting doses in Part 1 for subjects without previous opioid treatment
Subjects will start with the minimum dose (Dose level 1) of tapentadol PR (Table 2) or 
morphine PR (Table 3).
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10.2.3.2
Starting doses in Part 1 for subjects with previous opioid treatment
Subjects taking previous opioid treatment will start at 70% of the equi-analgesic dose of their 
previous treatment or lower; depending on the available dose, but using at least the minimum dose 
according to weight group (see Table 2 for tapentadol PR and Table 3 for morphine PR). 
Subjects pre-treated with morphine can continue on their previous dose or next lower dose 
according to Table 2 if the dose does not match a dose given on the dosing table, if randomized to 
morphine.
Conversion from other opioids to morphine should be done according to clinical routine. To 
calculate the dose of prolonged release opioids per intake, it is recommended to calculate the total 
daily dose of the immediate release opioid and divide the result by 2. To rotate subjects from other 
opioids to tapentadol PR, the morphine-equivalent dose should be calculated first followed by the 
calculation of the final tapentadol PR dose (1 mg morphine PR is equivalent to 2.5 mg 
tapentadol PR).
10.2.3.3
Starting dose of tapentadol PR in Part 2
Subjects converting from morphine PR (Treatment Period of Part 1) to tapentadol PR (Tapentadol 
Period of Part 2) will start tapentadol PR at 70% of the current morphine equivalent dose or lower, 
depending on the available dose, but using at least the minimum dose according to their weight 
group (Table 2). 
Subjects treated with tapentadol PR during Part 1 (Treatment Period) will continue on the last dose 
taken during Part 1 and the dose can be adjusted within the pre-defined limits as required during 
Part 2.
10.2.3.4
Titration
The dose of IMP will be titrated within the given limits for dosing according to the body weight 
measured during the last visit (see Table 2 for tapentadol PR and Table 3 for morphine PR).
Subjects will have the dose of IMP titrated up or down according to the pre-specified criteria 
defined below after consulting the investigator at visits throughout the trial or by using telephone 
contacts. However, a subject can reduce the dose at any time without consulting the investigator 
beforehand if a TEAE occurs. The subject should be informed by the investigator to report any dose 
reduction as soon as possible to the investigator.
The decision for a dose increase is at the investigator’s discretion, but should only be done after a 
minimum of 2 days (4 scheduled intakes of IMP) since the last increase to allow attainment of a 
steady state at the current dose.
Subjects who are already on the highest dose but who lose weight during the course of the trial may 
continue on that dose if needed.
10.2.3.4.1
Criteria for up-titration during Part 1 
Subjects will have their dose of IMP increased if the subject reports to the investigator that all of the 
criteria below are met:
•
Good tolerability (no signs of respiratory depression, tolerable nausea, constipation, etc.).
•
Last up-titration was 2 days ago (4 scheduled intakes of IMP). 
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•
1 of the following is true:
−
3 doses of rescue medication per 24 hours.
−
Average of pain assessments within the last 24 hours before dosing (“pain right now”) 
50 on VAS for subjects aged 12 years to less than 18 years at Visit V2.
−
Average of pain assessments within the last 24 hours before dosing (“pain right now”) 
on the FPS-R 5 for subjects aged 6 years to less than 12 years at Visit V2.
10.2.3.4.2
Criteria for up-titration during Tapentadol Period of Part 2
Subjects will have their dose of IMP increased if the subject reports to the investigator that all of the 
criteria below are met:
•
Good tolerability (no signs of respiratory depression, tolerable nausea, constipation, etc.).
•
Last up-titration was 2 days ago (4 scheduled intakes of IMP). 
10.2.3.4.3
Criteria for down-titration
Down-titration is recommended but not obligatory if at least 1 of the following criteria is met:
•
Pain <30 on VAS for the last 72 hours for subjects aged 12 years to less than 18 years at 
Visit V2.
•
Pain <3 on the FPS-R for the last 72 hours for subjects aged 6 years to less than 12 years at 
Visit V2.
•
The dose can be decreased any time due to TEAEs.
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10.2.4
Titration and dosing tables
Table 2:
Tapentadol PR dosing table
Weight
(kg)
Minimum/Starting 
dose a
Dose level 1
Titration
Maximum dose
Dose level 5
Dose level 2
Dose level 3
Dose level 4
M (mg)
E (mg)
M (mg)
E (mg)
M (mg)
E (mg)
M (mg)
E (mg)
M (mg)
E (mg)
17.5 to <22.5
25
25
50
50
-
-
-
-
75
75
22.5 to <27.5
25
25
50
50
75
75
-
-
100
100
27.5 to <32.5
25 b
50 b
75
75
100
100
-
-
125
125
32.5 to <40.0
50
50
75
75
100
100
125
125
150
150
40.0 to <45.0
50
50
100
100
125
125
150
150
175
175
45.0 to <50.0
75
75
100
100
150
150
175
175
200
200
50.0 to <55.0
75
75
100
100
150
150
200
200
225
225
55.0 to <60.0 c
75
75
100
100
150
150
200
200
250
250
60.0 c
100
100
125
125
150
150
200
200
250
250
a) Subjects taking less than the minimum dose according to their weight group may be discontinued from 
investigational medicinal product.
b) The first intake is 25 mg (irrespective whether first taken in the morning of evening) and the second and subsequent 
intakes are 50 mg.
c) Subjects with a bodyweight of 55.0 kg or higher will receive a maximum dose of tapentadol PR 250 mg twice daily.
M = morning; E = evening; PR = prolonged release.
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Table 3:
Morphine PR dosing table
Weight
(kg)
Minimum/Starting
dose a
Dose level 1
Titration
Maximum dose
Dose level 5
Dose level 2
Dose level 3
Dose level 4
M (mg)
E (mg)
M (mg)
E (mg)
M (mg)
E (mg)
M (mg)
E (mg)
M (mg)
E (mg)
17.5 to <22.5
10
10
20
20
-
-
-
-
30
30
22.5 to <27.5
10
10
20
20
30
30
40
40
27.5 to <32.5
10 b
20 b
30
30
40
40
-
-
50
50
32.5 to <40.0
20
20
30
30
40
40
50
50
60
60
40.0 to <45.0
20
20
40
40
50
50
60
60
70
70
45.0 to <50.0
30
30
40
40
60
60
70
70
80
80
50.0 to <55.0
30
30
40
40
60
60
80
80
90
90
55.0 to <60.0 c
30
30
40
40
60
60
80
80
100
100
60.0 c
40
40
50
50
60
60
80
80
100
100
a) Subjects taking less than the minimum dose according to their weight group may be discontinued from 
investigational medicinal product.
b) The first intake (irrespective whether first taken in the morning of evening) is 10 mg and the second and subsequent 
intakes are 20 mg.
c) Subjects with a bodyweight of 55 kg or higher will receive a maximum dose of morphine PR 100 mg twice daily.
M = morning; E = evening; PR = prolonged release.
10.3
Method of assigning subjects to treatment (allocation)
An interactive response technology system (voice and web based) will be used to assign a subject 
number at the Enrollment Visit (Visit V1) of Part 1 and to support the drug supply chain 
management processes of distribution and return. Details of the vendor and the system will be
defined in a separate document and filed in the trial master file at the end of trial.
The investigator or person assigned by the investigator must log into the system using their own 
user identification number and a password. The investigator or person assigned by the investigator 
will enter the subject’s number and other information required by the system to obtain a medication 
number. The medication number is then used to select the correct package of IMP to give to the 
subject.
10.3.1
Part 1
Subjects who comply with all inclusion criteria and do not meet any of the exclusion criteria will be 
randomly assigned to 1 of the 2 treatment arms at Visit V2 (Allocation Visit) for the duration of the 
Treatment Period. 
Subjects will be stratified using the interactive response technology system by age group (6 years to 
less than 12 years and 12 years to less than 18 years, at Visit V2 [Allocation Visit]) so that at least 
25% of the subjects are in the younger age group, and by underlying pain condition (cancer/non-
cancer-related pain).
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The following aspects will be requested by the interactive response technology system: body 
weight, age group of the subject, underlying pain condition, previous opioid treatment for first IMP 
supply, and preferred strength (25 mg or a combination of 25 mg and 100 mg), if applicable.
10.3.2
Part 2
At Visit VE, subjects will be discontinued from treatment in the interactive response technology 
system or be offered further treatment with tapentadol PR. Subjects who were treated with 
morphine PR will be offered further treatment with tapentadol PR in the interactive response 
technology system. 
The following aspects will be reflected by the system: body weight, previous treatment in Part 1 
(morphine PR or tapentadol PR) for first IMP supply in Part 2, and preferred strength (25 mg or a 
combination of 25 mg and 100 mg), if applicable.
10.4
Blinding and unblinding
This is an open-label trial.
10.5
Allowed and forbidden and prior/concomitant medications/therapies
Where appropriate, the following only apply to subjects taking IMP.
Restrictions apply to prior medication/therapy use, and subjects will be instructed to only use 
allowed concomitant medication/therapy during the trial. 
If, in the interests of the subject’s safety, the administration of forbidden concomitant 
medication/therapy is required, the sponsor should be informed in advance (or promptly after the 
instance).
For information about potential interactions with concomitant medication/therapy, see the current 
investigator’s brochure for tapentadol PR or the summary of product characteristics for 
morphine PR.
In emergency situations, medication according to standard medical knowledge should be initiated.
All medications/therapies that are not explicitly mentioned under allowed or forbidden treatments 
are also considered to be allowed.
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10.5.1
Allowed prior and concomitant medications/therapies
Allowed concomitant medications/therapies with timely or dose restrictions are:
On the day of allocation to IMP (Visit V2):
•
Weak and strong opioids up to a morphine-equivalent dose of <3.5 mg/kg per day.
During the Treatment Period (from Visit V2 to Visit VE):
•
Rescue medication (morphine oral solution) provided by the sponsor.
During the Treatment Period (from Visit V2 to Visit VE) and Tapentadol Period (from Visit VE 
until Visit ET/Visit F12M):
•
Intravenous opioids during surgery.
During the Tapentadol Period (from Visit VE until Visit ET/Visit F12M):
•
Immediate release strong opioids for treatment of breakthrough pain and incidental pain. 
10.5.2
Forbidden prior and concomitant medication/therapies
Forbidden prior and concomitant medication/therapies are:
Before allocation to IMP (Visit V2) and during the Treatment Period (from Visit V2 to Visit VE) 
and Tapentadol Period (from Visit VE until Visit ET/Visit F12M):
•
From 14 days prior to Visit V2 until the last intake of IMP: Monoamine oxidase inhibitors. 
•
From 30 days prior to Visit V2 until the last intake of IMP: Any medication or medical 
devices without a marketing authorization for human use.
Subjects may not undergo a washout of the above for the purposes of the trial.
During the Treatment Period (from Visit V2 to Visit VE) and Tapentadol Period (from Visit VE 
until Visit ET/Visit F12M):
•
Non-trial supplied opioids (unless covered by allowed concomitant treatments).
10.5.3
Cautionary use
Caution should be exercised with concomitant medication that:
•
May enhance the risk of central nervous or respiratory depression.
General anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics or other 
central nervous system depressants (including alcohol and illicit drugs) taken concomitantly 
with tapentadol may exhibit interactive effects resulting in respiratory depression, 
hypotension, profound sedation, or coma.
•
Is a serotoninergic medicinal product (e.g., selective serotonin re-uptake inhibitors).
In isolated cases, there have been reports of serotonin syndrome in a temporal connection 
with the therapeutic use of tapentadol in combination with serotoninergic medicinal 
products such as selective serotonin re-uptake inhibitors.
•
Is a strong enzyme inducer (e.g., rifampicin, phenobarbital, St John’s Wort) that is started
or stopped during the intake of IMP, since this may lead to decreased efficacy or risk of 
adverse effects, respectively.
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10.6
Rescue medication
During Part 1 (Treatment Period) only, morphine oral solution will be supplied by the sponsor as 
rescue medication for both treatment groups.
An interactive response technology system (voice and web based) will be used to assign subjects to 
rescue medication.
Name:
Morphine oral solution
Substance name:
Morphine sulfate or morphine hydrochloride
Active component(s): 
Morphine
Dose (strength): 
0.5% and/or 2.0% 
Final release of the 
re-packaged product:
Grünenthal GmbH, Aachen, Germany
During Part 2, the use of immediate release strong opioids for treatment of breakthrough pain and 
incidental pain is allowed.
10.6.1
Dose
The dose of morphine oral solution per intake of rescue medication is ~1/6 of the total daily dose of 
morphine PR treatment or ~1/6 of the morphine equivalent dose of tapentadol PR treatment.
The investigators and parent or legal guardian of the subject will be provided with a table showing 
clearly what dose of morphine oral solution the subject should take as rescue medication. 
Subjects on the highest dose of IMP are not allowed to take more than 4 doses of rescue medication 
per day on 2 consecutive days as this indicates a lack of efficacy (defined as a discontinuation 
criteria, see Section 9.3.1). No more than 10 doses of rescue medication at any dose level are 
allowed per day.
10.6.2
Reasons for administration
Rescue medication may be given in Part 1 for:
•
Breakthrough pain without clear cause.
•
End-of-dose failure indicating a requirement of adjustment of the dose of IMP.
•
Increased activity or movement (incidental pain).
•
Withdrawal symptoms such as hyperalgesia that appeared during the first days of titration 
after the previous treatment with an opioid were stopped.
•
Prevention of pain during titration, if considered necessary by the investigator.
10.6.3
Documentation
The intake of rescue medication (time and dose [mg]) will be documented by the subject, parent or 
legal guardian on a daily basis in the diary preferably after each intake of rescue medication in the 
Treatment Period.
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10.7
Documentation of drug accountability
For tapentadol PR and morphine PR tablets, drug accountability must be performed on a tablet basis 
per assigned IMP kit.
The bottles of rescue medication oral solution (morphine) will be weighed using appropriately 
calibrated scales before handing out to the subject/parent or legal guardian and at return to allow 
drug accountability. 
The investigator is obliged to keep documentation of the receipt, inventory, use, and destruction or 
return of unused, used, or partially used packages of trial treatment(s). The documentation must 
include trial treatment name, dates, quantities, subject numbers, batch/serial numbers or other 
identification numbers, expiration dates, and the means to identify the subject to whom it was 
given.
In addition to records in the documentation, e.g., source documents, CRF, the investigator must 
maintain documentation of drug accountability, i.e., separate records of the subject’s numbers, date 
of dispensing, and amount of trial treatment(s) dispensed to each subject and returned by each 
subject, and the return date.
Before the unused IMPs and other medications supplied to the investigator are returned or 
destroyed, the investigator must allow sponsor representatives to perform drug reconciliation. The 
entries in the documentation will be compared with the returned and residual trial treatment(s), and 
the administration/intake as documented in the CRF, with clarification of any discrepancies or 
inconsistencies. The documentation should also be checked regarding the expected amount to be 
returned according to the expected treatment dose.
See Section 12.8 for compliance limits.
11
TRIAL PROCEDURES
See Section 1.1 for a summary of the trial as a flow diagram and Section 1.2 for tabular schedules 
of events for each period. A trial site visit may be performed as a home visit after prior approval by 
the sponsor.
11.1
Course of the trial
11.1.1
Part 1
11.1.1.1
Enrollment Visit (Visit V1; Day -14 to Day 1)
During this period, the general suitability of the subjects for the trial will be assessed. Subjects will 
be considered to be trial participants when enrolled. The following procedures will be performed:
•
Obtain informed consent and (if required by local law) assent (see Section 4.2 for the 
procedure). The informed consent/assent may be obtained earlier than Day -14.
•
Record demographic data (date of signing the informed consent/assent form, sex, age, and 
race/ethnicity).
•
Record relevant medical history and pain history.
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•
Record prior and concomitant medication and therapies.
•
Perform a physical examination and document findings.
•
Record height and body weight. 
•
Record vital signs (respiratory rate, systolic and diastolic blood pressure, and pulse rate).
•
Record a 12-lead ECG. The inclusion as well as discontinuation of a subject will be based 
on the judgment of the investigator. If the subject has been included but fulfills any of the 
discontinuation criteria based on the ECG analysis report of the central ECG laboratory, the 
ECG must be repeated within 1 week of receiving the central ECG report and the subject 
must be discontinued if any of the discontinuation criteria is confirmed by the investigator.
•
Take blood for safety laboratory investigations (for both the central and local laboratories).
The local laboratory sample does not need to be taken at the Enrollment Visit if suitable 
results from the same local laboratory are available from a blood sample obtained in the 
14 days prior to Visit 2 for other reasons.
•
Collect urine/perform dip stick urinalysis.
•
Perform a urine test for drugs of abuse.
•
Evaluate subject suitability for trial participation according to the inclusion/exclusion 
criteria as applicable (e.g., excluding results of central laboratory tests not yet available).
Compliance with the exclusion criteria pertaining to laboratory analyses will be checked 
based on local laboratory values. The parameters needed for this assessment comprise: total 
serum bilirubin, serum albumin, aspartate transaminase, alanine transaminase, and serum 
creatinine. The creatinine clearance will be calculated by the electronic CRF.
•
Assess and record adverse events that occur after signing the informed consent form.
•
Dispense the subject trial card to the subject/parent/guardian.
11.1.1.2
Visit V2 (Allocation Visit; Day 1)
If Visit V1 and Visit V2 are on the same day, the following procedures will not be repeated:
•
Record age.
•
Record concomitant medication intake/therapies.
•
Perform a physical examination, document that it was performed, and record changes to 
previous assessment.
•
Record body weight.
•
Record vital signs (respiratory rate, systolic and diastolic blood pressure, and pulse rate).
•
Assess and record adverse events.
The following Day 1 specific evaluations will be carried out:
•
Perform a urine pregnancy test in female subjects who are post-menarchal or older than 
12 years at the time of the scheduled visit.
•
Check inclusion and exclusion criteria. Compliance with the exclusion criteria will be 
checked based on local laboratory values. The parameters needed for this assessment 
comprise: total serum bilirubin, serum albumin, aspartate transaminase, alanine 
transaminase, and serum creatinine. The creatinine clearance will be calculated 
automatically by the electronic CRF.
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•
Set up diary.
•
Dispense diary.
•
Instruct subject, parent(s), or legal guardian(s) on how to use diary.
−
Give instructions to record pain assessment twice daily in the diary (VAS and FPS-R)
until Visit VE.
−
Give instructions to record intake of IMP and rescue medication in the diary, including
time of administration.
•
Record “pain right now” in the diary (VAS and FPS-R) before any painful or unpleasant 
procedure, and before the first intake of IMP as a baseline value.
•
Complete the modified CAS.
•
Allocate subject to treatment (see Section 10.3).
•
Dispense IMP and rescue medication (see Section 10.6).
•
Administer the first dose of IMP to the subject (see Section 10.2.1). The first dose of IMP 
will be taken during this visit, within 24 hours after randomization. Day 1 is the day of first 
IMP intake. Record administration in the diary.
•
Train/instruct subject, parent(s), guardian(s), or caregiver on IMP/rescue medication use 
(handling and intake). 
•
Discuss IMP titration/dose adjustment.
•
Take a single blood sample for serum pharmacokinetics from subjects on tapentadol PR at 
1 hour to 6 hours after IMP for out-patients or at 3 hours to 6 hours after IMP intake for 
hospitalized subjects. 
11.1.1.3
Visit V3 (Day 8 ± 1)
The following procedures will be performed:
•
Record concomitant medication intake/therapies.
•
Record body weight.
•
Record vital signs (respiratory rate, systolic and diastolic blood pressure, and pulse rate).
•
Train/instruct subject(s), parent(s), or legal guardian(s) how to use the diary.
−
Give instructions to record pain assessment twice daily in diary (VAS and FPS-R) until 
Visit VE.
−
Give instructions to record intake of IMP and rescue medication in the diary, including
time of administration.
•
Check diary compliance.
•
Complete the modified CAS questionnaire.
•
Complete the acceptability and palatability of IMP questionnaire.
•
Collect returned IMP and rescue medication.
•
Perform drug accountability:
−
Confirm and document compliance with IMP intake.
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−
Confirm whether returned amount of rescue medication matches expected amount to be 
returned. 
−
Verify discrepancies with subject, or parent(s), legal guardian(s), or caregiver.
•
Dispense IMP and rescue medication.
•
Train/instruct subject, parent(s), guardian(s), or caregiver on IMP/rescue medication use 
(handling and intake). Exchange instruction sheet if necessary (e.g., due to weight change).
•
Discuss IMP titration/dose adjustment.
•
Take blood sample for serum pharmacokinetics (at any time during the visit, but after 
measuring the pain scores) from subjects on tapentadol PR. 
•
Assess and record adverse events.
•
Assess discontinuation criteria.
11.1.1.4
Visit VE (Day 15 ± 1, End of Treatment Visit)
This visit is planned for Day 15 ± 1, but must also be performed within 3 days after last intake of 
IMP if a subject discontinues IMP during the Treatment Period.
The following procedures will be performed:
•
Record age of subject.
•
Record concomitant medication intake/therapies.
•
Perform a physical examination, document that it was performed, and record changes to 
previous assessment.
•
Record height.
•
Record body weight.
•
Record vital signs (respiratory rate, systolic and diastolic blood pressure, and pulse rate).
•
Record a 12-lead ECG.
•
Record “pain right now” in the CRF (VAS and FPS-R) - only for subjects going into the 
Tapentadol Period.
•
Complete the following questionnaires:
−
Modified CAS.
−
Acceptability and palatability of IMP.
−
Dispense SOWS questionnaire for completion at home if this is the visit of the last 
intake of IMP (only for subjects going in to the Observation Period). To be completed 
once daily until the seventh day after the last intake of IMP. To be collected at 
Visit F7D.
•
Check diary compliance.
•
Collect the diary for subjects not entering the Tapentadol Period (Part 2).
•
Collect returned IMP and rescue medication.
•
Perform drug accountability:
−
Confirm and document compliance with IMP intake.
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−
Confirm whether returned amount of rescue medication matches expected amount to be 
returned. 
−
Verify discrepancies with subject, or parent(s), legal guardian(s), or caregiver.
•
Take blood sample for serum pharmacokinetics (at any time during the visit, but after 
measuring the pain scores) from subjects on tapentadol PR. 
•
Take blood for central laboratory (hematology, clinical chemistry).
•
Collect urine/perform dip stick urinalysis.
•
Perform a urine pregnancy test in female subjects who are post-menarchal or older than 
12 years at the time of the scheduled visit.
•
Assess and record adverse events. Document changes (e.g., in the intensity) of each 
ongoing adverse event.
•
Check discontinuation criteria for IMP intake.
•
Check subject eligibility and assign eligible subjects to the Tapentadol Period or 
Observation Periods.
For subjects entering the Tapentadol Period:
•
Instruct the subject, parent(s), legal guardian(s) or caregiver about the Tapentadol Period, 
including:
−
Discuss titration/dose adjustment if subject transfers from morphine PR.
−
Dispense IMP.
−
Retrain subject, parent(s), legal guardian(s), or caregiver on use of IMP (handling and 
intake).
•
Train/instruct subject(s), parent(s), or legal guardian(s) how to use the diary.
−
Give instructions to record intake of IMP in the diary, including time of administration.
Exchange instruction sheet if necessary (e.g., due to weight change).
For subjects assigned to the Observation Period:
•
Instruct the subject, parent(s), or legal guardian(s) about the Observation Period. 
11.1.2
Part 2 – Tapentadol Period
Subjects completing the Treatment Period (Part 1) with tapentadol PR or morphine PR and who 
have need for continued opioid treatment can enter the Tapentadol Period. Assignment to the 
Tapentadol Period needs to be documented in the CRF and the interactive response technology 
system. Subjects will be followed until Visit F12M. Subjects in the Tapentadol Period of Part 2 may 
stop treatment early (before Visit F12M) and switch to Observation period for the remainder of 
Part 2.
11.1.2.1
Visit M1 (Day 7 ± 2) and Visit M2 (Day 14 ± 2)
As withdrawal symptoms may occur in subjects transferring from morphine PR to tapentadol PR, 
because they start tapentadol PR at 70% of the equivalent morphine dose, these subjects will have 
2 additional visits at the beginning of the Part 2 Tapentadol Period (Visit M1 and Visit M2). 
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Visit M1 and Visit M2 in the Tapentadol Period are only for subjects who had been previously 
allocated to morphine PR in the Treatment Period.
The following procedures will be performed:
•
Record concomitant medication intake/therapies.
•
Record vital signs (respiratory rate, systolic and diastolic blood pressure, and pulse rate).
•
Record “pain right now” in the CRF (VAS and FPS-R).
•
Train/instruct subject(s), parent(s) or legal guardian(s) how to use the diary.
−
Give instructions to record intake of IMP in the diary, including time of administration.
•
Check diary compliance.
•
Collect returned IMP.
•
Perform drug accountability:
−
Confirm and document compliance with IMP intake.
−
Verify discrepancies with subject, or parent(s), legal guardian(s), or caregiver.
•
Dispense IMP.
•
Discuss titration/dose adjustment.
•
Train/instruct subject, parent(s), legal guardian(s), or caregiver on the use of IMP (handling 
and intake). Exchange instruction sheet if necessary (e.g., due to weight change).
•
Assess and record adverse events.
•
Check discontinuation criteria.
11.1.2.2
Visit TP1 to TP12 (every 28 days after Visit VE, range: ±5 days)
Visits TP1 to TP12 are performed at ~28 day intervals in all subjects in the Tapentadol Period. The 
following procedures will be performed:
•
Record concomitant medication intake/therapies.
•
Record body weight.
•
Record height (only at Visit TP3, Visit TP6, Visit TP9, and Visit TP12).
•
Record vital signs (respiratory rate, systolic and diastolic blood pressure, and pulse rate).
•
Record “pain right now” in the CRF (VAS and FPS-R).
•
Take blood for central laboratory (hematology, clinical chemistry; only at Visit TP3, 
Visit TP6, Visit TP9, and Visit TP12).
•
Collect urine/perform dip stick urinalysis (only at Visit TP3, Visit TP6, Visit TP9, and 
Visit TP12).
•
Perform a urine pregnancy test in female subjects who are post-menarchal or older than 
12 years (only at Visit TP3, Visit TP6, Visit TP9, and Visit TP12) at the time of the 
scheduled visit.
•
Train/instruct subject(s), parent(s), or legal guardian(s) how to use the diary.
−
Give instructions to record intake of IMP in the diary, including time of administration.
•
Check diary compliance.
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•
Collect returned IMP.
•
Perform drug accountability:
−
Confirm and document compliance with IMP intake.
−
Verify discrepancies with subject, or parent(s), legal guardian(s), or caregiver.
•
Dispense IMP.
•
Discuss titration/dose adjustment 
•
Train/instruct subject, parent(s), legal guardian(s), or caregiver on IMP (handling and 
intake). Exchange instruction sheet if necessary (e.g., due to weight change).
•
Assess and record adverse events.
•
Check discontinuation criteria.
11.1.2.3
Visit ET (Early Termination Visit)
Visit ET must be performed within 3 days after last intake of IMP if IMP is stopped before 
Visit F12M in Part 2. If Visit F12M and Visit ET are performed on the same day, assessments 
scheduled for both visits will not be repeated at Visit F12M.
The following procedures will be performed:
•
Record concomitant medication intake/therapies.
•
Perform a physical examination, document that it was performed, and record changes to 
previous assessment.
•
Record height.
•
Record body weight.
•
Record vital signs (respiratory rate, systolic and diastolic blood pressure, and pulse rate).
•
Complete the following questionnaires:
−
Modified CAS questionnaire.
−
Dispense SOWS questionnaire for completion at home if this is the visit of the last 
intake of IMP. To be completed once daily until the seventh day after the last intake of 
IMP. To be collected at Visit F7D. 
•
Record “pain right now” in the CRF (VAS and FPS-R).
•
Take blood for central laboratory (hematology, clinical chemistry).
•
Collect urine/perform dip stick urinalysis.
•
Perform a urine pregnancy test in female subjects who are post-menarchal or older than 
12 years at the time of the scheduled visit.
•
Check diary compliance.
•
Collect the diary.
•
Collect returned IMP.
•
Perform drug accountability:
−
Confirm and document compliance with IMP intake.
−
Verify discrepancies with subject, or parent(s), legal guardian(s), or caregiver.
•
Assess and record adverse events.
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11.1.2.4
Visit F12M (at 12 months after Visit VE, range ±14 days)
The following procedures will be performed:
•
Record concomitant medication intake/therapies.
•
Perform a physical examination, document that it was performed, and record changes to 
previous assessment.
•
Record height.
•
Record body weight.
•
Record vital signs (respiratory rate, systolic and diastolic blood pressure, and pulse rate).
•
Complete the following questionnaires:
−
Modified CAS questionnaire.
−
Dispense SOWS questionnaire for completion at home if this is the visit of the last 
intake of IMP. To be completed once daily until the seventh day after the last intake of 
IMP. To be collected at Visit F7D.
•
Record “pain right now” in the CRF (VAS and FPS-R).
•
Take blood for central laboratory (hematology, clinical chemistry).
•
Collect urine/perform dip stick urinalysis.
•
Perform a urine pregnancy test in female subjects who are post-menarchal or older than 
12 years at the time of the scheduled visit.
•
Check diary compliance.
•
Collect the diary if IMP has been stopped at this visit, if not already collected.
•
Collect returned IMP.
•
Perform drug accountability:
−
Confirm and document compliance with IMP intake.
−
Verify discrepancies with subject, or parent(s), legal guardian(s), or caregiver.
•
Assess and record adverse events.
11.1.3
Visit F7D (Final post treatment visit, at 7 days after stopping IMP, range
±2 days)
Visit F7D is the final post treatment visit, performed 7 days (±2) after stopping IMP, i.e., after 
Visit F12M, or after Visit VE for subjects stopping IMP in Part 1, or Visit ET for subjects stopping 
IMP before Visit F12M in Part 2.
The following procedures will be performed:
•
Record concomitant medication intake/therapies.
•
Perform a physical examination, document that it was performed, and record changes to 
previous assessment.
•
Record vital signs (respiratory rate, systolic and diastolic blood pressure, and pulse rate).
•
Collect the completed SOWS questionnaires.
•
Assess and record adverse events. 
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Complete end of trial tasks, e.g., collect subject trial cards (if the subject is discontinuing 
from the trial).
11.1.4
Part 2 – Observation Period
Subjects not completing the Treatment Period (Part 1), but who have taken at least 1 dose of IMP, 
and those who complete the Treatment Period but who do not want to continue with tapentadol PR, 
will enter the Observation Period (12 months). Assignment to the Observation Period needs to be 
documented in the CRF and the interactive response technology system Subjects will be followed 
until Visit F12M. Subjects in the Tapentadol Period of Part 2 may stop treatment early (before 
Visit F12M) and switch to Observation period for the remainder of Part 2. Subjects transferring 
before Visit F12M from the Tapentadol Period to the Observation Period will continue in the 
Observation Period starting from the same trial day number.
11.1.4.1
Visit OP3, Visit OP6, and Visit OP9 (at 3, 6, 9 months after Visit VE, range
±14 days)
The following procedures will be performed:
•
Record concomitant medication intake/therapies.
•
Assess and record adverse events.
11.1.4.2
Visit OPx (unscheduled final visit)
Visit OPx is an unscheduled visit during the Observation Period when the subject stops further 
participation in the trial. The assessments are performed for all subjects who discontinue from the 
Observation Period, unless informed consent is withdrawn.
The following procedures will be performed:
•
Record concomitant medication intake/therapies.
•
Perform a physical examination, document that it was performed, and record changes to 
previous assessment.
•
Record height.
•
Record body weight.
•
Record vital signs (respiratory rate, systolic and diastolic blood pressure, and pulse rate).
•
Complete the following questionnaires:
−
Modified CAS questionnaire.
•
Take blood for central laboratory (hematology, clinical chemistry).
•
Collect urine/perform dip stick urinalysis.
•
Assess and record adverse events.
•
Complete end of trial tasks, e.g., collect subject trial cards.
11.1.4.3
Visit F12M (at 12 months after Visit VE, range ±14 days)
The following procedures will be performed:
•
Record concomitant medication intake/therapies.
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•
Perform a physical examination, document that it was performed, and record changes to 
previous assessment.
•
Record height.
•
Record body weight.
•
Record vital signs (respiratory rate, systolic and diastolic blood pressure, and pulse rate).
•
Complete the following questionnaires:
−
Modified CAS questionnaire.
•
Take blood for central laboratory (hematology, clinical chemistry).
•
Collect urine/perform dip stick urinalysis.
•
Assess and record adverse events.
•
Complete end of trial tasks, e.g., collect subject trial cards.
11.1.5
Phone contacts
Phone contacts can be made at any time, e.g., if the subject wants to report adverse events, or has 
questions regarding concomitant medication intake/therapies. If no trial site visit takes place, phone 
contacts are mandatory if the subject would like to up or down titrate the IMP. A trial site visit may 
be performed as a home visit after prior approval by the sponsor.
The following will be recorded:
•
Record concomitant medication intake/therapies.
•
Discuss titration/dose adjustment.
•
Record reason for dose adjustment and new dose, if applicable.
•
Assess and record adverse events.
•
Check discontinuation criteria.
11.1.6
Additional trial site attendance
A parent or legal guardian (or subject if 18 years or older) may additionally visit the investigator’s 
site solely for the purpose of obtaining further supplies of IMP, especially at trial sites where 
provision of narcotics to subjects is limited. This may be performed without the presence of the 
subject.
11.2
Examination hierarchy and time windows
No procedures for this trial are allowed to be performed before the informed consent/(if required) 
assent is obtained.
Non-invasive procedures, e.g., recording of pain assessment, should be performed before invasive 
procedures. Blood samples for safety laboratory and pharmacokinetics should be taken after all 
non-invasive procedures are completed and should be taken together when scheduled for the same 
visit. The exact order in which procedures are performed may deviate due to local circumstances 
and will not constitute, per se, a protocol deviation.
The visit time windows are not cumulative, and visits should be performed at the times specified 
within the given time window (Section 1.2).
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11.3
Conditions during the trial
11.3.1
Medical care
For any adverse events, a causal or symptomatic treatment according to standard medical practice 
will be performed if deemed necessary by the investigator. The medical care given to, and medical 
decisions made on behalf of, the subjects will always be the responsibility of a qualified physician.
See the guidance for the investigator given in the investigator’s brochure for tapentadol PR and the 
summary of product characteristics for morphine PR for precautions and emergencies relevant for 
this trial, e.g., for the management of overdose.
11.3.2
General restrictions
Subjects must refrain from drinking beverages containing alcohol and recreational intake of drugs 
while on IMP.
All restrictions and precautions, e.g., regarding prior food intake, listed in the investigator’s 
brochure for tapentadol PR and in the summary of product characteristics for morphine PR must 
also be followed. Otherwise, there are no general restrictions on the subjects. 
11.3.3
Counseling of female subjects of reproductive age
All female subjects of childbearing potential (post-menarchal and not surgically incapable of 
childbearing), including those with the menarche during the trial or are or become 12 years old,
should be counseled on the need to practice medically acceptable methods of birth control during 
the trial and on the importance of avoiding pregnancy while on IMP. Counseling should take place 
at the start of the trial or during the trial if the child is post-menarchal. Counseling must be 
documented in the source documents and CRF.
Medically acceptable methods of birth control include:
•
Hormonal contraceptives.
•
Intra-uterine devices used according to the product’s instruction. 
•
Double-barrier methods (condom and occlusive cap [diaphragm or cervical/vault caps] with 
spermicidal foam/gel/film/cream/suppository). A female condom and a male condom 
should not be used together as friction between the two can result in either product failing.
All female subjects of childbearing potential will be counseled to contact the investigator or trial 
site staff immediately if pregnancy is suspected.
11.4
Subject trial cards
Subjects/parent(s)/legal guardian(s), as applicable, will receive a “subject trial card”. The trial card 
will list at a minimum the following information:
•
Name of the subject and a statement that he/she is currently participating in a clinical trial.
•
Trial code.
•
Dates of all individual visits.
•
Name of investigator.
•
Contact (telephone) number at the trial site.
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11.5
Provisions of any additional care of subject after trial termination
After stopping the IMP, subjects will be treated by their physicians according to the specific 
standard treatment in the country concerned.
11.6
Low enrollment
Trial sites with a low enrollment rate may be required by the sponsor/coordinating 
investigator/contract research organization to stop further recruitment at once or to cease 
participation in the trial.
A low recruitment rate is defined as no subject allocated to IMP within 16 weeks of IMP 
availability at the trial site, and no subject allocation to IMP within 1 year after the last subject was 
allocated to IMP.
12
DATA COLLECTION
12.1
Overview of blood sampling in this trial
The application of a local anesthetic (patch, cream or gel) to the skin of 2 potential locations for 
vein puncture before the blood samples are taken is recommended. Immediately before the blood 
sampling, the locations must be cleaned to remove any residuals of the local anesthetic.
Blood can be taken through a central venous line if in place and there is a spare line through which 
no medication is administered. The amount of blood that needs to be discarded when collecting it 
via the central line needs to be taken into account so as not to exceed the maximum allowed amount 
of blood.
If possible, blood samples for safety laboratory evaluations and serum pharmacokinetics should be 
taken at the same time. Sampling times are given in the schedule of events (Section 1.2). The local 
laboratory sample does not need to be taken at the Enrollment Visit if suitable results from the same 
local laboratory are available from a blood sample obtained in the 14 days prior to Visit 2 for other 
reasons.
Table 4:
Approximate volume of blood to be collected from each subject during Part 1
Examination
Blood per test
Number of samples
Total per test b
Blood sampling for serum pharmacokinetics a
0.5 mL
3
1.5 mL
Clinical chemistry – central laboratory
2 mL
2
4 mL
Hematology – central laboratory
2 mL
2
4 mL
Clinical chemistry – local laboratory
2 mL
1
2 mL
Total
11.5 mL
The volume of blood taken may be individually variable due to flushing, resampling etc.
a) Blood samples for serum pharmacokinetics will only be drawn from subjects on tapentadol PR.
b) Calculated as number of samples multiplied by amount of blood per sample.
PR = prolonged release.
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Table 5:
Approximate volume of blood to be collected from each subject during the 
Tapentadol Period of Part 2
Examination
Blood per test
Number of samples
Total per test a
Clinical chemistry – central laboratory
2 mL
6
12 mL
Hematology – central laboratory
2 mL
6
12 mL
Total
24 mL
The volume of blood taken may be individually variable due to flushing, resampling etc.
a) Calculated as number of samples multiplied by amount of blood per sample.
The expected total blood volume drawn per subject will not exceed 12 mL during the Part 1 of the 
trial, and 25 mL during the Tapentadol Period of Part 2. Approximately 4 mL blood (2 mL for 
hematology and 2 mL for clinical chemistry) will be taken at Visit F12M of the Observation Period.
Additional blood may be drawn if a (serious) adverse event occurs or if the investigator considers it 
necessary.
The volumes of blood taken for each assessment may vary due to trial site requirements; however,
the total planned blood volume drawn per subject during the trial (Part 1 and Part 2) should not 
generally exceed 37 mL (excluding any blood that is discarded), i.e., will stay well within the 
maximum acceptable level of blood loss recommended in a pediatric population (EMEA ad hoc 
working party 2008).
12.2
Collection of subject characteristics data
12.2.1
Demographic data
Demographic data (date of signing the informed consent/assent form, sex, age, and race/ethnicity)
will be recorded in the CRF. 
12.2.2
Medical history
The clinically relevant medical history of the subject per investigator’s opinion will be documented 
in the CRF.
12.2.3
Pain history
The history, underlying pain condition (cancer/non-cancer-related pain), and treatments given in the 
last 30 days for pain before enrollment will be recorded in the CRF.
12.2.4
Prior and concomitant medications and therapies
All therapies, medication requiring prescriptions (including oral contraceptives) and/or 
over-the-counter medication used within 30 days prior to enrollment and up to the end of the trial 
must be recorded in the CRF. 
All additions to or changes in therapy, prescriptions and/or over-the-counter medication after 
enrollment must be recorded in the CRF, for changes in therapy as a new entry.
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12.3
Collection of pharmacokinetic data
12.3.1
Blood sampling for serum pharmacokinetics
Blood samples for pharmacokinetic evaluations will only be drawn from subjects on tapentadol PR. 
No blood samples will be drawn from subjects on morphine PR for pharmacokinetic evaluations.
The instructions given in Section 12.1 should be followed for blood sampling for serum 
pharmacokinetics. No more than 2 attempts to collect blood for pharmacokinetic evaluations should 
be done at any visit. The exact dates and times of blood sample collection must be recorded in the 
CRF. See Section 19.8, for instructions for the handling and shipping of the pharmacokinetic 
samples.
12.3.2
Bioanalytical assays
Serum concentrations of tapentadol and tapentadol-O-glucuronide will be determined using a 
validated bioanalytical assay under the supervision of the sponsor’s department of 
pharmacokinetics.
The bioanalytical report, including a description of the assays and a summary of the assay 
performance data, will be included in the final integrated clinical trial report.
12.4
Collection of efficacy data
12.4.1
Pain intensity
During the trial, the following pain evaluations will be performed at the time points indicated in the 
schedule of events (see Section 1.2). Information related to the rationale for these evaluations and 
the validation of the pain scales is given in Section 12.7.
During Part 1, subjects will document the pain they have at present, twice daily (preferably directly 
before IMP administration) in their diary. Subjects will document the pain by using first the VAS
and directly thereafter the FPS-R. If required, the subjects may be helped by their parent or legal 
guardian or a health care provider.
For the Tapentadol Period of Part 2, the investigator will document the pain that the subject has at 
each visit in the CRF based on the FPS-R and VAS.
Documentation of the pain scales actually used will be maintained.
12.4.1.1
Visual analog scale
The subject will be asked to indicate the current level of pain intensity at the time of assessment on 
a validated vertical VAS scale (see example in Section 19.2). It will be scored such that a score of 0 
is equivalent to “no pain” and a score of 100 is equivalent to “pain as bad as it could be”.
12.4.1.2
Faces Pain Scale – Revised 
The subject will be asked to indicate the current level of pain intensity at the time of assessment 
using the FPS-R (see Section 19.3). The FPS-R is a validated self-reported 6 point scale with 0 
representing “no pain” and 10 representing “very much pain”. Facial representations are used to 
indicate how much the pain hurts.
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12.5
Questionnaires
The subject will fill in the questionnaires at the visits as described in the schedule of events 
(Section 1.2). The caregiver, parent, or legal guardian may assist the subject completing the 
questionnaires. If the subject is not able to read, the caregiver, parents, or legal guardians will fill in 
the questionnaires together with the subject. The investigator will document the scores of the 
questionnaires in the CRF. 
Documentation of the questionnaires actually used will be maintained.
12.5.1
Modified constipation assessment scale
The constipation assessment scale was developed and validated for people with cancer (McMillan 
and Williams 1989), and was revised for use in children with cancer (Woolery et al. 2006). Strong 
validity and reliability data have been obtained in several small samples, including adults and 
children with cancer. Because the assessment takes only 2 minutes to complete, it is useful in the 
clinical setting.
The scale has 8 items that inquire about subjective symptoms that commonly occur with 
constipation (see Section 19.4). Total scoring goes from 0 = no constipation to 16 = worst possible 
constipation.
12.5.2
Acceptability and palatability of investigational medicinal product
Responses for palatability and acceptability will be evaluated on 5 point hedonic scales in 
combination with a verbal rating (Guinard 2001) (see Section 19.6). 
Palatability will be assessed by asking the following question “How does the tablet taste”. The 
verbal rating is from really good, good, a bit good/a bit bad, bad, and really bad.
Acceptability will be assessed by asking the following question “Swallowing the tablet was ...”. The 
verbal rating is really easy, easy, a bit easy/a bit difficult, difficult, and really difficult.
12.5.3
Subjective opiate withdrawal scale
The SOWS questionnaire is a self-administered scale for grading opioid withdrawal symptoms 
(Handelsman et al. 1987). It contains 16 symptoms whose intensity the patient rates on a scale of 0 
(not at all) to 4 (extremely) (see Section 19.5). The original scale including 16 questions has been 
used in a detoxification setting of opioid addicts. More recently, it is being used in rapid 
detoxification with 15 questions. The first 15 questions of the 16-question SOWS questionnaire are 
appropriate for the studied population. It takes less than 10 minutes to complete. The scale has been 
demonstrated to be a valid and reliable indicator of the severity of the opiate withdrawal syndrome 
over a wide range of common signs and symptoms.
The SOWS questionnaire will be completed by the subjects at home daily until the seventh day 
after the last intake of IMP. It will be collected at Visit F7D.
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12.6
Collection of safety data
12.6.1
Adverse events
All adverse events will be documented from the time of enrollment (i.e., the time the informed 
consent form is signed) up to the time of the last protocol scheduled contact has occurred, i.e., date 
of last visit/contact (can be a phone call, e.g., in case of withdrawal).
Changes in any of the attributes of an ongoing adverse event will be documented separately, by 
recording a separate episode of the same adverse event (details will be given in the CRF completion 
guideline).
All adverse events will be sorted into the categories: non-treatment emergent adverse events (non-
TEAEs) and TEAEs.
Definition of adverse events
An adverse event is any untoward medical occurrence, i.e., any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease, in a subject enrolled in a clinical 
trial.
Pre-existing diseases or conditions occurring before enrollment are not considered to be adverse 
events unless there is an untoward change in intensity, frequency, or quality after enrollment. 
Lack of efficacy per se is not considered to be an adverse event.
A newly diagnosed pregnancy of an enrolled female subject will not be considered an adverse event
itself unless it is suspected that the trial treatment interacted with a contraceptive method. In this 
case, the pregnancy will be considered a TEAE. A congenital anomaly as an outcome of this 
pregnancy will be considered a serious TEAE.
All newly diagnosed pregnancies of enrolled female subjects will be reported to the sponsor’s Drug 
Safety Department within 24 hours after first knowledge. These pregnancies will be documented 
using a pregnancy reporting form with all available information provided and followed up to 
determine the outcome post parturition.
Definition of non-treatment emergent adverse events
All adverse events occurring after enrollment and prior to the administration of an IMP are defined 
as non-TEAEs.
Definition of treatment emergent adverse events
All adverse events occurring in a subject who was administered a trial treatment and that do not 
necessarily have a causal relationship with the trial treatment. In addition, pre-treatment adverse 
events which worsen during the treatment period are also considered TEAEs.
The therapeutic reach (i.e., the number of days after treatment completion that a subject is still 
considered to be potentially affected by IMP) will be defined in the statistical analysis plan (SAP).
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Definition of serious adverse events
A serious adverse event is any untoward medical occurrence that at any dose:
•
Results in death.
•
Is life-threatening.
•
Requires hospitalization or prolongation of existing hospitalization.
•
Results in persistent or significant disability/incapacity.
•
Is a congenital anomaly/birth defect.
•
Is considered medically important. The medical concepts included in Section 19.1 should 
be taken into account when applying the seriousness criterion.
An elective hospital admission, e.g., for pre-planned surgery, will not be considered a serious 
adverse event if documented at enrollment. Short-lasting (<24 hours) hospital admissions, e.g., for 
clinical check-ups, not meeting any of the other above mentioned criteria will also not be 
considered as serious adverse event.
Special procedures for serious adverse events
If serious adverse events occur that are not tolerable, the investigator will decide for that subject 
whether to stop the trial and/or treatment of the subject.
If possible, after serious adverse events considered related to IMP (possible: see the section 
Classification of causation), a blood sample for the quantitation of systemic exposure of tapentadol
and metabolites should be drawn in close temporal relationship to the serious adverse event.
Definition of expected treatment emergent adverse events
An unexpected TEAE is one where the nature or intensity is not consistent with the information in 
the investigator’s brochure for tapentadol PR or in the summary of product characteristics for 
morphine PR.
Expectedness will be assessed by the sponsor.
Furthermore, reports that add significant information about the specificity or severity of a known, 
already documented adverse reaction constitute unexpected TEAEs. For example, a TEAE more 
specific or more severe than expected would be considered “unexpected”. 
Definition of adverse drug reactions
Adverse drug reactions are all untoward and unintended responses to an IMP independent of the 
dose administered. 
All TEAEs judged by either the reporting investigator or the sponsor as having a reasonable causal 
relationship to a medicinal product qualify as adverse drug reactions. The expression “reasonable 
causal relationship” means to convey, in general, that there is evidence or argument to suggest a 
causal relationship. For guidance on the causal relationship, see the section Classification of 
causation.
A list of adverse drug reactions seen for the IMPs are given in the current version of the 
investigator’s brochure for tapentadol PR and in the summary of product characteristics for 
morphine PR.
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Classification of causation
The causal relationship of an adverse event to IMP will be classified using the following 
terminology. The given criteria for each term are for consideration and are neither exhaustive nor 
required to be fulfilled in total for the selection of the respective term: 
Terms for classification 
of causation
Criteria for the selection of causality classification terms
Conditional/ 
Unclassified:
Additional data for a proper assessment are under examination. 
Unassessable/ 
Unclassifiable:
The available data cannot be judged because information is 
insufficient or contradictory, and cannot be supplemented or verified. 
Not related:
Data with sufficient evidence to accept that there is no causal 
relationship to IMP administration (i.e., there is no temporal 
relationship to IMP administration or proved other cause). 
Unlikely:
Data without sufficient evidence to accept that there is no causal 
relationship to IMP administration, but also with no evidence or 
argument to suggest a causal relationship (e.g., the temporal 
relationship to IMP administration makes a causal relationship 
improbable and other drugs, chemicals, or underlying disease(s) 
provide plausible explanations). 
Possible:
Data with limited evidence or argument to suggest a causal 
relationship (e.g., there is a reasonable time sequence to 
administration of the drug, but the adverse event could also be 
explained by concurrent disease[s] or other drugs or chemicals. 
Information on drug withdrawal may be lacking or unclear). 
Probable/ likely:
Data with sufficient evidence or argument to suggest a causal 
relationship (e.g., there is a reasonable time sequence to 
administration of the drug, the adverse event is unlikely to be 
attributed to concurrent disease(s) or other drugs or chemicals, and a 
clinically reasonable response on withdrawal [dechallenge]).
Certain:
Data with clear evidence for a causal relationship (i.e., a clinical 
event, including laboratory test abnormality, occurs in a plausible 
time relationship to drug administration, and it cannot be explained 
by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the drug [dechallenge] should be clinically plausible. 
The event must be pharmacologically or phenomenologically 
definitive, using a satisfactory rechallenge procedure if necessary).
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Definition of intensity 
The clinical “intensity” of an adverse event will be classified as:
Mild:
Signs and symptoms that can be easily tolerated. Symptoms can be 
ignored and disappear when the subject is distracted.
Moderate:
Symptoms cause discomfort but are tolerable; they cannot be ignored 
and affect concentration.
Severe:
Symptoms which affect usual daily activity.
Definition of outcome at the time of last observation
The outcome at the time of last observation will be classified as:
•
Recovered/Resolved.
•
Recovered/Resolved with sequelae.
•
Fatal.
•
Recovering/Resolving.
•
Not recovered/Not resolved.
•
Unknown (unknown should only be used, if at the time of the last Visit for a subject in a 
trial, the outcome of the adverse event is unknown to the investigator, e.g., because the 
subject is lost to follow-up).
In the event of irreversible congenital anomalies, the choice “not resolved” should be used. “Fatal” 
should only be used when death is possibly related to the adverse event (note: the causal 
relationship of the IMP to the adverse event is not to be considered for this decision). If there is 
more than 1 adverse event, only the adverse event leading to death (possibly related) will be 
attributed with the outcome “fatal”.
Documentation of adverse events 
The subjects will be questioned about possible adverse events with non-leading questions before 
administration of the IMP and at regular intervals thereafter as defined in Section 1.2.
All adverse events reported spontaneously by subjects at any time point will also be documented in 
the CRF.
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All adverse events will be documented in the CRF with the following information where 
appropriate:
•
Description (adverse event verbatim term).
•
Start date and time.
•
End date and time or continuation.
•
Whether adverse event was serious.
•
Intensity.
•
Outcome.
•
Action taken with IMP.
•
Countermeasures.
•
Causal relationship to IMP.
Follow-up of subjects with an adverse event
Any adverse event or clinically relevant abnormal laboratory or vital sign result will be followed 
until it reaches a satisfactory resolution, or becomes stable, or can be explained by other causes 
(e.g., concurrent condition or medication), or clinical judgment indicates that further evaluation is 
not warranted. 
Definition of countermeasures 
“Countermeasures” will be defined as:
None:
No countermeasure given.
Newly started 
medication:
A newly started medication or change in dose or route of application of 
a concomitant medication due to the adverse event (to be listed on the 
medication chart) that is used as a countermeasure.
Trial discontinuation:
It was necessary to discontinue the subject from the trial due to the 
adverse event.
Others:
All other countermeasures, e.g., physical therapy, surgery.
Except for none, multiple countermeasures for 1 adverse event can be recorded.
Classification of action taken with IMP when an adverse event occurs:
•
Dose increased.
•
Dose reduced.
•
Drug interrupted.
•
Drug withdrawn.
•
Dose not changed.
•
Not applicable.
•
Unknown.
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Notification of serious adverse events
All serious adverse events (including death, irrespective of cause) during the trial, regardless of 
their relationship to IMP, must be reported to the sponsor’s Drug Safety Department as soon as 
possible but no later than 24 hours after learning of the event. The trial site will be provided with 
contact details for these personnel before any trial-related procedure is performed. 
The investigator has to submit a report, called a safety reporting form, which includes a description 
of the event, the therapy instituted, and trial procedures. The following information must be 
communicated with the first notification of an adverse event fulfilling the above criteria:
•
Trial identifier.
•
Subject’s identifier (i.e., subject number).
•
Subject’s date/year of birth (if available, see local data protection requirements) or age (at 
adverse event onset). 
•
Subject’s sex.
•
First administration of IMP (date and time, if available).
•
Last administration of IMP (date and time, if available).
•
Adverse event verbatim term (specific diagnosis, if possible).
•
Adverse event onset (date and time, if available).
•
A brief description of the event, the course, and the countermeasures taken.
•
Intensity.
•
Seriousness criterion.
•
Outcome.
•
Concomitant medication at onset of the event and whether one of the concomitant 
medications is also suspected to have caused the event.
•
Relevant history / preexisting medical conditions.
•
Investigator’s assessment of the relationship to IMP(s).
All additional information concerning the adverse event until trial termination or definite outcome 
should be communicated per follow-up report without delay.
The immediate and follow-up reports must only identify the subjects using the unique subject 
identifier. 
The investigator is obliged to comply with applicable regulatory requirement(s) related to the 
reporting of serious adverse events to the regulatory authorities and the relevant IEC or IRB.
Notification of serious adverse reactions
All suspected adverse reactions related to an IMP (the tested IMPs and comparators) that occur in 
this trial, and that are both unexpected and serious are subject to expedited reporting. 
The sponsor will ensure that all relevant information about suspected serious unexpected adverse 
reactions that are fatal or life-threatening is recorded and reported as soon as possible to the 
competent authorities in all the member states concerned, and to the IEC, and in any case no later 
than 7 days after knowledge by the sponsor of such a case, and that relevant follow-up information 
is subsequently communicated within an additional 8 days. All other suspected serious unexpected 
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adverse reactions will be reported to the competent authorities concerned and to the IEC concerned 
as soon as possible but within a maximum of 15 days of first knowledge by the sponsor.
The sponsor will also inform all investigators involved in the clinical trial.
Once a year throughout the clinical trial, the sponsor will provide the member states in whose 
territory the clinical trial is being conducted and the IEC with a listing of all suspected serious 
unexpected adverse reactions which have occurred over this period and a report of the subjects’
safety.
In addition, the sponsor will ensure that all serious adverse reactions are reported in compliance 
with applicable national regulatory requirements.
12.6.2
Vital signs
Vital signs (respiratory rate, systolic and diastolic blood pressure, and pulse rate) will be measured 
in a supine position after resting for at least 5 minutes and recorded in the CRF. While resting, the 
subject should not receive anything to drink or eat. 
12.6.3
Height and body weight
Height and body weight will be measured in light clothes and without shoes on and recorded in the 
CRF.
12.6.4
Twelve-lead electrocardiogram
Twelve-lead ECGs will be recorded in a supine position after resting for 5 minutes so that the ECG 
intervals (RR, PR, QRS, and QT) and heart rate can be measured. The ECG tracing must be printed 
and maintained as a source document by the investigator. Specific ECG procedures will be provided 
in a separate manual. 
The investigator will review the ECG for clinically relevant abnormalities prior to dosing subjects. 
The investigator will only record clinically relevant abnormalities and their medical interpretation in 
the CRF.
Cardiologists at a central ECG laboratory will read all ECGs. The ECG report from the central ECG 
laboratory will be considered a source document.
If there are discrepancies between the central ECG analysis report and the assessment of the 
investigator, the investigator will document these on the ECG analysis report. 
The inclusion as well as discontinuation of a subject will be based on the judgment of the 
investigator. If the subject has been included but fulfills any of the discontinuation criteria based on 
the ECG analysis report of the central ECG laboratory, the ECG must be repeated within 1 week of 
receiving the central ECG report and the subject must be discontinued if any of the discontinuation 
criteria is confirmed by the investigator.
12.6.5
Safety laboratory
Serum chemistry and hematology
For each subject, non-fasting venous blood samples for clinical chemistry (2 mL) and for 
hematology (2 mL) will be drawn at the times specified in the schedule of events (Section 1.2). The 
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total blood volume per subject is given in Section 12.1. If possible, blood samples for 
pharmacokinetic and safety laboratory evaluations will be taken at the same time.
The check of the exclusion criteria will be based on the local laboratory values. Local laboratory 
parameters needed are: total serum bilirubin, serum albumin, aspartate transaminase, alanine 
transaminase, and serum creatinine (the creatinine clearance will be calculated in the electronic 
CRF). The local laboratory sample does not need to be taken at the Enrollment Visit if suitable 
results from the same local laboratory are available from a blood sample obtained in the 14 days 
prior to Visit 2 for other reasons.
The central laboratory will calculate the creatinine clearance using a formula that is appropriate for 
the respective age group.
Discontinuation criteria will be based on central laboratory values.
Trial sites will follow the instructions provided in the laboratory manual regarding the specific 
procedures for the handling and shipment of blood samples.
The investigator must review the laboratory report, document this review in the source documents, 
and record any clinically relevant changes in the opinion of the investigator during the trial in the 
source documents and as adverse events in the CRF. 
The following tests will be performed:
Hematology panel
Hemoglobin
Red blood cell (RBC) count
Hematocrit
Red blood cell morphology
Mean cell volume (MCV)
White blood cell (WBC) count
White blood cell differential count
White blood cell morphology
Platelet count
Clinical chemistry panel 
Sodium
Lipase
Potassium
Triglycerides
Chloride
Total serum bilirubin
Blood urea nitrogen (BUN)
Alkaline phosphatase
Creatinine
Creatine phosphokinase
Uric acid
Lactic acid dehydrogenase (LDH)
Calcium
Alanine transaminase (ALT)
Phosphorus
Aspartate transaminase (AST)
Albumin
Gamma-glutamyltransferase (GGT)
Total protein
Glucose
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Urinalysis 
A urine sample for urinalysis will be taken at the times specified in the schedule of events (see 
Section 1.2). The assessment will be done locally with a dip stick. It must be documented clearly in 
source documents if and which abnormalities were observed. If no abnormalities were observed, 
then this needs to be documented in the source documents as well. If there are abnormalities, a urine 
sample will be sent to the central laboratory for sediment analysis. The decision not to send a 
sample to the central laboratory needs to be documented in the source documents. 
The following tests will be performed:
Dipstick by the local laboratory a
pH
Glucose
Protein
Blood
Ketones
Bilirubin
Urobilinogen
Nitrite
Leukocyte esterase
a) Including but not limited to.
12.6.6
Urine test for drugs of abuse
A urine sample will be collected to test for the following drugs, as a minimum, at the visits as 
described in the schedule of events (Section 1.2): cannabis, cocaine, opioids, methamphetamine, 
and amphetamines. The test may be positive in subjects who are receiving opioids or other 
medications for medical purposes (i.e., if prescribed). These subjects may participate even though 
the test is positive for these medications. A positive test that is not explained by prescribed 
medication will exclude the subject.
The assessment will be done locally, e.g., by the investigator, and documented in the CRF. 
Dip-stick test kits will be provided by the central laboratory.
12.6.7
Physical examination
During the physical examination, comprising but not limited to the general condition, skin, eyes, 
ears, nose, throat, head, neck, thyroid, heart, lungs, chest (including breasts), abdomen, kidneys, 
liver, lymphatic system, musculoskeletal system, neurological system, attention should be paid to 
abnormalities which may have a bearing on the conduct of the trial. The physical examinations will 
be documented in the CRF.
12.6.8
Pregnancy test
A urine sample will be provided for testing by a pregnancy-test dip stick at the visits as described in 
the schedule of events (Section 1.2). The assessment will be done locally, e.g., by the investigator, 
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and documented in the CRF. Dip-stick pregnancy test kits will be provided by the central 
laboratory.
12.7
Appropriateness of measurements
During the trial, subject-reported pain assessments will be collected. The 2 pain scales used in this 
trial are the VAS and FPS-R. Pain intensity assessments with the FPS-R will be performed 
immediately after pain intensity measurements with the VAS (Bulloch and Tenenbein 2002). Both 
will be recorded in all subjects. These data will be used to gather information relevant to the 
measures to be included in future clinical trials.
The VAS pain intensity rating scale (Scott and Huskisson 1976) has been established as a valid, 
self-reported measure of pain intensity in subjects aged 8 years to 18 years with juvenile chronic 
polyarthritis (Scott et al. 1977). 
The FPS-R has been established as a valid, paper-based self-reported measure of pain intensity in 
subjects aged 4 years to 15 years (Hicks et al. 2001, Miró and Huguet 2004). 
The pain scales used have a wider validated age range than the defined age groups of the trial, so 
that the measurement of pain remains valid even if a subject moves into an older age group during 
the trial.
“Pain right now” was selected as the question to ask children and adolescents, as this is easier to 
report than, for example, average pain over the last 24 hours.
12.8
Compliance
Compliance is the adherence to all trial-related requirements (including treatments), GCP, and 
applicable regulatory requirements.
Trial site compliance will be ensured by the implementation of a quality system and the 
performance of a combination of trial site visits, training, monitoring visits, and remote verification 
by the sponsor of appropriate use of electronic tools by the trial site and subjects. Non-compliance 
will lead to prompt action by the sponsor to secure compliance, and may result in closure of the trial
site and notification of the regulatory authorities and/or relevant IEC or IRB. Acceptable time 
windows for CRF completion will be described in a separate document.
Subject compliance with regards to IMP intake will be confirmed by the investigator or delegated 
qualified personnel during trial site visits and phone contacts. Compliance will be checked during 
regular drug accountability as outlined in Section 10.7. Subjects are considered compliant if they 
have consumed a minimum of 80% and a maximum of 120% of the scheduled tablet consumption
between 2 consecutive trial site visits. 
Subject compliance with regards to diary entries will be checked by the investigator or qualified 
delegated personnel on a regular basis. If subjects do not complete the diary correctly, the 
investigator or qualified delegated personnel is to contact the subject, or parent(s) or legal 
guardian(s) to ensure diary completion. A subject is considered to be compliant if a minimum of 
80% of all twice daily diary entries are available at the end of treatment. 
Monitoring of CRF completion, diary compliance, and compliance with IMP intake by the sponsor 
will be described in a separate document.
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13
DOCUMENTATION OF TRIAL DATA
13.1
Case report forms
Case report forms for each subject will be provided to the investigator by the sponsor in electronic 
format to document the trial data.
The investigator will use CRFs to record information required by the protocol to be reported on 
each trial subject. The investigator will be instructed on how to complete the CRFs.
The investigator will verify that the CRFs are complete, accurate, and compatible with source 
documents. All CRF entries, corrections, and alterations will be made by the investigator or other 
authorized personnel under their supervision. Entries will be checked against appropriate source 
documents by the sponsor’s representative (e.g., clinical research associate).
Electronic case report forms
The data will be processed using a validated system. Access to the system will be protected with a 
personal user name and password. The users are identified and receive access rights according to 
their role in the trial. All users will receive training on the CRF, and this training will be 
documented prior to access rights being granted.
The investigator, the clinical research associate, and designated persons at the trial site and from 
other parties involved (e.g., data management staff) will have access to review all captured data 
during the trial via a secure internet connection.
After source data verification, the applicable part of the CRF will be flagged as source data verified. 
Should subsequent changes be made, this flag will be reversed and source data verification must be 
repeated.
All entries and modifications to the CRF will be stored with the personal identification of the 
person who made the changes, a date/time stamp, and the reason for change.
The CRF must be signed electronically by the investigator. Any changes made to the CRF pages 
after the investigator has signed will require a re-signing by the investigator.
13.2
Subject reported outcomes
Diaries for each subject will be provided to the investigator by the sponsor in electronic format for 
Treatment Period of Part 1 to document the pain assessments (VAS and FPS-R) and intake of IMP 
and rescue medication, and for Tapentadol Period of Part 2 to document the intake of IMP. The 
other questionnaires will be reported on paper throughout the trial. An electronic version of the 
VAS will be used in the electronic diary (Part 1) and paper version of the VAS will be used in the 
CRF for the Tapentadol Period (Part 2). The electronic version and the paper version of the VAS 
are both validated.
Subjects will receive their diaries at the investigator’s site and will be instructed on how to use it.
Due to the fact that this is a pediatric trial, the possibility for caregivers to enter data in the diaries is 
possible and will be recorded with a personal identification of the person who made the entry.
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The data will be collected using an appropriately validated system. No queries will be issued to the 
investigator for these data, except for clarification of subject identifiers and any operational issues.
13.3
Data management
Data management will be performed by sponsor personnel or by authorized sponsor representatives 
defined by the sponsor prior to the trial start.
Electronic case report forms
During data entry in the electronic CRF, automatic queries will be raised to clarify missing data, 
inconsistencies, and incorrect values. After completion of the CRF, further queries will be issued to 
the investigator to clarify inconsistencies (e.g., resulting from additional electronic validation 
checks or medical and manual reviews). Resolutions of queries will be made by the investigator or 
the trial site’s designated persons. The query is to be answered directly in the electronic CRF 
system and the original value will be changed, if necessary.
Coding
Medication names will be coded using the WHO Drug Dictionary (WHO-DD). Medical history 
terms and adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). As required by the sponsor’s standard operating procedures (SOPs), the versions most 
recently implemented by the sponsor will be used at the time of database lock. Coding will be 
reviewed by the sponsor’s personnel according to standard procedures.
External data
Trial data not recorded in the CRF (e.g., safety laboratory data, ECG data, and e-diary data) will be 
reconciled against CRF data (details of reconciliation will be specified separately but may include 
trial number, trial site number, subject number, age, dates of visits). All external data will be 
transferred electronically to the data management center using a secure method at predefined 
intervals during the trial in a data structure defined by the data management center. At the end of 
the trial, the contract research organization(s) providing these data will provide the data 
management center with a complete and clean data transfer.
Database lock
When all data have been received and entered into the trial database, all data checks and quality 
control checks have been performed, all queries are resolved, and the final statistical review has 
been held without resulting in new queries, the trial database will be considered clean and the data 
will be locked. For the main analysis (Part 1 and the first 12 weeks of Part 2), the detailed procedure 
will be described in the data management plan.
13.4
Source data
Source data is defined by GCP as “all information in original records and certified copies of 
original records of clinical findings, observations, or other activities in a clinical trial necessary for 
the reconstruction and evaluation of the trial. Source data are contained in source documents 
(original records or certified copies)”.
Source data comprise clinical documentation, data, and records (e.g., clinic/hospital records, clinical 
and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
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dispensing records, recorded data from automated instruments, and data and records arising from 
departments such as the pharmacy, laboratory, and medico-technical departments) that describe or 
record the methods, conduct, or results of the trial, the factors affecting the trial, and the actions 
taken. 
All clinical documentation and data arising from the trial will be kept by the investigator, who has 
to provide direct access for trial-related monitoring, audits, IEC/IRB review, and regulatory 
inspection.
All data captured in the CRF need to be justified by relevant source data. In certain circumstances, 
data may only be recorded in the trial-specific CRF and not in other documents. If this occurs, the 
CRF is considered to be the source document. Data expected to be only recorded in the CRF are: 
race/ethnic group.
The nature and location of all source data/clinical documentation will be identified and documented 
by the investigator to ensure that all sources of original data required to complete the CRF are 
known to the sponsor and/or trial site personnel and are accessible for verification during 
trial-related monitoring, audits, relevant IEC/IRB review, and inspection(s).
For subject reported outcomes captured directly via a diary, source data is defined as the data 
residing in the vendor’s database. 
During trial conduct, the vendor is responsible for data security. 
All data captured from all subjects will be sent to the sponsor in human readable form on a 
read-only compact disc for filing/archiving according to sponsor SOPs.
The investigator will receive all data captured for his or her subjects, in a human readable form, on 
a read-only compact disc for his or her files after trial completion and finalization of data collection.
13.5
Investigator’s site file and the trial master file 
The investigator is responsible for the timely filing of all essential documents in an investigator’s 
site file and the sponsor is responsible for the timely filing of all essential documents in the trial 
master file. As applicable, these files must be available at monitoring visits and during audits or 
regulatory inspections.
After trial completion, the investigator will ensure that all source data/documentation arising from 
the trial is recorded, handled, and stored in a way that allows its accurate reporting, interpretation 
and verification. The investigator will take measures to prevent accidental or premature destruction 
of these documents.
The investigator will keep the investigator’s site file, the source data/documentation arising from 
the trial according to the prescribed record retention period in the country and/or according to the 
hospital policy, but at least until informed by the sponsor that the trial-related records are no longer 
required.
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14
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION
The statistical planning and analysis of the trial will be performed by sponsor personnel or by 
authorized sponsor delegates.
14.1
Sample size rationale 
The sample size was estimated to reject the null hypothesis of the inferiority of tapentadol PR to 
morphine PR when comparing responders evaluated at the end of the 14-day Treatment Period 
(Part 1, i.e., the primary endpoint). The percentage of responders in both treatment groups is 
estimated to be 80% based on data from previous trials and extrapolation to the trial population 
under investigation. The non-inferiority margin is set to a difference of 20% for the primary 
endpoint.
To show the non-inferiority of tapentadol PR compared to morphine PR using a Farrington-
Manning (1990) test by a non-inferiority margin of 20% with at least 80% power and a 1-sided 
significance level of alpha = 0.1, 69 subjects are required in the FAS, assuming a 2:1 randomization 
of tapentadol PR:morphine PR.
A one-sided alpha of 0.1 is considered appropriate based on a method proposed by Hlavin et al. 
(2016). The approach makes use of prior knowledge and the concept of extrapolation from a larger 
population to a small target population (i.e., pediatric population), to reduce the burden of evidence 
in pediatrics by relaxing the Type I error, while controlling a certain posterior belief, i.e., 
confidence after successful pediatric trials, in effectiveness of the drug in children.
Further details for the application of the concept of Hlavin et al. (2016) in the context of this trial 
are provided in a separate document that is available upon request.
The reviews of the safety data during the trial by the DMC (Section 5.4) have no impact on the 
sample size.
14.2
Analysis of the trial – statistical analysis
The statistical analysis of this trial will be performed as described and as summarized here in the 
protocol and given in detail in the SAP.
The statistical analysis of this trial will be planned, performed, and reported by sponsor personnel or 
by authorized sponsor delegates, in accordance with sponsor SOPs.
Main analysis of the trial
The main analysis of the trial will be performed after all subjects have completed the first 12 weeks
(Visit TP3 or Visit OP3) of Part 2.
14.2.1
Analysis populations (analysis sets)
Enrolled population
The Enrolled Set includes all subjects with a signed (by subject, parent(s) or legal guardian(s) as 
appropriate) informed consent form and if required by local law an assent form.
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Allocated Set
The Allocated Set includes all subjects who are allocated to treatment.
Safety Set
The Safety Set comprises all treated subjects, i.e., all subjects in whom IMP was administered (at 
least once). 
Full Analysis Set
The FAS comprises all allocated and treated subjects, i.e., all allocated subjects who were 
administered any amount of IMP.
Per Protocol Set
The Per Protocol Set defines a subset of the subjects in the FAS without any major protocol 
deviation affecting the primary endpoint. The Per Protocol Set is only relevant for analyses during 
Part 1. No protocol deviation during Part 2 leads to exclusion from the Per Protocol Set. 
Further details of the Per Protocol Set definitions will be specified in the SAP.
Pharmacokinetic Analysis Set
All subjects who have quantifiable serum concentrations during the Treatment Period will be 
included in the descriptive pharmacokinetic analysis.
Data from subjects who vomit within 6 hours of administration of IMP during the Treatment Period 
will be carefully assessed to decide if the data should be included in the pharmacokinetic analysis.
Subgroups
The primary endpoint will also be analyzed according to predefined age group and underlying pain 
condition. Further details, and also further subgroups, will be specified in the SAP.
14.2.2
General descriptive and graphical methods
Analyses will be performed within the specified subject populations as described in Section 14.2.1. 
Separate analyses will be performed for Part 1 and Part 2. The analysis for Part 1 will take into 
consideration the Treatment Period of Part 1. The analysis for Part 2 will take into consideration the 
Tapentadol Period and Observation Period of Part 2.
Part 1
For the Treatment Period, baseline measurements are defined as the last evaluation performed 
before starting IMP (i.e., Visit V1, Visit V2, or an unscheduled visit). For pain assessments, the 
baseline pain is defined as “pain right now” at Visit V2, and will be assessed before any painful or 
unpleasant procedure, and before the first intake of IMP.
Part 2
For the Tapentadol Period, baseline measurements are defined as the last evaluation performed 
before or at Visit VE.
For the Observation Period, baseline measurements are defined as the last evaluation performed 
before or at:
•
Visit VE for subjects entering the Observation Period directly after Part 1.
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•
Visit ET for subjects switching from the Tapentadol Period to the Observation Period.
General
For continuous variables, descriptive statistics will include number of observations, arithmetic 
mean, standard deviation, minimum, first quartile (Q1), median, third quartile (Q3), and maximum.
For categorical variables, frequency counts and percentages will be used to summarize the results. If 
applicable, changes from the baseline or predefined time points will be presented descriptively.
Data will also be listed and summarized using graphical displays, as appropriate. 
Further analyses are outlined below.
14.2.3
Analysis of subject characteristics data
Subject characteristics data will be analyzed for the Safety Set as described in Section 14.2.2.
14.2.4
Analysis of subject disposition
Subject disposition data will be analyzed for the Safety Set as described in Section 14.2.2.
14.2.5
Analysis of pharmacokinetic data
As described in Section 14.2.2, descriptive statistics and graphical displays will be used to 
summarize the tapentadol and tapentadol-O-glucuronide serum concentration time data for each 
time interval specified during the Treatment Period for subjects in the pharmacokinetic analysis set.
The tapentadol and tapentadol-O-glucuronide data will also be subject to a population 
pharmacokinetic analysis described in a separate analysis plan (see Section 14.3).
14.2.6
Analysis of efficacy data
Unless otherwise stated, efficacy analyses will be performed on the FAS. 
14.2.6.1
Primary endpoint (proportion of subjects classified as responders in Part 1)
The analysis of the primary endpoint will be performed on the data collected during the Treatment 
Period (Part 1). The FAS will be the primary analysis set and the Per Protocol Set will be used as a 
sensitivity analysis set.
Hypotheses
Null hypothesis: H0: pT- pC -δ
“Treatment with tapentadol” is inferior to “treatment with morphine”.
Alternative hypothesis: HA: pT- pC >-δ
“Treatment with tapentadol” is non-inferior to “treatment with morphine”.
T = treatment with tapentadol; C = treatment with morphine; δ = non-inferiority margin; pi = responder rate in 
investigational treatment (T) or active control (C).
As this endpoint is a binomial event rate, it will be summarized by descriptive statistics grouped by 
treatment group. The standard maximum likelihood estimators for the proportion of subjects 
classified as responders in each group will be the estimated proportions adjusted for the baseline 
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pain intensity, age group, and underlying pain condition. To obtain these estimators, a logistic 
regression model will be fitted to the response using the baseline pain intensity, age group, 
treatment, and underlying pain condition as explanatory variables. The Farrington-Manning (1990)
test will then be applied and an 80% confidence interval calculated. The non-inferiority of 
tapentadol PR compared to morphine PR will be established if the lower limit of this 2-sided 80% 
confidence interval of the difference in the above estimated proportions is above the non-inferiority 
margin of -20%.
A sensitivity analysis will be carried out by fitting a Bayesian logistic regression model to compare 
the proportion of responders under tapentadol PR and morphine PR. Odds ratios will be calculated. 
Treatment response is the dependent variable and treatment group, age group at baseline (ageg), 
underlying pain condition (cancer/non-cancer-related pain), age group x baseline VAS, and age 
group x baseline FPS-R are possible (but not limited to) explanatory variables. The age group refers 
to a variable indicating whether, on the basis of the subject’s age, to use the VAS pain assessment 
(for subjects aged 12 years to less than 18 years) in the model, or to use the FPS-R score (for 
subjects aged 6 years to less than 12 years).
Specifically, if Xi is the response indicator for subject i, then we will assume: 
Xi ~ Bernoulli(i)
log(i /(1-i)) = 0 + 1 agegi + 2 canceri + 3 (ageg*baseline VAS) + 4 (1-ageg)*baseline FPS-R 
+ 5 treatmenti + i
Non-informative flat normal priors with zero mean and variance equal to 1000 will be assigned to 
the regression coefficients 1 to 4. The prior for the treatment effect 5 (on the log-odds scale) will 
be a normal distribution with mean = 0.10 and standard deviation = 0.48; this prior distribution has 
been derived from the 
 trial (in subjects with moderate to severe chronic malignant 
tumor-related pain) using a down-weighting factor a = 0.4. The prior for the subject-specific 
random effects i, will be normal (0, σ2). A non-informative Gamma (0.001, 0.001) prior will be 
assigned to the precision of the random effects 1/σ2.
The posterior distribution for the regression coefficients will not have an analytically closed form. 
Therefore, Markov chain Monte-Carlo methods will be used to obtain a sample from the posterior 
distribution for the difference between the response rates in tapentadol PR and morphine PR groups. 
This sample will be summarized by means of the posterior mean, median, standard deviation and 
80% credibility interval. If the lower limit of the 80% credibility interval for the difference of the 
2 response rates is >-0.2, then this would support non-inferiority by this sensitivity analysis. 
Further sensitivity analyses are planned (but not limited to), e.g., keeping the criteria for response 
unchanged except for classifying subjects who stop treatment earlier than 14 days because of no 
further need for opioid treatment as responders rather than non-responders.
More details on the sensitivity analyses and strategies for handling missing data and discontinued 
subjects will be described in the SAP. 
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14.2.6.2
Pain scale assessed using a VAS and FPS-R
Descriptive statistics will be provided to evaluate the daily average pain (Part 1) or pain at each visit 
during the Tapentadol Period (Part 2) as well as changes to baseline for the different trial periods
and respective treatment groups, as described in Section 14.2.2.
14.2.6.3
Rescue medication
The descriptive analyses of the use of rescue medication during the Treatment Period will focus on 
mean number of daily doses and the mean total daily dose (mg/kg). The morphine equivalent dose 
of tapentadol will be calculated so that a comparison of rescue medication with respect to the 
amount of IMP taken can be made. Comparisons will be made across time and also for subgroups 
of different ages.
14.2.6.4
Time to discontinuation
A survival analysis of the time to discontinuation of IMP overall, due to lack of efficacy, and due to 
TEAE will be performed for tapentadol PR and morphine PR for Part 1 (Treatment Period) and for 
tapentadol PR during the Tapentadol Period of Part 2 if at least 10% of the subjects per group 
discontinue.
14.2.7
Analysis of safety data
The analysis of safety data will be performed on the Safety Set.
Unless otherwise specified, separate analyses will be performed for the different trial periods and 
respective treatment groups.
14.2.7.1
Adverse events
The original terms used in the CRFs by investigators to identify adverse events will be coded using 
the most recent version of Medical Dictionary for Regulatory Activities (MedDRA) implemented
by the sponsor. 
Adverse events will be categorized by seriousness, intensity, outcome, countermeasures, and 
relationship to IMP and will be tabulated by system organ class and preferred term. Adverse events 
will be tabulated separately for the treatment periods.
Those TEAEs which started in Treatment Period and are carried over into Tapentadol Period will be 
considered as ongoing TEAEs. A worsening of a TEAE in Tapentadol Period in a subject 
previously treated with morphine PR in Treatment Period will be considered as a new TEAE.
The frequency and severity of adverse events will be analyzed descriptively as described in 
Section 14.2.2 both on a subject and event-based level.
All adverse events will be listed. Serious adverse events will be listed separately. Non-TEAEs will 
be listed separately.
Special attention will be given to those subjects who have discontinued treatment due to an adverse 
event or who experienced a severe or a serious adverse event. Such cases will be analyzed 
individually. 
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14.2.7.2
Safety laboratory tests
Safety laboratory data will be summarized by the type of safety laboratory test as described in 
Section 14.2.2. The safety laboratory analysis will be based on the data from the central laboratory.
Normal reference ranges and markedly abnormal results (specified in the SAP) will be used in the 
summary of safety laboratory data. Descriptive statistics will be calculated for each safety 
laboratory parameter at baseline (see Section 14.2.2) and at each scheduled time point. Changes 
from baseline will be presented descriptively as well as in pre- versus post-treatment cross 
tabulations (with classes for below, within, and above normal ranges). A listing of subjects with any 
laboratory results outside the reference ranges will be provided.
14.2.7.3
Electrocardiogram
The ECG variables that will be analyzed are heart rate, RR interval, PR interval, QRS interval, QT 
interval, and QTcF (Fridericia) interval.
The ECG measurements will be summarized at each time point of measurement during the 
treatment period. The change from baseline will also be summarized. A categorical analysis for 
outliers will be performed as per the guidance “Clinical evaluation of QT/QTc interval prolongation 
and proarrhythmic potential for non-antiarrhythmic drugs” (ICH Topic E14).
All important abnormalities from the ECG readings, including changes in general and changes in 
T wave morphology, or the occurrence of U waves versus baseline recordings, will be reported.
14.2.7.4
Vital signs (pulse rate, systolic/diastolic blood pressure, and respiratory rate)
As described in Section 14.2.2, descriptive statistics as well as changes to baseline for the different 
trial periods will be presented. Frequency tabulations of abnormalities will be included. 
14.2.7.5
Physical examination
Physical examination findings will be listed.
14.2.7.6
Height and weight
Height and weight will be analyzed as described in Section 14.2.2 for the different trial periods.
14.2.7.7
Constipation
Constipation, as assessed by the modified CAS will be descriptively analyzed per time point as 
described in Section 14.2.2 for the different trial periods. Further details concerning subgroups of 
interest e.g., subjects receiving treatment for constipation versus those who are not, will be 
specified in the SAP. Constipation will be assessed by changes from baseline (Visit V2) of total 
scores for the modified CAS.
14.2.7.8
Subjective opiate withdrawal scale
The SOWS questionnaire scores and changes from baseline (defined for the SOWS as the 
assessment made on the day of the last intake of IMP) will be descriptively analyzed per scheduled 
time point according to the last IMP taken. The total score of the full questionnaire (all 
16 questions) will be used for a first analysis. Additionally the total score of the first 15 questions of 
the SOWS questionnaire will be analyzed in the same manner, being more appropriate for the 
studied population. 
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14.2.8
Acceptability and palatability
In order to assess acceptability and palatability, verbal rating responses will be tabulated per time 
point and changes from Visit V3 to Visit VE will be compared within treatment groups, as 
described in Section 14.2.2.
14.2.9
Final analysis
The main analysis of the trial will be performed after all subjects have completed Part 1 and the first 
12 weeks (Visit TP3 or Visit OP3) of Part 2 of the trial. 
The final analysis of Part 2 will be performed after all subjects have completed Part 2 of the trial 
and the final database has been locked.
Further details regarding the analyses will be provided in the SAP.
14.3
Population pharmacokinetic modeling and simulation
Pharmacokinetic data collected in this trial will be used to validate exposure predictions obtained 
with a pediatric tapentadol PR population pharmacokinetic model developed previously by the 
sponsor. The validation process will enable assessment of tapentadol accumulation in this pediatric 
population during administration of tapentadol PR. The model will be subsequently updated with 
the pharmacokinetic data collected in this trial. Population pharmacokinetic modeling and 
simulation will be performed using the non-linear mixed effect modeling approach as implemented 
in NONMEM(version 7.2, ICON plc). These analyses will be planned, performed, and reported 
by sponsor personnel, or by authorized sponsor delegates in accordance with sponsor’s SOPs.
15
QUALITY SYSTEM, AUDIT AND INSPECTION
15.1
Quality system
The sponsor is responsible for implementing and maintaining quality assurance and quality control 
systems with written SOPs.
The trial documentation must be adequate for the reconstruction of the trial.
15.2
Data quality assurance
The accuracy and reliability of the trial data will be assured by careful contract research 
organization/investigator selection and oversight by the performance of a combination of trial site 
visits, training, monitoring visits, remote verification by the sponsor of appropriate use of electronic 
tools by trial site and subject, data cleaning, and audits.
15.2.1
Clinical research organization/investigator selection 
The accuracy and reliability of the trial data will be assured by the selection of suitably qualified 
and experienced investigators and trial sites, and the introduction of the investigator and associated 
personnel to protocol requirements and procedures prior to the trial. 
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15.2.2
Trial site monitoring
Trial site monitoring as defined in GCP will be performed by sponsor personnel or by authorized 
sponsor delegates at pre-defined intervals depending on the progress of the trial. The authorized 
delegates, applicable SOPs, the frequency of monitoring visits, and the reporting modus, will be 
defined in writing as required by sponsor SOPs. Monitored trial sites will be informed about visit
outcomes using a follow-up letter.
The investigator(s) will permit monitoring visits at agreed times. Corrections, amendments, or 
clarifying statements resulting from the monitoring visits will be made by the investigator where 
necessary. 
15.2.3
Audits
Audits as defined by GCP will be performed for this trial. The investigator will permit sponsor 
personnel or authorized delegates to audit the trial facilities and documentation at agreed times. The
auditors will be independent of the trial and its performance.
15.3
Inspections 
The investigator, the sponsor, or personnel at other establishments, are obliged to cooperate with 
any inspection of the documents, facilities, records, and other resources deemed appropriate by the 
inspecting authorities to be related to the trial and that may be located at the trial site, at the sponsor, 
or at other establishments. 
The investigator or personnel at other establishments should notify the sponsor as soon as possible 
about any upcoming regulatory authority inspection. 
16
GENERAL CONDITIONS AND AGREEMENTS
16.1
Insurance
If insurance for subjects is required by applicable regulatory requirements in the participating 
countries, the sponsor will arrange suitable insurance for the subjects included in this trial and
provide the investigator with the relevant terms and conditions of this insurance.
If insurance for subjects is required by applicable regulatory requirements in the participating 
countries, the investigator must inform all subjects/parents/legal guardians about this insurance and 
(if requested) be prepared to explain the relevant terms and conditions of this insurance to the 
subjects/parents/legal guardians.
If changes to the trial are implemented after the initial insurance was arranged, e.g., due to protocol 
amendments, the sponsor will notify the insurance company of these changes in accordance with 
the insurance conditions. If changes to insurance arise, the sponsor will inform the investigators
who will then inform their subjects/parents/legal guardians about relevant changes.
16.2
Legal regulations
This trial will be carried out in compliance with any applicable regulatory requirements. 
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Before initiating the trial, if required by the applicable regulatory requirements, the sponsor or its 
authorized legal representative and/or the investigator will submit any required documents to the 
appropriate authorities for review, acceptance, and/or permission to begin the trial. 
This trial will be carried out in compliance with applicable regulatory requirements with respect to 
the use of narcotics.
16.3
Contracts
Specific contracts between the relevant parties, i.e., between the investigator/other parties at the trial 
site(s) and the sponsor or its local offices or contract research organization or its affiliates 
authorized by the sponsor, will be used to set out any arrangements on delegation and distribution 
of tasks and obligations and, if appropriate, on financial matters. This protocol and other 
documentation, e.g., the “investigator confirmation sheet”, may serve as the basis of such contracts.
In addition, responsibility for insurance or indemnity to cover any liability of the investigator that 
may arise directly or indirectly from the investigator’s participation in the trial will be specified in a 
contract between the investigator and sponsor, if applicable.
16.4
Subject data and data protection
Subject trial data will be stored in a manner maintaining confidentiality in accordance with 
applicable regulatory requirements.
The investigator is required to ensure that any documents or data given to the sponsor or its 
representatives do not contain information that would affect the anonymity of the subjects.
The investigator will obtain permission for direct access to subject data from the 
subject/parent/legal guardian as part of the written informed consent procedure (see Section 4.2). 
This gives permission to examine, analyze, verify, and reproduce any records and reports that are 
important to the evaluation of the trial. Any party (e.g., domestic and foreign regulatory authorities, 
sponsor personnel or its representatives, and auditors) with direct access must take all reasonable 
precautions within the constraints of the applicable regulatory requirement(s) to maintain the 
confidentiality of the subject’s identity and sponsor’s proprietary information.
16.5
Publication policy
The results of this trial will be publically disclosed in accordance with applicable regulatory 
guidance (e.g., on ClinicalTrials.gov). The results of this trial may also be published as a full 
publication (e.g., journal publication) or publically disclosed as a poster or presentation at a 
congress. The sponsor reserves the right to review any proposed presentation of the results of this 
trial before they are submitted for publication or public disclosure. Neither party (e.g., the sponsor 
or the coordinating investigator) has the right to prohibit publication or public disclosure unless it
can be shown to affect possible patent rights. 
In case of discrepancies with other contracts, the provisions of the protocol shall prevail.
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16.6
Final report and reporting of the trial
An integrated clinical trial report, integrating clinical, pharmacokinetic, and statistical results of 
Part 1 (Treatment Period) and the first 12 weeks of Part 2 will be prepared by the sponsor once all 
subjects have completed the first 12 weeks (Visit TP3 or Visit OP3) of Part 2. A second report
(optionally as an amendment) will be prepared once all subjects have completed Part 2. 
The international coordinating investigator will approve the reports on behalf of the participating 
investigators. 
The sponsor will provide the competent authority and relevant IEC or IRB with a summary of the 
reports in accordance with applicable regulatory requirements. 
All investigators will be provided with a summary of the final report. 
The modeling and simulation analysis will be reported separately.
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16.7
Approval
16.7.1
Sponsor 
This protocol has been approved in accordance with sponsor SOPs. 
16.7.2
International coordinating investigator
This protocol has been approved by the international coordinating investigator.
17
REFERENCES
Investigator’s brochure for tapentadol, current edition.
Guidelines
EMEA ad hoc working party. Ethical considerations for clinical trials on medicinal products 
conducted with the paediatric population. Recommendations of the ad hoc group for the 
development of implementing guidelines for Directive 2001/20/EC relating to good clinical practice 
in the conduct of clinical trials on medicinal products for human use. 2008.
ICH Topic E14.The clinical evaluation of QT/QTc interval prolongation and proarrhythmic 
potential for non-antiarrhythmic drugs (CHMP/ICH/2/04). 2005.
WHO guidelines on the pharmacological treatment of persisting pain in children with medical 
illnesses. World Health Organization 2012. 
Publications
Anderson BJ, Holford NH. Mechanistic basis of using body size and maturation to predict clearance 
in humans. Drug Metab Pharmacokinet 2009; 24 (1): 25-36.
Benedetti MS, Whomsley R, Canning M. Drug metabolism in the paediatric population and in the 
elderly. Drug Discov Today 2007; 12 (15/16): 599-610.
Berde BC, Walco GA, Krane EJ, Anand KJS, Aranda JV, Kenneth D, et al. Pediatric Analgesic 
Clinical Trial Designs, Measures, and Extrapolation: Report of an FDA Scientific Workshop. 
Pediatrics 2012; 129: 354-64. 
Broomhead A, Kerr R, Tester W, O'Meara P, Maccarrone C, Bowles R, et al. Comparison of a 
once-a-day sustained-release morphine formulation with standard oral morphine treatment for 
cancer pain. J Pain Symptom Manage 1997; 14: 63-73.
Bulloch B, Tenenbein M. Validation of 2 Pain Scales for Use in the Pediatric Emergency 
Department. Pediatrics 2002; 110 (3): e33.
Czarnecki ML, Jandrisevits MD, Theiler SC, Huth MM, Weisman SJ. Controlled-release 
oxycodone for the management of pediatric postoperative pain. J Pain Symptom Manage 2004; 27: 
379-86.
de Beer JdeV, Winemaker MJ, Donnelly GAE, Miceli PC, Reiz JL, Harsanyi Z, et al. Efficacy and 
safety of controlled-release oxycodone and standard therapies for postoperative pain after knee or 
hip replacement. Can J Surg 2005; 48 (4): 277-83. 
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De Conno F, Kress HG. Opioids in palliative care: Differentiation and clinical relevance. Palliative 
Medicine 2006; 20: S1.
Edginton AN, Schmitt W, Voith B, Willmann S. A mechanistic approach for the scaling of 
clearance in children. Clin Pharmacokinet 2006; 45 (7): 683-704.
Farrington CP, Manning G. Test statistics and sample size formulae for comparative binomial trials 
with null hypothesis of nonzero risk difference or non-unity relative risk. Stat Med 1990; 9: 1447-
54.
Finkel JC, Finley A, Greco C, Weisman SJ, Zeltzer L. Transdermal fentanyl in the management of 
children with chronic severe pain: results from an international study. Cancer 2005; 104: 2847-57.
Goldman A, Bowman A. The role of oral controlled-release morphine in pain relief in children with 
cancer. Palliat Med 1990; 4: 279-85.
Guinard JX. Sensory and consumer testing with children. Trends in Food Science & Technology 
2001; 11: 273-83.
Handelsman L, Cochrane KJ, Aronson M, Ness R, Rubinstein KJ, Kanof PD. Two new rating 
scales for opiate withdrawal. Am J Drug Alcohol Abuse 1987; 13 (3): 293-308.
Hayton WL. Maturation and growth of renal function: Dosing renally cleared drugs in children. 
AAPS Pharm Sci 2002; 2 (1) E3.
Hicks CL, von Baeyer CL, Spafford PA, van Korlaar I, Goodenough B. The Faces Pain Scale–
Revised: toward a common metric in pediatric pain measurement. Pain 2001; 93 (2): 173-83.
Hlavin G, Koenig F, Male C, Posch M, Bauer P. Evidence, eminence and extrapolation. Stat Med 
2016; 35 (13): 2117-32.
Kadan-Lottick NS. Epidemiology of childhood and adolescent cancer. In Kliegman RM, Behrman 
RE, Jenson HB, Stanton BF, Eds. Kliegman: Nelson Textbook of Pediatrics. 18th ed. Philadelphia, 
Pa: WB Saunders Co; 2007: Chap 491; 2097-100. 
Lasky T, Greenspan J, Ernst FR, Gonzalez L. Morphine use in hospitalized children in the United 
States: a descriptive analysis of data from pediatric hospitalizations in 2008. Clin Ther 2012; 34 (3): 
720-7.
Martin-Herz SP, Patterson DR, Honari S, Gibbons J, Gibran N, Heimbach DM. Pediatric pain 
control practices of North American Burn Centers. J Burn Care Rehabil 2003; 24: 26-36.
McMillan SC, Williams FA. Validity and reliability of the Constipation Assessment Scale. Cancer 
Nurs 1989; 12: 183-8.
Miró J, Huguet A. Evaluation of reliability, validity, and preference for a pediatric pain intensity 
scale: the Catalan version of the faces pain scale – revised. Pain 2004; 111 (1-2): 59-64.
Rhodin M, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, et al. Human renal 
function maturation; a quantitative description using weight and postmenstrual age. Pediatr Nephrol 
2009; 24 (1): 67-76.
Scott J, Huskisson EC. Graphic representation of pain. Pain 1976; 2 (2): 175-84.
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Scott PJ, Ansell BM, Huskisson EC. Measurement of pain in juvenile chronic polyarthritis. Ann 
Rheum Dis 1977; 36 (2): 186-7. 
Woolery M, Carroll E, Fenn E, Wieland H, Jarosinski P, Corey B, et al. A constipation assessment 
scale for use in pediatric oncology. J Pediatr Oncol Nurs 2006; 23: 65-74.
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18
PROTOCOL AMENDMENTS
18.1
Protocol amendment 01
Amendment rationale
Although there is no information on the excretion of tapentadol in human milk, there are pre-
clinical data indicating that tapentadol is excreted in animal milk. Morphine is known to be excreted 
in breast milk, and may thus cause respiratory depression in the newborn. Therefore, an additional 
exclusion criterion was added to exclude female subjects who are breast-feeding a child. 
In addition, a textual change has been made for consistency.
Detailed description of changes
Minor editorial changes, such as the correction of typing errors, are not specifically listed.
In the table below, deleted text is crossed out and new text is highlighted using italics.
Changes to this protocol include:
Formerly read:
Now reads: 
Section 1.3.2: Exclusion criteria
Section 9.2.2: Exclusion criteria
The following will be checked at Visit V1 and Visit V2:
[new exclusion criterion inserted, and subsequent 
numbering of criteria adjusted]
The following will be checked at Visit V1 and Visit V2:
13.
Female subject breast-feeding a child.     Safety.
Section 8.5: Benefit/risk analysis
Risks
Lack of efficacy
Tapentadol may not be as efficacious in children and 
adolescents as it is in adults, even if the exposure is 
comparable. However, this is considered to be unlikely. 
During the Treatment Period, rescue medication, in the 
form of morphine oral solution, will be available for use 
as rescue medication if pain relief is insufficient. 
Thereafter, subjects will receive rescue medication as per 
standard of treatment.
Risks
Lack of efficacy
Tapentadol may not be as efficacious in children and 
adolescents as it is in adults, even if the exposure is 
comparable. However, this is considered to be unlikely. 
During the Treatment Period, rescue medication, in the 
form of morphine oral solution, will be available for use 
as rescue medication if pain relief is insufficient. 
Thereafter, subjects may receive immediate release 
strong opioids for treatment of breakthrough pain and 
incidental pain.
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Changes to this protocol include:
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Now reads: 
Section 1: Protocol synopsis: Definition of the primary endpoint
Section 8.1.1: Primary endpoint definition
Part 1 (primary analysis of the trial)
The primary efficacy endpoint is the proportion of 
subjects classified as responders. Responders are 
subjects who meet both of the following criteria:
...
Age groups are determined at Visit V2. Baseline pain is 
defined as “pain right now” at Visit V2, and will be 
assessed before any painful or unpleasant procedure, and 
before the first intake of IMP.
Part 1 (primary analysis of the trial)
The primary endpoint is a binary variable “responder”. 
A subject is defined as “responder” if both of the 
following criteria are met:
...
The proportion of subjects classified as responders will 
be assessed and compared between the treatment groups.
Age groups are determined at Visit V2. Baseline pain is 
defined as “pain right now” at Visit V2, and will be 
assessed before any painful or unpleasant procedure, and 
before the first intake of IMP.
Section 1: Protocol synopsis
Definition of the exploratory endpoints.
Definition of other endpoints.
Section 8.1: Definition of endpoints
8.1.3 Exploratory endpoints
8.1.3 Other endpoints
Exploratory endpoints compared between treatment 
groups at each measurement time point are:
...
Treatment Period endpoints (baseline is the value at Visit 
V2):
...
• Palatability and acceptability as assessed by differences 
within treatment groups of the verbal rating score at Visit 
V3 and Visit VE (the End of Treatment Visit).
...
Tapentadol Period endpoints (baseline is the value at 
Visit VE):
...
Observation Period endpoints (baseline is the value at 
Visit VE or Visit ET [Early Termination Visit]):
...
Part 1 or Part 2 exploratory endpoints:
Other endpoints compared between treatment groups at 
each measurement time point are:
...
Part 1 - Treatment Period, other endpoints (baseline is 
the value at Visit V2):
...
• Palatability and acceptability as assessed by differences 
within treatment groups of the 5-point hedonic faces 
scale with the verbal rating score at Visit V3 and Visit 
VE (the End of Treatment Visit).
...
Part 2 - Tapentadol Period, other endpoints (baseline is 
the value at Visit VE):
...
Part 2 - Observation Period, other endpoints (baseline is 
the value at Visit VE or Visit ET [Early Termination 
Visit]):
...
Part 1 or Part 2 - other endpoints:
Section 1: Protocol synopsis: Rescue medication
During Part 1 only, morphine oral solution (0.5% and 
2%) will be supplied by the sponsor as rescue medication 
for both treatment groups.
During Part 1 only, morphine oral solution will be 
supplied by the sponsor as rescue medication for both 
treatment groups.
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Changes to this protocol include:
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Section 1: Protocol synopsis: Concomitant medications/therapies
Section 10.5: Allowed and forbidden and prior/concomitant medications/therapies
...
Subjects suffering from cancer-related pain will be 
allowed to participate in trials of marketed therapeutic 
medications and therapies.
...
Subjects suffering from cancer-related pain will be 
allowed to participate in trials of marketed therapeutic 
medications and therapies (including trials of antibody 
therapies).
Section 1: Protocol synopsis: Statistical methods 
Section 14.2.2: General descriptive and graphical methods
Separate analyses will be performed for Part 1 (primary 
analysis of the trial) and Part 2. The analysis for Part 2 
will take into consideration the different trial periods: 
Treatment Period of Part 1, and Tapentadol Period and 
Observation Period of Part 2.
Part 1
For the Treatment Period, baseline measurements are 
defined as the last evaluation performed before starting 
IMP (i.e., Visit V1 or Visit V2).
Part 2
For the Tapentadol Period, baseline measurements are 
defined as those taken at Visit VE.
For the Observation Period, baseline measurements are 
defined as those taken at Visit VE or Visit ET.
Separate analyses will be performed for Part 1 and 
Part 2. The analysis for Part 1 will take into 
consideration the Treatment Period of Part 1. The 
analysis for Part 2 will take into consideration the 
Tapentadol Period and Observation Period of Part 2.
Part 1
For the Treatment Period, baseline measurements are 
defined as the last evaluation performed before starting 
IMP (i.e., Visit V1, Visit V2, or an unscheduled visit).
For pain assessments, the baseline pain is defined as 
“pain right now” at Visit V2, and will be assessed before 
any painful or unpleasant procedure, and before the first 
intake of IMP.
Part 2
For the Tapentadol Period, baseline measurements are 
defined as the last evaluation performed before or at 
Visit VE.
For the Observation Period, baseline measurements are 
defined as the last evaluation performed before or at:
•
Visit VE for subjects entering the Observation 
Period directly after Part 1.
•
Visit ET for subjects switching from the 
Tapentadol Period to the Observation Period.
Section 1.2: Schedule of events
Section 1.2.4: Phone contacts
Section 11.1.5: Phone contacts
...
Phone contacts can be made at any time, e.g., if the 
subject wants to report adverse events, or has questions 
regarding concomitant medication intake/therapies. In 
case no site visit takes place, phone contacts are 
mandatory if the subject would like to up or down titrate 
the IMP.
...
Phone contacts can be made at any time, e.g., if the 
subject wants to report adverse events, or has questions 
regarding concomitant medication intake/therapies. If no 
trial site visit takes place, phone contacts are mandatory 
if the subject would like to up or down titrate the IMP. A 
trial site visit may be performed as a home visit after 
prior approval by the sponsor.
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Section 1.2.1: Part 1: Enrollment Visit and Treatment Period (Visit V1 to Visit VE)
[Table]
Obtain informed consent/assent
...
Dispense IMP (the first dose of IMP will be taken at the 
site)
[Footnotes]
a) Visit VE should also be performed if IMP is stopped 
during the Treatment Period.
...
e) Local laboratory parameters needed are: serum 
albumin, total serum bilirubin, total protein, and serum 
creatinine (the creatinine clearance will be calculated).
...
m) Complete once daily starting from visit with the last 
intake of IMP (normally Visit VE) until Visit F7D. At 
Visit VE, or earlier if applicable, dispense the 
questionnaires. At Visit F7D, collect the completed 
questionnaires.
...
[New footnote]
[Table] 
Obtain informed consent/assent s
...
Dispense IMP (the first dose of IMP will be taken during 
Visit V2, within 24 hours after randomization. Day 1 is 
the day of first IMP intake)
[Footnotes]
a) Visit VE must also be performed within 3 days of last 
IMP intake if IMP is stopped during the Treatment 
Period.
...
e) Local laboratory parameters needed are: total serum 
bilirubin, serum albumin, aspartate transaminase, 
alanine transaminase, and serum creatinine (the 
creatinine clearance will be calculated in the electronic 
CRF). The local laboratory sample does not need to be 
taken at the Enrollment Visit if suitable results from the 
same local laboratory are available from a blood sample 
obtained in the 14 days prior to Visit 2 for other reasons.
...
m) Complete once daily until the seventh day after the 
last intake of IMP. At Visit VE, or earlier if applicable, 
dispense the questionnaires. At Visit F7D, collect the 
completed questionnaires.
...
s) The informed consent/assent may be obtained earlier 
than Day -14.
Section 1.2.2: Part 2: Tapentadol Period
[Table]
Height
[Footnote]
g) Once daily starting at the visit of the last intake of 
IMP (normally Visit F12M or at Visit ET in case of early 
termination) until Visit F7D. At Visit F12M, or as 
applicable, dispense the questionnaires. At Visit F7D, 
collect the completed questionnaires.
[Table]
[measurements added at TP3, TP6, TP9, and TP12].
[Footnote]
g) Once daily until the seventh day after the last intake of 
IMP (normally Visit F12M or at Visit ET in case of early 
termination). At Visit F12M, or as applicable, dispense 
the questionnaires. At Visit F7D, collect the completed 
questionnaires.
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Section 3: Abbreviations and definition of terms: Definition of terms
Treated subjects: Allocated subjects with at least 
1 administration of IMP.
Trial completers Part 2: Subjects who have completed 
the 12 month Extension Period, either with tapentadol 
treatment (Tapentadol Period) or without treatment
(Observation Period).
Treated subjects: Subjects with at least 1 administration 
of IMP.
Trial completers Part 2: Subjects who fully completed the 
extension period, i.e., either subjects completing the
Tapentadol Period and the follow-up visit (F7D) or 
subjects completing the Observation Period (F12M) not 
earlier than 351 days after Visit VE).
Section 8.4: Discussion of the trial design: Dosing
...
Based on the pharmacokinetic evidence described above 
for tapentadol, the sponsor considers it justified to move 
into an adolescent safety and efficacy trial without a 
prior pharmacokinetic trial in this age group using the 
prolonged release formulation. However, a trial 
 that also assesses pharmacokinetic 
parameters in children and adolescents is ongoing with 
tapentadol oral solution (see Section 6.2). An advisory 
committee meeting (in March 2012) initiated by the FDA 
to discuss “clinical pharmacology aspects of pediatric 
clinical trial design and dosing to optimize pediatric drug 
development” recommended, based on an FDA review 
of 22 products recently approved for adolescent use, that 
for dose confirmation in adolescents (12 years to less 
than 18 years), no pharmacokinetic trials are needed, but 
that doses can be derived using adult data.
...
Based on the pharmacokinetic evidence described above 
for tapentadol, the sponsor considers it justified to move 
into an adolescent safety and efficacy trial without a 
prior pharmacokinetic trial in this age group using the 
prolonged release formulation. An advisory committee 
meeting (in March 2012) initiated by the FDA to discuss 
“clinical pharmacology aspects of pediatric clinical trial 
design and dosing to optimize pediatric drug 
development” recommended, based on an FDA review 
of 22 products recently approved for adolescent use, that 
for dose confirmation in adolescents (12 years to less 
than 18 years), no pharmacokinetic trials are needed, but 
that doses can be derived using adult data.
Section 8.5: Benefit/risk analysis: Risks
Independent statistical center
To allow for the conduct of the planned interim analysis, 
an independent statistical center will be established. The 
independent statistical center will re assess the sample 
size after stage 1 of the trial. The independent statistical 
center will provide recommendations to the sponsor’s 
steering committee as described in the independent 
statistical center charter.
[Paragraph deleted as not applicable]
Section 9.3.3: Procedure for the handling of prematurely discontinued subjects
...
Treated subjects will not be replaced. Allocated subjects 
who were not treated with IMP will be replaced. See 
Section 3 for a definition of allocated and treated 
subjects.
...
Subjects turning 18 years old before Visit VE may 
continue in the trial. However, an additional subject will 
then be enrolled and allocated to IMP. Otherwise treated 
subjects will not be replaced. See Section 3 for a 
definition of allocated and treated subjects.
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Section 10.2.1: Administration
...
The first dose of IMP will be taken at the site.
...
The first dose of IMP will be taken during visit V2
(Allocation Visit).
A dose must not be repeated if a subject vomits or 
regurgitates part or all of a dose. Vomiting and/or 
regurgitation of a dose must be recorded as an adverse 
event.
Section 10.2.3.4: Titration
The dose of IMP will be titrated within the given limits 
for dosing according to the body weight measured during 
the last visit at the site (...
The dose of IMP will be titrated within the given limits 
for dosing according to the body weight measured during 
the last visit (...
Section 10.6: Rescue medication
During Part 1 (Treatment Period) only, morphine oral 
solution will be supplied by the sponsor as rescue 
medication for both treatment groups.
Subjects with a bodyweight <45.0 kg will receive 
morphine oral solution 0.5% and subjects with a body 
weight ≥45.0 kg will receive morphine oral solution 2% 
as rescue medication.
...
Substance name: Morphine sulfate
...
Dose (strength): 0.5% and 2.0%
...
[new paragraph]
During Part 1 (Treatment Period) only, morphine oral 
solution will be supplied by the sponsor as rescue 
medication for both treatment groups.
An interactive response technology system (voice and 
web based) will be used to assign subjects to rescue 
medication.
...
Substance name: Morphine sulfate or morphine 
hydrochloride
...
Dose (strength): 0.5% and/or 2.0%
...
During Part 2, the use of immediate release strong 
opioids for treatment of breakthrough pain and 
incidental pain is allowed.
Section 11: Trial procedures
See Section 1.1 for a summary of the trial as a flow 
diagram and Section 1.2 for tabular schedules of events 
for each period.
See Section 1.1 for a summary of the trial as a flow 
diagram and Section 1.2 for tabular schedules of events 
for each period. A trial site visit may be performed as a 
home visit after prior approval by the sponsor.
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Section 11.1.1.1: Enrollment Visit (Visit V1; Day -14 to Day 1)
...
• Obtain informed consent and (if required by local law) 
assent (see Section 4.2 for the procedure).
...
• Take blood for safety laboratory investigations (for 
both the central and local laboratories).
...
• Obtain informed consent and (if required by local law) 
assent (see Section 4.2 for the procedure). The informed 
consent/assent may be obtained earlier than Day -14.
...
• Take blood for safety laboratory investigations (for 
both the central and local laboratories). The local 
laboratory sample does not need to be taken at the 
Enrollment Visit if suitable results from the same local 
laboratory are available from a blood sample obtained 
in the 14 days prior to Visit 2 for other reasons.
Section 11.1.1.2: Visit V2 (Allocation Visit; Day 1)
...
• Administer the first dose of IMP to the subject at the 
investigator’s site. Record administration in the diary.
...
• Administer the first dose of IMP to the subject (see 
Section 10.2.1). The first dose of IMP will be taken 
during this visit, within 24 hours after randomization.
Day 1 is the day of first IMP intake. Record 
administration in the diary. 
Section 11.1.1.4: Visit VE (Day 15 ± 1, End of Treatment Visit)
This visit is planned for Day 15 ± 1, but should also be 
performed if a subject discontinues IMP during the 
Treatment Period.
This visit is planned for Day 15 ± 1, but must also be 
performed within 3 days of last IMP intake if a subject 
discontinues IMP during the Treatment Period.
Section 11.1.1.4: Visit VE (Day 15 ± 1, End of Treatment Visit)
Section 11.1.2.3: Visit ET (Early Termination Visit)
Section 11.1.2.4: Visit F12M (at 12 months after Visit VE, range ± 14 days)
...
- Dispense SOWS questionnaire for completion at home 
if this is the visit of the last intake of IMP (only for 
subjects going in to the Observation Period). To be 
completed once daily until Visit F7D.
...
- Dispense SOWS questionnaire for completion at home 
if this is the visit of the last intake of IMP (only for 
subjects going in to the Observation Period). To be 
completed once daily until the seventh day after the last 
intake of IMP. To be collected at Visit F7D.
Section 11.1.2.2: Visit TP1 to TP12 (every 28 days after Visit VE, range: ± 5 days)
• Record body weight.
• Record vital signs (respiratory rate, systolic and 
diastolic blood pressure, and pulse rate).
• Record body weight.
• Record height (only at Visit TP3, Visit TP6, Visit TP9, 
and Visit TP12).
• Record vital signs (respiratory rate, systolic and 
diastolic blood pressure, and pulse rate).
Section 11.4: Subject trial cards
Subjects/parent(s)/legal guardian(s), as applicable, will 
receive a “subject trial card”. The trial card will list the 
following information:
Subjects/parent(s)/legal guardian(s), as applicable, will 
receive a “subject trial card”. The trial card will list at a 
minimum the following information:
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Section 12.1: Overview of blood sampling in this trial
If possible, blood samples for safety laboratory 
evaluations and serum pharmacokinetics should be taken 
at the same time. Sampling times are given in the 
schedule of events (Section 1.2).
If possible, blood samples for safety laboratory 
evaluations and serum pharmacokinetics should be taken 
at the same time. Sampling times are given in the 
schedule of events (Section 1.2). The local laboratory 
sample does not need to be taken at the Enrollment Visit 
if suitable results from the same local laboratory are 
available from a blood sample obtained in the 14 days 
prior to Visit 2 for other reasons.
Section 12.2.3: Pain history
The history, underlying pain condition (cancer/non-
cancer-related pain), and treatments for pain in the last 
30 days before enrollment will be recorded in the CRF.
The history, underlying pain condition (cancer/non-
cancer-related pain), and treatments given in the last 
30 days for pain before enrollment will be recorded in 
the CRF.
Section 12.4.1: Pain intensity
...
For the Tapentadol Period of Part 2, the investigator will 
document the pain that the subject has at each visit in the 
CRF using a paper based VAS.
...
For the Tapentadol Period of Part 2, the investigator will 
document the pain that the subject has at each visit in the 
CRF based on the FPS-R and VAS.
Section 12.5.3: Subjective opiate withdrawal scale
...
The 15 question SOWS questionnaire is more
appropriate for the studied population. It takes less than 
10 minutes to complete. The scale has been 
demonstrated to be a valid and reliable indicator of the 
severity of the opiate withdrawal syndrome over a wide 
range of common signs and symptoms.
The SOWS questionnaire will be completed by the 
subjects at home daily for 7 days after discontinuation of 
IMP.
...
The first 15 questions of the 16-question SOWS 
questionnaire are appropriate for the studied population. 
It takes less than 10 minutes to complete. The scale has 
been demonstrated to be a valid and reliable indicator of 
the severity of the opiate withdrawal syndrome over a 
wide range of common signs and symptoms.
The SOWS questionnaire will be completed by the 
subjects at home daily until the seventh day after the last 
intake of IMP. It will be collected at Visit F7D.
Section 12.6.1: Adverse events: Special procedures for serious adverse events
...
If possible, after serious adverse events considered 
related to IMP (possible: see the section Classification 
of causation), a blood sample for the quantitation of 
systemic exposure of tapentadol (or morphine), and 
metabolites, should be drawn in close temporal 
relationship to the serious adverse event.
...
If possible, after serious adverse events considered 
related to IMP (possible: see the section Classification 
of causation), a blood sample for the quantitation of 
systemic exposure of tapentadol and metabolites should 
be drawn in close temporal relationship to the serious 
adverse event.
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Section 12.6.5: Safety laboratory
...
The check of the exclusion criteria will be based on the 
local laboratory values. Local laboratory parameters 
needed are: total serum bilirubin, serum albumin, 
aspartate transaminase, alanine transaminase, and serum 
creatinine (the creatinine clearance will be calculated in 
the electronic CRF).
Serum chemistry and hematology
...
The following tests will be performed:
Red blood cell (RBC) count
White blood cell (WBC) count (if WBC abnormal, also 
differential count)
Platelet count
Urinalysis 
...
Sediment by the central laboratory
Red blood cells (RBC)
White blood cells (WBC)
Epithelial cells
Crystals
Casts
Bacteria
...
The check of the exclusion criteria will be based on the 
local laboratory values. Local laboratory parameters 
needed are: total serum bilirubin, serum albumin, 
aspartate transaminase, alanine transaminase, and serum 
creatinine (the creatinine clearance will be calculated in 
the electronic CRF). The local laboratory sample does 
not need to be taken at the Enrollment Visit if suitable 
results from the same local laboratory are available 
from a blood sample obtained in the 14 days prior to 
Visit 2 for other reasons.
Serum chemistry and hematology
...
The following tests will be performed:
Red blood cell (RBC) count
Red blood cell morphology
White blood cell (WBC) count 
White blood cell differential count
White blood cell morphology
Platelet count
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Section 14.2.1: Analysis populations (analysis sets)
Enrolled population
All subjects for whom an informed consent form was 
signed.
Safety Set
The Safety Set comprises all treated subjects. 
Full Analysis Set
The FAS comprises all allocated and treated subjects.
Per Protocol Set
The Per Protocol Set is a subset of the FAS, excluding
subjects with protocol deviations that may have an 
impact on the results of the efficacy analyses. 
Enrolled population
The Enrolled Set includes all subjects with a signed (by 
subject, parent(s) or legal guardian(s) as appropriate)
informed consent form and if required by local law an 
assent form.
Allocated Set
The Allocated Set includes all subjects who are allocated 
to treatment.
Safety Set
The Safety Set comprises all treated subjects, i.e., all 
subjects in whom IMP was administered (at least once). 
Full Analysis Set
The FAS comprises all allocated and treated subjects, 
i.e., all allocated subjects who were administered any 
amount of IMP.
Per Protocol Set
The Per Protocol Set defines a subset of the subjects in 
the FAS without any major protocol deviation affecting 
the primary endpoint. The Per Protocol Set is only 
relevant for analyses during Part 1. No protocol 
deviation during Part 2 leads to exclusion from the Per 
Protocol Set. 
Section 14.2.6.1: Primary endpoint (proportion of subjects classified as responders in Part 1)
...
Further sensitivity analyses are planned (but not limited 
to), e.g., keeping the criteria for response unchanged,
except for classifying subjects who stop treatment earlier 
than 14 days or use IMP intermittently because of no 
further need for opioid treatment as responders rather 
than non-responders.
...
Further sensitivity analyses are planned (but not limited 
to), e.g., keeping the criteria for response unchanged 
except for classifying subjects who stop treatment earlier 
than 14 days because of no further need for opioid 
treatment as responders rather than non-responders.
Section 14.2.6.2: Pain scale assessed using a VAS and FPS-R
...
Descriptive statistics will be provided to evaluate the 
changes at each scheduled time point as well as changes 
to baseline for the different trial periods and respective 
treatment groups, as described in Section 14.2.2.
...
Descriptive statistics will be provided to evaluate the 
daily average pain (Part 1) or pain at each visit during 
the Tapentadol Period (Part 2) as well as changes to 
baseline for the different trial periods and respective 
treatment groups, as described in Section 14.2.2.
Section 14.2.6.3: Rescue medication
...
Comparisons will be made across time, for subgroups of 
body weight and for different ages.
...
Comparisons will be made across time and also for 
subgroups of different ages.
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Section 14.2.7.5: Physical examination
Changes in physical examination findings compared to 
the previous assessment will be listed and summarized 
by body system. Further details concerning subgroups of 
interest will be specified in the SAP.
Physical examination findings will be listed. 
Section 14.2.7.8: Subjective opiate withdrawal scale
The SOWS questionnaire score will be descriptively 
analyzed per scheduled time point according to the last 
IMP taken. Changes to Visit ET will also be presented.
The SOWS questionnaire scores and changes from 
baseline (defined for the SOWS as the assessment made 
on the day of the last intake of IMP) will be descriptively 
analyzed per scheduled time point according to the last 
IMP taken. The total score of the full questionnaire (all 
16 questions) will be used for a first analysis. 
Additionally the total score of the first 15 questions of 
the SOWS questionnaire will be analyzed in the same 
manner, being more appropriate for the studied 
population.
Section 14.2.9: Final analysis
The final analysis of both Part 1 and Part 2 of the trial 
will be performed after all subjects have completed 
Part 2. Further analysis details will be specified in the 
SAP.
The final analysis of Part 1 will be performed after all 
subjects have completed Part 1 of the trial and the data 
has been locked for analyses of Part 1.
The final analysis of Part 2 will be performed after all 
subjects have completed Part 2 of the trial and the final 
data base has been locked.
Section 19.9.1: Labeling
The labels of the pharmacokinetic samples will be 
provided by the central laboratory and include at least the 
following information (pre printed, i.e., manual writing 
has to be avoided):
•
Trial Number.
•
Unique Subject Identifier.
•
Visit Number.
•
Sample time.
The labels of the pharmacokinetic samples will be 
provided by the central laboratory and include at least 
the following information:
•
Trial Number.
•
Unique Subject Identifier.
•
Accession Number.
•
Visit Number.
18.3
Protocol amendment 03
Amendment rationale
Protocol amendment 03 was been enacted to implement changes required by US authorities:
•
Specify titration for subjects who were opioid naive at Visit V1.
•
Add CSSRS, University of Michigan sedation score, and measurement of oxygen saturation 
(SpO2).
The amendment was subsequently withdrawn.
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18.4
Protocol amendment 04
Protocol amendment 04 is based on protocol amendment 02, and does not reflect changes 
introduced in protocol amendment 03 as this protocol amendment was withdrawn.
Amendment rationale
Protocol amendment 04 has been enacted to implement the following changes:
•
The alpha for the primary endpoint analysis has been updated based on the methodology 
proposed by Hlavin et al. (2016). As a consequence of the alpha adjustment, the sample 
size has been reduced. Further details for the derivation of the adjusted alpha are provided
in a separate document that is available upon request.
•
A definition of long-term pain has been added.
•
Specifications of the trial population have been modified, requiring the inclusion of fewer 
subjects in the lower age group. The expectation that at least 15 subjects will be treated 
with tapentadol PR for a minimum of 12 weeks has been introduced.
•
The estimated dates of last subject out for Part 1 and Part 2 have been updated.
•
The main analysis has been rescheduled such that it will be performed after all subjects 
have completed the first 12 weeks (Visit TP3 or Visit OP3) of Part 2.
•
The interim analysis for sample size re-assessment has been removed due to the reduced 
sample size. The adaptive 2-stage design of the trial has been simplified to a fixed 1-stage 
design.
•
Instructions pertaining to ECG-related discontinuation have been added.
•
The timing of the Early Termination Visit has been explicitly defined.
•
History of complex regional pain syndrome and history of a pain indication that is unlikely 
to respond to opioids have been added to the exclusion criteria.
•
Safety experience from post-marketing data has been updated.
•
Instructions for calculating the starting dose in Part 1 and Part 2 have been revised.
•
Requirements for adverse event reporting during the Observation Period of Part 2 have 
been modified.
In addition, textual change has been made for consistency and, where necessary, to provide more 
detailed descriptions.
Detailed description of changes
Minor editorial changes, such as the correction of typing errors, are not specifically listed.
In the table below, deleted text is crossed out and new text is highlighted using italics.
Changes to this protocol include:
Formerly read:
Now reads: 
Section 1: Protocol synopsis: Trial design
Part 1 is a 14-day (Treatment Period) Phase II/III, 
randomized, multi-site, open-label, active-controlled, 
parallel group trial in subjects aged 6 years to less than 
18 years, suffering from long-term pain requiring 
Part 1 is a 14-day (Treatment Period) Phase II/III, 
randomized, multi-site, open-label, active-controlled, 
parallel group trial in subjects aged 6 years to less than 
18 years, suffering from long-term pain requiring 
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prolonged release opioid treatment. The target is to 
allocate at least 129 subjects (with a maximum of 200 
subjects) in a ratio of 2:1 to treatment with tapentadol PR 
or morphine PR twice daily. An interim analysis will be 
performed to check the sample size.
prolonged release opioid treatment. The target is to 
allocate 69 subjects in a ratio of 2:1 to treatment with 
tapentadol PR or morphine PR twice daily.
Section 1: Protocol synopsis: Trial population
Subjects will be enrolled who are aged 6 years to less 
than 18 years (for the duration of Part 1 of the trial) and 
suffer from long-term pain requiring prolonged release 
opioid treatment for at least 14 days after Visit V2 
(Allocation Visit; Day 1), and who comply with the 
inclusion/exclusion criteria given in Section 1.3.
The age groups of 6 years to less than 12 years and 
12 years to less than 18 years are predefined. 
At least 50% of the subjects will be allocated to IMP at 
Visit V2 in the age group of 6 years to less than 12 years.
Subjects will be enrolled who are aged 6 years to less 
than 18 years (for the duration of Part 1 of the trial) and 
suffer from long-term pain requiring prolonged release 
opioid treatment for at least 14 days after Visit V2 
(Allocation Visit; Day 1), and who comply with the 
inclusion/exclusion criteria given in Section 1.3. Long-
term pain is defined as any pain condition that requires a 
minimum of 14 days of treatment with a strong oral 
opioid. Subjects that could be considered for the trial 
include, but not exclusively, those with expected long-
term post-surgical pain (e.g., spinal surgery), cancer-
related pain (including pain caused by treatment) as well
as chronic indications with moderate to severe pain.
The age groups of 6 years to less than 12 years and 
12 years to less than 18 years are predefined. 
At least 25% of the subjects will be allocated to IMP at 
Visit V2 in the age group of 6 years to less than 12 years.
At least 15 subjects must be treated with tapentadol PR 
for a minimum of 12 weeks.
Section 1: Protocol synopsis: Concomitant medications/therapies
All medications/therapies that are not explicitly 
mentioned under allowed or forbidden treatments are 
also considered to be allowed.
Subjects suffering from cancer related pain will be 
allowed to participate in trials of marketed therapeutic 
medications and therapies (including trials of antibody 
therapies).
All medications/therapies that are not explicitly 
mentioned under allowed or forbidden treatments are 
also considered to be allowed.
Subjects will be allowed to participate in trials of 
marketed therapeutic medications and therapies 
(including trials of antibody therapies) at the same time 
as participating in this trial.
Section 1: Protocol synopsis: Trial period
Section 8: Trial design: Trial period
Estimated date of first subject in: Oct 2014. 
Part 1, estimated date of last subject out: Sep 2016.
Part 2, estimated date of last subject out: Sep 2017.
Estimated date of first subject in: Oct 2014. 
Part 1, estimated date of last subject out: Sep 2018.
Part 2, estimated date of last subject out: Sep 2019.
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Section 1: Protocol synopsis: Sample size rationale
The design of the trial is an adaptive 2 stage design with 
possible sample size re estimation after the first stage, 
with no early stopping for success or futility foreseen 
(see “Interim Analysis”). As a result of the interim 
analysis, the overall number of subjects in the FAS will 
be between N = 129 and an upper sample size limit of 
Nmax = 200.
To show the non-inferiority of tapentadol PR compared 
to morphine PR using a Farrington-Manning test by a 
non-inferiority margin of 20% with at least 80% power 
and a 1-sided significance level of alpha = 0.025, 
129 subjects are required in the FAS, assuming a 2:1 
randomization of tapentadol PR:morphine PR. Using the 
proposed method for sample size re assessment, the final 
analysis does not have to be adjusted for the interim 
analysis.
The operating characteristics of the trial design and the 
sample size was assessed in 2 steps. First, a sample size 
calculation was carried out using Adaptive Designs 
Plans and Analyses software package ADDPLAN 
version 6.0.8 provided by Aptiv Solutions, for an 
adaptive 2 stage design without stopping at interim after 
75% of data are available. The resulting total number of 
subjects (N = 129) was then implemented in a simulation 
process using the response rate as the primary endpoint 
and computing the empirical statistical power for several 
values of the overall sample size. These simulations were 
carried out using R version 2.12.2. The simulations were 
validated by an independent statistician.
To show the non-inferiority of tapentadol PR compared 
to morphine PR using a Farrington-Manning test by a 
non-inferiority margin of 20% with at least 80% power 
and a 1-sided significance level of alpha = 0.1, 
69 subjects are required in the Full Analysis Set (FAS), 
assuming a 2:1 randomization of tapentadol 
PR morphine PR.
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Section 1: Protocol synopsis: Statistical methods
The analysis for Part 2 will take into consideration the 
Tapentadol Period and Observation Period of Part 2. The 
primary analysis will be conducted after the end of 
stage 2 of the trial, meaning that all subjects have 
completed Part 1 of the trial.
...
Primary analysis of the trial
The primary analysis of the trial will be performed after 
all subjects have completed Part 1 (Treatment Period).
Primary efficacy endpoint
...
The Farrington-Manning test will then be applied and a 
95% confidence interval calculated.
...
Analysis of safety data
...
Adverse events will be tabulated separately for the 
treatment periods and additionally by visit, as long as a 
sufficient number of subjects are available.
Interim analysis
The trial will be conducted using an adaptive 2 stage 
design with possible sample size re estimation after the 
first stage, with no stopping for futility foreseen. The 
sample size re estimation will be done in an unblinded 
manner as the trial is open label. The interim analysis 
aims for verification of the assumptions for the sample 
size calculation by using a so called “promising zone” 
approach. This interim analysis is planned to be 
conducted after 75% of the initially proposed number of 
subjects in the FAS (i.e., 97 subjects) complete Part 1 of 
the trial.
The analysis for Part 2 will take into consideration the 
Tapentadol Period and Observation Period of Part 2.
...
Main analysis of the trial
The main analysis of the trial will be performed after all 
subjects have completed the first 12 weeks (Visit TP3 or 
Visit OP3) of Part 2.
Primary efficacy endpoint
...
The Farrington-Manning test will then be applied and an
80% confidence interval calculated.
...
Analysis of safety data
...
Adverse events will be tabulated separately for the 
treatment periods.
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Section 1.2.1: Part 1: Enrollment Visit and Treatment Period (Visit V1 to Visit VE): footnotes
a) Visit VE must also be performed within 3 days of last 
IMP intake if IMP is stopped during the Treatment 
Period.
...
s) The informed consent/assent may be obtained earlier 
than Day -14.
a) Visit VE must also be performed within 3 days after
last intake of IMP if IMP is stopped during the Treatment 
Period.
...
s) The informed consent/assent may be obtained earlier 
than Day -14.
t) The inclusion as well as discontinuation of a subject 
will be based on the judgment of the investigator. If the 
subject has been included but fulfills any of the 
discontinuation criteria based on the ECG analysis 
report of the central ECG laboratory, the ECG must be 
repeated within 1 week of receiving the central ECG 
report and the subject must be discontinued if any of the 
discontinuation criteria is confirmed by the investigator.
Section 1.2.2: Part 2: Tapentadol Period: footnotes
c) The Early Termination Visit (Visit ET) is for subjects 
stopping IMP before Visit F12M in Part 2.
c) Visit ET must be performed within 3 days after last 
intake of IMP if IMP is stopped before Visit F12M in 
Part 2.
Section 1.3.1: Inclusion criteria
Subjects are eligible for the trial at Visit V1 if all the 
following apply:
...
3. Subject has an underlying long-term pain condition 
that is, according to the judgment of the investigator, 
expected to require a twice-daily prolonged release 
opioid treatment until at least the end of the 14-day 
Treatment Period (Visit VE).
Subjects are eligible for the trial at Visit V1 if all the 
following apply:
...
3. Subject has an underlying long-term pain condition
(e.g., cancer, chronic disease, planned or performed 
surgery) that is, according to the judgment of the 
investigator, expected to require a twice-daily prolonged 
release opioid treatment until at least the end of the 14-
day Treatment Period (Visit VE).
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Section 8: Trial design
Part 1 is a 14-day (Treatment Period) Phase II/III, 
randomized, multi-site, open-label, active-controlled, 
parallel group trial in subjects aged 6 years to less than 
18 years, suffering from long-term pain requiring 
prolonged release opioid treatment. The target is to 
allocate at least 129 subjects (with a maximum of 200 
subjects) in a ratio of 2:1 to treatment with tapentadol PR 
or morphine PR twice daily.
...
Trial population
Subjects will be enrolled who are aged 6 years to less 
than 18 years (for the duration of Part 1 of the trial) and 
suffer from severe long-term pain requiring prolonged 
release opioid treatment for at least 14 days after 
Visit V2, and who comply with the inclusion/exclusion 
criteria given in Section 9.2.
Age groups of 6 years to less than 12 years and 12 years 
to less than 18 years are predefined. 
At least 50% of the subjects will be allocated to IMP at 
Visit V2 in the age group of 6 years to less than 12 years.
Part 1 is a 14-day (Treatment Period) Phase II/III, 
randomized, multi-site, open-label, active-controlled, 
parallel group trial in subjects aged 6 years to less than 
18 years, suffering from long-term pain requiring 
prolonged release opioid treatment. The target is to 
allocate 69 subjects in a ratio of 2:1 to treatment with 
tapentadol PR or morphine PR twice daily.
...
Trial population
Subjects will be enrolled who are aged 6 years to less 
than 18 years (for the duration of Part 1 of the trial) and 
suffer from severe long-term pain requiring prolonged 
release opioid treatment for at least 14 days after 
Visit V2 (Allocation Visit; Day 1), and who comply with 
the inclusion/exclusion criteria given in Section 1.3. 
Long-term pain is defined as any pain condition that 
requires a minimum of 14 days of treatment with a 
strong oral opioid. Subjects that could be considered for 
the trial include, but not exclusively, those with expected 
long-term post-surgical pain (e.g., spinal surgery), 
cancer-related pain (including pain caused by treatment) 
as well as chronic indications with moderate to severe 
pain.
The age groups of 6 years to less than 12 years and 
12 years to less than 18 years are predefined. 
At least 25% of the subjects will be allocated to IMP at 
Visit V2 in the age group of 6 years to less than 12 years.
At least 15 subjects must be treated with tapentadol PR 
for a minimum of 12 weeks.
Section 8.4: Discussion of the trial design
Choice of population and trial sites
Tapentadol PR has shown to be an efficacious and safe 
drug for the treatment of different chronic pain 
indications that are common in the adult population, such 
as low back pain, osteoarthritis and cancer-related pain. 
...
Chronic daily pain can occur in children in the context of 
chronic daily headaches, neurodegenerative disorders, 
Choice of population and trial sites
The trial includes children with different indications 
requiring treatment with an oral strong opioid for at 
least 14 days. Subjects that could be considered for the 
trial include, but not exclusively, those with expected 
long-term post-surgical pain (e.g., orthopedic surgery), 
cancer-related pain (including pain caused by 
treatment), as well as chronic indications with moderate 
to severe pain.
Tapentadol PR has shown to be an efficacious and safe 
drug for the treatment of different chronic pain 
indications that are common in the adult population, such 
as low back pain, osteoarthritis and cancer-related pain. 
...
Chronic daily pain can occur in children in the context of 
chronic daily headaches, neurodegenerative disorders, 
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inflammatory disorders, post-traumatic neuropathic pain 
conditions (including complex regional pain syndromes),
and in children with advanced cancer and other 
life-limiting diseases. 
...
Multiple trial sites, e.g., specialized in pediatric oncology 
and hematology, burns and orthopedics, in multiple 
countries will be required for the recruitment of at least 
129 subjects in the specified time.
...
Interim analysis
The trial will include 1 interim analysis, to decide on the 
adequacy of the chosen sample size. The interim analysis 
is planned to be conducted after 75% of the initially 
planned number of subjects in the FAS (i.e., 97 subjects) 
complete Part 1 of the trial (Section 14.2.10). The 
rationale for the interim analysis is that information 
about the primary endpoint and the treatment effect 
measured in the population under investigation is 
limited. Therefore, assumptions needed for an 
appropriate sample size calculation to achieve a specified 
power in a fixed sample design are subjected to 
uncertainty. An adaptive design allows for sample size 
re assessment at the interim analysis under control of the 
overall Type I error rate.
To ensure the integrity and validity of the trial results, an 
independent statistician will conduct the sample size re
assessment at the interim analysis. The rules for the 
sample size re assessment and final analysis are pre
specified, see Section 14.2.10.
...
Stratification
...
The predefined age groups are 6 years to less than 
12 years, and 12 years to less than 18 years, and subjects 
will be stratified so that at least 50% of the subjects will 
be allocated to IMP at Visit V2 in the age group of 
6 years to less than 12 years.
...
Dosing
...
Based on these results, a starting dose of ~1.25 mg/kg to 
1.5 mg/kg every 12 hours, with a maximum dose of 
~4.5 mg/kg every 12 hours, were chosen in this trial. As 
the IMP used in this trial is only available as tapentadol 
PR 25 mg and tapentadol PR 100 mg tablets, the doses in 
the age sub groups (Table 2) are chosen to be as close as 
possible to the estimated doses.
In subjects previously taking an opioid, a conversion 
inflammatory disorders, post-traumatic neuropathic pain 
conditions, and in children with advanced cancer and 
other life-limiting diseases. 
...
Multiple trial sites, e.g., specialized in pediatric oncology 
and hematology, burns and orthopedics, in multiple 
countries will be required for the recruitment of 
69 subjects in the specified time.
...
Stratification
...
The predefined age groups are 6 years to less than 
12 years, and 12 years to less than 18 years, and subjects 
will be stratified so that at least 25% of the subjects will 
be allocated to IMP at Visit V2 in the age group of 
6 years to less than 12 years.
...
Dosing
...
Based on these results, a starting dose of ~1.25 mg/kg to 
1.5 mg/kg every 12 hours, with a maximum dose of 
~4.5 mg/kg every 12 hours, were chosen in this trial. As 
the IMP used in this trial is only available as tapentadol 
PR 25 mg and tapentadol PR 100 mg tablets, the doses in 
the age subgroups (Table 2) are chosen to be as close as 
possible to the estimated doses.
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factor will be used to calculate the starting dose 
(Section 19.8).
Section 9.2: Inclusion/exclusion criteria
[Inclusion and exclusion criteria deleted from section.]
[Links set to Section 1.3.]
Section 9.3: Trial discontinuation and treatment not completed
Subjects may, however, also discontinue participation in 
the trial completely.
Subjects may, however, also discontinue participation in 
the trial completely (trial not completed).
Section 10.2.3.2 Starting doses in Part 1 for subjects with previous opioid treatment
Subjects with previous opioid treatment will start at 70% 
of the equi-analgesic dose of their previous treatment or 
lower; depending on the available dose, but using at least 
the minimum dose according to weight group (see 
Table 2 for tapentadol PR and Table 3 for morphine PR). 
Subjects pre treated with morphine can continue on their 
previous dose or next lower dose according to Table 3 if 
the dose does not match a dose given on the dosing table.
A conversion table to calculate equi analgesic doses of 
common opioids to tapentadol PR and morphine PR is 
provided in Section 19.8.
Subjects taking previous opioid treatment will start at 
70% of the equi-analgesic dose of their previous 
treatment or lower; depending on the available dose, but 
using at least the minimum dose according to weight 
group (see Table 2 for tapentadol PR and Table 3 for 
morphine PR). 
Subjects pre-treated with morphine can continue on their 
previous dose or next lower dose according to Table 2 if 
the dose does not match a dose given on the dosing table, 
if randomized to morphine.
Conversion from other opioids to morphine should be 
done according to clinical routine. To calculate the dose 
of prolonged release opioids per intake, it is 
recommended to calculate the total daily dose of the 
immediate release opioid and divide the result by 2. To 
rotate subjects from other opioids to tapentadol PR, the 
morphine-equivalent dose should be calculated first 
followed by the calculation of the final tapentadol PR 
dose (1 mg morphine PR is equivalent to 2.5 mg 
tapentadol PR).
Section 10.2.3.3: Starting dose of tapentadol PR in Part 2
Subjects converting from morphine PR (Treatment 
Period of Part 1) to tapentadol PR (Tapentadol Period of 
Part 2) will start tapentadol PR with 70% of the current 
morphine equivalent dose or lower, depending on the 
available dose, but using at least the minimum dose 
according to their weight group (Table 2). As 
tapentadol PR 2.5 mg is equivalent to morphine PR 
1 mg, the suggested starting total daily dose of 
tapentadol PR in mg is 1.75 x total daily dose of 
morphine PR in mg.
Subjects converting from morphine PR (Treatment 
Period of Part 1) to tapentadol PR (Tapentadol Period of 
Part 2) will start tapentadol PR at 70% of the current 
morphine equivalent dose or lower, depending on the 
available dose, but using at least the minimum dose 
according to their weight group (Table 2). 
Section 10.3.1: Part 1
Subjects will be stratified using the interactive response 
technology system by age group (6 years to less than 
12 years and 12 years to less than 18 years, at Visit V2 
[Allocation Visit]) so that at least 50% of the subjects are 
in the younger age group, and by underlying pain 
condition (cancer/non-cancer-related pain).
Subjects will be stratified using the interactive response 
technology system by age group (6 years to less than 
12 years and 12 years to less than 18 years, at Visit V2 
[Allocation Visit]) so that at least 25% of the subjects are 
in the younger age group, and by underlying pain 
condition (cancer/non-cancer-related pain).
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Section 10.5: Allowed and forbidden and prior/concomitant medications/therapies
...
All medications/therapies that are not explicitly 
mentioned under allowed or forbidden treatments are 
also considered to be allowed.
Subjects suffering from cancer related pain will be 
allowed to participate in trials of marketed therapeutic 
medications and therapies (including trials of antibody 
therapies).
...
All medications/therapies that are not explicitly 
mentioned under allowed or forbidden treatments are 
also considered to be allowed. 
Section 11.1.1.1: Enrollment Visit (Visit V1; Day -14 to Day 1)
...
• Record a 12-lead ECG.
...
• Record a 12-lead ECG. The inclusion as well as 
discontinuation of a subject will be based on the 
judgment of the investigator. If the subject has been 
included but fulfills any of the discontinuation criteria 
based on the ECG analysis report of the central ECG 
laboratory, the ECG must be repeated within 1 week of 
receiving the central ECG report and the subject must be 
discontinued if any of the discontinuation criteria is 
confirmed by the investigator.
Section 11.1.1.4: Visit VE (Day 15 ± 1, End of Treatment Visit)
This visit is planned for Day 15 ± 1, but must also be 
performed within 3 days of last IMP intake if a subject 
discontinues IMP during the Treatment Period.
This visit is planned for Day 15 ± 1, but must also be 
performed within 3 days after last intake of IMP if a 
subject discontinues IMP during the Treatment Period.
Section 11.1.2.3: Visit ET (Early Termination Visit)
The Early Termination Visit (Visit ET) is for subjects 
stopping IMP before Visit F12M in Part 2. If Visit F12M 
and Visit ET are performed on the same day, 
assessments scheduled for both visits will not be 
repeated at Visit F12M.
Visit ET must be performed within 3 days after last 
intake of IMP if IMP is stopped before Visit F12M in 
Part 2. If Visit F12M and Visit ET are performed on the 
same day, assessments scheduled for both visits will not 
be repeated at Visit F12M.
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Section 12.6.1: Adverse events
All adverse events will be documented from the time of 
enrollment (i.e., the time the informed consent form is 
signed) up to the time of the last protocol scheduled 
contact has occurred, i.e., date of last visit/contact (can 
be a phone call, e.g., in case of withdrawal).
...
Notification of serious adverse events
All serious adverse events (including death, irrespective 
of cause) during the trial, regardless of their relationship 
to IMP, must be reported to the sponsor’s Drug Safety 
Department as soon as possible but no later than 24 
hours after learning of the event.
During Part 1 and during the Tapentadol Period of 
Part 2 and until Visit OP3 of the Observational Period 
all adverse events will be documented from the time of 
enrollment (i.e., the time the informed consent form is 
signed) up to the time of the last protocol scheduled 
contact has occurred, i.e., date of last visit/contact (can 
be a phone call, e.g., in case of withdrawal). 
After Visit OP3 of the Observation Period of Part 2, only 
adverse events and serious adverse events that, in the 
judgment of the investigator, are at least possibly related 
to IMP will be reported.
...
Notification of serious adverse events
All serious adverse events (including death, irrespective 
of cause) during the trial, regardless of their relationship
to IMP, must be reported to the sponsor’s Drug Safety 
Department as soon as possible but no later than 24 
hours after learning of the event, with the following 
exception: after Visit OP3 of the Observation Period of 
Part 2, only adverse events and serious adverse events 
that, in the judgment of the investigator, are at least 
possibly related to IMP will be reported.
Section 12.6.2: Vital signs
Vital signs (respiratory rate, systolic and diastolic blood 
pressure, and pulse rate) will be measured in a supine 
position after resting for 5 minutes and recorded in the 
CRF. While resting, the subject should not receive 
anything to drink or eat.
Vital signs (respiratory rate, systolic and diastolic blood 
pressure, and pulse rate) will be measured in a supine 
position after resting for at least 5 minutes and recorded 
in the CRF. While resting, the subject should not receive 
anything to drink or eat. 
Section 12.6.4: Twelve-lead electrocardiogram
...
Cardiologists at a central ECG laboratory will read all 
ECGs. The ECG report from the central ECG laboratory 
will be considered a source document.
...
Cardiologists at a central ECG laboratory will read all 
ECGs. The ECG report from the central ECG laboratory 
will be considered a source document.
If there are discrepancies between the central ECG 
analysis report and the assessment of the investigator, 
the investigator will document these on the ECG analysis 
report. 
The inclusion as well as discontinuation of a subject will 
be based on the judgment of the investigator. If the 
subject has been included but fulfills any of the 
discontinuation criteria based on the ECG analysis 
report of the central ECG laboratory, the ECG must be 
repeated within 1 week of receiving the central ECG 
report and the subject must be discontinued if any of the 
discontinuation criteria is confirmed by the investigator.
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Section 13.3: Data management
Database lock
For each defined reporting time point, when all data have 
been received and entered, all data checks and quality 
control checks have been performed, all queries are 
resolved, and a final data review meeting has been held 
without resulting in new queries, the trial database will 
be considered clean and can be frozen. For the primary
analysis after Part 1, the database will be frozen after 
every subject has completed Part 1 or has terminated 
early.
Database lock
When all data have been received and entered into the 
trial database, all data checks and quality control checks 
have been performed, all queries are resolved, and the
final statistical review has been held without resulting in 
new queries, the trial database will be considered clean 
and the data will be locked. For the main analysis (Part 1
and the first 12 weeks of Part 2), the detailed procedure 
will be described in the data management plan.
Section 14.1: Sample size rationale
The design of the trial is an adaptive 2 stage design with 
possible sample size re estimation after the first stage, 
with no early stopping for success or futility foreseen. 
This interim analysis aims for verification of the 
assumptions for the sample size calculation by using a so 
called “promising zone” approach (see Section 14.2.10), 
stopping for any reason is not foreseen based in the 
results of the interim analysis. As a result of the interim 
analysis, the overall number of subjects in the FAS will 
be between N = 129 and an upper sample size limit of 
Nmax = 200.
To show the non-inferiority of tapentadol PR compared 
to morphine PR using a Farrington-Manning (1990) test 
by a non-inferiority margin of 20% with at least 80% 
power and a 1-sided significance level of alpha = 0.025, 
129 subjects are required in the FAS, assuming a 
2:1 randomization of tapentadol PR:morphine PR. Using 
the proposed method for sample size re assessment, the 
final analysis does not have to be adjusted for the interim 
analysis.
The operating characteristics of the trial design and the 
sample size was assessed in 2 steps. First, a sample size 
calculation was carried out using Adaptive Designs 
Plans and Analyses software package ADDPLAN 
version 6.0.8 provided by Aptiv Solutions, for an 
adaptive 2 stage design without stopping at the interim 
analysis after 75% of data are available. The resulting 
total number of subjects (N = 129) was then 
implemented in a simulation process using the response 
rate as the primary endpoint and computing the empirical 
statistical power for several values of the overall sample 
size. These simulations were carried out using R version 
2.12.2. The simulations were validated by an 
independent statistician.
A detailed description of the process can be found the 
sponsor’s trial master files.
To show the non-inferiority of tapentadol PR compared 
to morphine PR using a Farrington-Manning (1990) test 
by a non-inferiority margin of 20% with at least 80% 
power and a 1-sided significance level of alpha = 0.1, 
69 subjects are required in the FAS, assuming a 
2:1 randomization of tapentadol PR:morphine PR.
A one-sided alpha of 0.1 is considered appropriate based 
on a method proposed by Hlavin et al. (2016). The 
approach makes use of prior knowledge and the concept 
of extrapolation from a larger population to a small 
target population, (i.e., pediatric population), to reduce 
the burden of evidence in pediatrics by relaxing the 
Type I error, while controlling a certain posterior belief, 
i.e., confidence after successful pediatric trials, in 
effectiveness of the drug in children.  
Further details for the application of the concept of 
Hlavin et al. (2016) in the context of this trial are 
provided in a separate document that is available upon 
request.  
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Section 14.2: Analysis of the trial – statistical analysis
Primary analysis of the trial
The primary analysis of the trial will be performed after 
all subjects have completed Part 1 (Treatment Period),
i.e., after the end of stage 2 of the trial (see 
Section 14.2.10).
Main analysis of the trial
The main analysis of the trial will be performed after all 
subjects have completed the first 12 weeks (Visit TP3 or 
Visit OP3) of Part 2.
Section 14.2.6.1: Primary endpoint (proportion of subjects classified as responders in Part 1): Hypotheses
...
The Farrington-Manning (1990) test will then be applied 
and a 95% confidence interval calculated. The non-
inferiority of tapentadol PR compared to morphine PR 
will be established if the lower limit of this 2-sided 95% 
confidence interval of the difference in the above 
estimated proportions is above the non-inferiority margin 
of -20%.
The method chosen for sample size re assessment allows 
for an unchanged test statistic to be used for final 
analysis.
...
This sample will be summarized by means of the 
posterior mean, median, standard deviation and 95% 
credibility interval. If the lower limit of the 95% 
credibility interval for the difference of the 2 response 
rates is >-0.2, then this would support non-inferiority by 
this sensitivity analysis.
...
The Farrington-Manning (1990) test will then be applied 
and an 80% confidence interval calculated. The non-
inferiority of tapentadol PR compared to morphine PR 
will be established if the lower limit of this 2-sided 80% 
confidence interval of the difference in the above 
estimated proportions is above the non-inferiority margin 
of -20%.
...
This sample will be summarized by means of the 
posterior mean, median, standard deviation and 80% 
credibility interval. If the lower limit of the 80% 
credibility interval for the difference of the 2 response 
rates is >-0.2, then this would support non-inferiority by 
this sensitivity analysis.
Section 14.2.7.1: Adverse events
Adverse events will be tabulated separately for the 
treatment periods and additionally by visit, as long as a 
sufficient number of subjects are available.
Adverse events will be tabulated separately for the 
treatment periods.
Section 14.2.7.4: Vital signs (pulse rate, systolic/diastolic blood pressure, and respiratory rate)
As described in Section 14.2.2, descriptive statistics as 
well as for changes to baseline for the different trial 
periods will be presented. Frequency tabulations of 
abnormalities will be included. 
As described in Section 14.2.2, descriptive statistics as 
well as changes to baseline for the different trial periods 
will be presented. Frequency tabulations of abnormalities 
will be included. 
Section 14.2.9: Final analysis
The final analysis of Part 1 will be performed after all 
subjects have completed Part 1 of the trial and the data 
has been locked for analyses of Part 1.
The final analysis of Part 2 will be performed after all 
subjects have completed Part 2 of the trial and the final 
data base has been locked.
The main analysis of the trial will be performed after all 
subjects have completed Part 1 and the first 12 weeks
(Visit TP3 or Visit OP3) of Part 2 of the trial. 
The final analysis of Part 2 will be performed after all 
subjects have completed Part 2 of the trial and the final 
database has been locked.
Further details regarding the analyses will be provided 
in the SAP.
Section 14.2.10: Interim analysis
Section 14.2.10: [deleted]
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Section 16.6: Final report and reporting of the trial
An integrated clinical trial report, integrating clinical, 
pharmacokinetic, and statistical results of Part 1 
(Treatment Period) will be prepared by the sponsor once 
all subjects have completed Part 1.
An integrated clinical trial report, integrating clinical, 
pharmacokinetic, and statistical results of 
Part 1(Treatment Period) and the first 12 weeks of Part 2
will be prepared by the sponsor once all subjects have 
completed the first 12 weeks (Visit TP3 or Visit OP3) of 
Part 2.
Section 17: References: Publications
...
Mehta CR, Pocock, SJ. Adaptive increase in sample size 
when interim results are promising: A practical guide 
with examples. Statistics in Medicine 2011; 30(28): 
3267 84.
Hlavin G, Koenig F, Male C, Posch M, Bauer P. 
Evidence, eminence and extrapolation. Stat Med 2016; 
35(13): 2117-32.
...
Section 19: Appendix
Section 19.8: Conversion factors for opioids
Section 19.8: [deleted]
Section 19.10: Interim analysis using the promising zone 
approach
Section 19.11: [deleted]
18.5
Protocol amendment 05
Protocol amendment 05 is implemented to reverse a change introduced in amendment 04 relating to 
the recording of adverse events after Visit OP3.
Detailed description of changes
Minor editorial changes, such as the correction of typing errors, are not specifically listed.
In the table below, deleted text is crossed out and new text is highlighted using italics.
Changes to this protocol include:
Formerly read:
Now reads: 
Section 12.6.1: Adverse events
During Part 1 and during the Tapentadol Period of Part 2 
and until Visit OP3 of the Observational Period all
adverse events will be documented from the time of 
enrollment (i.e., the time the informed consent form is 
signed) up to the time of the last protocol scheduled 
contact has occurred, i.e., date of last visit/contact (can 
be a phone call, e.g., in case of withdrawal). 
After Visit OP3 of the Observation Period of Part 2, only 
adverse events and serious adverse events that, in the 
judgment of the investigator, are at least possibly related 
to IMP will be reported.
All adverse events will be documented from the time of 
enrollment (i.e., the time the informed consent form is 
signed) up to the time of the last protocol scheduled 
contact has occurred, i.e., date of last visit/contact (can 
be a phone call, e.g., in case of withdrawal).
...
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...
Notification of serious adverse events
All serious adverse events (including death, irrespective 
of cause) during the trial, regardless of their relationship 
to IMP, must be reported to the sponsor’s Drug Safety 
Department as soon as possible but no later than 24 
hours after learning of the event, with the following 
exception: after Visit OP3 of the Observation Period of 
Part 2, only adverse events and serious adverse events 
that, in the judgment of the investigator, are at least 
possibly related to IMP will be reported.
Notification of serious adverse events
All serious adverse events (including death, irrespective 
of cause) during the trial, regardless of their relationship 
to IMP, must be reported to the sponsor’s Drug Safety 
Department as soon as possible but no later than 24 
hours after learning of the event.
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19
APPENDIX
19.1
List of medical concepts for consideration of seriousness stratified by 
system organ class
Blood and lymphatic system disorders
agranulocytosis
aplastic anaemia
blast cell proliferation 
(myeloproliferative and 
lymphoprolipherative disorders)
bone marrow depression
disseminated intravascular coagulation 
(DIC)
haemolytic anaemia 
histiocytosis
loss of anticoagulation control 
pancytopenia 
splenic haemorrhage, infarction or 
thrombosis
thrombocytopenia (<30000)
thrombotic thrombocytopenic purpura
Cardiac disorders
angina unstable
atrial flutter
atrioventricular block complete
cardiac arrest
cardiac failure acute
cardiac fibrillation
cardiac tamponade 
cardiogenic shock 
cardiomyopathy acute 
coronary artery spasm
cor pulmonale decompensated
myocardial infarction
torsade de pointes
ventricular fibrillation
ventricular tachycardia
Ear and labyrinth disorders
deafness
vestibular ataxia
Endocrine disorders
adrenocortical insufficiency acute
Eye disorders
cataract/lens opacity
glaucoma
keratitis/corneal opacification
macular degeneration 
optic neuropathy, atrophy 
papilloedema 
ptosis 
retinal artery/vein occlusion 
retinitis 
scotoma
sudden visual loss
uveitis
vitreous detachment
Gastrointestinal disorders
colitis haemorrhagic
gastric ulcer haemorrhage
gastric ulcer perforation
haematemesis
haemoperitoneum
illeus 
intestinal ischaemia 
intestinal perforation 
melaena 
mesenteric occlusion 
mesenteric vein thrombosis
pancreatitis
peritonitis
General disorders and administration site conditions
malignant hyperthermia
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Hepatobiliary disorders
hepatic failure
hepatitis fulminant
hepatic necrosis
hepatorenal syndrome
portal hypertension
Reye's syndrome
Immune system disorders
amyloidosis
anaphylactic reaction
anaphylactic shock
graft versus host disease
Infections and infestations
endotoxic shock
sepsis
toxic shock syndrome
transmission of an infectious agent via 
a medicinal product
Injury, poisoning and procedural complications 
transplant failure
wound dehiscence
Metabolism and nutrition disorders
diabetic coma
failure to thrive 
hypercalcaemia (CTC IV)
hyperkalaemia (CTC IV)
hypocalcaemia (CTC IV)
hypokalaemia (CTC IV)
lactic acidosis
porphyria
shock hypoglycaemic 
tetany
Musculoskeletal and connective tissue disorders
aseptic necrosis bone
fracture pathological 
muscle necrosis 
osteomalacia 
rhabdomyolysis
systemic lupus erythematosus
systemic sclerosis
Nervous system disorders
amnesia
anticholinergic syndrome
aphasia
cerebral oedema
chorea
coma
convulsions
demyelination
encephalitis
encephalopathy 
epilepsy
Guillain-Barré syndrome
hydrocephalus
intracranial haemorrhage
meningitis 
multiple sclerosis
myasthenia gravis
myelitis
neuroleptic malignant syndrome
opisthotonus
paralysis
paresis
Parkinson’s syndrome
serotonin syndrome
stroke
tunnel vision
Pregnancy, puerperium and perinatal conditions
abortion
eclampsia
intra-uterine death
Psychiatric disorders
anorexia nervosa
delirium
drug abuse
drug dependence
homicidal ideation
intentional misuse
self-injurious ideation/attempt
suicidal ideation/attempt
suicide completed
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Renal and urinary disorders
anuria
Goodpasture's syndrome
haemolytic uraemic syndrome
nephritis/nephritic syndrome
nephrotic syndrome
oliguria
renal failure acute
renal tubular necrosis
urinary obstruction/retention
Reproductive system and breast disorders
metrorrhagia/uterine heamorrhage
priapism
Respiratory, thoracic and mediastinal disorders
acute respiratory failure
adult respiratory distress syndrome 
alveolitis allergic
asphyxia
bronchospasm
laryngeal oedema
pulmonary fibrosis
pulmonary haemorrhage
pulmonary infarction
pulmonary vasculitis
respiratory arrest
status asthmaticus
pulmonary oedema
Skin and subcutaneous tissue disorders
angioneurotic oedema
erythema nodosum 
pemphigus
Stevens-Johnson syndrome
toxic epidermal necrolysis
vascular purpura
Vascular disorders
acute circulatory failure 
embolism
malignant hypertension
necrosis ischaemic
thrombosis
CTC = Common Toxicity Criteria also referred to as the Common Terminology Criteria for Adverse Events (CTCAE).  
Source: 
.
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19.2
Visual analog scale
This is an example and the version used may differ.
The subject will evaluate pain intensity by answering the following question:
“My pain right now is”
Pain as bad as it could be
No pain
Pain intensity will be scored such that a score of 0 is equivalent to “no pain” and a score of 100 is 
equivalent to “pain as bad as it could be”.
An electronic version of the VAS will be used in the electronic diary (Part 1) and paper version of 
the VAS will be used in the CRF for the Tapentadol Period (Part 2). The electronic version and the 
paper version of the VAS are both validated.
The subject will be instructed to make a mark on the line to indicate the pain intensity.
For the paper version, the line will be 100 mm in length. A trained observer (an individual under the 
supervision of the principal investigator who observes and instructs subjects regarding trial 
procedures) will measure the distance in millimeters from the bottom of the scale to the subject’s 
mark using a standard ruler. This value will be recorded in the CRF.
DMS version: 
 
ID: 
 
9.0
0631997

Confidential
Protocol KF5503-66
including Amendment 05
Page 131 of 137
DMS version 9.0
27 Jul 2017
19.3
Faces Pain Scale – Revised
DMS version: 
 
ID: 
 
9.0
0631997

Confidential
Protocol KF5503-66
including Amendment 05
Page 135 of 137
DMS version 9.0
27 Jul 2017
19.7
Algorithm to detect potential severe cases of drug-induced liver 
injury
The detection of potential severe cases of drug-induced liver injury will be based on laboratory data 
from the central laboratory.
Check laboratory values at the times specified in the trial protocol for increases of alanine 
transaminase, aspartate transaminase, and total serum bilirubin after administration of IMP.
If alanine transaminase or aspartate transaminase is >3 x upper limit of normal, repeat the lab test 
within 48 hours to 72 hours. The test should be performed for aspartate transaminase, alanine 
transaminase, creatine kinase, total, direct and indirect bilirubin, alkaline phosphate, lipase and 
gamma-glutamyl transferase. 
If alanine transaminase or aspartate transaminase is >3 x upper limit of normal, (confirmed by 
retesting), and total serum bilirubin is <2 x upper limit of normal, the investigator and the sponsor 
should discuss the following recommendations: 
•
Initiate a close observation of the subject/patient. 
•
Repeat testing of alanine transaminase, aspartate transaminase, alkaline phosphate, total, 
direct and indirect bilirubin, creatine kinase, gamma-glutamyltransferase, international 
normalized ratio, eosinophilic granulocytes and lipase 2 times to 3 times weekly. 
•
Decrease the frequency of retesting to once a week or less if abnormalities stabilize or if the 
IMP has been discontinued. 
If alanine transaminase or aspartate transaminase is >3 x upper limit of normal and total serum 
bilirubin is >2 x upper limit of normal, the investigator and the sponsor should discuss following 
recommendations: 
•
Repeat testing of alanine transaminase, aspartate transaminase, alkaline phosphate, total, 
direct and indirect bilirubin, creatine kinase, gamma-glutamyltransferase, international 
normalized ratio, eosinophilic granulocytes and lipase. 
•
Consult a hepatologist/gastroenterologist who must then conduct an obligatory abdominal 
ultrasound and other examinations (e.g., liver biopsy) as necessary. 
•
Obtain more detailed history of symptoms (fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia [>5%]). 
•
Obtain history of concomitant medication, including herbal drugs, alcohol use or other 
drugs of abuse. 
•
Obtain laboratory tests as listed in Table 6.
DMS version: 
 
ID: 
 
9.0
0631997

Confidential
Protocol KF5503-66
including Amendment 05
Page 136 of 137
DMS version 9.0
27 Jul 2017
Table 6:
Laboratory tests to be performed for the evaluation of alternative causes of 
drug-induced liver injury
Cause 
Test/parameter 
Hepatitis A 
Anti-HAV-IgM 
Hepatitis B 
HBsAg and Anti-HBc IgM 
Hepatitis C 
Anti-HCV (if positive, HCV-RNA by PCR) 
Hepatitis D 
HBsAG and Anti-HDV IgM 
Hepatitis E 
Anti-HEV 
Autoimmune hepatitis 
ANA or SMA, elevated IgG-levels, Liver-Kidney-Microsomal Antibodies 
Primary biliary cirrhosis 
Mitochondrial antibody, elevated IgM-levels 
Primary sclerosing cholangitis 
P-ANCA 
Epstein-Barr virus 
Anti-VCA IgG and IgM 
Cytomegalovirus 
Anti-CMV IgM and IgG 
Alcoholic liver disease 
CDT (Carbohydrate-Deficient-Transferrin) 
α1 Antitrypsin disease 
α1 Antitrypsin 
Wilson disease 
Ceruloplasmin 
Hemochromatosis 
Ferritin or optionally genetic testing (e.g., in unclear cases) 
Hepatocellular cancer 
α –fetoprotein
IG = immune globulin; HB = hemoglobin; AG = antigen; RNA = ribonucleic acid; PCR = polymerase chain reaction; 
V = virus; ANA = anti-nuclear antibody; SMA = smooth muscle antibody; VCA = viral capsid antigen.
DMS version: 
 
ID: 
 
9.0
0631997

Confidential
Protocol KF5503-66
including Amendment 05
Page 137 of 137
DMS version 9.0
27 Jul 2017
19.8
Collecting, handling, and shipment of pharmacokinetic serum 
samples
19.8.1
Labeling
The labels of the pharmacokinetic samples will be provided by the central laboratory and include at 
least the following information:
•
Trial Number.
•
Unique Subject Identifier.
•
Accession Number.
•
Visit Number.
19.8.2
Devices
•
S-Monovette® (e.g., 1.2 mL, Sarstedt, Order No.06.1663.001)
•
Cryovials (e.g., 1.5 mL, VWR, Order No. 479-3225)
Other devices may be used if equivalent after approval by the sponsor.
19.8.3
Procedure
•
Fill S-Monovette® with 0.5 mL of blood.
•
Register sample collection date and time in the CRF.
•
Before processing: mix immediately by inverting the S-Monovette gently 1-2 times and 
incubate at room temperature for 20 minutes to 3 hours.
•
Centrifuge at room temperature at 1500 g for 10 minutes. Clot and serum must be well 
separated. If necessary, centrifuge once again.
•
Carefully pipette all the serum into appropriately labeled cryotubes. 
•
Discard collection tube.
•
Freeze cryovial at –15°C or lower until shipment on dry ice.
19.8.4
Shipment
The samples will be sent to the bioanalytical facility according to the schedule stated in the Scope 
of Work with the Central Laboratory. An inventory list must be included with each shipment. The 
inventory list must note each specimen drawn for each subject, and note any missing specimens.
•
For shipment, ensure that the samples are packed with sufficient dry ice to maintain frozen 
state throughout transport.
•
Send the samples by premium courier door-to-door delivery to the bioanalytical laboratory
(the address will be supplied in a separate document). Choice of courier has to be approved 
by the sponsor.
•
Notify sponsor contact by e-mail and the bioanalytical laboratory before shipment of the 
samples.
DMS version: 
 
ID: 
 
9.0
0631997