Clinical trial NCT02081391
Conditions: Acute Pain
Keywords: Acute Pain Post-operative Tapentadol Opioid Treatment Pediatric Participants
Sponsor: Grünenthal GmbH
Start date: 2015-02-19; Completion date: 2019-03-14
Enrollment: 216 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study was to evaluate the efficacy of tapentadol oral solution, based on the total amount of supplemental opioid analgesic used over 12 hours or 24 hours after initiation of investigational medicinal product (IMP) in children and adolescents who had undergone surgery that would produce moderate to severe pain during opioid treatment.

Detailed description:
The supplemental opioid medication reflecting the standard of care was available as patient- or nurse-controlled intravenous (i.v.) morphine or hydromorphone. This supplemental opioid analgesic medication (SOAM) was given to control pain, as needed, in both the treatment and placebo groups.

Children and adolescents 6 months and older were dosed with a dose regimen of 1.25 mg/kg body weight for the first 24 hours of treatment. 24 hours after the start of study medication (and based on clinical judgment), a dose reduction to 1.0 mg/kg was allowed.

Participants 30 days to less than 6 months old were dosed with a regimen of 0.5 mg/kg for the first 24 hours of treatment. The dose of IMP could be reduced after 24 hours to 0.3 mg/kg (if there was a reduced need for analgesia according to the investigator's judgment).

Participants aged from birth to less than 30 days old were dosed with a regimen of 0.1 mg/kg for the first 24 hours of treatment. The dose of the IMP could be reduced after 24 hours to 0.075 mg/kg (if there was a reduced need for analgesia according to the investigator's judgment).

The decision to maintain or alter the dose based on the effectiveness of the analgesia (pain killer) and the adverse event profile observed in each participant over the first 24-hour dosing period was made based on the investigator's judgment.

In exceptional cases, if a participant had unbearable pain despite using nurse-controlled analgesia (NCA) or patient-controlled analgesia (PCA), an additional bolus (defined as a clinician bolus) of morphine or hydromorphone could have been administered. The clinician bolus could have been given either using the NCA/PCA pump system or by an intravenous bolus injection. The opioid given as a clinician bolus or if the NCA/PCA intravenous line failed, had to be the same opioid used in the NCA/PCA pump system.

Dosing with IMP was stopped if:

* A switch to exclusively oral opioid analgesic medication was indicated according to the local standard of care.
* Opioid analgesic medication was no longer needed.
* IMP had been administered for 72 hours.

Safety evaluations included assessment of adverse events, physical examination, vital signs, laboratory parameters, electrocardiogram, oxygen saturation, and, only for children older than 6 years of age, a scale to assess suicidal ideation (Columbia Suicide Severity Rating Scale \[C-SSRS\]). The maximum study duration for each participant was 42 days.

The evaluation of the safety and efficacy data was performed by age groups as aligned with European and United States agencies. Within the tapentadol treatment group, no analysis by tapentadol dose was conducted. Results for participants aged 2 years to \<18 years were provided to the Pediatric Committee of the European Medicines Agency (EU PDCO) before recruitment of the children less than 6-month old required for the US Food and Drug Administration \[FDA\] analysis was completed. Participants from birth to \<2 years old were analyzed separately for the US FDA only and not included in the analysis of the population aged from 2 years to \<18 years.

Arms: arm 1: In the first 24 hours, tapentadol oral solution at a dose of 1.25 mg/kg body weight was given every 4 hours (±15 min) to participants aged 6 months to less than 18 years (maximum individual dose of tapentadol was 100 mg). Participants from 30 days to less than 6 months were dosed with 0.5 mg/kg body weight every 4 hours. Participants from birth to less than 30 days of age were dosed with 0.1 mg/kg body weight every 4 hours.

After 24 hours and up to 72 hours, the dose could be reduced based on the investigator's judgment. arm 2: Matching placebo oral solution was administered every 4 hours (±15 min) up to 72 hours.
Interventions: intervention 1: Tapentadol oral solution 4 mg/mL intervention 2: Tapentadol oral solution 20 mg/mL intervention 3: Placebo
Intervention descriptions: intervention 1: Participants aged 6 months to less than 18 years old with a body weight below 20 kg received tapentadol oral solution 4 mg/mL by mouth every 4 hours for up to 72 hours.

Participants from birth to less than 6 months received tapentadol oral solution, diluted 4 fold. intervention 2: Participants aged from 6 months to less than 18 years with a body weight greater than or equal to 20 kg received tapentadol oral solution 20 mg/mL by mouth every 4 hours for up to 72 hours. intervention 3: Matching placebo oral solution was administered by mouth every 4 hours up to 72 hours.

Protocol documents:
Prot_000.pdf: 
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SDR-PRO-RBC-03
CONFIDENTIAL
No part of this document may be passed on, reproduced or published without written permission of Grünenthal. This information is 
provided to you solely for the purpose of conducting this clinical trial. You may disclose the contents of this protocol to the trial 
personnel under your supervision who are bound by a similar confidentiality obligation and need to know the contents for this 
purpose, and to your appointed independent ethics committee or institutional review board which must be advised of the confidential 
character of the document. The contents of this document may not be disclosed to any other person without written permission from 
the sponsor, unless required by Good Clinical Practice or applicable regulatory requirements. Prompt notice of disclosure in these 
circumstances is required by the sponsor. Any supplemental documentation for the clinical trial is also covered by this provision.
PROTOCOL
Tapentadol (code numbers CG5503 and R331333, respectively) is being developed under a Licensing agreement 
between Ortho-McNeil Pharmaceutical Inc., Janssen Research & Development, L.L.C., and Grünenthal GmbH that was 
executed in February 2003, the United States rights to which were subsequently acquired by Depomed, Inc. in April 
2015. Subsequent to investigational new drug (IND) and new drug application (NDA) acquisition, Depomed Inc. has 
further transferred sponsor regulatory obligations for this trial to Grünenthal.
This trial will be conducted in accordance with United States (U.S.) Food and Drug Administration Investigational New 
Drug regulations (CFR Part 312) and the European Directive 2001/20/EC of the European Parliament and of the council 
of 04 Apr 2001; Directive 2001/83/EC of the European Parliament and of the council of 06 Nov 2001 and Directive 
2005/28/EC of the European Parliament and of the council of 08 Apr 2005.
Trial numbers:
KF5503/65
R331333PAI3037
Title of trial:
An evaluation of the efficacy and safety of tapentadol oral solution in 
the treatment of post-operative acute pain requiring opioid treatment in 
pediatric subjects aged from birth to less than 18 years old.
EudraCT number:
2012-004359-35
IND number:
108134
Sponsor:
Grünenthal GmbH, 52099 Aachen, Germany.
International 
coordinating 
investigator:
Prof Dr 
Division of Clinical Pharmacology, Children’s National Health System, 
111 Michigan Avenue, N.W. Washington, D.C. 20010, United States of 
America. a
Trial sites:
Multi-site trial. A list of sites will be maintained.
Trial design:
This is a Phase III, randomized, multi-site, double-blind, placebo-
controlled, parallel group, multiple oral dose trial of tapentadol oral 
solution.
Investigational 
medicinal products:
Tapentadol oral solution.
Placebo.
a) Contact detail changes during the course of the trial will be documented.
EudraCT = European Union drug regulating authorities clinical trials; IND = investigational new drug.
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Sponsor’s medically 
qualified person:
Dr 
, Senior International Clinical Lead,
Grünenthal GmbH
Phone: +1 (908) 745
 
 a
Sponsor’s signatory:
Dr 
, Senior International Clinical Lead,
Grünenthal GmbH
Collaborator:
Depomed, Inc, Newark, California.
Collaborator’s 
signatories:
Dr 
 Chief Medical Officer & Senior Vice President,
Dr 
, Vice President, Clinical Affairs,
Depomed, Inc, Newark, California
Publication number:
a) Contact detail changes during the course of the trial will be documented.
Version
Date
DMS version:
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Original
16 Sep 2013
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1
PROTOCOL SYNOPSIS
Trial objectives:
This protocol is part of a pediatric development program that fulfills differing requirements of the 
Pediatric Committee of the European Medicines Agency (EU PDCO) and the Food and Drug 
Administration of the United States of America (US FDA). For the EU PDCO, to assess the 
efficacy and safety of tapentadol in the treatment of acute pain, subjects between 2 years and less 
than 18 years old will be evaluated. For the US FDA, subjects between birth and less than 17 years 
old will be evaluated.
The clinical hypothesis of this trial is that tapentadol oral solution reduces the total amount of 
supplemental opioid analgesic medication used over 12 hours (primary objective for US FDA) or 
24 hours (primary objective for EU PDCO) following initiation of investigational medicinal product 
(IMP), compared to placebo, in children and adolescents who have undergone surgery that, in the 
investigator’s opinion, would reliably produce moderate to severe pain requiring opioid treatment.
The primary efficacy objective (either 12 hours or 24 hours) for 1 region is considered as the 
secondary efficacy objective in the other, for the different age range, as described below.
Subjects can be treated for up to 72 hours, and efficacy and safety information will also be collected 
throughout this time period.
Primary objectives:
For EU PDCO: To evaluate the efficacy of tapentadol oral solution, based on the total amount of 
supplemental opioid analgesic medication used over 24 hours following initiation of IMP, in 
children and adolescents aged 2 years to less than 18 years who have undergone surgery that, in the 
investigator’s opinion, would reliably produce moderate to severe pain requiring opioid treatment.
For US FDA: To evaluate the efficacy of tapentadol oral solution, based on the total amount of 
supplemental opioid analgesic medication used over 12 hours following initiation of IMP, in 
children and adolescents aged from birth to less than 17 years who have undergone surgery that, in 
the investigator’s opinion, would reliably produce moderate to severe pain requiring opioid 
treatment.
For both EU PDCO and US FDA: To evaluate the safety of tapentadol oral solution in children and 
adolescents aged 2 years to less than 18 years (EU PDCO) and children and adolescents aged from 
birth to less than 17 years (US FDA) who have undergone surgery that, in the investigator’s 
opinion, would reliably produce moderate to severe pain requiring opioid treatment.
Secondary objectives:
To assess the efficacy of tapentadol oral solution using multiple subjective and objective measures 
of the subject’s response to treatment (see secondary endpoints).
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Definition of endpoints:
All endpoints compare the results in the group of subjects treated with tapentadol oral solution to 
the group treated with placebo. As applicable and appropriate for the individual endpoint, these 
endpoints will be analyzed in the age ranges of 2 years to less than 18 years for the EU PDCO and 
from birth to less than 17 years for the US FDA.
The primary efficacy endpoint for the EU PDCO is considered a secondary efficacy endpoint for 
the US FDA and vice versa.
The primary efficacy endpoints are:
•
EU PDCO: The total amount of supplemental opioid analgesic medication (morphine 
equivalents in mg/kg body weight) used within the first 24 hours after first IMP intake.
•
US FDA: The total amount of supplemental opioid analgesic medication (morphine 
equivalents in mg/kg body weight) used within the first 12 hours after first IMP intake.
The secondary efficacy endpoints are: 
•
The total amount of supplemental opioid analgesic medication (morphine equivalents in 
mg/kg body weight) used within the first 12 hours (EU PDCO) or within the first 24 hours 
(US FDA) after first IMP intake.
•
The total amount of supplemental opioid analgesic medication received, assessed in 
12 hour intervals from 24 hours to 96 hours after the first dose of IMP.
•
Palatability and acceptability of the IMP after the first and last doses of IMP in subjects 
aged 2 years to less than 18 years old (EU PDCO).
•
Changes from baseline in pain intensity over the Treatment Period using age-appropriate 
pain scales (Face, Legs, Activity, Cry, Consolability [FLACC] scale for ages birth to less 
than 6 years or in older children who are not able to report their pain using the other scales, 
Faces Pain Scale–Revised [FPS-R] for ages 6 years to less than 12 years, and visual analog 
scale [VAS] for ages 12 years to less than 18 years). 
•
Clinical Global Impression of Change (CGIC) by investigator/clinician after completion of 
double-blind IMP treatment.
•
Patient Global (overall) Impression of Change (PGIC) by subject/parent/legal guardian 
after completion of double-blind IMP treatment.
•
Time to first and time to second nurse controlled analgesia (NCA)/patient controlled 
analgesia (PCA) after the first dose of IMP.
•
Time from first dose of IMP until IMP treatment discontinuation due to lack of efficacy.
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Safety endpoints:
•
Percentage of subjects with treatment emergent adverse events (TEAEs).
•
Percentages of subjects who develop abnormal:
−
Vital signs.
−
Laboratory parameters.
−
12-lead electrocardiogram (ECG) parameters.
•
Changes from baseline in vital signs parameters.
•
Sedation scores using the University of Michigan Sedation Scale.
•
Changes from baseline in safety laboratory parameters.
•
Changes from baseline in 12-lead ECG parameters.
•
Percentage of subjects discontinuing the trial due to TEAEs and drug-related adverse 
events.
•
Suicidal ideation/behavior in subjects aged 6 years or older using the Columbia Suicide 
Severity Rating Scale (C-SSRS) scores before IMP and at the end of the trial.
Trial design:
This is a Phase III, randomized, multi-site, double-blind, placebo-controlled, parallel group, 
multiple oral dose trial of tapentadol oral solution.
Trial population:
The trial population will comprise male and female subjects aged from birth to less than 18 years 
old who have undergone surgery that, in the investigator’s opinion, would reliably produce 
moderate to severe pain requiring opioid treatment via NCA/PCA. Examples of surgeries suitable 
for this trial include, but are not limited to, spinal fusions, cleft palate repair, Nuss procedures, 
scoliosis repair, nephrectomy, pyeloplasty, and orthopedic procedures such as club foot repair, leg 
lengthening, open reduction and internal fixation of long bone fractures. Subjects must remain 
hospitalized until the End of Treatment Visit.
The trial enrollment will be initiated in a staggered approach, starting with enrollment of an older 
age group until pharmacokinetic data are available in younger age groups from other trials in the 
pediatric clinical development program of tapentadol. Initially, subjects aged 2 years to less than 
18 years will be recruited. Subjects from birth to less than 2 years of age will be recruited after 
pharmacokinetic and safety data are obtained and the dose selection has been defined for younger 
age groups.
The trial population must comply with the inclusion and exclusion criteria given in Section 1.3.
Course of the trial:
By definition, Enrollment Period is synonymous with Screening Period and allocation is 
synonymous with randomization.
The trial consists of an Enrollment Period starting up to 28 days before allocation/randomization to 
IMP and lasting up to the time of allocation/randomization to IMP, whereby subjects may be 
enrolled in the trial either pre- or post-operatively; a Treatment and Evaluation Period (up to 
96 hours); and a Follow-Up Period (10 days to 14 days after the first dose of IMP). A flow diagram 
of the trial is provided in Section 1.1 and a schedule of events in Section 1.2.
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Trial treatments:
The subject will undergo a scheduled surgery. This surgery is not part of the trial, but would be 
performed as per standard of care. Subjects may start enrollment before or after surgery.
At some time after the surgery, the subject must have been started on NCA/PCA with morphine or 
hydromorphone, with or without a background infusion, according to the standard of care. The
background infusion (if any) must be with a low dose infusion of the same opioid as that used for 
the NCA/PCA, i.e., morphine or hydromorphone.
When the subject is able to tolerate liquids, meets the inclusion criteria, and does not meet any 
exclusion criterion, the subject will be allocated/randomized to IMP (tapentadol oral solution or 
placebo) using an interactive voice/web response system (IVRS/IWRS). Doses of IMP will be given 
at intervals explained below.
The first dose of IMP is given when IMP is available on the ward and the investigator determines it 
is medically appropriate for the subject to receive the IMP.
At the time of the first IMP administration, the background opioid infusion (if any) will be 
discontinued.
After the first dose of IMP (see table below), NCA/PCA will be continued with the same opioid as 
used previously (i.e., morphine or hydromorphone, defined as supplemental opioid analgesia),
according to investigator judgment and standard of care. 
Subjects must be carefully observed, especially during the first hour after the initiation of IMP.
Dosing with IMP will be stopped if:
•
A switch to exclusively oral opioid analgesic medication is indicated according to the local 
standard of care.
•
Opioid analgesic medication is no longer needed. 
•
IMP has been administered for 72 hours.
Investigational medicinal products
The 2 IMPs are:
•
Tapentadol 4 mg/mL oral solution and tapentadol 20 mg/mL oral solution.
•
Placebo.
The dosing regimen is as follows:
Age of subject
Dose for the first 
24 hours
Dose after the first
24 hours 
Body 
weight
Tapentadol oral 
solution or placebo
6 months to 18 years old
1.25 mg/kg
1.25 mg/kg or 1.0 mg/kg
20 kg
4 mg/mL
20 kg
20 mg/mL
30 days to 6 months old
0.5 mg/kg
0.5 mg/kg or 0.3 mg/kg
-
4 mg/mL
Birth to <30 days old
0.1 mg/kg
0.1 mg/kg or 0.075 mg/kg
-
4 mg/mL
Each dose of tapentadol oral solution (or equivalent for placebo) will not exceed 100 mg (i.e., 
subjects weighing 80 kg or more will receive a maximum dose of 100 mg [5 mL of the 20 mg/mL 
solution]).
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The IMP will be administered as an oral solution. The dosing interval is 4 hours (range 
±15 minutes). The reason for any delay in dosing beyond 4 hours 15 minutes needs to be 
documented. If the subject is sleeping at the time of the scheduled dose, they must be woken to take 
the IMP within a maximum of 6 hours after the previous dose. The dose of IMP must be taken as 
soon as possible after the subject is awake.
The administration of IMP is based on the investigator’s judgment of the subject’s condition and 
sedation level.
Dose reduction after 24 hours
The dose of IMP may be reduced after 24 hours if there is a reduced need for analgesia according to 
the investigator’s judgment, as follows:
•
Age 6 months or more: 1.0 mg/kg.
•
Age 30 days to less than 6 months: 0.3 mg/kg.
•
Age birth to less than 30 days old: 0.075 mg/kg.
Stratification
Allocation/randomization to IMP will be stratified by 7 age groups (birth to <30 days, 30 days to 
<6 months, 6 months to <2 years, 2 years to <6 years, 6 years to <12 years, 12 years to <17 years, 
17 years to <18 years) and by use of morphine or hydromorphone as supplemental opioid analgesia.
Concomitant medications/therapies:
Allowed prior and concomitant medications
Unless explicitly prohibited, all prior and concomitant medications are allowed.
Benzodiazepines may be used to treat muscle spasms or anxiety, consistent with local standard of 
care. They should be used with caution as they may potentiate central nervous system depression
that may occur with tapentadol or other opioids.
Medications for the treatment of adverse events are allowed according to the investigator’s 
judgment and post-operative standard of care. For example, clinically relevant respiratory 
depression may be treated with naloxone, and nausea/vomiting can be treated with antiemetics, 
which may also be given prophylactically according to the standard of care.
If the NCA/PCA intravenous line fails for any reason, it should be restarted/repaired immediately. 
During the interim, morphine or hydromorphone may be administered intravenously.
In exceptional cases, if a subject has unbearable pain despite using NCA/PCA, an additional bolus 
(defined as a clinician bolus) of morphine or hydromorphone may be administered. The clinician 
bolus can be given either using the NCA/PCA pump system or by an intravenous bolus injection.
The opioid given as a clinician bolus or if the NCA/PCA intravenous line fails must be the same as 
that used in the NCA/PCA pump system.
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Prohibited medication from 14 days before allocation/randomization to IMP until 24 hours after 
the last administration of IMP
•
Monoamine oxidase inhibitors.
•
Strong enzyme inducing drugs (e.g., rifampicin, phenobarbital, St John’s Wort [hypericum 
perforatum]).
•
Neuroleptics, anticonvulsants (except for gabapentin used in association with surgery), 
antiparkinsonian drugs, and all serotonergic drugs including selective 
serotonin/norepinephrine reuptake inhibitors, tricyclic antidepressants, linezolid, triptans, 
and St. John’s Wort (hypericum perforatum).
•
Methadone.
Prohibited medication from 6 hours before allocation/randomization to IMP until 4 hours after the 
last administration of IMP
•
Long-acting opioids.
•
Medication used for sedation (as noted above, benzodiazepines may be used to treat muscle 
spasms or anxiety).
•
Peri- or post-operative analgesia supplied by a continuous regional technique (e.g., nerve 
block, wound infiltration catheter) or subject controlled epidural analgesia.
Prohibited medication/therapy from time of allocation/randomization to IMP until 4 hours after the 
last administration of IMP
•
Opioids (other than protocol defined morphine, hydromorphone, or IMP).
•
Continuous positive airway pressure or mechanical ventilation.
Restrictions for the mother of a newborn or breastfeeding mother
•
For monoamine oxidase inhibitors, neuroleptics, anticonvulsants, antiparkinsonian drugs, 
methadone, and all serotonergic drugs including selective serotonin/norepinephrine 
reuptake inhibitors, tricyclic antidepressants, linezolid, and triptans:
−
Prepartum intake by a mother of a newborn subject is prohibited in the 14 days prior to 
the subject’s allocation/randomization to IMP.
−
The intake of these medications by the breastfeeding mother of a subject is prohibited 
from 14 days prior to the subject’s allocation/randomization to IMP until the end of 
treatment with the IMP.
•
For opioid medication (including tapentadol formulations) and medication used for 
sedation:
−
The intake of opioid medication (including tapentadol formulations) and medication 
used for sedation by the breastfeeding mother of a subject is prohibited from 48 hours 
prior to the subject’s allocation/randomization to IMP until the end of treatment with 
the IMP. 
−
The intake of opioid medication (including tapentadol formulations) and medication 
used for sedation taken prepartum by the mother of a newborn subject is prohibited 
from 48 hours prior to the subject’s allocation/randomization to IMP.
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Trial duration:
Each subject is expected to be in the trial for up to about 42 days (up to 28 days for enrollment, and 
a treatment and follow-up period of up to 14 days).
Dosing of IMP will be for up to 72 hours.
Sample size rationale:
The sample size determination was based on the primary efficacy endpoint variable for the 
respective Full Analysis Sets. A linear relationship is assumed between the 12 hour and 24 hour 
supplemental opioid analgesic use for the purposes of the sample size calculation and the final 
analyses.
The sample size calculation was based on results from previously conducted trials in post-surgical 
pediatric subjects where supplemental opioid was measured. A value of 0.20 mg/kg in 24 hours 
(0.10 mg/kg in 12 hours) for the between-treatment group difference and a more conservative value 
of 0.42 mg/kg in 24 hours (0.21 mg/kg in 12 hours) for the standard deviation were considered 
adequate assumptions. Assuming α = 0.05 (two-sided), 80% power (β = 0.2), and a randomization 
ratio of 2:1 (tapentadol to placebo) results in a sample size of 106 tapentadol-treated subjects and 
53 placebo-treated subjects. 
Due to the overlapping age groups as per regulatory requirements, it is expected that approximately 
168 subjects will be treated with IMP in this trial.
Completion of trial enrollment
The trial enrollment for the EU PDCO set (see Section 14.2.1 for the definition of the analysis 
populations) will complete when the following criterion is met:
•
At least 159 treated subjects in the age range 2 years to less than 18 years of age (EU 
PDCO).
The trial enrollment for the US FDA set will complete when the following 2 criteria are met:
•
At least 159 treated subjects in the age range birth to less than 17 years of age (US FDA).
•
100 subjects in the age range birth to less than 17 years of age on tapentadol for at least 
2 doses (US FDA). Based on estimates from adult trials in acute pain, it is assumed that 
approximately 5% of subjects (approximately 8 subjects) may discontinue prior to 
receiving 2 doses of IMP, which is covered by the targeted sample size.
An additional objective of the study is to meet a US FDA request to evaluate at least 25 subjects in 
the age range birth to less than 17 years of age who have been exposed to tapentadol for at least 
48 hours. As medically appropriate, every effort will be made to enroll subjects in this trial to meet 
this objective.
Reporting
Two reports will be prepared for the trial. The first report will be prepared after the date of the last 
contact with the last subject according to the protocol for the EU PDCO set (last subject out - EU 
PDCO). The second report will be prepared after the date of the last contact with the last subject 
according to the protocol for the US FDA set (last subject out - US FDA).
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Blood sampling:
The total blood volume drawn per subject will not exceed approximately 15 mL for subjects aged 
2 years and older or 2.4 mL/kg for subjects aged less than 2 years during the trial (even when
additional blood is drawn for a pharmacokinetic analysis if a serious adverse event occurs).
Key data collected:
Demographic data, background data, and other subject characteristics:
•
Date of signing the informed consent/assent form, sex, age at time of 
allocation/randomization (years for subjects aged 2 years and older, months for subjects 
aged 2 months [i.e., 60 days] to less than 2 years, and days for subjects aged less than 
2 months [i.e., less than 60 days] – the day of birth is counted as day 1), race/ethnicity, 
height, and weight. The body mass index (BMI) will be calculated automatically.
•
Prior and concomitant medications and therapies, excluding anesthetics and medication 
used during the surgery.
•
The trade name, date, time, dose, and route of administration of opioid and non-opioid 
analgesic medication given post-operatively for pain before the first IMP dose. The detailed 
recording of these medications is limited to after surgery, for a period of (maximum) 
24 hours before the first IMP dose. 
•
Clinically relevant medical and surgical history.
•
The indication, the type of surgical procedure, the date of surgery, the start time and 
completion time of surgery.
•
Pain intensity scores (FLACC in subjects from birth to less than 6 years or in older children 
who are not able to report their pain using the other scales, FPS-R in subjects aged 6 years 
to less than 12 years old, and VAS in subjects aged 12 years to less than 18 years old) 
before each NCA/PCA activation, whenever possible, after the first dose of IMP.
Safety:
•
Adverse events.
•
Safety laboratory.
•
Pregnancy test for female subjects aged 12 years or older, or post-menarchal, or sexually 
active.
•
12-lead ECG.
•
Vital signs (respiratory rate, systolic and diastolic blood pressure, and pulse rate).
•
Reporting of clinically relevant values arising from continuous monitoring of respiratory 
rate and heart rate as adverse events.
•
Oxygen saturation (by pulse oximetry), including values below 92% for at least 60 seconds.
•
Physical examination.
•
C-SSRS score in subjects aged 6 years or older.
•
University of Michigan Sedation Scale score.
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Efficacy: 
•
Dose and time of administration of IMP.
•
Trade name, dose, and time of each administration of NCA/PCA supplemental opioid 
analgesia from first dose of IMP up to the End of Treatment Visit.
•
Trade name, dose, and time of each administration of intravenous morphine or 
hydromorphone given if the NCA/PCA line fails, or a clinician bolus is given.
•
Global impression of change using CGIC (by investigator/clinician) and PGIC (completed 
by the subject or parent/legal guardian).
•
Acceptability and palatability of IMP in subjects aged 2 years to less than 18 years old.
•
Pain intensity scores before and after first dose of IMP, before each subsequent dose of 
IMP, and at the End of Treatment Visit (FLACC in subjects from birth to less than 6 years 
or in older children who are not able to report their pain using the other scales, FPS-R in 
subjects aged 6 years to less than 12 years old, and VAS in subjects aged 12 years to less 
than 18 years old).
•
The trade name, date, time, dose, dose unit, formulation, and route of administration of 
non-opioid analgesic medication. The detailed recording of these medications is limited to 
after surgery (starting up to 24 hours before first IMP dose) up to End of Treatment Visit.
•
Time from the first dose of IMP to treatment discontinuation due to lack of efficacy.
Statistical methods:
The primary efficacy analysis will be based on the respective Full Analysis Set. The primary null 
hypothesis to be tested for the trial is that the tapentadol group is not different from the placebo 
group for the primary efficacy endpoint. The alternative hypothesis is that the tapentadol group is 
different from the placebo group for the primary efficacy endpoint. For the primary efficacy 
endpoint, descriptive statistics will be presented by treatment group and the endpoint will be
analyzed using an analysis of variance model (ANOVA), which includes treatment, baseline age 
group, and the supplemental opioid analgesic used (morphine versus hydromorphone) as factors. 
Treatment effects will be estimated based on least-squares means of the difference. The 95% 
confidence intervals and p-value will be presented for tapentadol compared with placebo. The test 
for the primary efficacy analysis will be 2-sided at a 0.05 level of significance. Summary statistics 
for the primary efficacy endpoint will be provided by age group (birth to <30 days, 30 days to 
<6 months, 6 months to <2 years, 2 years to <6 years, 6 years to <12 years, 12 years to <17 years, 
and 17 years to <18 years, as applicable for the EU PDCO set and US FDA set) and by method of 
supplemental opioid administration (NCA vs. PCA) among other subgroup analyses.
Each secondary endpoint will be analyzed using appropriate statistical methods. There will be no 
multiplicity adjustments for any of the secondary endpoints.
Adverse events will be coded using the most current version of the Medical Dictionary for 
Regulatory Activities (MedDRA) used by the sponsor. For each adverse event, the percentage of 
subjects who experienced at least 1 occurrence of the given event will be summarized by treatment 
group. The incidence, type, intensity, onset, relationship, treatment, and outcome of TEAEs will be 
listed and presented descriptively according to treatment group. Serious adverse events will be 
listed.
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Descriptive statistics, changes from baseline, frequency tabulations of abnormalities and subject 
listings will be provided for summarizing safety laboratory parameters (only for blood samples 
analyzed at the central laboratory), 12-lead ECG, vital signs, and oxygen saturation across treatment 
group. Descriptive statistics will be provided for the sedation scores.
Changes in physical examination findings compared to Visit 1 will be summarized by body system
and results will be listed. The C-SSRS results will be listed.
1.1
Flow diagram summary of the trial
NCA = Nurse controlled analgesia; PCA = Patient controlled analgesia; IMP = Investigational medicinal product.
Figure 1:
Immediate post-operative timeline
Background infusion (if any) 
according to standard of care
NCA/PCA with morphine or hydromorphone
Verify subject 
eligibility.
Complete 
enrollment.
Allocation/
randomization to IMP
Per investigator judgment:

Start IMP dosing (tapentadol 
oral solution or placebo).

Continue NCA/PCA without 
background infusion (if any).
IMP (tapentadol oral solution or placebo)
Careful safety monitoring of the subject
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1.2
Schedule of events
Period:
Visit:
Enrollment
Treatment and evaluation
Follow
-up
1
2
3 a
4 b
Time:
28 days before 
allocation/
randomization
First dose
Day 1
Subsequent 
doses
End of 
Treat-
ment
Day 10 
to 
Day 14
Before
After
Before
After
Any 
time
After 
surgery
Obtain informed consent/assent c
X
Record date of signing the informed 
consent/assent form, sex, race/ethnicity, 
and height.
X e
Record weight after surgery (can be 
measured before surgery if the surgery is 
not expected to notably change the 
weight) d
X
Record age at time of 
allocation/randomization z
X
Record clinically relevant medical/surgical 
history
X e
Record details about the surgery
X f
Perform a physical examination
X e
X g
Record intake of prior/concomitant 
medication and therapies, as appropriate h
X
X
<------------------------------------>
X
Detailed recording of analgesics i
X
X
X
X
Record C-SSRS j
X
X
Continuous heart- and respiratory-rate 
recording for 24 hours after first IMP k
          <---------------------------->
Record vital signs l
X m
X n
X n
X
Record sedation score
X n
X n
Continuous oxygen saturation 
measurement until 4 hours after the last 
administration of IMP o
         <------------------------------->
Record oxygen saturation
X m
X n
X n
X
Record 12-lead electrocardiogram
X
X
Take blood for safety laboratory
X p
X
Perform a pregnancy test
X q
Check inclusion/exclusion criteria
X
Allocate subject to IMP
X
Stop background infusion (if any) of 
opioids at time of first IMP dose
X
Detailed recording of NCA/PCA and 
background infusion (if any) r
X
<---------------------------------->
no background infusion
Administer IMP (record time and dose) s
X
X
Record pain intensity u
X n
X v
X n
X
Record pain intensity before each 
NCA/PCA activation u, t
<---------------------------------->
Record palatability and acceptability w
X
X
Global impression of change x
X
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Period:
Visit:
Enrollment
Treatment and evaluation
Follow
-up
1
2
3 a
4 b
Time:
28 days before 
allocation/
randomization
First dose
Day 1
Subsequent 
doses
End of 
Treat-
ment
Day 10 
to 
Day 14
Before
After
Before
After
Perform and document drug accountability
X
Assess and record adverse events y
<-------------------------------------------------------------------------->
Assess discontinuation criteria (Table 1)
X
X
X
Dispense subject trial card
X
Day 1 is defined as the day of first administration of IMP. Trade names should be given in preference to generic names 
when recording medication in the CRF. The generic name may be used if the trade name is not available.
a) To be performed between 4 hours and 24 hours after the last administration of IMP, or if the subject is prematurely 
discontinued from the trial. The visit must be performed before discharge from hospital.
b) Can be performed by phone.
c) Subjects from whom assent is requested after surgery will be asked to give assent when they are properly stable and 
able to give assent according to the investigator’s judgment.
d) The body mass index will be calculated automatically.
e) May be extracted from the hospital charts if already available according to the standard of care.
f) Includes the date of surgery, the indication, type of surgical procedure, start time and completion time of surgery.
g) Record that a full examination has been performed and record changes to Visit 1 only.
h) Record all medications, including opioid and non-opioid analgesics but excluding anesthetics and medication used 
during the surgery (Section 12.1.2). This includes the recording of prohibited medication used by breastfeeding mothers
and prohibited prior medication used by mothers of a newborn subject.
i) Recording of detailed information is limited to after surgery (starting up to 24 hours before first IMP dose) up to the 
End of Treatment Visit (Section 12.1.2.2).
j) In subjects aged 6 years or older. The administration of the C-SSRS “children’s baseline” must be performed after 
surgery. A refusal to answer the questions in the questionnaire that are appropriate for the subject must be recorded with 
the reason. The initials of the interviewer are to be recorded. The C-SSRS will only be used at a trial site if its use has 
not been rejected by the responsible ethics committee.
k) Record clinically relevant values as adverse events.
l) Respiratory rate, systolic and diastolic blood pressure, and pulse rate.
m) Directly before allocation/randomization to IMP.
n) Directly before IMP (i.e., within 10 minutes).
o) Using pulse oximetry. Record values below 92% for at least 60 seconds (excluding technical failures or artifacts).
p) When the subject is considered clinically stable after surgery. The values of the local laboratory will be used for 
verification of exclusion criteria.
q) For female subjects if aged 12 years or older, or post-menarchal, or sexually active. Within 48 hours prior to
allocation/randomization to IMP.
r) Recording of detailed information is limited to after surgery (starting up to 24 hours before first IMP dose) up to the 
End of Treatment Visit (Section 12.1.2.1). NCA/PCA is with morphine or hydromorphone in accordance with the 
standard of care at the site. Detailed information on use will be recorded at times consistent with the memory of the 
NCA/PCA pump. Details will be recorded of dosing of intravenous morphine or hydromorphone used if the NCA/PCA 
fails, or a clinician bolus is given.
s) IMP will be administered as an oral solution. The dosing interval is 4 hours (range ±15 minutes). The reason for any 
delay in dosing beyond 4 hours 15 minutes needs to be documented. If the subject is sleeping at the time of the 
scheduled dose they must be woken to take the IMP within a maximum of 6 hours after the previous dose. The dose of 
IMP must be taken as soon as possible after the subject is awake. After 24 hours, the investigator may decrease the dose 
of IMP to 1.0 mg/kg according to the investigator’s judgment of the subject’s reduced need for analgesia.
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t) Pain intensity scores should be obtained before each NCA/PCA activation, whenever possible. However, the 
NCA/PCA activation should not be unduly delayed by the pain intensity assessment. Pain intensity scores should also 
be obtained if intravenous morphine or hydromorphone is given if the NCA/PCA line fails, or if a clinician bolus is 
given.
u) The different pain scales are recorded in different age ranges: FLACC – birth to less than 6 years or in older children 
who are not able to report their pain using the other scales; FPS-R – 6 years to less than 12 years old; VAS – 12 years to 
less than 18 years old.
v) Between 30 minutes and 60 minutes after IMP. Subjects do not need to be woken for this assessment.
w) In subjects aged 2 years to less than 18 years old.
x) Clinical Global Impression of Change completed by investigator/clinician, and Patient Global (overall) Impression of 
Change by subject if capable of completing the questionnaire (or parent/legal guardian).
y) Adverse events are to be recorded from the time after signing the informed consent form/assent form. Adverse events 
are to be recorded and assessed at the time when they occur. A blood sample for analysis of serum concentrations of 
tapentadol needs to be drawn if there is a serious adverse event.
z) Years for subjects aged 2 years and older, months for subjects aged 2 months (i.e., 60 days) to less than 2 years, and 
days for subjects aged less than 2 months (i.e., less than 60 days).
CRF = case report form; C-SSRS = Columbia-Suicide Severity Rating Scale; FPS-R = Faces Pain Scale–Revised; 
FLACC = Face, Legs, Activity, Cry, and Consolability (scale); IMP = investigational medicinal product (tapentadol 
oral solution or placebo); NCA = Nurse controlled analgesia; PCA = Patient controlled analgesia; VAS = visual analog 
scale. 
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1.3
Inclusion/exclusion criteria
1.3.1
Inclusion criteria
Subjects are eligible for the trial if all the following apply:
Inclusion criteria
Rationale for criterion
1.
Informed consent, and if applicable assent, given according to local regulations.
Legal and ethical 
requirement.
2.
Male or female subject aged from birth (37 weeks gestational age) to less than 
18 years.
Standardization of the trial 
population.
Safety.
3.
A female subject must be pre-menarchal, or surgically incapable of childbearing, 
or sexually abstinent, or if a female subject is sexually active, then she must be
practicing an effective method of birth control (e.g., prescription hormonal 
contraceptives, intra-uterine devices used according to the product’s instruction, 
double-barrier methods) before trial entry and throughout the trial.
Safety.
4.
A female subject must have a negative pregnancy test if aged 12 years or older, 
or is post-menarchal, or is sexually active.
Safety.
5.
Subject has undergone surgery (other than brain surgery or gastrointestinal
surgery expected to affect the absorption of tapentadol [in the investigator’s 
judgment]) that, in the investigator’s opinion, would reliably produce moderate to 
severe pain requiring opioid treatment for at least 24 hours after first dose of 
IMP. Subjects must remain hospitalized until the End of Treatment Visit.
Standardization of the trial 
population.
6.
Subject has received post-operative morphine or hydromorphone by NCA/PCA, 
with or without a background infusion of the same opioid, according to standard 
of care prior to allocation/randomization to IMP and subject is expected to 
require this morphine or hydromorphone by NCA/PCA after starting IMP.
Standardization of the trial 
population.
7.
Subject is able to tolerate liquids at the time of allocation/randomization to IMP.
Standardization of the trial 
population.
Note: Subjects will only receive IMP if documentation is available showing that they comply with these inclusion 
criteria. 
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1.3.2
Exclusion criteria
Subjects are not eligible for the trial if any of the following applies:
Exclusion criteria 
Rationale for criterion
1.
Subject, parent or the legal representative is an employee of the investigator or 
trial site, with direct involvement in the proposed trial or other trials under the 
direction of that investigator or trial site, or family member of the employees or 
the investigator.
Good clinical practice (GCP).
2.
Subject has been previously exposed to tapentadol.
Ethics and interference with 
trial assessments.
3.
Subject has received an experimental drug or used an experimental medical 
device within 28 days before allocation/randomization to IMP, or within a period 
less than 10 times the drug’s half-life, whichever is longer. 
Safety.
4.
Subject has a history or current condition of any one of the following:
•
Non-febrile seizure disorder.
•
Epilepsy.
•
Serotonin syndrome.
•
Traumatic or hypoxic brain injury, brain contusion, stroke, transient 
ischemic attack, intracranial hematoma, post-traumatic amnesia, brain 
neoplasm, or episode(s) of unconsciousness of more than 24 hours.
Safety and interference with 
trial assessments.
5.
Subject has a 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).
Safety and interference with 
trial assessments.
6.
Subject has a concomitant disease or disorder (e.g., endocrine, metabolic, 
neurological, psychiatric, infection, febrile seizure, paralytic ileus) that in the 
opinion of the investigator may affect or compromise subject safety during the 
trial participation.
Safety.
7.
Subject has history of suicidal ideation or behavior.
Safety.
8.
Subject is obese in the investigator’s judgment. Obesity can be determined based 
on appropriate BMI charts or tables; e.g., a BMI above the 97th percentile for 
children based on the World Health Organization growth charts (see 
Section 19.9).
or
Subject weight is less than 2500 gm.
Standardization of the trial 
population.
9.
Subject has a clinically relevant history of hypersensitivity, allergy, or 
contraindication to the supplemental opioid analgesic medication or tapentadol, 
or the excipients (see the investigator’s brochure), or naloxone.
Safety.
10. 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.
Ethics and interference with 
trial assessments. 
11. Subject has a history of alcohol and/or substance abuse in the investigator’s 
judgment based on subject’s history and physical examination.
Safety.
12. Subject is taking prohibited concomitant medication. For details, see the synopsis 
section Concomitant medications/therapies.
Standardization of the trial 
population and safety.
13. Subject has received a long-acting opioid for the treatment of pain following 
surgery within 6 hours of allocation/randomization to IMP.
Interference with trial 
assessments.
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Exclusion criteria 
Rationale for criterion
14. Subject has clinically relevant (in the investigator’s judgment) abnormal values 
for clinical chemistry or hematology (local laboratory sample taken after 
surgery). 
A subject aged 6 months to less than 18 years old is excluded if the:
•
Aspartate transaminase or alanine transaminase is >3-times upper limit of 
normal.
•
Total bilirubin is >2-times upper limit of normal (except if the cause is due 
to Gilbert’s syndrome).
•
Glomerular filtration rate <60 mL/min (calculated according to Schwartz et 
al. 1984).
A subject aged from birth to less than 6 months old is excluded if::
•
Aspartate transaminase or alanine transaminase is >3-times upper limit of 
normal.
•
There is pathological jaundice in the opinion of the investigator.
•
Glomerular filtration rate (calculated according to Schwartz et al. 1984) is:
−
<20 mL/min/1.73 m2 for subjects <1 week post-partum.
−
<30 mL/min/1.73 m2 for subjects 1 week to 8 weeks post-partum.
−
<50 mL/min/1.73 m2 for subjects >8 weeks post-partum to <6 months 
old.
Safety.
15. Subject has:
•
Clinically relevant abnormal ECG.
•
Signs of pre-excitation syndrome.
•
Brugada’s syndrome.
•
QT or QTc interval >470 ms for children aged 6 years to less than 18 years 
old.
•
QT or QTc interval >460 ms for children aged from birth to less than 6 years 
old.
Safety.
16. Peri- or post-operative analgesia supplied by a continuous regional technique 
(e.g., nerve block, wound infiltration catheter) or subject controlled epidural 
analgesia that was terminated less than 6 hours before allocation/randomization
to IMP.
Standardization of the trial 
population.
17. Subject has post-operative clinically unstable systolic and diastolic blood 
pressure, heart rate, respiratory depression, or clinically unstable upper or lower 
airway conditions (in the investigator’s judgment), or a saturation of peripheral 
oxygen (SpO2) <92% at the time of randomization (allocation/randomization to 
IMP).
Safety.
18. Female subject is breastfeeding a child.
Safety.
19. Subject requires continuous positive airway pressure or mechanical ventilation, at 
the time of allocation to IMP.
Safety.
20. The mother of a newborn subject or the breastfeeding mother of a subject was 
administered a prohibited medication (see Restrictions for the mother of a 
newborn or breastfeeding mother).
Standardization of trial 
population.
Note: Subjects will only receive IMP if documentation is available showing that they do not meet any of these exclusion 
criteria.
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2
TABLE OF CONTENTS
1
PROTOCOL SYNOPSIS
3
1.1
Flow diagram summary of the trial
12
1.2
Schedule of events
13
1.3
Inclusion/exclusion criteria
16
1.3.1
Inclusion criteria
16
1.3.2
Exclusion criteria
17
2
TABLE OF CONTENTS
19
3
ABBREVIATIONS AND DEFINITION OF TERMS
25
4
ETHICS
27
4.1
Independent ethics committee(s) or institutional review board(s)
27
4.2
Subject information and informed consent
27
4.3
Informing the subject’s healthcare provider
28
5
INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE
28
5.1
Investigators and trial site personnel
28
5.1.1
Investigators
28
5.1.2
Trial site personnel assigned trial-related duties
28
5.2
Contract research organizations
29
5.3
The sponsor and sponsor’s personnel
29
5.4
Data monitoring committee
29
6
INTRODUCTION AND TRIAL BACKGROUND
29
6.1
Background to the investigational medicinal product
29
6.2
Relevant non-clinical and clinical data
30
7
TRIAL OBJECTIVES
34
8
TRIAL DESIGN
35
8.1
Definition of endpoints
35
8.2
Trial rationale
36
8.3
Special agreements with regulatory authorities
37
8.4
Discussion of the trial design
37
8.5
Benefit/risk analysis
39
9
SUBJECT ENROLLMENT AND TRIAL DISCONTINUATION
41
9.1
Subject enrollment procedure
41
9.2
Inclusion/exclusion criteria
42
9.2.1
Inclusion criteria
42
9.2.2
Exclusion criteria
43
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9.3
Trial discontinuation or discontinuation of a subject from investigational 
medicinal product
45
9.3.1
Reasons for discontinuation of a subject
45
9.3.2
Procedure for the handling of prematurely discontinued subjects
46
9.3.3
Premature termination or suspension of the trial
46
10
TREATMENTS
47
10.1
Investigational medicinal product
47
10.1.1
Identity and composition – tapentadol oral solution (test)
47
10.1.2
Identity and composition – placebo (comparator)
47
10.1.3
Preparation
48
10.1.4
Packaging and labeling
48
10.1.5
Delivery, storage and disposal
48
10.1.6
Special requirements
48
10.2
Administration of trial treatments
48
10.2.1
Dose
48
10.2.2
Total dosing time and dosing interval
49
10.2.3
Administration
49
10.3
Method of assigning subjects to treatment groups 
(allocation/randomization)
50
10.4
Blinding and unblinding
50
10.4.1
Methods of blinding
50
10.4.2
Methods of unblinding
50
10.4.3
Identification of investigational medicinal products
51
10.5
Other medication
51
10.5.1
Supplemental opioid analgesic medication
51
10.6
Allowed and prohibited prior/concomitant medications
52
10.6.1
Prior medications
52
10.6.2
Concomitant medications
52
10.6.3
Allowed prior and concomitant medications
52
10.6.4
Prohibited prior and concomitant medications/therapy
53
10.7
Documentation of drug accountability
54
11
TRIAL PROCEDURES
54
11.1
Course of the trial
54
11.1.1
Enrollment Period (Visit 1)
54
11.1.2
Treatment and Evaluation Period (Visit 2 and Visit 3)
56
11.1.3
Follow-up Visit (Visit 4; Day 10 to Day 14)
60
11.2
Examination hierarchy and time windows
60
11.3
Conditions during the trial
60
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11.3.1
Medical care
60
11.3.2
General restrictions
60
11.3.3
Counseling of female subjects of childbearing potential
61
11.4
Subject trial cards
61
11.5
Provisions of any additional care of subject after trial termination
61
11.6
Handling of low enrollment
61
11.7
Overview of blood sampling in this trial
61
12
DATA COLLECTION
62
12.1
Collection of subject characteristics data
62
12.1.1
Demographic data
62
12.1.2
Prior and concomitant medications
63
12.1.3
Prior and concomitant therapies
63
12.1.4
Medical and surgical history
63
12.1.5
Surgery
63
12.1.6
Other data
64
12.2
Collection of efficacy data
64
12.2.1
Amount of supplemental opioid used
64
12.2.2
Amount of non-opioid analgesic medication used
64
12.2.3
Global impression of change
64
12.2.4
Palatability and acceptability of IMP
64
12.2.5
Pain intensity
65
12.3
Collection of safety data
66
12.3.1
Adverse events
66
12.3.2
Safety laboratory
71
12.3.3
Pregnancy test
73
12.3.4
Twelve-lead electrocardiogram
73
12.3.5
Vital signs (respiratory rate, systolic and diastolic blood pressure, and 
heart rate) and oxygen saturation
73
12.3.6
Continuous monitoring of respiratory rate and heart rate
73
12.3.7
Continuous monitoring of oxygen saturation
74
12.3.8
Physical examination
74
12.3.9
Columbia–suicide severity rating scale
74
12.3.10
University of Michigan Sedation Scale
74
12.4
Appropriateness of measurements
74
12.5
Compliance
75
13
DOCUMENTATION OF TRIAL DATA
75
13.1
Case report forms
75
13.2
Subject reported outcomes
76
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13.3
Data management
76
13.4
Source data
77
13.5
Investigator’s site file and the trial master file
77
14
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION
78
14.1
Sample size rationale
78
14.2
Analysis of the trial – statistical analysis
80
14.2.1
Analysis populations (analysis sets)
80
14.2.2
General descriptive and graphical methods
80
14.2.3
Analysis of subject characteristics data
81
14.2.4
Analysis of subject disposition
81
14.2.5
Analysis of efficacy data
81
14.2.6
Analysis of safety data
83
14.2.7
Interim analysis
84
14.2.8
Data monitoring committee
84
15
QUALITY SYSTEM, AUDIT AND INSPECTION
85
15.1
Quality system
85
15.2
Data quality assurance
85
15.2.1
Clinical research organization/investigator selection
85
15.2.2
Trial site monitoring
85
15.2.3
Audits
85
15.3
Inspections
85
16
GENERAL CONDITIONS AND AGREEMENTS
86
16.1
Insurance
86
16.2
Legal regulations
86
16.3
Contracts
86
16.4
Subject data and data protection
86
16.5
Publication policy
87
16.6
Final report
87
16.7
Approval
87
16.7.1
Sponsor
87
16.7.2
Coordinating investigator
87
17
REFERENCES
88
18
PROTOCOL AMENDMENTS
90
18.1
Protocol Amendment 01
90
18.2
Protocol Amendment 02
90
18.3
Protocol Amendment 03
119
18.4
Protocol Amendment 04
127
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18.5
Protocol Amendment 05
136
18.6
Protocol Amendment 06
143
18.7
Protocol Amendment 07
150
19
APPENDIX
157
19.1
List of medical concepts for consideration of seriousness stratified by 
system organ class
157
19.2
Face, Legs, Activity, Cry, Consolability scale
160
19.3
Faces pain scale – Revised
161
19.4
Visual analog scale
162
19.5
Columbia–Suicide Severity Rating Scale
163
19.5.1
Columbia–Suicide Severity Rating Scale – children’s baseline
163
19.5.2
Columbia–Suicide Severity Rating Scale – children’s since last visit
166
19.6
Palatability and acceptability questionnaire
169
19.7
Algorithm to detect potential severe cases of drug-induced liver injury
170
19.8
Global impression of change
172
19.9
World Health Organization body mass index growth charts
173
19.10
Collecting, handling and shipment of pharmacokinetic serum samples
177
19.10.1
Labeling
177
19.10.2
Devices
177
19.10.3
Procedure
177
19.10.4
Shipment
177
19.10.5
Contact
178
19.11
University of Michigan Sedation Scale
178
LIST OF TABLES
Table 1:
Reasons for compulsory and optional discontinuation of subjects from 
trial participation (discontinuation criteria)
45
Table 2:
Determination of tapentadol dose and oral solution concentration
49
Table 3:
Approximate volume of blood to be collected from each subject
62
Table 4:
Differences in amount of supplemental opioid use in previously 
conducted trials in post-surgical pediatric subjects
78
Table 5:
Approximate volume of blood to be collected from each subject
155
Table 6:
Approximate volume of blood to be collected from each subject
155
Table 7:
Local laboratory tests to be performed for the evaluation of alternative 
causes of drug-induced liver injury
171
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LIST OF FIGURES
Figure 1:
Immediate post-operative timeline
12
Figure 2:
Depictions of regulatory-required age ranges
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3
ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviations
Abbreviation
Explanation
ANOVA
Analysis of variance model
BMI
Body mass index
C-SSRS
Columbia–Suicide Severity Rating Scale
CGIC
Clinical Global Impression of Change
CL/F
Apparent clearance after oral administration
CRF
Case report form(s)
CMH
Cochran–Mantel–Haenszel (test)
DMC
Data monitoring committee
ECG
Electrocardiogram
US FDA
Food and Drug Administration of the United States of America
FLACC
Face, Legs, Activity, Cry, Consolability (scale)
FPS-R
Faces Pain Scale–Revised
GCP
Good clinical practice
IEC
Independent ethics committee
IMP(s)
Investigational medicinal product(s)
IR
Immediate-release
IRB
Institutional review board
IVRS/IWRS
Interactive voice/web response system
MedDRA
Medical Dictionary for Regulatory Activities
NCA
Nurse controlled analgesia
PCA
Patient controlled analgesia
EU PDCO
Pediatric Committee (of the European Medicines Agency)
PGIC
Patient Global (overall) Impression of Change
PR
Prolonged-release
QTc
Corrected QT interval (ECG)
QTcF
Corrected QT interval using the Fridericia correction (ECG)
SOP(s)
Standard operating procedure(s)
TEAE
Treatment emergent adverse event
TRF
Tamper resistant formulation
VAS
Visual analog scale
V/F
Apparent volume of distribution of the central compartment
Note: Système International d’Unités units and standard pharmacokinetic, hematological and biochemical abbreviations 
are not listed.
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Definition of terms
Term
Definition
Allocated subjects
Enrolled subjects who are allocated (randomized) 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.
Clinician bolus
An additional bolus of morphine or hydromorphone given either using the NCA/PCA 
pump system or by an intravenous bolus injection. The clinician bolus can only be given 
in exceptional cases if a subject suffers unbearable pain despite using NCA/PCA.
Discontinuation
The act of concluding the participation of an enrolled subject in a trial prior to 
completion of all activities required by the protocol.
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/assent given according to local regulations, and subject given a subject 
identification number by the IVRS/IWRS.
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 (IMP)
A generic term describing the preparations under investigation in this trial, i.e., 
tapentadol oral solution and placebo.
Last subject out - EU 
PDCO
Date of last contact with the last subject according to the protocol for the EU PDCO set.
Last subject out - US 
FDA
Date of last contact with the last subject according to the protocol for the US FDA set. 
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 period 
completers
Two sets of treatment period completers will be defined for subjects in accordance with 
the time points of the primary endpoint, i.e., 12 hours and 24 hours.
Treatment period completers are defined for each of these sets as subjects who do not 
discontinue the treatment period before 12 hours and 24 hours, respectively.
Trial completers
Trial completers are defined as treatment period completers who have completed the 
Follow-up Visit.
For purposes of compliance with a US FDA request, completers beyond 24 hours and up 
to 72 hours will be tracked and data reported.
Day 1 is defined as the day of first administration of IMP.
By definition, Enrollment Period is synonymous with Screening Period, and allocation is 
synonymous with randomization.
End of surgery is defined as the time the subject leaves the operating room.
An allocation/randomization failure is a subject who was allocated to IMP but was discharged from 
hospital or the trial without taking IMP.
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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.
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 required so that the IEC/IRB responsibilities can be 
fulfilled. Any updates thereof will be provided according to GCP and applicable regulatory 
requirements.
Trial activities will only start after approval from the relevant IRB/IEC is available.
Documentation of all involved IEC/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/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. An 
assent form should be signed by the child in adherence to local regulations. Subjects from whom 
assent is requested after surgery will be asked to give assent when they are properly stable and able 
to give assent according to the investigator’s judgment.
As the inclusion of exclusively minors 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, and an assent form signed as
appropriate/applicable for the age of the subject.
All communication with the child or adolescent must be done by staff having experience dealing 
with minors. 
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4.3
Informing the subject’s healthcare provider
In applicable countries, and only if the subject, parent, or legal guardian agrees in writing in the 
informed consent form and assent form as applicable, the subject’s healthcare provider (e.g., 
general practitioner), if the subject is treated by a healthcare provider, will be informed about the 
subject’s participation in the trial at trial enrollment. The opinion of the subject, subject’s parent(s), 
and/or legal guardian(s) must be taken into consideration. The opinion and action is to be 
documented in the case report form (CRF) and 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/principal investigator will be required to sign 
a declaration of their responsibilities (the “Investigator Confirmation Sheet”) before any trial-
related procedure is performed. 
A 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. 
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.
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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.
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 GmbH, 52099 Aachen, accepts the responsibility to be the sponsor of this clinical trial.
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 
safety data and serum concentration data (tapentadol and tapentadol-O-glucuronide), as applicable.
The DMC members will neither be employees of the sponsor or collaborator nor be directly 
involved in the ongoing pediatric trials with tapentadol. Further details describing the data to be 
assessed and operational aspects of the DMC will be given in a charter which will be issued before 
the first subject is enrolled in this trial.
Based on the reviewed data, the DMC may recommend the implementation of additional measures 
or dose changes. The final decision on how to further proceed with the trial will be made by the 
sponsor or collaborator on the basis of the DMC recommendation. 
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.
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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
In various animal models of acute, chronic, inflammatory, and neuropathic pain, tapentadol exerted 
potent antinociceptive effects. This broad antinociceptive profile reflects its combined mode of 
action (mu-opioid receptor agonist and an inhibitor of noradrenaline reuptake). Both opioid and 
non-opioid properties are relevant for the management of clinical pain. 
Effects in humans
Tapentadol has been given to adults as an oral solution, intravenous solution, immediate-release 
(IR) tablets or capsules, and as prolonged-release (PR) tablets (including a tamper resistant 
formulation [TRF]). To date, tapentadol has been administered to children aged 2 years to less than 
18 years in the pediatric clinical program. The oral solution has been given to these children as a 
single dose in 2 pharmacokinetic trials (KF5503/68 and KF5503/59).
Pharmacodynamics in adults
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 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 in adults
Tapentadol was rapidly and completely absorbed after oral administration of tapentadol IR. Mean 
absolute bioavailability after single-dose administration (fasting) was approximately 32%, most 
probably due to an extensive first-pass metabolism. Peak serum concentrations of tapentadol were 
observed at approximately 1.25 hours (tapentadol IR) and approximately 3 hours to 6 hours
(tapentadol PR or tapentadol TRF) post-dose. The tapentadol terminal half-life was approximately 
4 hours (tapentadol IR) and approximately 5 hours to 6 hours (tapentadol PR). The serum protein 
binding of tapentadol was approximately 20%.
After oral administration, approximately 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 approximately 4.1 hours and total 
clearance was 1530 ± 177 mL/min. Systemic exposure to tapentadol (area under the concentration-
time curve; AUC) and accumulation factors following multiple dosing were found to be consistent 
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with single-dose data. Steady-state was attained approximately 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. The accumulation ratio of tapentadol 
based on the maximum serum concentrations at steady-state (Cmax,ss) was consistent with linear 
pharmacokinetics and close to the theoretically expected value. 
The pharmacokinetics of an oral solution was similar to those of the immediate-release tablet 
formulation.
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 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.
Pharmacokinetics in children
A population pharmacokinetic model was developed by means of the non-linear mixed effect 
approach using the data available from 2 single-dose pharmacokinetic trials in children aged 2 years 
to less than 18 years (KF5503/68 and KF5503/59). A 1 compartment model was found to describe 
the data adequately. The pharmacokinetic parameters of the allometrically scaled base model were 
as follows: CL/F = 172 L.h-1, V/F = 677 L (the CL/F and V/F are typical estimates for a subject 
with a body weight of 45 kg), first order absorption rate constant (Ka) = 2.01 h-1, time delay 
between drug administration and beginning of absorption (TLAG) = 0.247 h. The modeled 
pharmacokinetic parameters in children aged 2 years to less than 18 years old are in line with the 
corresponding modeled pharmacokinetic parameters in adults. The coefficients of weight on CL/F 
and V/F were estimated to be 0.635 and 0.853, respectively. The inter-individual variabilities on 
CL/F, V/F, and Ka were 22.4%, 17.3%, and 145.3%, respectively.
The addition of data from KF5503/72, i.e., adding data from children aged birth to less than 2 years,
resulted in minor changes to the model (comprising children from birth to 18 years old) and was 
best described by incorporation of an Emax type maturation function. The pharmacometric 
parameters changed to: CL/F = 155 L.h-1, V/F = 533 L (the CL/F and V/F are typical estimates for a
subject with a body weight of 32.6 kg), Ka = 2.44 h-1, TLAG = 0.267 h, with the coefficients of 
weight on CL/F and V/F being estimated as 0.562 and 0.827, respectively. The maturation function, 
which describes the age at which half the maximum CL/F in the data set was estimated as 39 weeks. 
The inter-individual variabilities on CL/F, V/F, and Ka remained virtually the same.
Safety in Phase I trials in adults (tapentadol intravenous, tapentadol oral solution, 
tapentadol IR, and tapentadol PR including TRF)
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 
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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 
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 corrected QT (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 results from trials in which tapentadol was given as an oral solution or intravenously were 
generally consistent with those observed with tapentadol IR with the exception of a stronger 
influence on the respiratory system after intravenous administration.
Safety in Phase II trials in children (tapentadol oral solution)
In a single dose trial (KF5503/68) of 66 children undergoing dental, ear, nose, or throat surgery, 
there were no deaths. There was 1 serious adverse event (post-operative bleeding 6 days after a 
tonsillectomy), and 6 subjects were discontinued due to an adverse event (vomiting, which was also 
considered a stopping criteria). In a second trial (KF5503/59 [R33133PAI2005]) of similar design,
but which included a greater variety of surgical procedures, in 45 children, there were no deaths, 
serious adverse events, or discontinuations due to an adverse event.
Safety Phase II and Phase III in adults (tapentadol IR)
Adverse drug reactions, the most common (10% subjects) being nausea, dizziness, vomiting, 
somnolence, and headache, were observed with tapentadol IR treatment in the dose range of 50 mg
to 100 mg, and are as expected for a centrally-acting analgesic. Most adverse drug reactions 
reported with tapentadol IR were of mild or moderate intensity. Apart from withdrawal classified as 
mild in most cases, prolonged use of tapentadol IR (for up to 90 days) was not associated with a 
change in the safety profile of tapentadol IR. With prolonged use, the incidence of nausea and 
vomiting decreased with time, whereas constipation remained at the same level.
Safety Phase II and Phase III in adults (tapentadol PR)
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.
Safety experience from post-marketing data in adults
The total cumulative post-authorization patient exposure to tapentadol (IR and PR) since the first 
launch in Jul 2008 up to 20 May 2016 was 314 million patient treatment days with an estimated 
average daily dose for tapentadol IR of 280 mg. In the time period from first launch to 
20 May 2016, 7556 spontaneous, medically confirmed cases were received, reporting tapentadol 
either as the suspect, co-suspect, or suspect-interacting drug. Among the 7556 cases, there were 
188 cases with a fatal outcome, 2195 serious nonfatal cases, and 5173 not serious cases. Age was 
reported in 3687 cases and ranged from 0 years to 100 years. The cases involved 3690 female 
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patients and 2243 male patients (the sex was not reported or was reported as unknown in 
1623 cases). Overall, the most frequently reported preferred terms for these events were (in 
descending order of frequency) nausea, drug ineffective, dizziness, somnolence, vomiting, and 
headache.
Two important potential risks (serotonin syndrome with concomitant use of serotonergic 
medications, and suicidal ideation and behavior) were included in the reference safety information 
and the risk management plan of tapentadol. Currently, neither clinical nor post-authorization safety 
data provide sufficient evidence to include these potential risks as adverse drug reactions of 
tapentadol.
Efficacy of tapentadol IR
The efficacy of tapentadol IR was shown in all Phase III trials, encompassing several different pain 
models, including a visceral pain model, for all doses employed in the trials, i.e., 50 mg, 75 mg, and 
100 mg taken every 4 hours to 6 hours. These trials examined subjects with moderate to severe pain 
following abdominal hysterectomy, bunionectomy, hip replacement (the treatment duration was
3 days for all 3 indications), and in subjects with pain due to end-stage degenerative joint disease 
(10 days of treatment in an outpatient population). 
Tapentadol IR showed a rapid onset of action (ranging from 24 minutes to 46 minutes) that was at 
least as fast as the onset observed for the active comparators oxycodone IR and morphine IR.
The efficacy of tapentadol IR in the dose range of 50 mg to 100 mg every 4 hours to 6 hours in 
trials with an active comparator appeared similar to that of oxycodone IR in the dose range of 
10 mg to 15 mg every 4 hours to 6 hours in trials of pain following bunionectomy (3 trials), hip 
replacement (1 trial), and end-stage degenerative joint disease (1 trial). Tapentadol IR 75 mg and 
morphine IR 20 mg had similar efficacy in the trial of pain following abdominal hysterectomy 
(1 trial).
Efficacy of tapentadol PR
Efficacy of tapentadol PR (100 mg to 250 mg twice daily) for the treatment of moderate to severe 
chronic pain was demonstrated in 3 representative pain conditions: 2 trials in chronic painful 
osteoarthritis, 1 trial in chronic low back pain, and 2 trials in painful diabetic peripheral neuropathy. 
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7
TRIAL OBJECTIVES
This protocol is part of a pediatric development program that fulfills differing requirements of the 
EU PDCO and the US FDA. For the EU PDCO, to assess the efficacy and safety of tapentadol in 
the treatment of acute pain, subjects between 2 years and less than 18 years old will be evaluated. 
For the US FDA, subjects between birth and less than 17 years old will be evaluated.
The clinical hypothesis of this trial is that tapentadol oral solution reduces the total amount of 
supplemental opioid analgesic medication used over 12 hours (primary objective for US FDA) or 
24 hours (primary objective for EU PDCO) following initiation of IMP, compared to placebo, in 
children and adolescents who have undergone surgery that, in the investigator’s opinion, would 
reliably produce moderate to severe pain requiring opioid treatment.
The primary efficacy objective (either 12 hours or 24 hours) for 1 region is considered as the 
secondary efficacy objective in the other, for the different age range, as described below.
Two reports will be prepared for the trial. The first report will be prepared after the last subject out 
of the EU PDCO set. The second report will be prepared after the last subject out of the US FDA 
set.
Subjects can be treated for up to 72 hours, and efficacy and safety information will also be collected 
throughout this time period.
Primary objectives:
For EU PDCO: To evaluate the efficacy of tapentadol oral solution, based on the total amount of 
supplemental opioid analgesic medication used over 24 hours following initiation of IMP, in 
children and adolescents aged 2 years to less than 18 years who have undergone surgery that, in the 
investigator’s opinion, would reliably produce moderate to severe pain requiring opioid treatment.
For US FDA: To evaluate the efficacy of tapentadol oral solution, based on the total amount of 
supplemental opioid analgesic medication used over 12 hours following initiation of IMP, in 
children and adolescents aged from birth to less than 17 years who have undergone surgery that, in 
the investigator’s opinion, would reliably produce moderate to severe pain requiring opioid 
treatment.
For both EU PDCO and US FDA: To evaluate the safety of tapentadol oral solution in children and 
adolescents aged 2 years to less than 18 years (EU PDCO) and children and adolescents aged from 
birth to less than 17 years (US FDA) who have undergone surgery that, in the investigator’s 
opinion, would reliably produce moderate to severe pain requiring opioid treatment.
Secondary objectives:
To assess the efficacy of tapentadol oral solution using multiple subjective and objective measures 
of the subject’s response to treatment (see secondary endpoints, Section 8.1).
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TRIAL DESIGN
This is a Phase III, randomized, multi-site, double-blind, placebo-controlled, parallel group, 
multiple oral dose trial of tapentadol oral solution.
Trial duration
Each subject is expected to be in the trial for up to about 42 days (up to 28 days for enrollment, and 
a treatment and follow-up period of up to 14 days). Dosing of IMP will be for up to 72 hours.
8.1
Definition of endpoints
All endpoints compare the results in the group of subjects treated with tapentadol oral solution to 
the group treated with placebo. As applicable and appropriate for the individual endpoint, these
endpoints will be analyzed in the age ranges of 2 years to less than 18 years for the EU PDCO and 
from birth to less than 17 years for the US FDA.
The primary efficacy endpoint for the EU PDCO is considered a secondary efficacy endpoint for 
the US FDA and vice versa.
The primary efficacy endpoints are:
•
EU PDCO: The total amount of supplemental opioid analgesic medication (morphine 
equivalents in mg/kg body weight) used within the first 24 hours after first IMP intake.
•
US FDA: The total amount of supplemental opioid analgesic medication (morphine 
equivalents in mg/kg body weight) used within the first 12 hours after first IMP intake.
The secondary efficacy endpoints are: 
•
The total amount of supplemental opioid analgesic medication (morphine equivalents in 
mg/kg body weight) used within the first 12 hours (EU PDCO) or within the first 24 hours 
(US FDA) after first IMP intake.
•
The total amount of supplemental opioid analgesic medication received, assessed in 
12 hour intervals from 24 hours to 96 hours after the first dose of IMP.
•
Palatability and acceptability of the IMP after the first and last doses of IMP in subjects 
aged 2 years to less than 18 years old (EU PDCO).
•
Changes from baseline in pain intensity over the Treatment Period using age-appropriate 
pain scales (FLACC scale for ages birth to less than 6 years or in older children who are not 
able to report their pain using the other scales, FPS-R for ages 6 years to less than 12 years, 
and VAS for ages 12 years to less than 18 years). 
•
CGIC by investigator/clinician after completion of double-blind IMP treatment.
•
PGIC by subject/parent/legal guardian after completion of double-blind IMP treatment.
•
Time to first and time to second NCA/PCA after the first dose of IMP.
•
Time from first dose of IMP until IMP treatment discontinuation due to lack of efficacy.
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Safety endpoints:
•
Percentage of subjects with TEAEs.
•
Percentages of subjects who develop abnormal:
−
Vital signs.
−
Laboratory parameters.
−
12-lead ECG parameters.
•
Changes from baseline in vital signs parameters.
•
Sedation scores using the University of Michigan Sedation Scale.
•
Changes from baseline in safety laboratory parameters.
•
Changes from baseline in 12-lead ECG parameters.
•
Percentage of subjects discontinuing the trial due to TEAEs and drug-related adverse 
events.
•
Suicidal ideation/behavior in subjects aged 6 years or older using the C-SSRS scores before 
IMP and at the end of the trial.
8.2
Trial rationale 
Although there is a lack of controlled clinical trials investigating the use of opioids for pain relief in 
the pediatric population, opioids are often used off-label as analgesics in this population. Given this 
lack of information on the use of strong analgesics in children and adolescents, confirmatory trials
have been requested by the EU PDCO and US FDA. The design of this trial reflects the joint 
requirements of both authorities.
Tapentadol is approved in various regions of the world, such as Australia, Canada, the European 
Union, and the United States, for the relief of acute pain in adults with an immediate-release 
formulation, and as an oral solution in the European Union and United States. Tapentadol IR was 
shown to be efficacious and well-tolerated in adults for the treatment of acute pain. The better 
gastrointestinal tolerability profile compared to that of oxycodone may make tapentadol a better 
alternative for use in children.
This trial is designed to assess the efficacy and safety of multiple doses of a tapentadol oral solution 
in children aged from birth to less than 18 years. The efficacy will be evaluated by assessing the 
opioid sparing effect in subjects treated with tapentadol compared to subjects treated with placebo. 
Based on the known efficacy of tapentadol in adults, it is assumed that this efficacy will also be 
present in children and adolescents. Thus, it is expected that subjects treated with tapentadol will 
require less supplemental opioid analgesic medication (given via NCA/PCA) for additional pain
control than children in the placebo group who, because they should not experience more pain than
they would if not enrolled in a clinical trial, are expected to require more supplemental opioid 
analgesia. Overall, there should be no difference in the intensity of pain measured between the 
2 treatment groups. Hence, the opioid sparing effect (i.e., lower expected use of supplemental 
opioid analgesic in the tapentadol treatment group than in the placebo-treated group) can be 
considered a surrogate for more direct measures of analgesia, such as changes in pain intensity. The 
use of NCA/PCA will allow subjects on placebo to receive analgesia.
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8.3
Special agreements with regulatory authorities
This protocol is part of a pediatric development program that fulfills differing requirements of the 
EU PDCO and the US FDA. The complete clinical program for the use of tapentadol in children 
and adolescents is designed to characterize the efficacy, tolerability, safety, and pharmacokinetics 
of tapentadol in different pediatric age groups.
8.4
Discussion of the trial design
This is a Phase III, randomized, multi-site, double-blind, placebo-controlled, parallel group, 
multiple oral dose trial of tapentadol oral solution.
Choice of population and sites
The age ranges selected for the trial conform to the requirements for development of medicines in 
children (see Section 8.3). The types of surgery allowed are restricted to those that are expected to 
produce pain severe enough to require opioid analgesic treatment via NCA/PCA. Examples of 
surgeries suitable for this trial include, but are not limited to, spinal fusions, cleft palate repair, Nuss 
procedures, scoliosis repair, nephrectomy, pyeloplasty, and orthopedic procedures such as club foot 
repair, leg lengthening, open reduction and internal fixation of long bone fractures. Subjects must 
remain hospitalized until the End of Treatment Visit.
Multiple sites in multiple countries will be required for the recruitment of required subjects in the 
specified time.
See Section 14.1 for the sample size rationale.
Comparator and use of NCA/PCA
In this double-blind trial, the efficacy of tapentadol oral solution, compared to placebo, will be 
evaluated based on the amount of supplemental opioid analgesic medication required to achieve
adequate pain relief. All subjects will receive supplemental opioid analgesic medication (via 
NCA/PCA) for additional pain control during the period of administration of IMP. Morphine or 
hydromorphone (via NCA/PCA) are allowed as supplemental opioid analgesic medication. Both are 
frequently used in the clinical setting chosen for this trial, i.e., post-operative pain. Hence, due to 
the use of NCA/PCA as per usual routine, children should not be subjected to more pain than they 
would otherwise experience in the selected post-operative setting. 
This trial will compare the amount of supplemental opioid analgesic medication given by 
NCA/PCA used in the tapentadol oral solution and placebo groups. The expectation is that the level 
of use of supplemental opioid analgesic medication will be higher in the placebo group than in the 
tapentadol oral solution group.
A subject will be discontinued from the trial if their pain is not controlled by the IMP plus 
NCA/PCA, requiring treatments other than those defined in the protocol.
Blinding
The trial is double-blinded to prevent bias. The EU PDCO set will be locked and unblinded before 
recruitment of the under 2 year olds in the US FDA set is completed. All subjects in the EU PDCO 
set (which includes completed subjects aged 2 years or older in the US FDA set) will remain locked 
after the analysis for the first report. Subjects under 2 years old in the US FDA set will remain 
blinded, as independent randomization lists are used for subjects aged less than 2 years old.
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Dosing
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 
children aged above 3 years compared with adults. 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). 
Data from a multiple dose trial in healthy adult subjects (HP5503/13) 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 approximately 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 will be 
predictable and time independent after both single and multiple dosing.
Non-linear mixed effects modeling was performed to develop a population pharmacokinetic model 
in the pediatric population for tapentadol oral solution. The data from 2 dedicated single-dose 
pharmacokinetic trials (KF5503/68 and KF5503/59 [R33133PAI2005]) were used for the 
population pharmacokinetic model and served as a basis for dose selection in the current trial for 
children aged 2 years to less than 18 years old. The doses for children aged from birth to less than 
2 years are predicted from additional pharmacokinetic sampling in children of the same age group.
Simulations were performed to identify tapentadol doses that would produce total exposures (i.e., 
serum AUC for tapentadol) in pediatric subjects that are similar to those reported in adults. The 
approved adult therapeutic dose range that is generally associated with efficacy and good 
tolerability in adults, 50 mg to 100 mg, was used for comparison. These simulations showed that
tapentadol doses of 1.25 mg/kg every 4 hours in subjects aged 2 years to less than 18 years old are 
expected to produce exposures similar to those after administration of 50 mg to 100 mg every 
4 hours, given as an immediate-release formulation in adults. The median steady state simulated 
AUCs after a 50 mg, 75 mg, and 100 mg dose in adults are 217 ng.h/mL, 325 ng.h/mL, and 
433 ng.h/mL, respectively. In comparison, the median simulated steady state AUC in subjects aged 
2 years to 17 years old receiving 1.25 mg/kg is 306 ng.h/mL.
The population pharmacokinetic model used for the pediatric dose simulations was updated with 
exposure data obtained from children aged birth to less than 2 years (KF5503/72), the simulations 
were then redone to determine the appropriate dose for the age group 6 months to less than 2 years. 
The simulations specified that the dose of 1.25 mg/kg would give similar exposures as that 
observed in the age group 2 years to less than 18 years. For the younger groups, a lower dose is 
required.
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Based on these results, a dose regimen of 1.25 mg/kg will be used for the first 24 hours of treatment 
in this trial in children aged 6 months to less than 18 years old. After 24 hours after the start of IMP, 
and based on clinical judgment, the dose may either be continued at 1.25 mg/kg or it may be
decreased to 1.0 mg/kg. A decision to maintain or alter the dose will depend on the investigator’s 
judgment of the effectiveness of the analgesia and the adverse event profile observed in each child 
over the first 24 hour dosing period. For children aged 1 month to less than 6 months, and birth to 
less than 1 month old, doses of 0.5 mg/kg and 0.1 mg/kg, respectively, are expected to produce 
similar exposures as that observed in the age group 6 months to less than 18 years.
The maximum single dose for this trial is 100 mg because this is the maximum approved dose for 
adults.
Pain measurements
To measure pain intensity, 3 pain intensity scales will be used to cover the different age-related 
abilities to report pain. These assessments are discussed in Section 12.4. In addition, the 
investigator/delegate or subject will record a pain intensity score prior to each NCA/PCA activation, 
whenever possible (as requested by the US FDA). Pain intensity data collected for this purpose, i.e., 
directly before each NCA/PCA activation, will be used only for the purpose of exploratory 
descriptive analysis.
Blood sampling
The total withdrawn blood volume in this trial is given in Section 11.7, and this will not exceed the 
maximum safe blood loss that is recommended in a pediatric population (e.g., EMEA ad hoc 
working party 2008).
Safety
The safety of tapentadol oral solution in the studied population will be assessed by evaluating the 
safety parameters listed in Section 12.3.
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). Data on the efficacy of tapentadol in children are preliminary and limited. It is not 
expected that the efficacy of tapentadol in children will deviate notably from that observed in 
adults.
Risks
Lack of efficacy
Tapentadol may not be as efficacious in children as in adults. In addition, some subjects will receive 
placebo. The risk of lack of efficacy with tapentadol, or no efficacy with placebo, is mitigated as all 
subjects in this trial will have access to supplemental opioid analgesic medication using NCA/PCA.
Due to the chosen trial design, subjects are not expected to experience undue pain. 
Safety - background procedures
All subjects will undergo a surgical procedure. The surgical procedure and anesthesia have inherent 
risks. However, these surgical procedures and the need for opioid treatment are independent of 
participation in this trial.
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Risks to subjects also include discomfort, inconvenience, and the number and volume of blood 
samples required by this trial protocol. These risks will be minimized by:
•
Limiting the number of venipunctures.
•
Possibly obtaining blood samples at the same time as routine blood sampling.
•
Permitting the use of analgesic patches, creams, etc., to reduce pain due to venipuncture.
•
Use of laboratories with expertise in handling, monitoring, and analyzing biologic samples 
using small volumes.
•
Involving trial site staff experienced with treating children.
Safety - tapentadol
A potential risk to subjects in this trial is the exposure to tapentadol, with possible side effects.
Although there is a tapentadol oral solution available for the adult population, the assessment of risk 
for the tapentadol oral solution for use in children is mainly based on the much greater experience 
with the solid oral formulations tapentadol IR and tapentadol PR (and a related tamper resistant 
formulation). This experience is considered to be applicable to the tapentadol oral solution as well.
The safety profile of tapentadol has been well characterized through a completed clinical program 
in adults and post-marketing experience is now available. Furthermore, 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 already observed in KF5503/68 and KF5503/59 
(R33133PAI2005).
Safety - tapentadol multiple dosing
To optimize exposure to tapentadol, a weight-adjusted treatment dose of tapentadol oral solution 
was chosen (see Section 8.4). Multiple oral dose administration of tapentadol in children is not 
expected to have an additional inherent risk above that seen in the adult population.
Safety - monitoring
To assure proper safety surveillance, the subjects will be kept in a monitored and well controlled 
environment as generally recommended when opioid-naïve subjects are treated with strong opioids. 
Subjects will be monitored for adverse events throughout the trial, and experts in pediatric 
investigations will be chosen to conduct the trial. Measures will be taken to ensure that all subjects 
will be closely supervised for anticipated side effects known to occur with opioids or with 
tapentadol. Subjects will be confined to the trial site until completion of Visit 3 (End of Treatment 
Visit) assessments. 
Safety - selection of sites
The chosen investigative trial sites and the investigators will have experience in the care of patients 
following pediatric surgery and the trial sites will be properly prepared to conduct a clinical trial. 
The trial site staff will be trained in the use of the scales and instruments included in this trial to 
ensure that trial procedures and evaluations are carried out according to GCP, and in accordance 
with standard medical practice.
Safety - general
This trial has been designed to protect the interests of the subjects, including minimizing the risk to 
subjects and ensuring compliance with the recommendations made by an EMEA ad hoc working 
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party (2008) regarding the amount of blood to be drawn as well as the monitoring of children in a 
controlled environment (post-operative setting that provides intensive monitoring).
Data monitoring committee
A DMC will oversee this trial. For more details about the planned monitoring by the DMC, see 
Section 5.4.
Conclusion
The efficacy of tapentadol is expected to be similar in children to that seen in adults. The risks 
associated with the trial, and the risks associated with the administration of tapentadol, are 
adequately addressed by the mitigation procedures. 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 may be 
screened to identify subjects who could potentially be enrolled into the trial. If a subject is identified 
to be potentially eligible, the subject, parent(s), or legal guardian(s) will be asked by the investigator 
to give consent for the subject’s enrollment in the trial as described in Section 4.2. If allowed by 
applicable regulatory requirements, the investigator will keep a subject screening log and a subject 
identification and enrollment log.
The trial enrollment will be initiated in a staggered approach. Enrollment starts with an older age 
group until pharmacokinetic data are available in younger age groups from other trials in the 
pediatric clinical development program of tapentadol. Initially, subjects aged 2 years to less than 
18 years are to be recruited. The recruitment of subjects aged 6 months to less than 2 years is 
allowed following Amendment 05 and the recruitment of subjects aged from birth to less than 
6 months of age is allowed following Amendment 07, based on pharmacokinetic and safety data 
gathered from a separate trial in the same age groups. Allocation/randomization to IMP will be 
stratified by 7 age groups and by use of morphine or hydromorphone as supplemental opioid 
analgesia (Section 10.3).
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9.2
Inclusion/exclusion criteria
9.2.1
Inclusion criteria
Subjects are eligible for the trial if all the following apply:
Inclusion criteria
Rationale for criterion
1.
Informed consent, and if applicable assent, given according to local regulations.
Legal and ethical 
requirement.
2.
Male or female subject aged from birth (37 weeks gestational age) to less than 
18 years.
Standardization of the trial 
population.
Safety.
3.
A female subject must be pre-menarchal, or surgically incapable of childbearing, 
or sexually abstinent, or if a female subject is sexually active, then she must be 
practicing an effective method of birth control (e.g., prescription hormonal 
contraceptives, intra-uterine devices used according to the product’s instruction, 
double-barrier methods) before trial entry and throughout the trial.
Safety.
4.
A female subject must have a negative pregnancy test if aged 12 years or older, 
or is post-menarchal, or is sexually active.
Safety.
5.
Subject has undergone surgery (other than brain surgery or gastrointestinal 
surgery expected to affect the absorption of tapentadol [in the investigator’s 
judgment]) that, in the investigator’s opinion, would reliably produce moderate to 
severe pain requiring opioid treatment for at least 24 hours after first dose of 
IMP. Subjects must remain hospitalized until the End of Treatment Visit.
Standardization of the trial 
population.
6.
Subject has received post-operative morphine or hydromorphone by NCA/PCA, 
with or without a background infusion of the same opioid, according to standard 
of care prior to allocation/randomization to IMP and subject is expected to 
require this morphine or hydromorphone by NCA/PCA after starting IMP.
Standardization of the trial 
population.
7.
Subject is able to tolerate liquids at the time of allocation/randomization to IMP.
Standardization of the trial 
population.
Note: Subjects will only receive IMP if documentation is available showing that they comply with these inclusion 
criteria. 
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9.2.2
Exclusion criteria
Subjects are not eligible for the trial if any of the following applies:
Exclusion criteria 
Rationale for criterion
1.
Subject, parent or the legal representative is an employee of the investigator or 
trial site, with direct involvement in the proposed trial or other trials under the 
direction of that investigator or trial site, or family member of the employees or 
the investigator.
Good clinical practice (GCP).
2.
Subject has been previously exposed to tapentadol.
Ethics and interference with 
trial assessments.
3.
Subject has received an experimental drug or used an experimental medical 
device within 28 days before allocation/randomization to IMP, or within a period 
less than 10 times the drug’s half-life, whichever is longer. 
Safety.
4.
Subject has a history or current condition of any one of the following:
•
Non-febrile seizure disorder.
•
Epilepsy.
•
Serotonin syndrome.
•
Traumatic or hypoxic brain injury, brain contusion, stroke, transient 
ischemic attack, intracranial hematoma, post-traumatic amnesia, brain 
neoplasm, or episode(s) of unconsciousness of more than 24 hours.
Safety and interference with 
trial assessments.
5.
Subject has a 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).
Safety and interference with 
trial assessments.
6.
Subject has a concomitant disease or disorder (e.g., endocrine, metabolic, 
neurological, psychiatric, infection, febrile seizure, paralytic ileus) that in the 
opinion of the investigator may affect or compromise subject safety during the 
trial participation.
Safety.
7.
Subject has history of suicidal ideation or behavior.
Safety.
8.
Subject is obese in the investigator’s judgment. Obesity can be determined based 
on appropriate BMI charts or tables; e.g., a BMI above the 97th percentile for 
children based on the World Health Organization growth charts (see 
Section 19.9).
or
Subject weight is less than 2500 gm.
Standardization of the trial 
population.
9.
Subject has a clinically relevant history of hypersensitivity, allergy, or 
contraindication to the supplemental opioid analgesic medication or tapentadol, 
or the excipients (see the investigator’s brochure), or naloxone. 
Safety.
10. 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.
Ethics and interference with 
trial assessments. 
11. Subject has a history of alcohol and/or substance abuse in the investigator’s 
judgment based on subject’s history and physical examination.
Safety.
12. Subject is taking prohibited concomitant medication. For details, see 
Section 10.6.4.
Standardization of the trial 
population and safety.
13. Subject has received a long-acting opioid for the treatment of pain following 
surgery within 6 hours of allocation/randomization to IMP.
Interference with trial 
assessments.
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Exclusion criteria 
Rationale for criterion
14. Subject has clinically relevant (in the investigator’s judgment) abnormal values 
for clinical chemistry or hematology (local laboratory sample taken after 
surgery). 
A subject aged 6 months to less than 18 years old is excluded if the:
•
Aspartate transaminase or alanine transaminase is >3-times upper limit of 
normal.
•
Total bilirubin is >2-times upper limit of normal (except if the cause is due 
to Gilbert’s syndrome). 
•
Glomerular filtration rate <60 mL/min (calculated according to Schwartz et 
al. 1984).
A subject aged from birth to less than 6 months old is excluded if:
•
Aspartate transaminase or alanine transaminase is >3-times upper limit of 
normal.
•
There is pathological jaundice in the opinion of the investigator.
•
Glomerular filtration rate (calculated according to Schwartz et al. 1984) is: 
−
<20 mL/min/1.73 m2 for subjects <1 week post-partum.
−
<30 mL/min/1.73 m2 for subjects 1 week to 8 weeks post-partum
−
<50 mL/min/1.73 m2 for subjects >8 weeks post-partum to <6 months 
old.
Safety.
15. Subject has:
•
Clinically relevant abnormal ECG.
•
Signs of pre-excitation syndrome.
•
Brugada’s syndrome.
•
QT or QTc interval >470 ms for children aged 6 years to less than 18 years 
old.
•
QT or QTc interval >460 ms for children aged from birth to less than 6 years 
old.
Safety.
16. Peri- or post-operative analgesia supplied by a continuous regional technique 
(e.g., nerve block, wound infiltration catheter) or subject controlled epidural 
analgesia that was terminated less than 6 hours before allocation/randomization 
to IMP.
Standardization of the trial 
population.
17. Subject has post-operative clinically unstable systolic and diastolic blood 
pressure, heart rate, respiratory depression, or clinically unstable upper or lower 
airway conditions (in the investigator’s judgment), or a saturation of peripheral 
oxygen (SpO2) <92% at the time of randomization (allocation/randomization to 
IMP).
Safety.
18. Female subject is breastfeeding a child.
Safety.
19. Subject requires continuous positive airway pressure or mechanical ventilation, at 
the time of allocation to IMP.
Safety.
20. The mother of a newborn subject or the breastfeeding mother of a subject was 
administered a prohibited medication (see Section 10.6.4).
Standardization of trial 
population.
Note: Subjects will only receive IMP if documentation is available showing that they do not meet any of these exclusion 
criteria.
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9.3
Trial discontinuation or discontinuation of a subject from 
investigational medicinal product
9.3.1
Reasons for discontinuation of a subject
The investigator must discontinue subjects from the trial for the compulsory reasons given in 
Table 1. If the reason is given as optional, then the investigator may decide to stop the participation 
of the subject in the trial if the benefit/risk ratio is not favorable for the continued participation of 
the subject. The evaluation of optional reasons for discontinuation must be documented by the 
investigator in the CRF.
Table 1:
Reasons for compulsory and optional discontinuation of subjects from trial 
participation (discontinuation criteria)
Discontinuation
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, safety 
laboratory parameters, vital signs, or other safety parameters (e.g., ECG).
X
•
A confirmed QT or QTc interval >470 ms for children aged 6 years to less 
than 18 years old.
X
•
A confirmed QT or QTc interval >460 ms for children aged from birth to less 
than 6 years old.
X
•
Clinically relevant change in liver parameters after dosing if the result is 
confirmed by 1 additional laboratory assessment (see Section 19.7): 
−
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 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
X
Lack of efficacy
•
The subject has pain needing other treatments than defined in the protocol to 
control it.
X
Pregnancy
X
Enrollment failure
X
Protocol deviation
•
The subject is non-compliant with requirements of the trial.
X
•
Participation in another investigational trial.
X
•
The subject or mother of a newborn or breastfeeding mother has taken
prohibited medication/therapy (see Section 10.6.4).
X
•
The subject continues or starts a background infusion of opioid medication 
after the first dose of IMP.
X
Lost to follow-up
X
Technical reasons
•
Technical or logistical grounds (e.g., important technical equipment fails).
X
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Discontinuation
Reason
Compulsory
Optional
Withdrawal of informed consent
X
Trial terminated by the sponsor
X
Further trial procedures should be performed as scheduled including Visit 3 (End of Treatment 
Visit) and Visit 4 (Follow-up Visit).
9.3.2
Procedure for the handling of prematurely discontinued subjects
The investigator must inform the sponsor within 24 hours about any discontinuation of a subject. 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/IRB must be informed 
with a detailed written explanation. Also, any technical devices issued must be collected.
The following information must be documented for all discontinued subjects:
•
Demographic data.
•
Reason for discontinuation.
•
Status of all new and ongoing adverse events (both serious and non-serious). Any adverse 
event should be followed up until it reaches a satisfactory resolution, or becomes stable, or 
can be explained by other causes, or clinical judgment indicates that further evaluation is 
not warranted.
For treated discontinued subjects, the following should be done in addition:
•
Ensure return of partially used and unused medication kits.
•
Final drug accountability must be performed. 
•
All data captured until discontinuation as required at all attended visits, including the 
recording of concomitant medication taken until the day of discontinuation.
If the subject/parent/legal guardian agrees:
•
Perform all tests as defined for Visit 3 (End of Treatment Visit) and Visit 4 (Follow-up 
Visit). 
All efforts should be made to collect data from subjects who are discontinued because of clinically 
relevant changes in liver parameters so that a valid causality assessment can be made.
9.3.3
Premature termination or suspension of the trial
The relevant IEC/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/IRB, the regulatory authorities, the sponsor/the 
sponsor’s authorized delegate, and the DMC, as applicable). 
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In addition, the investigator must promptly inform the subjects, ensure appropriate follow-up for 
any enrolled subjects, and provide the relevant IEC/IRB and the sponsor or the sponsor’s authorized 
delegate, as applicable, with a detailed written explanation of the termination or suspension.
The coordinating investigator has to be informed immediately if the trial is prematurely terminated 
or suspended.
9.3.3.1
Criteria to terminate or suspend the whole trial
A suspension or discontinuation of this trial will be considered based on clinically relevant changes 
of safety laboratory parameters, 12-lead ECG parameters, or serious adverse events.
A risk benefit committee organized by the sponsor will convene to decide on further action, which 
could include immediate stopping of the trial.
The DMC may recommend stopping the trial, but the final decision will rest with the sponsor and 
collaborator.
The trial may be restarted following a thorough evaluation by the sponsor and collaborator.
10
TREATMENTS
10.1
Investigational medicinal product
10.1.1
Identity and composition – tapentadol oral solution (test)
Name:
Tapentadol oral solution
Substance code:
CG5503/R331333
Substance name:
Tapentadol hydrochloride
Active component(s): 
Tapentadol
Dose (strength): 
Tapentadol 4 mg/mL and 20 mg/mL oral solutions
Manufacturer:
Grünenthal GmbH, Aachen, Germany.
For further information about the identity and composition of tapentadol oral solution, see the 
current investigator’s brochure and the clinical supply specification.
10.1.2
Identity and composition – placebo (comparator)
Name:
Placebo
Substance name:
Placebo
Active component(s): 
Not applicable
Dose (strength): 
Not applicable
Manufacturer:
Grünenthal GmbH, Aachen, Germany.
The placebo formulation contains the same excipients as tapentadol oral solution 4 mg/mL (i.e., 
citric acid monohydrate, sucralose, raspberry flavor, sodium benzoate, and purified water).
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10.1.3
Preparation
The IMP will be supplied as a liquid in 100 mL bottles intended for multiple use per subject. A 
dosing syringe for oral use (either a syringe supplied by the sponsor or a suitable sponsor-approved 
alternative, as defined in Section 10.2.1 and in the Investigational Product Preparation Instructions
supplied by the sponsor) must be used for IMP administration.
10.1.4
Packaging and labeling
For detailed information about the packaging and labeling, see the clinical supply specification.
The IMP will be labeled according to local requirements in local languages with booklet labels or 
single panel labels if applicable.
10.1.5
Delivery, storage and disposal
The sponsor or designee is responsible for supplying the investigator with IMP. These will not be 
delivered until all required documentation (IEC/IRB approval, authority approval, signed contract 
and protocol, curriculum vitae) is present at the sponsor or designee.
Further storage conditions will be specified on the labeling of the IMPs.
For countries in which tapentadol has been classified as a controlled or scheduled substance, all 
local requirements for the handling, storage, and distribution of opioid analgesics will be followed.
Controls will be implemented at the trial site to ensure documented compliance with these 
requirements.
10.1.6
Special requirements
Due to the scheduling status of tapentadol, the investigator may need country-specific approval for 
handling tapentadol in accordance with the applicable regulations for narcotics.
10.2
Administration of trial treatments
10.2.1
Dose
The doses to be administered are given in Table 2.
The maximum individual dose of tapentadol oral solution (or equivalent for placebo) is 100 mg, i.e., 
subjects weighing 80 kg or more will receive a maximum dose of 100 mg (5 mL of the 20 mg/mL 
solution).
The “to be used” oral solution stock (4 mg/mL or 20 mg/mL) will depend on the subject’s body 
weight. The subject’s weight will be recorded before the first dose of IMP. The weight should be 
measured after surgery if the surgery notably changes the weight of the child.
Dosing charts will be provided by the sponsor.
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Table 2:
Determination of tapentadol dose and oral solution concentration
Age of subject
Dose for the first 
24 hours
Dose after the first 
24 hours 
Body 
weight
Tapentadol oral 
solution or placebo
6 months to 18 years old
1.25 mg/kg
1.25 mg/kg or 1.0 mg/kg
20 kg
4 mg/mL
20 kg
20 mg/mL
30 days to 6 months old
0.5 mg/kg
0.5 mg/kg or 0.3 mg/kg
-
4 mg/mL
Birth to <30 days old
0.1 mg/kg
0.1 mg/kg or 0.075 mg/kg
-
4 mg/mL
The IMP does not require preparation unless very small volumes would need to be administered, in 
which case the IMP may be suitably diluted. This may be necessary, for example, for subjects less 
than 6 months old. The investigators will be supplied with instruction sheets for the preparation of 
the IMP. 
Volumes of 1 mL or less will be given using a 1 mL syringe with 0.05 mL graduations. Volumes of 
more than 1 mL will be given using a 5 mL syringe with 0.1 mL graduations.
10.2.2
Total dosing time and dosing interval
The IMP will be administered as an oral solution. The dosing interval is 4 hours (range 
±15 minutes). The reason for any delay in dosing beyond 4 hours 15 minutes needs to be 
documented. If the subject is sleeping at the time of the scheduled dose, they must be woken to take 
the IMP within a maximum of 6 hours after the previous dose. The dose of IMP must be taken as 
soon as possible after the subject is awake.
The administration of IMP is based on the investigator’s judgment of the subject’s condition and 
sedation level.
The dose of IMP may be reduced after 24 hours if there is a reduced need for analgesia according to 
the investigator’s judgment, as follows:
•
Age 6 months or more: 1.0 mg/kg. 
•
Age 30 days to less than 6 months: 0.3 mg/kg.
•
Age birth to less than 30 days old: 0.075 mg/kg.
Dosing with IMP will be stopped if:
•
A switch to exclusively oral opioid analgesic medication is indicated according to the local 
standard of care.
•
Opioid analgesic medication is no longer needed. 
•
IMP has been administered for 72 hours.
10.2.3
Administration
The route of IMP administration is oral. Subjects will be encouraged to take a small drink 
(approximately 25 mL of e.g., water or juice) after dosing to help ensure all medication is 
completely swallowed.
The IMP may be administered through, for example, a nasogastric tube (according to standard of 
care). The use of a nasogastric tube will be documented in the CRF. An interaction study of 
tapentadol with polyurethane, silicone, and polyvinyl chloride (PVC) tubes showed no interactions 
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or degradation of tapentadol, so the compound can be considered to be compatible with this method 
of dosing.
The administration must not be repeated if the subject vomits or regurgitates a complete dose. If 
only part of the dose is swallowed before vomiting or regurgitation, the remainder of the dose may 
be administered at the investigator’s discretion. Vomiting and/or regurgitation must be recorded as 
an adverse event.
10.3
Method of assigning subjects to treatment groups 
(allocation/randomization)
An IVRS/IWRS will be used to assign a subject number at the Enrollment Visit (Visit 1) and to 
support the drug supply chain management processes of distribution and return.
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 in a 2:1 tapentadol oral solution to placebo ratio. 
Computer-generated randomization will be implemented by using permuted blocks of treatments 
and stratified by predefined age groups (birth to <30 days, 30 days to <6 months, 6 months to 
<2 years, 2 years to <6 years, 6 years to <12 years, 12 years to <17 years, 17 years to <18 years) 
and supplemental opioid used (morphine versus hydromorphone).
Randomization numbers will be allocated in ascending order within each age group, and by 
ascending age group. 
The investigators must log into the system using their own user identification number and a 
password. The investigator will enter the subject’s number and other information required by the 
system to obtain the medication number of the IMP package for the subject.
10.4
Blinding and unblinding
10.4.1
Methods of blinding
Randomization and blinding will be done in accordance with the sponsor’s standard operating 
procedures (SOPs).
There are 4 randomization lists for this trial; 1 randomization list for each of the 3 youngest age 
groups (birth to <30 days, 30 days to <6 months, 6 months to <2 years), each stratified by 
supplemental opioid used (morphine versus hydromorphone), and 1 randomization list for the older 
age groups stratified by age group (2 years to <6 years, 6 years to <12 years, 12 years to <17 years, 
17 years to <18 years) and supplemental opioid use. Unblinding can be performed for 1 or more of 
these lists individually.
10.4.2
Methods of unblinding
The investigator, the responsible department of the sponsor, the responsible drug safety department, 
and contract research organization will receive appropriate methods for unblinding of single cases, 
i.e., via the IVRS/IWRS.
Personnel in the sponsor’s departments of clinical trials supply will be unblinded during the trial 
according to the sponsor’s SOPs for randomization and unblinding during the trial. Once the EU 
PDCO set has completed recruitment and data for these subjects is locked, unblinding will be 
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performed for those subjects aged 2 years and older. The additional age groups under 2 years old 
will be unblinded at the end of the trial. The qualified person for pharmacovigilance may be 
unblinded at any time during the trial.
Persons involved in the conduct (including subjects and investigators), data management, and 
analysis of the trial will remain blinded until unblinding is performed after data is locked. 
Unblinding will be initiated by the sponsor’s department of biostatistics according to the sponsor’s 
SOPs for randomization and unblinding.
Data will be unblinded for the DMC (Section 5.4).
10.4.3
Identification of investigational medicinal products
The blinding code may be broken if it is necessary and in that subject’s interest in order to identify 
the IMPs given, e.g., if knowing the identification of the treatment arm would lead to the 
investigator treating the subject differently. 
In addition, within drug safety, the blinding code may be broken for regulatory reporting, medico-
scientific assessment of adverse events, or on request of the qualified person for pharmacovigilance.
For every subject whose blinding code was broken, the following information must be documented 
on an “unblinding an individual subject form”:
•
The reason for, the date, and time of unblinding.
•
The person performing the unblinding.
•
The person(s) informed of the treatment allocation/randomization must be identified.
In order to maintain the double-blind nature of the trial, the allocation/randomization of IMPs for 
the subject must not be communicated further unless required for the surveillance of the subject or 
if necessary for urgent risk to benefit re-evaluation and/or measures for urgent risk minimization.
If required by local regulations, it may be that the IEC/IRB or the coordinating investigator needs to 
be informed.
10.5
Other medication
10.5.1
Supplemental opioid analgesic medication
Intravenous morphine or hydromorphone (supplemental opioid analgesic medication) will be 
administered by a controlled infusion pump using NCA/PCA for additional pain control during the 
period of IMP administration. 
The placement or replacement of the catheter and the settings for the NCA/PCA system will be 
predefined by the investigator and medically qualified staff according to the site’s standard of care. 
The settings include the doses of morphine/hydromorphone administered and lock-out times, which 
may be overridden as required. The device will be triggered by the subject, nurse, or treating 
physician. It is important for the sites to monitor subjects to ensure that they are using the device 
properly.
At some time after the surgery, the subject must have been started on NCA/PCA with morphine or 
hydromorphone, with or without a background infusion, according to the standard of care. The 
background infusion (if any) must be with a low dose infusion of the same opioid as that used for 
the NCA/PCA, i.e., morphine or hydromorphone.
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At the time of the first IMP administration, the background opioid infusion (if any) will be 
discontinued.
No background infusion is allowed after the first dose of IMP.
After the first dose of IMP (see Table 2), NCA/PCA will be continued with the same opioid as used 
previously (i.e., morphine or hydromorphone, defined as supplemental opioid analgesia), according 
to investigator judgment and standard of care.
The supplemental opioid analgesic medication must be purchased by the trial site unless otherwise 
agreed upon with the sponsor.
If the NCA/PCA intravenous line fails for any reason, it should be restarted/repaired immediately. 
During the interim, morphine or hydromorphone may be administered intravenously.
In exceptional cases, if a subject has unbearable pain despite using NCA/PCA, an additional bolus 
(defined as a clinician bolus) of morphine or hydromorphone may be administered. The clinician 
bolus can be given either using the NCA/PCA pump system or by an intravenous bolus injection.
10.6
Allowed and prohibited prior/concomitant medications
10.6.1
Prior medications
Restrictions apply to prior medication use (see Section 10.6.3 and Section 10.6.4).
10.6.2
Concomitant medications
Subjects will be instructed to only use allowed concomitant medications during the trial. 
If, in the interests of the subject’s safety, the administration of prohibited concomitant medications 
is required, the sponsor should be informed in advance (or promptly after the instance).
For information about potential interactions with concomitant medications, see the current 
investigator’s brochure.
Medication according to standard medical knowledge should be initiated in emergency situations.
10.6.3
Allowed prior and concomitant medications
Unless explicitly prohibited, all prior and concomitant medications are allowed.
Benzodiazepines may be used to treat muscle spasms or anxiety, consistent with local standard of 
care. They should be used with caution as they may potentiate central nervous system depression 
that may occur with tapentadol or other opioids.
Medications for the treatment of adverse events are allowed according to the investigator’s 
judgment and post-operative standard of care. For example, clinically relevant respiratory 
depression may be treated with naloxone, and nausea/vomiting can be treated with antiemetics, 
which may also be given prophylactically according to the standard of care.
If the NCA/PCA intravenous line fails for any reason, it should be restarted/repaired immediately.
During the interim, morphine or hydromorphone may be administered intravenously.
In exceptional cases, if a subject has unbearable pain despite using NCA/PCA, an additional bolus 
(defined as a clinician bolus) of morphine or hydromorphone may be administered. The clinician 
bolus can be given either using the NCA/PCA pump system or by an intravenous bolus injection.
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The opioid given as a clinician bolus or if the NCA/PCA intravenous line fails must be the same as 
that used in the NCA/PCA pump system.
The trade name of the medication, dose, and time will be recorded in the CRF.
10.6.4
Prohibited prior and concomitant medications/therapy
Prohibited medication from 14 days before allocation/randomization to IMP until 24 hours after 
the last administration of IMP
•
Monoamine oxidase inhibitors.
•
Strong enzyme inducing drugs (e.g., rifampicin, phenobarbital, St John’s Wort [hypericum 
perforatum]).
•
Neuroleptics, anticonvulsants (except for gabapentin used in association with surgery), 
antiparkinsonian drugs, and all serotonergic drugs including selective 
serotonin/norepinephrine reuptake inhibitors, tricyclic antidepressants, linezolid, triptans, 
and St. John’s Wort (hypericum perforatum).
•
Methadone.
Prohibited medication from 6 hours before allocation/randomization to IMP until 4 hours after the 
last administration of IMP
•
Long-acting opioids.
•
Medication used for sedation (as noted above, benzodiazepines may be used to treat muscle 
spasms or anxiety).
•
Peri- or post-operative analgesia supplied by a continuous regional technique (e.g., nerve 
block, wound infiltration catheter) or subject controlled epidural analgesia.
Prohibited medication/therapy from time of allocation/randomization to IMP until 4 hours after the 
last administration of IMP
•
Opioids (other than protocol defined morphine, hydromorphone, or IMP).
•
Continuous positive airway pressure or mechanical ventilation.
Restrictions for the mother of a newborn or breastfeeding mother
•
For monoamine oxidase inhibitors, neuroleptics, anticonvulsants, antiparkinsonian drugs, 
methadone, and all serotonergic drugs including selective serotonin/norepinephrine 
reuptake inhibitors, tricyclic antidepressants, linezolid, and triptans:
−
Prepartum intake by a mother of a newborn subject is prohibited in the 14 days prior to 
the subject’s allocation/randomization to IMP.
−
The intake of these medications by the breastfeeding mother of a subject is prohibited 
from 14 days prior to the subject’s allocation/randomization to IMP until the end of 
treatment with the IMP.
•
For opioid medication (including tapentadol formulations):
−
The intake of opioid medication (including tapentadol formulations) and medication 
used for sedation by the breastfeeding mother of a subject is prohibited from 48 hours 
prior to the subject’s allocation/randomization to IMP until the end of treatment with 
the IMP. 
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−
The intake of opioid medication (including tapentadol formulations) and medication 
used for sedation taken prepartum by the mother of a newborn subject is prohibited 
from 48 hours prior to the subject’s allocation/randomization to IMP.
10.7
Documentation of 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 and 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. The drug accountability log contains the source data for drug 
accountability.
The bottles of oral solution (tapentadol or placebo) will be weighed to determine the amount used. 
The instructions for weighing will be given separately. The weighing scales used must be 
appropriately calibrated and verified. Instructions for drug accountability will be given in the drug 
accountability log.
Before the unused and residual IMPs and other medications supplied to the investigator are returned 
or destroyed, the investigator must allow the sponsor’s representative 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.
11
TRIAL PROCEDURES
See Section 1.1 for a flow diagram summary of the trial and Section 1.2 for a tabular schedule of 
events.
Unless otherwise specified, all recordings are in the CRF.
11.1
Course of the trial
The trial consists of an Enrollment Period starting up to 28 days before allocation/randomization to 
IMP and lasting up to the time of allocation/randomization to IMP, whereby subjects may be 
enrolled in the trial either pre- or post-operatively; a Treatment and Evaluation Period (up to 
96 hours); and a Follow-Up Period (10 days to 14 days after the first dose of IMP).
11.1.1
Enrollment Period (Visit 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 duration of this period will be as per standard of care for the concerned surgery, but the start of 
enrollment is not to exceed 28 days before allocation/randomization to IMP. 
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The subject will undergo a scheduled surgery. This surgery is not part of the trial, but would be 
performed as per standard of care. Subjects may start enrollment before or after surgery.
At some time after the surgery, the subject must have been started on NCA/PCA with morphine or 
hydromorphone, with or without a background infusion, according to the standard of care. The 
background infusion (if any) must be with a low dose infusion of the same opioid as that used for 
the NCA/PCA, i.e., morphine or hydromorphone.
The Enrollment Period will be completed when the subject is allocated to IMP using IVRS/IWRS.
The following procedures will be performed during this period:
•
Obtain informed consent/assent (see Section 4.2). Subjects from whom assent is requested 
after surgery will be asked to give assent when they are properly stable and able to give 
assent according to the investigator’s judgment.
•
Record date of signing the informed consent/assent form, sex, race/ethnicity, and height. 
The data may be extracted from the hospital charts if already available according to the 
standard of care.
•
Record weight after surgery (can be measured before surgery if the surgery is not expected 
to notably change the weight). The BMI will be calculated automatically.
•
Record clinically relevant medical and surgical history. The data may be extracted from the 
hospital charts if already available according to the standard of care.
•
Record details about the surgery (the date of surgery, the indication, the type of surgical 
procedure, the start time and completion time of surgery). Surgery should be performed 
according to the usual standard of care at the site.
•
Perform a physical examination. The data may be extracted from the hospital charts if 
already available according to the standard of care; in this case, the physical examination 
need not be repeated for the trial.
•
Record prior medication and therapies, as appropriate (excluding anesthetics and 
medication used during the surgery). This includes the recording of prohibited medication 
used by breastfeeding mothers and prohibited prior medication used by mothers of a 
newborn subject.
•
Complete the C-SSRS “children’s baseline” questionnaire if the subject is aged 6 years or 
older. The C-SSRS will be explained and demonstrated at the time of the informed consent 
procedure. The administration of the C-SSRS must be performed after surgery. A refusal to 
answer the questions in the questionnaire that are appropriate for the subject must be 
recorded with the reason. Referrals to mental health professionals will be made as 
determined by the investigator. Record the initials of the interviewer.
•
Record vital signs (respiratory rate, systolic and diastolic blood pressure, and pulse rate)
after surgery directly before allocation/randomization to IMP.
•
Record oxygen saturation after surgery directly before allocation/randomization to IMP.
•
Record a 12-lead ECG. This must be performed after surgery.
•
Take blood for both local and central (children aged 2 years or older) or local (children 
younger than 2 years old) safety laboratory investigations when the subject is considered 
clinically stable after surgery. The values of the local laboratory will be used for 
verification of exclusion criteria.
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•
Perform a pregnancy test in female subjects if aged 12 years or older, or post-menarchal, or 
sexually active, within 48 hours prior to allocation/randomization to IMP.
•
Assess and record adverse events occurring after signing the informed consent/assent form.
•
Evaluate suitability for participation according to the inclusion/exclusion criteria.
•
Dispense subject trial card.
When the subject is able to tolerate liquids, meets the inclusion criteria, and does not meet any 
exclusion criterion, the subject will be allocated/randomized to IMP (tapentadol oral solution or 
placebo) using IVRS/IWRS. 
•
Record age at time of allocation/randomization (years for subjects aged 2 years and older, 
months for subjects aged 2 months [i.e., 60 days] to less than 2 years, and days for subjects 
aged less than 2 months [i.e., less than 60 days] – the day of birth is counted as day 1).
11.1.2
Treatment and Evaluation Period (Visit 2 and Visit 3)
11.1.2.1
Visit 2
Visit 2 starts once the subject has been allocated to IMP.
Before first dose of investigational medicinal product
•
Record the following details about opioid analgesic medication given by NCA/PCA and
given by background infusion (if any) after surgery. The recording is for a maximum of 
24 hours before the first IMP dose:
−
The trade names of the opioid analgesic medications used.
−
The routes of administration.
−
The times of each administration for NCA/PCA.
−
The doses of each administration for NCA/PCA.
−
The doses of the background infusion.
−
The times of starting and stopping the background infusion.
−
The lockout time.
•
Record the trade name, date, time, dose, dose unit, formulation, and route of administration 
of opioid and non-opioid analgesic medication given to the subject for the time period 
indicated in the schedule of events for analgesic medication (Section 1.2). 
•
Record intake of other concomitant medication and use of therapies as appropriate (the use 
of concomitant medication and therapies is to be recorded when they are started, stopped, 
or the dose changed), excluding anesthetics and medication used during the surgery. This 
includes the recording of prohibited medication used by breastfeeding mothers. 
•
Record the following directly before (i.e., within 10 minutes) administration of IMP:
−
Vital signs (respiratory rate, systolic and diastolic blood pressure, and pulse rate).
−
Sedation score (see Section 12.3.10).
−
Oxygen saturation.
−
Pain intensity (see Section 12.2.5).
•
Assess and record adverse events (adverse events are to be recorded and assessed at the 
time when they occur).
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•
Assess discontinuation criteria (Table 1, Section 9.3.1).
•
Start or continue continuous monitoring of heart rate and respiratory rate. This is to be 
continued for 24 hours after the first administration of IMP. 
−
Record clinical relevant values as adverse events.
•
Start or continue continuous measurement of oxygen saturation by pulse oximetry. This is 
to be continued until 4 hours after the last administration of IMP. 
−
Record values below 92% for at least 60 seconds (excluding technical failures or 
artifacts).
Administration of first dose of investigational medicinal product (Day 1)
The subject will only receive IMP if the SpO2 does not drop below 92% for a period of 60 seconds
in the 10 minutes before IMP administration.
The first dose of IMP is given when IMP is available on the ward and the investigator determines it 
is medically appropriate for the subject to receive the IMP. The time between allocation to IMP and 
first administration should be kept as short as possible.
At the time of the first IMP administration, the background opioid infusion (if any) will be 
discontinued.
The IMP will be administered as an oral solution as described in Section 10.2.
•
Record dose and time of administration of IMP.
Dosing with IMP will be stopped if:
•
A switch to exclusively oral opioid analgesic medication is indicated according to the local 
standard of care.
•
Opioid analgesic medication is no longer needed. 
•
IMP has been administered for 72 hours.
After the first dose of investigational medicinal product
After the first dose of IMP, NCA/PCA will be continued with the same opioid as used previously 
(i.e., morphine or hydromorphone, defined as supplemental opioid analgesia), according to 
investigator judgment and standard of care. Subjects must be carefully observed, especially during 
the first hour after the initiation of IMP.
•
Administer supplemental opioid analgesic medication as required (by NCA/PCA, see 
Section 10.5.1). Record the following at times consistent with the memory of the 
NCA/PCA pump for the time period indicated in the schedule of events (Section 1.2):
−
The trade names of the supplemental opioid analgesic medications used.
−
The times of each administration.
−
The doses of each administration.
−
The lockout time.
−
The trade name of intravenous morphine or hydromorphone, dose, and time of dosing if 
the NCA/PCA fails, or a clinician bolus is given.
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•
Pain intensity scores should be obtained before each NCA/PCA activation, whenever 
possible. However, the NCA/PCA activation should not be unduly delayed by the pain 
intensity assessment. Pain intensity scores should also be obtained if intravenous morphine 
or hydromorphone is given if the NCA/PCA line fails, or if a clinician bolus is given.
•
Record pain intensity within 30 minutes to 60 minutes after the first dose of IMP only (see 
Section 12.2.5). Subjects do not need to be woken for this assessment.
•
Record the palatability and acceptability of the oral solution after the first dose of IMP in 
subjects aged 2 years to less than 18 years old.
•
Record intake of concomitant medication and use of therapies as appropriate (the use of 
concomitant medication and therapies is to be recorded when they are started, stopped, or 
the dose changed). This includes the recording of prohibited medication used by 
breastfeeding mothers.
•
Record the trade name, date, time, dose, dose unit, formulation, and route of administration 
of non-opioid analgesic medication given to the subject for the time period indicated in the 
schedule of events (Section 1.2). The same details of any additional opioid medication used 
inadvertently must be collected.
•
Assess and record adverse events (adverse events are to be recorded and assessed at the 
time when they occur).
Before subsequent doses of investigational medicinal product
The subject will only receive IMP if the SpO2 does not drop below 92% for a period of 60 seconds 
in the 10 minutes before IMP administration.
The following procedures will be performed before the administration of each subsequent dose of 
IMP:
•
Record the following directly before (i.e., within 10 minutes) administration of IMP:
−
Vital signs (respiratory rate, systolic and diastolic blood pressure, and pulse rate).
−
Sedation score (see Section 12.3.10).
−
Oxygen saturation.
−
Pain intensity (see Section 12.2.5).
•
Record the following details about the use of supplemental opioid analgesic medication (by 
NCA/PCA) at times consistent with the memory of the NCA/PCA pump for the time period 
indicated in the schedule of events (Section 1.2):
−
The trade names of the supplemental opioid analgesic medication used.
−
The times of each administration.
−
The doses of each administration.
−
The lockout time.
−
The trade names of intravenous morphine or hydromorphone, dose, and time of dosing 
if the NCA/PCA fails, or a clinician bolus is given.
•
Pain intensity scores should be obtained before each NCA/PCA activation, whenever 
possible. However, the NCA/PCA activation should not be unduly delayed by the pain 
intensity assessment. Pain intensity scores should also be obtained if intravenous morphine 
or hydromorphone is given if the NCA/PCA line fails, or if a clinician bolus is given.
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•
Record intake of concomitant medication and use of therapies as appropriate (the use of 
concomitant medication and therapies is to be recorded when they are started, stopped, or 
the dose changed). This includes the recording of prohibited medication used by 
breastfeeding mothers.
•
Record the trade name, date, time, dose, dose unit, formulation, and route of administration 
of non-opioid analgesic medication given to the subject for the time period indicated in the 
schedule of events (Section 1.2). The same details of any additional opioid medication used 
inadvertently must be collected.
•
Assess and record adverse events (adverse events are to be recorded and assessed at the 
time when they occur).
•
Assess discontinuation criteria (Table 1, Section 9.3.1).
11.1.2.2
Administration of investigational medicinal product
•
Record dose and time of administration of each dose of IMP.
11.1.2.3
Visit 3 (End of Treatment Visit)
Visit 3 will be performed between 4 hours and 24 hours after the last administration of IMP, or if 
the subject is prematurely discontinued from the trial. The visit must be performed before discharge 
from hospital.
The following procedures will be performed:
•
Perform a physical examination (record that a full examination has been performed and 
only record changes to Visit 1).
•
Record the trade name, date, time, dose, dose unit, formulation, and route of administration 
of non-opioid analgesic medication given to the subject for the time period indicated in the 
schedule of events (Section 1.2). The same details of any additional opioid medication used 
inadvertently must be collected.
•
Record intake of other concomitant medication and therapies as appropriate (the use of 
concomitant medication and therapies is to be recorded when they are started, stopped, or 
the dose changed). This includes the recording of prohibited medication used by 
breastfeeding mothers.
•
Complete the C-SSRS questionnaire “children’s since last visit” if the subject is aged 
6 years or older. A refusal to answer the questions in the questionnaire that are appropriate 
for the subject must be recorded with the reason. Record the initials of the interviewer.
•
Record vital signs (respiratory rate, systolic and diastolic blood pressure, and pulse rate).
•
Record oxygen saturation.
•
Record a 12-lead ECG.
•
Take blood for safety laboratory (to be sent to the central laboratory for children aged 
2 years or older or local laboratory for children younger than 2 years old).
•
Record pain intensity (see Section 12.2.5). Pain intensity scores should be obtained before 
each NCA/PCA activation, whenever possible. However, the NCA/PCA activation should 
not be unduly delayed by the pain intensity assessment. Pain intensity scores should also be 
obtained if intravenous morphine or hydromorphone is given if the NCA/PCA line fails, or 
if a clinician bolus is given.
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•
Record the palatability and acceptability of the oral solution in subjects aged 2 years to less 
than 18 years old.
•
Record global impression of change by investigator/clinician (CGIC) and subject (PGIC) if 
capable of completing the questionnaire (or parent/legal guardian).
•
Perform and document drug accountability.
•
Assess and record adverse events (adverse events are to be recorded and assessed at the 
time when they occur).
•
Assess discontinuation criteria (Table 1, Section 9.3.1).
The subjects will be discharged from the site according to site routine.
11.1.3
Follow-up Visit (Visit 4; Day 10 to Day 14)
This visit may be performed by telephone.
The following procedures will be performed at the Follow-up Visit:
•
Record intake of concomitant medication and therapies as appropriate.
•
Assess and record adverse events.
11.2
Examination hierarchy and time windows
Non-invasive procedures (including completion of questionnaires) should generally be performed 
first. Blood samples for safety laboratory should be taken after all non-invasive procedures have 
been completed. The order that procedures are performed may deviate due to local circumstances 
and a change in the order does not constitute, per se, a protocol deviation.
Time windows for procedures are given, where applicable, in the schedule of events (Section 1.2).
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 precautions and 
emergencies, e.g., for the management of overdose, relevant for this trial.
11.3.2
General restrictions
Subjects must be willing to adhere to the following conditions and restrictions during the course of 
the trial to be eligible for participation:
•
Subjects must remain at the trial site for at least 4 hours after the last administration of IMP.
•
Subjects may not drink beverages containing alcohol until the Visit 3 (End of Treatment 
Visit) has been completed.
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11.3.3
Counseling of female subjects of childbearing potential
All female subjects who are capable of childbearing, who are post-menarchal or sexually active, 
should be counseled on the need to practice medically acceptable methods of birth control during 
the trial and on the importance of avoiding pregnancy. 
Sexually active girls must use one of the following acceptable methods of birth control:
•
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 site 
staff immediately if pregnancy is suspected within 30 days after the last dose of IMP.
11.4
Subject trial cards
Subjects who are enrolled in the trial will receive a “subject trial card”. The trial card will list the 
following information:
•
Name of the subject and the name(s) of the parent(s) or legal guardian and a statement that 
the subject is currently participating in a clinical trial.
•
Trial code.
•
Dates of the trial periods.
•
Name of investigator.
•
Contact (telephone) number at the trial site.
11.5
Provisions of any additional care of subject after trial termination
After completion of the End of Treatment Visit (Visit 3), subjects will be treated by their physicians 
according to the specific standard treatment at the site concerned.
11.6
Handling of low enrollment
Sites with a low recruitment rate and/or which persistently deviate from the protocol 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 8 weeks of IMP availability at the site.
11.7
Overview of blood sampling in this trial
Blood sampling
Blood samples may be collected using a central venous line or an indwelling cannula (e.g., with a 
Mandrin) inserted either during surgery or shortly thereafter or by venipuncture according to the 
standard of care at the site. 
Repeat or unscheduled samples may be taken for safety reasons. For details of steps taken to reduce 
the risk to the subjects regarding blood sampling, please see Section 8.5.
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The approximate amount of blood drawn for this trial is given in Table 3. Local laboratories can use 
microsampling, especially for subjects aged <2 years old, so these blood volumes may be lower.
Table 3:
Approximate volume of blood to be collected from each subject
Assessment
Approximate 
blood 
volume per 
sample
Number of samples
Approximate total blood 
volume per test a
2 years to <18 years
<2 years b
2 years to <18 years
<2 years
Clinical chemistry
2 mL
2 for central, 1 for local
2 for local
6 mL
4 mL
Hematology
2 mL
2 for central, 1 for local
2 for local
6 mL
4 mL
Total
12 mL
8 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.
b) For subjects with a low body weight, blood sampling for clinical chemistry and hematology may be limited to a 
subset of clinical chemistry evaluations only to keep the total blood volume drawn low.
The volume of blood drawn from subjects who participate in the trial will not exceed the 
recommended limits (Section 8.4).
For subjects aged 2 years and older, the total blood volume drawn per subject will not exceed 
approximately 15 mL during the trial (even if additional blood is drawn for a pharmacokinetic 
analysis if a serious adverse event occurs) (Table 3). 
For subjects aged less than 2 years old, blood sampling for clinical chemistry and hematology 
should be performed such that blood volumes taken do not exceed 0.8 mL/kg body weight for each 
sampling time point, and 2.4 mL/kg in total (EMEA ad hoc working party 2008). 
For subjects less than 6 months old with a low body weight, such that the drawing of sufficient 
blood sample volumes for both clinical chemistry and hematology are precluded, the tests may be 
limited to a subset of clinical chemistry evaluations only (the tests to be performed are alanine 
transaminase and aspartate transaminase, alkaline phosphatase, and creatinine [with calculation of 
the glomerular filtration rate]). Local site-specific guidelines must also be adhered to. Other 
chemistry and hematology values from samples taken for the standard of care may be used to 
supplement the safety laboratory profile.
12
DATA COLLECTION
The following data collected for this trial will be recorded/documented in the CRF.
12.1
Collection of subject characteristics data
12.1.1
Demographic data
Demographic data to be collected and recorded for this trial includes date of signing the informed 
consent/assent form, sex, age at time of allocation/randomization (years for subjects aged 2 years 
and older, months for subjects aged 2 months [i.e., 60 days] to less than 2 years, and days for 
subjects aged less than 2 months [i.e., less than 60 days] – the day of birth is counted as day 1), 
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race/ethnicity, height, and weight. The BMI will be calculated automatically by the IVRS/IWRS or 
electronic CRF. 
12.1.2
Prior and concomitant medications
All medication requiring prescriptions (including oral contraceptives) and/or over-the-counter 
medication used within 28 days before allocation/randomization to IMP and up to the end of the 
trial must be recorded, excluding anesthetics and medication used during the surgery.
All additions to or changes after enrollment must be recorded. Any change in dosage (analgesics 
only), regimen, or route, must be recorded as a new entry.
Trade names should be given in preference to generic names when recording medication. The 
generic name may be used if the trade name is not available.
Prohibited medication used by the mother of a newborn or breastfeeding mother will be recorded.
12.1.2.1
Opioid analgesic medication given by NCA/PCA and background infusion
The following details about opioid analgesic medication given by NCA/PCA and by background 
infusion (if any) after surgery will be recorded. The recording is from up to 24 hours before first 
dose of IMP until the End of Treatment Visit:
•
The trade names of the opioid analgesic medications used.
•
The routes of administration.
•
The times of each administration for NCA/PCA.
•
The doses of each administration for NCA/PCA.
•
The doses of the background infusion.
•
The times of starting and stopping the background infusion.
•
The lockout time.
12.1.2.2
Detailed information for other analgesic (opioid and non-opioid) medication
The trade name, date, time, dose, dose unit, formulation, and route of administration of analgesic 
medication will be recorded, irrespective of the indication. The detailed recording of these 
medications is limited to after surgery (starting up to 24 hours before first IMP dose) until the End 
of Treatment Visit, as indicated in the schedule of events (see Section 1.2). 
12.1.3
Prior and concomitant therapies
All therapies used within 28 days before allocation/randomization to IMP and up to the end of the 
trial must be recorded. 
12.1.4
Medical and surgical history
The clinically relevant medical and surgical history of the subject per investigator’s opinion is 
required to be documented.
12.1.5
Surgery
The following details about the surgical procedure will be recorded: date of surgery, the indication, 
type of surgical procedure, and start time and completion time of surgery.
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12.1.6
Other data
The times of starting and stopping the continuous monitoring of pulse oximetry, respiration rate, 
and heart rate will be recorded. If the IMP is given via a nasogastric tube, this will be documented.
Pain intensity scores (see Section 12.2.5 for a description of the pain intensity scales) will be 
collected before each NCA/PCA activation, whenever possible.
12.2
Collection of efficacy data
During the trial, the evaluations described in Section 12.2.1 to Section 12.2.5 will be performed at 
the time points indicated in the schedule of events (see Section 1.2). Where appropriate, information 
related to the rationale for these evaluations is in Section 12.4.
12.2.1
Amount of supplemental opioid used
The details of the supplemental opioid analgesic medication used (see Section 12.1.2.1) will be 
recorded at times consistent with the memory of the NCA/PCA pump from the first dose of IMP, as 
indicated in the schedule of events (see Section 1.2).
Details of intravenous morphine or hydromorphone used if the NCA/PCA line fails, or a clinician 
bolus is given will also be recorded.
12.2.2
Amount of non-opioid analgesic medication used
Detail of the administration of non-opioid analgesic medication will be recorded as given in 
Section 12.1.2.2, irrespective of the indication.
12.2.3
Global impression of change
12.2.3.1
Patient Global (overall) Impression of Change
The PGIC will be assessed at the End of Treatment Visit (Visit 3) as specified in Section 1.2 if the 
subject is capable of completing the questionnaire (the parent/legal guardian may complete the 
questionnaire on behalf of the subject – it will be documented if help was given) (Section 1.2). 
Subjects verbally rate their impression of overall status with 1 of 7 possible responses (very much 
improved, much improved, minimally improved, no change, minimally worse, much worse, very 
much worse) (Section 19.8).
12.2.3.2
Clinical Global Impression of Change
The CGIC will be assessed at the End of Treatment Visit (Visit 3) as specified in Section 1.2.
The investigators will rate the subject’s global improvement and satisfaction with the treatment on a 
7-point scale that ranges from “very much improved” to “very much worse” with “no change” as 
the mid-point (Section 19.8). The CGIC (Schneider et al. 1997) was chosen as a complementary 
assessment of analgesic efficacy. 
Inter-rater reliability will be assessed for the CGIC as part of site training.
12.2.4
Palatability and acceptability of IMP
Responses for palatability and acceptability will be evaluated in subjects aged 2 years to less than 
18 years old on 5-point hedonic scales in combination with a verbal rating and documented 
(Guinard 2001), unless the subject is administered the IMP by a nasogastric tube.
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Palatability will be assessed by asking the following question “How does the medication 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 medication is ...”. 
The verbal rating is really easy, easy, a bit easy/a bit difficult, difficult, and really difficult
(Section 19.6).
12.2.5
Pain intensity
The investigator or deputy will record the results of the pain measurements in the subject’s medical 
file before recording the data.
Documentation of the pain scales actually used will be maintained.
Subjects will continue using the same pain scale that they started with even if they change age 
group during the trial. The pain scales will be used in the following age groups:
•
FLACC – birth to less than 6 years or in older children who are not able to report their pain 
using the other scales.
•
FPS-R – 6 years to less than 12 years old.
•
VAS – 12 years to less than 18 years old.
The sites will be supplied with a manual on how to implement the pain scales.
12.2.5.1
Face, Legs, Activity, Cry, and Consolability scale
The FLACC scale is a measurement used to assess pain in this trial for children aged from birth to 
less than 6 years, or in subjects unable to communicate their pain (Merkel et al. 1997). The scale 
has a range of 0 to 10, with 0 representing no pain, calculated from 5 criteria (relating to the face, 
legs, activity, crying, and consolability) that are each assigned a score of 0, 1 or 2 (see example in 
Section 19.2). The investigator will record the results of these measurements in the subject’s 
questionnaire before recording the data in the CRF. The total score will not be captured by the CRF 
but will be calculated during the analysis of the trial. Inter-rater reliability will be evaluated for the 
FLACC as part of site training.
12.2.5.2
Faces Pain Scale - revised
The FPS-R will be recorded in children aged 6 years (if possible) to less than 12 years (see example 
in 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. The investigator or designee will record the results of these measurements in the subject’s 
medical file before recording the data. It will be documented if help was given by a parent/legal 
guardian.
12.2.5.3
Visual analog scale
For children aged 12 years to less than 18 years, the pain intensity will be assessed by use of a VAS 
(see example in Section 19.4). The subject will be asked to draw a single line to indicate the current 
level of pain intensity at the time of assessment on a 100 mm long VAS. The scoring is the distance 
in millimeters across the scale. The investigator will record the results of these measurements in the 
subject’s medical file before recording the data. It will be documented if help was given by a 
parent/legal guardian.
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12.3
Collection of safety data
The following safety data will be collected:
•
Adverse events.
•
Safety laboratory.
•
Pregnancy test for female subjects aged 12 years or older, or post-menarchal, or sexually 
active.
•
12-lead ECG.
•
Vital signs (respiratory rate, systolic and diastolic blood pressure, and pulse rate).
•
Reporting of clinically relevant values arising from continuous monitoring of respiratory 
rate and heart rate as adverse events.
•
Oxygen saturation (by pulse oximetry), including values below 92% for at least 60 seconds.
•
Physical examination.
•
C-SSRS score in subjects aged 6 years or older.
•
University of Michigan Sedation Scale score.
Clinically relevant values (investigator’s judgment) will be recorded as adverse events.
12.3.1
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).
All adverse events will be classified as non-TEAEs or TEAEs by the sponsor or sponsor’s designee.
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.
Pregnancy
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.
All pregnant subjects will be discontinued from the trial/trial treatment.
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. Non-TEAEs are also those adverse events occurring after start of trial treatment, but 
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beyond the therapeutic reach (i.e., the number of days after treatment completion that a subject is 
still considered to be potentially affected by IMP as defined in the statistical analysis plan).
Definition of treatment emergent adverse events
All adverse events occurring in a subject administered a trial treatment and which do not necessarily 
have a causal relationship with this treatment. The therapeutic reach relevant for this determination 
(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. In addition, pre-treatment adverse 
events which worsen during the treatment period are also considered TEAEs.
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 events.
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. The investigator should consider whether 
discontinuation from the IMP or trial is needed, based on the characteristics of a particular serious 
adverse event, e.g., if the serious adverse event precludes further safe participation in the trial.
If possible, after all serious adverse events, a blood sample for the central laboratory quantitation of 
systemic exposure of tapentadol and tapentadol-O-glucuronide should be drawn in close temporal 
relationship to the serious adverse event.
Definition of unexpected treatment emergent adverse events
Expectedness will be assessed by the sponsor.
An unexpected TEAE is one where the nature or intensity is not consistent with the information in 
the investigator’s brochure. 
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 (synonymous with drug-related adverse events) are all untoward and 
unintended responses to an IMP independent of the dose administered. 
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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 IMP is given in the current version of the investigator’s 
brochure.
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.
For adverse events where the intensity changes over time, the maximum intensity observed during 
the whole duration of the adverse event will be documented.
Definition of outcome at the time of last observation
The outcome at the time of last observation (see Section 11.1.3) 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.
All adverse events will be documented in the CRF with the following information where 
appropriate:
•
Description (adverse event verbatim term).
•
Start date/time.
•
End date/time or continuation.
•
Whether adverse event was serious.
•
Intensity.
•
Outcome.
•
Action taken with IMP.
•
Countermeasures.
•
Causal relationship to IMP.
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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 investigational medicinal product when an adverse event 
occurs:
•
Drug withdrawn.
•
Dose not changed.
•
Dose decreased.
•
Not applicable.
•
Unknown.
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 (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).
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•
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).
•
Whether and when blinding was broken.
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/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 all 
competent authorities in all the member states concerned, FDA, and to the IEC/IRB, 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 adverse reactions will be reported to the competent authorities concerned and to the 
IEC/IRB 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/IRB 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.
12.3.2
Safety laboratory
For details regarding blood sampling, including volumes of blood taken, please see Section 11.7. 
Blood samples for this trial should, if possible, be taken at the same time as routine blood sampling.
Before allocation/randomization to IMP, the required blood samples may be taken together and 
separated by the laboratory.
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The following tests will be performed unless the weight of the subject precludes full blood 
sampling, in which case the tests may be limited (see Section 11.7):
Hematology panel
Hemoglobin
Mean corpuscular volume (MCV)
Hematocrit
Mean corpuscular hemoglobin (MCH)
Red blood cell (RBC) count
Mean corpuscular hemoglobin concentration (MCHC)
Platelet count
White blood cell (WBC) count with differential count
Clinical chemistry panel 
Sodium
Lipase (not required for the local laboratory assessment)
Potassium
Triglycerides
Chloride
Total bilirubin
Bicarbonate
Alkaline phosphatase
Blood urea nitrogen (BUN)
Creatine kinase
Creatinine
Lactic acid dehydrogenase (LDH)
Uric acid
Alanine transaminase (ALT)
Calcium
Aspartate transaminase (AST)
Phosphorus
Glucose
Total protein
Clinical chemistry and hematology – central laboratory (for subjects aged 2 years to less than 
18 years)
Blood samples will be drawn for clinical chemistry and hematology for central safety laboratory 
testing after surgery when the subject is considered clinically stable before allocation/randomization
to IMP. A further sample will be taken at the End of Treatment (see schedule of events, 
Section 1.2).
The samples will be analyzed at a central laboratory. The results of the central laboratory will be 
transferred electronically to the sponsor. 
The trial site will follow the instructions provided in the laboratory manual regarding the specific 
procedures for collection of all blood samples.
The investigator must review the laboratory report, document this review, and record any clinically 
relevant changes during the trial in the adverse event section of the CRF. Appropriate action should 
be taken if necessary.
The glomerular filtration rate will be estimated according to Schwartz et al. 1984. 
If the red or white blood cell analyses are clinically relevantly abnormal, the red or white cell 
morphologies must be reported, respectively.
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Clinical chemistry and hematology – local laboratory (all subjects)
Blood samples for clinical chemistry and hematology for the local laboratory will be taken at the 
same time as the blood sample for the central laboratory before allocation/randomization to IMP for 
subjects aged 2 years to less than 18 years. For subjects less than 2 years old, only the blood sample 
for local analysis will be taken.
The results of blood analyzed in a local laboratory for clinical chemistry and hematology will be 
used for verification of the exclusion criteria. The results of the tests must be available for review 
before a subject is allocated to IMP. Parameters specified in the exclusion criteria need to be 
reviewed. This does not preclude the need to take a sample for central laboratory analysis for 
subjects aged 2 years to less than 18 years.
12.3.2.1
Serum concentrations of tapentadol
A 0.5 mL blood sample for analysis of serum concentrations of tapentadol needs to be drawn if 
there is a serious adverse event. Instructions for handling the pharmacokinetic samples are given in 
Section 19.10.
Serum samples will be analyzed to determine concentrations of tapentadol and, optionally, 
tapentadol-O-glucuronide using a validated liquid chromatography-tandem mass spectrometry 
bioanalytical assay under the supervision of the department of pharmacokinetics at the sponsor.
12.3.3
Pregnancy test
For female subjects if aged 12 years or older, or post-menarchal, or sexually active, a pregnancy test 
will be performed within 48 hours prior to allocation/randomization to IMP. This may be done on a 
serum sample according to local routine, or using a urine dipstick test (either supplied by the 
sponsor or a local test capable of detecting human chorionic gonadotropin levels of 25 mIU/mL or 
greater and a sensitivity/specificity of >99%).
12.3.4
Twelve-lead electrocardiogram
Twelve-lead ECGs will be recorded after surgery prior to allocation/randomization to IMP and at 
End of Treatment. The measured ECG intervals will be RR, PR, QRS, and QT; the corrected 
[Fridericia] QTcF will be calculated. The investigator will review the 12-lead ECG for clinically 
relevant abnormalities prior to dosing subjects. The investigator will document all abnormal 12-lead 
ECG results, with a judgment whether the abnormality is clinically relevant.
12.3.5
Vital signs (respiratory rate, systolic and diastolic blood pressure, and 
heart rate) and oxygen saturation
Vital signs (respiratory rate, systolic and diastolic blood pressure, and pulse rate) and oxygen 
saturation (by pulse oximetry) will be measured as per standard of care and recorded at the times 
specified in the schedule of events (see Section 1.2).
12.3.6
Continuous monitoring of respiratory rate and heart rate
Respiratory rate and heart rate will be monitored continuously for 24 hours after the first 
administration of IMP. The monitoring outside of this time period is according to standard of care.
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12.3.7
Continuous monitoring of oxygen saturation 
Oxygen saturation will be monitored continuously using pulse oximetry from before the first dose 
of IMP until 4 hours after the last administration of IMP. If the oxygen saturation falls below 92% 
for at least 60 seconds (excluding technical failures or artifacts), the lowest value, the length of time 
the oxygen saturation is below 92%, and vital signs are to be recorded. The event is to be recorded 
as an adverse event as well. The monitoring outside of this time period is according to standard of 
care.
12.3.8
Physical examination
The physical examination comprises but is 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, and 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.
12.3.9
Columbia–suicide severity rating scale
The C-SSRS (Section 19.5, Oquendo et al. 2003) will be completed at the specified times in 
Section 1.2 in subjects aged 6 years or older. There are 2 versions, 1 version for children’s baseline
(used at Enrollment after surgery) and 1 version for children’s since last visit (used at End of 
Treatment Visit). The C-SSRS reports the severity of both suicidal ideation and suicidal behavior. 
The evaluation will be recorded. A refusal to answer the questions in the questionnaire that are 
appropriate for the subject must be recorded with the reason.
The C-SSRS also captures information about the intensity of ideation, specifically the frequency, 
duration, controllability, deterrents, and reasons for the most severe types of ideation. 
The C-SSRS will be administered by a clinician who has been certified to administer the C-SSRS.
The C-SSRS will be explained and shown to the parents/legal guardians prior to use.
The C-SSRS will only be used at a trial site if its use has not been rejected by the responsible ethics 
committee.
12.3.10
University of Michigan Sedation Scale
The University of Michigan Sedation Scale (Section 19.11) is a validated (Malviya et al. 2002) 
observational pediatric 5-point sedation scale. It will be used to assist in accurately assessing the 
depth of sedation before the administration of IMP. The investigator will record the sedation score 
at the times specified in the schedule of events (see Section 1.2).
12.4
Appropriateness of measurements
During the trial, exploratory subject-reported pain assessments and supplemental analgesic (opioid 
and non-opioid) medication dosing information will be collected. 
In children aged from birth to less than 6 years, or in older children who are not able to report their 
pain using the other scales, pain intensity will be assessed with the FLACC scale (Merkel et al. 
1997). The FLACC scale has been validated for measuring post-operative pain in children with 
mild to severe cognitive impairment. It has also been validated for the assessment of pain secondary 
to surgery, trauma, cancer or other painful diseases for all pre-verbal children (including infants).
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In children aged 6 years to less than 12 years, pain intensity will be assessed with the FPS-R. The 
FPS-R scale has been established as a valid, self-reported measure of pain intensity in children aged 
4 years to 15 years (Hicks et al. 2001, Miró and Huguet 2004).
In children aged 12 years to less than 18 years, pain intensity will be assessed with a VAS. The 
VAS pain intensity rating scale (Scott and Huskisson 1976) has been established as a valid, self-
reported measure of pain intensity in children aged 8 years to 18 years with juvenile chronic 
polyarthritis (Scott et al. 1977).
The global impressions of change were chosen as a complementary assessment of analgesic 
efficacy (Section 12.2.3). It is a recommended and responsive outcome measure for pain-related 
clinical trials (Dworkin et al. 2005, Farrar et al. 2001).
12.5
Compliance
Compliance is the adherence to all trial-related requirements (including treatments), GCP, and 
applicable regulatory requirements.
Site compliance will be assured by the implementation of a quality system and the performance of a 
combination of trial site visits, training, and monitoring visits. 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/IRB.
The IMP will be administered in the controlled environment of a clinical research site, and the 
direct observation of the administration of IMP by trial staff will ensure compliance with trial 
requirements. Dose, date, and time of the administration of the IMP will be recorded in the CRF and 
the source documents.
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.
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.
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The investigator, the clinical research associate, and designated persons at the site and from other 
parties involved (e.g., data management) will be able to review all captured data during the trial via 
a secure internet connection.
After source data verification, the corresponding 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 re-signing by the investigator.
13.2
Subject reported outcomes
All subject reported outcomes will stay as source data at the site. The investigator is responsible for 
the accurate transfer of these data into the CRFs.
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 World Health Organization-Drug Dictionary. Medical 
history terms and adverse events will be coded using MedDRA. As required by the sponsor’s SOPs, 
the version 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 and 12-lead ECG data) will be 
reconciled against CRF data (details of reconciliation will be specified separately but may include 
trial number, site number, patient 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 final data transfer.
Database lock
There will be 2 data locks for this trial. For the first report, only data for the EU PDCO set will be 
locked within the electronic CRF, the CRF will not be shut down. Any potential subsequent 
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unlocking of this set of data will be performed according to the sponsor’s SOPs for database unlock. 
The subjects’ data will be locked as soon as all data for the EU PDCO set are considered clean (i.e.,
all data have been received and entered, all data checks and quality control checks on these data 
have been performed, and all queries for these data are resolved). The same procedure will apply for 
the final data lock at the end of the trial.
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 
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, ethics committee review, and regulatory 
inspection.
In certain circumstances, data may only be recorded in the trial-specific CRF and not in other 
documents. When this occurs, the CRF is considered to be the source document. Data expected to 
be only recorded in the CRF are: race/ethnic group, and the result of the estimation of the 
glomerular filtration rate according to Schwartz et al. 1984.
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).
During trial conduct, vendors are responsible for data security with oversight from the sponsor. 
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.
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 
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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 
clinic/hospital policy, but at least until informed by the sponsor that the trial-related records are no 
longer required.
14
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION
There are different requirements for the EU PDCO and US FDA including the age range of the 
patient population (EU PDCO: 2 years to <18 years of age, US FDA: birth to <17 years of age) and 
the timing of the primary efficacy endpoint (EU PDCO: 24 hours, US FDA: 12 hours) that impact 
the statistical methods and are reflected in the following sections.
As applicable and appropriate for the individual endpoint, the endpoints will be analyzed in the age 
ranges for the EU PDCO and for the US FDA.
Two reports will be prepared for the trial. The first report will be prepared after the last subject out 
of the EU PDCO set. The second report will be prepared after the last subject out of the US FDA 
set. Further details on the reports are given in Section 16.6.
14.1
Sample size rationale 
The sample size determination was based on the primary efficacy endpoint variable for the 
respective Full Analysis Sets. A linear relationship is assumed between the 12 hour and 24 hour 
supplemental opioid analgesic use for the purposes of the sample size calculation and the final 
analyses. 
The sample size calculation was based on results, summarized in Table 4, from previously 
conducted trials in post-surgical pediatric subjects where supplemental opioid was measured.
Table 4:
Differences in amount of supplemental opioid use in previously conducted trials in 
post-surgical pediatric subjects
Reference
Supplemental opioid use (morphine or 
morphine-equivalent) in original units
Converted to cumulative 
use over 24 hours (mg/kg)
Treatment group 
difference based on 
cumulative use over 
24/12 hours (mg/kg)
Rusy et al.
2010
Placebo: 0.055 ± 0.017 mg/kg per h
Gabapentin: 0.046 ± 0.016 mg/kg per h
Placebo: 1.32 ± 0.408
Gabapentin: 1.10 ± 0.384
0.22/0.11
Rugyte
and Kokki 
2007
Placebo: 0.028 ± 0.0083 mg/kg per h
Ketoprofen: 0.020 ± 0.0100 mg/kg per h
Placebo: 0.67 ± 0.20
Ketoprofen: 0.49 ± 0.24
0.18/0.09
For the current trial, a value of 0.20 mg/kg in 24 hours (0.10 mg/kg in 12 hours) for the between-
treatment group difference and a more conservative value of 0.42 mg/kg in 24 hours (0.21 mg/kg in 
12 hours) for the standard deviation were considered adequate assumptions. The standardized effect 
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size based on these values (0.20/0.42 = 0.48) is more conservative than the standardized effect sizes 
observed in Rusy et al. 2010 (approximately 0.55) or Rugyte and Kokki 2007 (approximately 0.80).
Assuming α = 0.05 (two-sided), 80% power (β = 0.2), and a randomization ratio of 2:1 (tapentadol 
to placebo) results in a sample size of 106 tapentadol-treated subjects and 53 placebo-treated 
subjects. 
No multiplicity adjustment will be performed.
The target is to have approximately 159 randomized (allocated) subjects treated with IMP in the EU 
PDCO age range (2 years to less than 18 years of age) and in the US FDA age range (birth to less 
than 17 years of age) (Figure 2). 
N = target number of treated subjects; PDCO = Pediatric Committee (of the European Medicines Agency); FDA = Food 
and Drug Administration (of the United States of Amrica).
Figure 2:
Depictions of regulatory-required age ranges
The treatment of at least 159 subjects with IMP in the EU PDCO age range and US FDA age range 
is the target for the minimum required number of subjects to meet the statistical power calculation 
for the primary efficacy endpoints of the trial and regulatory requirements. 
Due to the overlapping age groups as per regulatory requirements, it is expected that approximately 
168 subjects will be treated with IMP in this trial.
The trial enrollment for the EU PDCO set (see Section 14.2.1 for the definition of the analysis 
populations) will complete when the following criterion is met:
•
At least 159 treated subjects in the age range 2 years to less than 18 years of age (EU 
PDCO).
The trial enrollment for the US FDA set will complete when the following 2 criteria are met:
•
At least 159 treated subjects in the age range birth to less than 17 years of age (US FDA).
•
100 subjects in the age range birth to less than 17 years of age on tapentadol for at least 
2 doses (US FDA). Based on estimates from adult trials in acute pain, it is assumed that 
approximately 5% of subjects (approximately 8 subjects) may discontinue prior to 
receiving 2 doses of IMP, which is covered by the targeted sample size.
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An additional objective of the study is to meet a US FDA request to evaluate at least 25 subjects in 
the age range birth to less than 17 years of age who have been exposed to tapentadol for at least 
48 hours. As medically appropriate, every effort will be made to enroll subjects in this trial to meet 
this objective.
The sample size calculation was performed using the sample size program nQuery v7.0 (Dixon and 
Massey 1983, O’Brien and Muller 1993) for unequal group sizes and the above assumptions 
regarding the effect size and the allocation ratio of 2:1 (tapentadol:placebo).
14.2
Analysis of the trial – statistical analysis
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.
The statistical analysis of this trial will be performed as summarized in this protocol and given in 
detail in the statistical analysis plan. The statistical analysis plan will be finalized before the first 
subject in.
14.2.1
Analysis populations (analysis sets)
Safety Set
The Safety Set comprises all treated subjects in the required age ranges for the EU PDCO and US 
FDA. The overall Safety Set will include all treated subjects in the trial. The EU PDCO Safety Set
will include subjects 2 years to less than 18 years of age; the US FDA Safety Set will include 
subjects from birth to less than 17 years of age. A subject will be considered as treated if 
administered any amount of IMP.
If by error a subject does not receive the allocated medication, the subject will be evaluated 
according to the received IMP.
Full Analysis Set
The overall Full Analysis Set includes all subjects that are allocated and treated. The EU PDCO 
Full Analysis Set will include allocated and treated subjects aged 2 years to less than 18 years old; 
the US FDA Full Analysis Set will include allocated and treated subjects from birth to less than 
17 years of age. 
If by error a subject does not receive the allocated medication, the subject will be evaluated as 
allocated within the Full Analysis Set following the intention-to-treat principle.
Per Protocol Set
The EU PDCO or US FDA Per Protocol Set is a subset of the respective Full Analysis Set, 
excluding subjects with protocol deviations that may have an impact on the results of the primary 
efficacy analyses. Further details of the Per Protocol Set definition will be specified in the statistical 
analysis plan.
14.2.2
General descriptive and graphical methods
Descriptive and graphical methods will be used in the data analyses. Analyses will consider the trial 
populations, described in Section 14.2.1. 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 
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be used to summarize the results. The main analysis will focus on the treatment; subgroup analyses, 
e.g., according to age categories, may also be explored as appropriate. For variables collected at 
multiple visits, descriptive summaries will be provided for each time point.
Baseline measurements are defined as the last evaluation performed immediately before IMP 
administration, unless otherwise stated.
14.2.3
Analysis of subject characteristics data
Subject characteristics data, and pregnancy tests, will be analyzed as described in Section 14.2.2.
Subjects will be allocated to an age category based on their age recorded at baseline.
Pain intensity scores collected before each NCA/PCA activation will be analyzed descriptively by 
treatment group.
Prohibited medication used by the mother of a newborn or breastfeeding mother will be listed by 
subject.
14.2.4
Analysis of subject disposition
Subject disposition data will be analyzed as described in Section 14.2.2.
An allocation/randomization failure is a subject who was allocated to IMP but was discharged from 
hospital or the trial without taking IMP. Allocation/randomization failures will be listed.
14.2.5
Analysis of efficacy data
14.2.5.1
Primary efficacy endpoint
The primary efficacy endpoints for the EU PDCO and US FDA are the amount of supplemental 
opioid analgesic medication (morphine equivalents in mg/kg body weight) used within the first 
12 hours and 24 hours after first IMP intake, respectively. The primary efficacy endpoint that is 
used in 1 region will be considered as a secondary efficacy endpoint in the other. The primary 
efficacy endpoints will be summarized using the respective Full Analysis Sets.
For subjects who withdraw from the trial prior to the 12-hour or 24-hour time point due to any other 
reason than no further need of opioid analgesic medication or switch to exclusively oral opioid 
analgesic medication, cumulative supplemental opioid analgesia over the respective time period will 
be based on the observed supplemental opioid use up to the time of the subject’s discontinuation. If 
a subject used a total of X mg/kg of supplemental opioid through Hour T (24 hours), cumulative 
use over 24 hours will be estimated as (X/T)*24 mg/kg. If T is <12 hours, cumulative use over 
12 hours will be estimated as (X/T)*12. This extrapolation assumes a constant use (in mg/kg per 
hour) of supplemental opioid over 24 hours. For subjects who withdraw from the trial due to no 
further need of opioid analgesic medication or switch to exclusively oral opioid analgesic 
medication, the cumulative use of supplemental opioid will equal the total amount of supplemental 
opioid used up to the time of withdrawal. Other imputation methods will be used for sensitivity 
analyses. These will be described in detail in the statistical analysis plan.
Supplemental opioid analgesia will be expressed in mg/kg of morphine-equivalents. 
Hydromorphone doses will be multiplied by 5 to obtain the morphine equivalent. 
The primary null hypothesis to be tested for the trial is that the tapentadol group is not different 
from the placebo group for the primary endpoint. The alternative hypothesis is that the tapentadol 
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group is different from the placebo group for the primary endpoint. For the primary efficacy 
endpoint, descriptive statistics will be presented by treatment group, and the endpoint will be 
analyzed using an ANOVA, which includes treatment, baseline age group, and the supplemental 
opioid analgesic used (morphine versus hydromorphone) as factors. Treatment effects will be 
estimated based on least-squares means of the difference. The 95% confidence intervals and p-value 
will be presented for tapentadol compared with placebo. The test for the primary efficacy analysis 
will be 2-sided at a 0.05 level of significance.
A sensitivity analysis will be performed using the respective Per Protocol Set and analyzed using 
the same ANOVA model.
The primary endpoint will also be evaluated using Bayesian statistics as a supportive analysis (EU 
PDCO). The methodology will be described in the statistical analysis plan.
14.2.5.2
Secondary endpoints and subgroup analyses
Unless otherwise noted, all secondary efficacy endpoints will be summarized using the respective 
Full Analysis Set. There will be no multiplicity adjustments for any of the secondary endpoints.
The amount of supplemental opioid analgesic medication (morphine equivalents in mg/kg body 
weight) used within the first 12 hours or 24 hours after first IMP intake will be a secondary efficacy 
endpoint for the EU PDCO or US FDA, respectively. The same ANOVA model as defined above 
for the primary efficacy endpoint will be used to assess treatment group differences. Treatment 
effects will be estimated based on least-squares means of the difference. The 95% confidence 
intervals and p-values will be presented for tapentadol compared with placebo.
In addition, the total amount of supplemental opioid analgesic medication received, assessed in 
12 hour intervals from 24 hours to 96 hours, will be summarized descriptively. The intervals will be 
>24 to 36 hours, >36 to 48 hours, >48 to 60 hours, >60 to 72 hours, >72 to 84 hours, and >84 to 
96 hours. For each interval, only subjects who have their End of Treatment Visit after the start of 
the interval will be included. If a subject has their End of Treatment Visit during a given interval, 
the missing data for the remainder of the given interval will be imputed using a similar 
methodology as for the primary efficacy endpoint, but using only data from within the given 
interval. The subject will then not be included in the subsequent intervals.
The CGIC and PGIC, both using a 7-point rating scale at the End of Treatment Visit (Visit 3), will 
be described descriptively.
The acceptability and palatability of IMP will be assessed using 5-point rating scales after the first 
dose of IMP and at the End of Treatment Visit (Visit 3). The results will be tabulated by treatment 
group.
Pain intensity scores recorded relative to IMP intake, and at the End of Treatment Visit, with
changes from baseline values, will be summarized descriptively over time by treatment group and 
age categories (respective age-defined pain scale), as well as being listed. Figures will also be 
produced, where required.
The number and proportion of subjects taking non-opioid analgesic medications (irrespective of the 
indication) within the first 12 hours and 24 hours after first IMP intake will be grouped according to 
the Anatomical Therapeutic Chemical Classification System (World Health Organization Drug 
Dictionary coding), and presented in tables by treatment group.
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The time to first and time to second NCA/PCA after the first dose of IMP will be summarized 
descriptively and displayed by treatment group and by treatment group and age categories. Figures 
will also be produced, where required. Any supplemental opioid analgesic medication given 
intravenously if the NCA/PCA pump fails and any clinician bolus will be included in this analysis.
The distributions of the time from the first dose of IMP to treatment discontinuation due to lack of 
efficacy will be evaluated by Kaplan-Meier estimates and compared between the treatment groups 
using the log-rank test. Subjects who complete the End of Treatment Visit (Visit 3) will be censored 
at the last observation time point. Subjects who discontinue during the treatment period for reasons 
other than lack of efficacy will be censored at the time of discontinuation.
Subgroup analyses
Summary statistics for the primary efficacy endpoint will be provided by age group (birth to 
<30 days, 30 days to <6 months, 6 months to <2 years, 2 years to <6 years, 6 years to <12 years, 
12 years to <17 years, and 17 years to <18 years, as applicable for the EU PDCO set and US FDA 
set) and by method of supplemental opioid administration (NCA vs. PCA) among other subgroup 
analyses.
14.2.6
Analysis of safety data
The analysis of safety data will be performed for the EU PDCO Safety Set for the EU PDCO report 
and for the overall Safety Set for the US FDA report. 
14.2.6.1
Analysis of adverse events
The original terms used in the CRFs by investigators to identify adverse events will be coded using 
the most recent version of MedDRA used by the sponsor. All reported adverse events with onset 
during the treatment period or during the tapentadol therapeutic reach (i.e., TEAEs occurring in the
days after treatment completion that a subject is still considered to be potentially affected by IMP as 
defined in the statistical analysis plan) will be included in the analysis. For each adverse event, the 
percentage of subjects who experienced at least 1 occurrence of the given event will be summarized 
by treatment group. An adverse event starting before the first dose of IMP and getting worse in 
intensity during the treatment period will also qualify as a TEAE. The incidence, type, intensity, 
onset, relationship, treatment, and outcome of TEAEs will be listed and presented descriptively 
according to treatment group. Serious adverse events will be listed. Subgroup categories (e.g., by 
age) will be analyzed as appropriate.
The distributions of the time from the first dose of IMP to treatment discontinuation due to an 
adverse event will be evaluated by time-to-event estimates, including a Kaplan-Meier graphical 
description. For subjects who complete the End of Treatment Visit (Visit 3), time to discontinuation 
due to an adverse event will be censored at the end of the treatment period. For subjects who 
discontinue during the treatment period for reasons other than adverse events, time to 
discontinuation due to an adverse event will be censored at the time of treatment discontinuation.
Special attention will be given to those subjects who died, or who discontinued treatment due to an 
adverse event, or who experienced a severe or a serious adverse event (e.g., summaries, listings, and 
narrative preparation may be provided, as appropriate).
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14.2.6.2
Analysis of safety laboratory data
Safety laboratory data will be summarized by the type of safety laboratory test. Normal reference 
ranges and markedly abnormal results (specified in the statistical analysis plan) will be used in the 
summary of safety laboratory data. Descriptive statistics (only for blood samples analyzed at the 
central laboratory) will be calculated for each safety laboratory parameter at baseline and at each 
scheduled time point as described in Section 1.2. Changes from baseline results will be presented 
descriptively as well as in pre- versus post-treatment cross tabulations (with classes for below, 
within, and above predefined potentially clinically important ranges). A listing of subjects with any 
laboratory results outside the reference ranges will be provided.
14.2.6.3
Analysis of electrocardiographic data
The 12-lead ECG variables that will be analyzed are heart rate, RR interval, PR interval, 
QRS interval, QT interval, and QTcF (Fridericia) interval.
The 12-lead ECG measurements will be summarized at each time point of measurement as 
described in Section 1.2. The change from baseline will be summarized. Changes from baseline 
results will be presented descriptively as well as in pre- versus post-treatment cross tabulations 
(with classes for below, within, and above predefined potentially clinically important ranges). A 
categorical analysis for QT interval and QTcF (Fridericia) interval outliers will be performed as per 
ICH E14 guidance.
All other clinically important 12-lead ECG abnormalities (e.g., changes in T wave morphology or 
the occurrence of U waves) will be listed.
14.2.6.4
Analysis of vital signs and oxygen saturation
Descriptive statistics of pulse, respiratory rate, blood pressure (systolic and diastolic) and oxygen 
saturation (by pulse oximetry) values and change from baseline will be provided at each scheduled 
time point as described in Section 1.2. Frequency tabulations of clinically-significant abnormalities 
will be included. Age-specific normal ranges will be detailed in the statistical analysis plan. 
14.2.6.5
Analysis of physical examination data
The physical examination findings will be listed per time point as described in Section 1.2.
14.2.6.6
Analysis of Columbia–Suicide Severity Rating Scale
The C-SSRS results will be listed per time point as described in Section 1.2 according to the 
accepted practice for reporting these data as discussed in Nilsson et al. 2013.
14.2.6.7
Analysis of sedation scores
Descriptive statistics of sedation scores will be provided at each scheduled time point as described 
in Section 1.2.
14.2.7
Interim analysis
No interim analysis is planned. 
14.2.8
Data monitoring committee
A DMC will be supplied a relevant set of data on a regular basis for ensuring their oversight of the 
subjects’ safety and the scientific validity of the trial (see Section 5.4).
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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 clinical 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 the site, 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. 
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 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 visit 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. 
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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 
subject.
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, if required.
16.2
Legal regulations
This trial will be carried out in compliance with any applicable regulatory requirements. 
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). 
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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 the sponsor’s disclosure 
policy (e.g., on ClinicalTrials.gov), according to the European Federation of Pharmaceutical 
Industries and Associations (EFPIA) Principles for Responsible Clinical Trial Data Sharing, and 
applicable regulatory guidance. The sponsor will post clinical trial information in a lay person 
understandable form in a freely accessible sponsor internet portal. Due to the preparation of 
2 reports, the data presented in the databases may differ.
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, 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.
16.6
Final report
Two reports for the trial, integrating clinical and statistical results, will be prepared by the sponsor. 
The first report will be prepared after the last subject out of the EU PDCO set. For the first report 
the efficacy and safety data will be reported for the EU PDCO set, the subgroup of subjects aged 
2 years to less than 18 years old.
The second report will be prepared after the last subject out of the US FDA set. For the second 
report the safety data will be reported for all subjects in the study; that is the subjects reported in the 
first report combined with subjects aged less than 2 years old. The second report will include 2 sets 
of efficacy results; the previously reported results for the EU PDCO set and the efficacy results for 
the US FDA set.
The coordinating investigator will approve the reports on behalf of the participating investigators. 
The sponsor will provide the competent authority and relevant IEC/IRB with summaries of the 
reports in accordance with applicable regulatory requirements. 
The coordinating investigator will be provided with summaries of the reports.
16.7
Approval
16.7.1
Sponsor
This protocol has been approved in accordance with sponsor SOPs.
16.7.2
Coordinating investigator
This protocol has been approved by the international coordinating investigator.
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Oquendo MA, Halberstam B, Mann JJ. Risk factors for suicidal behavior: utility and limitations of 
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(1993) pp. 297–344.
Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, et al. Human renal 
function maturation: a quantitative description using weight and postmenstrual age. Paediatr 
Nephrol 2009; 24(1): 67–76.
Rusy LM, Hainsworth KR, Nelson TJ, Czarnecki ML, Tassone JC, Thometz JG, et al. Gabapentin 
use in pediatric spinal fusion patients: a randomized, double-blind, controlled trial. Anesth Analg 
2010; 110(5): 1393–8. 
Rugyte D, Kokki H. Intravenous ketoprofen as an adjunct to patient-controlled analgesia morphine 
in adolescents with thoracic surgery: A placebo controlled double-blinded study. Eur J Pain 2007; 
11 (6): 694–9.
Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, Reisberg B, et al. Validity and reliability 
of the Alzheimer's disease cooperative study-clinical global impression of change. Alzheimer Dis 
Assoc Disord 1997; 11 (Suppl 2): S22–S32.
Scott J, Huskisson EC. Graphic representation of pain. Pain 1976; 2(2): 175–84.
Scott PJ, Ansell BM, Huskisson EC. Measurement of pain in juvenile chronic polyarthritis. Ann 
Rheum Dis 1977; 36(2): 186–7. 
Schwartz GJ, Feld LG, Langford DJ. A simple estimate of glomerular filtration rate in full-term 
infants during the first year of life. J Pediatr 1984; 104(6): 849–54.
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18
PROTOCOL AMENDMENTS
18.1
Protocol Amendment 01
Amendment rationale
The site of manufacture of the IMP (tapentadol oral solution and placebo) was changed for logistic 
reasons.
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 10.1.1 Identity and composition – tapentadol oral solution (test)
Section 10.1.2 Identity and composition – placebo (comparator)
Manufacturer: Grünenthal GmbH, Aachen, Germany.
Manufacturer: Janssen Pharmaceutica NV, Beerse, 
Belgium.
18.2
Protocol Amendment 02
Amendment rationale
This amendment has been enacted for clarification and to comply with US FDA requirements:
•
Not all endpoints will be analyzed according to the regional age ranges (2 years to less than 
18 years for the EU PDCO and from birth to less than 17 years for the US FDA). This has 
been clarified in the text, and will be elucidated in the statistical analysis plan. In addition, 
the additional analysis of the primary endpoint by predefined narrow age strata has been 
introduced.
•
Based on a request from US FDA, the following data will be collected: when possible, the 
investigator/delegate or subject will record a pain intensity score prior to each 
administration of NCA/PCA. Pain data collected for this purpose, i.e., directly before each 
administration of NCA/PCA, whenever possible, will be used only for the purpose of 
exploratory analysis.
•
The definition of completers has been amended.
•
The address of the international coordinating investigator was updated. The operational 
lead’s, and sponsor’s medically qualified person and signatories were changed.
•
Examples of suitable surgeries have been added to the population descriptions to assist 
investigators to identify suitable subjects.
•
Subjects who are cognitively impaired in the investigator’s judgment such that they cannot 
comply with the protocol are now excluded from participation in the trial.
•
The age range of the palatability and taste questionnaire has been extended downwards 
from 3 years to 2 years as the younger subjects will now start recruitment and are capable 
of performing the assessment.
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•
It is no longer necessary that any background infusion to the NCA/PCA is at a “constant”
low dose rate.
•
The dose of tapentadol oral solution for subjects between 2 years and less than 6 years has 
now been defined. 
•
Instructions on whether to use a 1 mL or 5 mL syringe for dosing have been added.
•
It has been clarified that dosing should take place as soon as possible after a subject is 
woken if dosing has been delayed because the subject was sleeping.
•
The list of prohibited medication taken within 14 days of allocation/randomization to IMP 
has been extended to include all serotonergic drugs, including selective 
serotonin/norepinephrine reuptake inhibitors, tricyclic antidepressants, linezolid, triptans, 
and St. John’s Wort (hypericum perforatum) for safety reasons. The time medication for 
sedation is prohibited has been extended to 6 hours before allocation to IMP. The use of 
benzodiazepines for muscle cramps and anxiety has been explicitly allowed.
•
The use of IMP after 24 hours has been modified to reflect medical practice by allowing its 
use every 4 hours to 6 hours, and by extending use up to 72 hours to comply with a 
requirement to assess for at least 48 hours.
•
The use of the University of Michigan Sedation Scale has been added for assessing 
sedation.
•
Maximum blood sampling for subjects aged less than 2 years has been defined.
•
The time span for recording opioid and non-opioid analgesic medication was redefined to 
give an adequate coverage for recording these data.
•
The length of time the oxygen saturation is below 92% was made consistent across
descriptions in the protocol. The phrasing was also aligned in other sections.
•
The primary endpoint will also be evaluated using Bayesian statistics as a supportive 
analysis. The methodology will be described in the statistical analysis plan.
•
The information on safety experience from post-marketing data in adults has been updated.
In addition, a number of discrepancies and inconsistencies have been corrected.
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: 
Title page: 
International coordinating investigator:
Prof Dr 
Sophia Kindergeneeskunde B.V., Dr Molewaterplein 60, 
3015 GJ Rotterdam, The Netherlands. a
Children’s National Medical Center, Pharmacology & 
Physiology, George Washington University School of 
Medicine and Health Sciences, 111 Michigan Avenue, 
N.W. Washington, D.C. 20010. United States of 
America. a
International coordinating investigator:
Prof Dr 
Children’s National Medical Center, Pharmacology & 
Physiology, George Washington University School of 
Medicine and Health Sciences, 111 Michigan Avenue, 
N.W. Washington, D.C. 20010. United States of 
America. a
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Now reads: 
Sponsor’s medically qualified person:
Dr 
, Clinical Leader, 
Janssen Research & Development, LLC
Phone: +1 609 730-
@its.jnj.com a
Sponsor’s signatory:
Dr 
, Clinical Leader, 
Operational lead’s medically qualified person:
Dr 
, Global Late Stage Clinical 
Development
Operational lead’s signatory:
, Global Late Stage Clinical 
Development,
Sponsor’s medically qualified person:
Dr 
, Clinical Leader, 
Janssen Research & Development, LLC
Phone: +1 609-730-
@ITS.JNJ.com a
Sponsor’s signatory:
Dr 
, Clinical Leader
Operational lead’s medically qualified person:
Dr 
, Head Global Clinical 
Development Strategy
Operational lead’s signatory:
Dr 
, Head Global Clinical 
Development Strategy,
Section 1: Protocol Synopsis – Trial objectives:
Section 7: Trial objectives
The clinical hypothesis of this trial is that tapentadol oral 
solution reduces the total amount of supplemental opioid 
analgesic medication used over 12 hours or 24 hours 
following initiation of investigational medicinal product 
(IMP), compared to placebo, in children and adolescents 
who have undergone surgery that, in the investigator’s 
opinion, would reliably produce moderate to severe pain 
requiring opioid treatment.
The primary efficacy objective for 1 region is considered 
a secondary efficacy objective in the other.
The clinical hypothesis of this trial is that tapentadol oral 
solution reduces the total amount of supplemental opioid 
analgesic medication used over 12 hours (primary 
objective for US FDA) or 24 hours (primary objective for 
EU PDCO) following initiation of investigational 
medicinal product (IMP), compared to placebo, in 
children and adolescents who have undergone surgery 
that, in the investigator’s opinion, would reliably 
produce moderate to severe pain requiring opioid 
treatment.
The primary efficacy objective (either 12 hours or 24 
hours) for 1 region is considered as the secondary 
efficacy objective in the other, for the different age 
range, as described below.
Subjects can be treated for up to 72 hours, and efficacy 
and safety information will also be collected throughout 
this time period.
Section 1: Protocol Synopsis – Definition of endpoints:
Section 8.1: Definition of endpoints
All endpoints compare the results in the group of 
subjects treated with tapentadol oral solution to the group 
treated with placebo. All endpoints will be analyzed in 
the age ranges of 2 years to less than 18 years for the EU 
PDCO and from birth to less than 17 years for the US 
FDA.
...
The secondary efficacy endpoints are:
...
• The total amount of supplemental opioid analgesic 
medication received during treatment with IMP over a 
maximum period of 48 hours after the first dose of IMP.
All endpoints compare the results in the group of 
subjects treated with tapentadol oral solution to the group 
treated with placebo. As applicable and appropriate for 
the individual endpoint, these endpoints will be analyzed 
in the age ranges of 2 years to less than 18 years for the 
EU PDCO and from birth to less than 17 years for the 
US FDA.
...
The secondary efficacy endpoints are:
...
• The total amount of supplemental opioid analgesic 
medication received, assessed in 12 hour intervals from
24 hours to 96 hours after the first dose of IMP.
• The total amount of non-opioid analgesics used 
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• The total amount of non-opioid analgesics used 
(irrespective of the indication) during the double-blind 
IMP treatment period within the first 24 hours (EU
PDCO) or within the first 12 hours (US FDA) after the 
first dose of IMP.
• Palatability and acceptability of the IMP after the first 
and last doses of IMP in subjects aged 3 years to less 
than 18 years old (EU PDCO).
• Changes from baseline in pain intensity over 12 hours, 
24 hours, and 48 hours after the first dose of IMP using 
age-appropriate pain scales (Face, Legs, Activity, Cry, 
Consolability [FLACC] scale for ages birth to less than 6 
years or in older children who are not able to report their 
pain using the other scales, Faces Pain Scale–Revised 
[FPS-R] for ages 6 years to less than 12 years, and visual 
analog scale [VAS] for ages 12 years to less than 18 
years).
...
Safety endpoints:
...
• Changes from baseline in vital signs parameters.
• Changes from baseline in safety laboratory parameters.
(irrespective of the indication, e.g., acetaminophen, 
which can also be given as antipyretic medication) 
during the treatment period within the first 24 hours (EU 
PDCO) or within the first 12 hours (US FDA) after the 
first dose of IMP.
• Palatability and acceptability of the IMP after the first 
and last doses of IMP in subjects aged 2 years to less 
than 18 years old (EU PDCO).
• Changes from baseline in pain intensity over the 
Treatment Period using age-appropriate pain scales 
(Face, Legs, Activity, Cry, Consolability [FLACC] scale 
for ages birth to less than 6 years or in older children 
who are not able to report their pain using the other 
scales, Faces Pain Scale–Revised [FPS-R] for ages 6 
years to less than 12 years, and visual analog scale 
[VAS] for ages 12 years to less than 18 years).
...
Safety endpoints:
...
• Changes from baseline in vital signs parameters.
• Sedation scores using the University of Michigan 
Sedation Scale.
• Changes from baseline in safety laboratory parameters.
Section 1: Protocol Synopsis – Trial population:
The trial population will comprise male and female 
subjects aged from birth to less than 18 years old who 
have undergone surgery that, in the investigator’s 
opinion, would reliably produce moderate to severe pain 
requiring opioid treatment.
The trial population will comprise male and female 
subjects aged from birth to less than 18 years old who 
have undergone surgery that, in the investigator’s 
opinion, would reliably produce moderate to severe pain 
requiring opioid treatment via NCA/PCA. Examples of 
surgeries suitable for this trial include, but are not 
limited to, spinal fusions, cleft palate repair, Nuss 
procedures, scoliosis repair, nephrectomy, pyeloplasty, 
and orthopedic procedures such as club foot repair, leg 
lengthening, open reduction and internal fixation of long 
bone fractures. Subjects must remain hospitalized until 
the End of Treatment Visit.
Section 1: Protocol Synopsis – Trial population:
Section 9.1: Subject enrollment procedure
...
The trial enrollment will be initiated in a staggered 
approach, starting with enrollment of an older age group 
until pharmacokinetic data are available in younger age 
groups. Initially, subjects aged 6 years to less than 18 
years will be recruited. Subjects from 2 years old to less 
than 6 years old, and subsequently from birth to less than 
2 years of age will be recruited after pharmacokinetic 
and safety data are obtained and the dose selection has 
been defined for younger age groups.
...
The trial enrollment will be initiated in a staggered 
approach, starting with enrollment of an older age group 
until pharmacokinetic data are available in younger age 
groups. Initially, subjects aged 2 years to less than 18 
years will be recruited. Subjects from birth to less than 2 
years of age will be recruited after pharmacokinetic and 
safety data are obtained and the dose selection has been 
defined for younger age groups.
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Section 1: Protocol Synopsis – Course of the trial: 
...
The trial consists of an Enrollment Period starting up to 
28 days before allocation/randomization to IMP and 
lasting up to the time of allocation/randomization to 
IMP, whereby subjects may be enrolled in the trial either 
pre- or post-operatively; a Treatment and Evaluation 
Period (up to 48 hours); and a Follow-Up Period (10 
days to 14 days after the first dose of IMP).
...
The trial consists of an Enrollment Period starting up to 
28 days before allocation/randomization to IMP and 
lasting up to the time of allocation/randomization to 
IMP, whereby subjects may be enrolled in the trial either 
pre- or post-operatively; a Treatment and Evaluation 
Period (up to 96 hours); and a Follow-Up Period (10 
days to 14 days after the first dose of IMP).
Section 1: Protocol Synopsis – Trial treatments:
Section 10.5.1: Supplemental opioid analgesic medication
Section 11.1.1: Enrollment Period (Visit 1)
...
At some time after the surgery, the subject must have 
been started on NCA/PCA with morphine or 
hydromorphone, with or without a background infusion, 
according to the standard of care. The background 
infusion (if any) must be with a constant low dose 
infusion of the same opioid as that used for the 
NCA/PCA, i.e., morphine or hydromorphone.
...
At some time after the surgery, the subject must have 
been started on NCA/PCA with morphine or 
hydromorphone, with or without a background infusion, 
according to the standard of care. The background 
infusion (if any) must be with a low dose infusion of the 
same opioid as that used for the NCA/PCA, i.e., 
morphine or hydromorphone.
Section 1: Protocol Synopsis – Trial treatments:
...
When the subject is able to tolerate liquids, meets the 
inclusion criteria, and does not meet any exclusion 
criterion, the subject will be allocated/randomized to 
IMP (tapentadol oral solution or placebo) using an 
integrated voice/web response system (IVRS/IWRS). 
Doses of IMP will be given at intervals explained below.
...
When the subject is able to tolerate liquids, meets the 
inclusion criteria, and does not meet any exclusion 
criterion, the subject will be allocated/randomized to 
IMP (tapentadol oral solution or placebo) using an 
interactive voice/web response system (IVRS/IWRS). 
Doses of IMP will be given at intervals explained below.
Section 1: Protocol Synopsis – Trial treatments:
Section 11.1.2.1: Visit 2 - Administration of first dose of investigational medicinal product (Day 1)
...
The first dose of IMP is given when IMP is available on 
the ward, per investigator judgment.
...
The first dose of IMP is given when IMP is available on 
the ward and the investigator determines it is medically 
appropriate for the subject to receive the IMP.
Section 1: Protocol Synopsis – Trial treatments: Investigational medicinal products (dosing regimen table)
Section 10.2.1: Dose, Table 2: Determination of tapentadol dose and oral solution concentration
...
Age of subject
6 years to 18 years old
Birth to 6 years old
Dose for the second 24 hours
Footnote: a) The dosing interval is 4 hours (range ±15 
minutes) except if the subject is sleeping: Subjects are 
required to be woken to take the IMP within 6 hours of 
...
Age of subject
2 years to 18 years old
Birth to 2 years old
Dose after the first 24 hours
Footnote: 
Footnote a) The doses for subjects aged less than 2 years
old (as determined at the time of allocation to IMP) will 
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the previous dose.
Footnote b) The doses for subjects aged less than 6 years
old will be defined based on forthcoming 
pharmacokinetic data. Recruitment of this age group will 
commence when the dose has been defined.
be defined based on forthcoming pharmacokinetic data. 
Recruitment of this age group will commence when the 
dose has been defined.
Section 1: Protocol Synopsis – Trial treatments: Investigational medicinal products
Section 10.2.2: Total dosing time and dosing interval
...
The dosing interval is 4 hours (range ±15 
minutes).Within the first 24 hours after the first dose of 
IMP, if the subject is sleeping at the time of the 
scheduled dose they must be woken to take the IMP 
within a maximum of 6 hours after the previous dose. 
The reason for any delay in dosing beyond 4 hours 15 
minutes needs to be documented.
After 24 hours, the dosing interval may be lengthened up 
to a maximum of 10 hours, and the IMP dose may 
remain the same or may be decreased to 1.0 mg/kg 
according to the investigator’s judgment of the subject’s 
reduced need for analgesia.
Dosing with IMP will be stopped when opioid analgesic 
medication is no longer needed, or after a maximum of 
48 hours.
...
The IMP will be administered as an oral solution. The 
dosing interval is 4 hours (range ±15 minutes). The 
reason for any delay in dosing beyond 4 hours 15 
minutes needs to be documented. If the subject is 
sleeping at the time of the scheduled dose, they must be 
woken to take the IMP within a maximum of 6 hours 
after the previous dose. The dose of IMP must be taken 
as soon as possible after the subject is awake.
The administration of IMP is based on the investigator’s 
judgment of the subject’s condition and sedation level.
After 24 hours, the investigator may decrease the dose of 
IMP to 1.0 mg/kg according to the investigator’s 
judgment of the subject’s reduced need for analgesia.
Dosing with IMP will be stopped when opioid analgesic 
medication is no longer needed, or 72 hours after first 
IMP administration.
Section 1: Protocol Synopsis – Concomitant medications/therapies: Allowed prior and concomitant medication
Section 10.6.3: Allowed prior and concomitant medication
Unless explicitly forbidden, all prior and concomitant 
medications are allowed.
Medications for the treatment of adverse events are 
allowed according to the investigator’s judgment and 
post-operative standard of care. For example, clinically 
relevant respiratory depression may be treated with 
naloxone, and nausea/vomiting can be treated with 
antiemetics. Antiemetics may also be given 
prophylactically according to the standard of care.
Unless explicitly prohibited, all prior and concomitant 
medications are allowed.
Benzodiazepines may be used to treat muscle spasms or 
anxiety, consistent with local standard of care. They 
should be used with caution as they may potentiate 
central nervous system depression that may occur with 
tapentadol or other opioids.
Medications for the treatment of adverse events are 
allowed according to the investigator’s judgment and 
post-operative standard of care. For example, clinically 
relevant respiratory depression may be treated with 
naloxone, and nausea/vomiting can be treated with 
antiemetics, which may also be given prophylactically 
according to the standard of care.
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Section 1: Protocol Synopsis – Concomitant medications/therapies:
Section 10.6.4: Prohibited prior and concomitant medication
Forbidden medication from 28 days before 
allocation/randomization to IMP until 24 hours after 
the last administration of IMP
...
• Neuroleptics, anticonvulsants (except for gabapentin 
used in association with surgery), antiparkinsonian 
drugs, and serotoninergic drugs such as selective 
serotonin/norepinephrine reuptake inhibitors and
tricyclic antidepressants.
Forbidden medication from 6 hours prior to time of 
allocation/randomization to IMP until 4 hours after 
the last administration of IMP
• Long-acting opioids.
Forbidden medication from time of 
allocation/randomization to IMP until 4 hours after 
the last administration of IMP
• Medication used for sedation.
• Opioids (other than morphine, hydromorphone, or 
IMP).
Prohibited medication from 14 days before 
allocation/randomization to IMP until 24 hours after 
the last administration of IMP
...
• Neuroleptics, anticonvulsants (except for gabapentin 
used in association with surgery), antiparkinsonian 
drugs, and all serotoninergic drugs including selective 
serotonin/norepinephrine reuptake inhibitors, tricyclic 
antidepressants, linezolid, triptans, and St. John’s Wort 
(hypericum perforatum).
• Methadone.
Prohibited medication from 6 hours prior to time of 
allocation/randomization to IMP until 4 hours after 
the last administration of IMP
• Long-acting opioids. 
• Medication used for sedation (as noted above, 
benzodiazepines may be used to treat muscle spasms or 
anxiety).
Prohibited medication from time of 
allocation/randomization to IMP until 4 hours after 
the last administration of IMP
• Opioids (other than morphine, hydromorphone, or 
IMP).
Section 1: Protocol Synopsis – Trial duration:
Section 8: Trial design
Each subject is expected to be in the trial for up to about 
42 days (up to 28 days for enrollment, 2 days of 
treatment, and up to 12 days of follow up).
Dosing of IMP will be for a maximum of 48 hours.
Each subject is expected to be in the trial for up to about 
42 days (up to 28 days for enrollment, and a treatment 
and follow-up period of up to 14 days).
Dosing of IMP will be for up to 72 hours.
Section 1: Protocol Synopsis – Sample size rationale:
The trial enrollment will then complete when the 
following 4 criteria are met:
...
• 100 subjects in the age range birth to less than 17 years 
of age on tapentadol for at least 2 doses. Based on 
estimates from adult trials in acute pain, it is assumed 
that approximately 5% of subjects (approximately 8 
subjects) may discontinue prior to receiving 2 doses of 
IMP, which is covered by the targeted sample size (i.e., 
approximately 168 subjects).
• 25 subjects in the age range birth to less than 17 years 
of age (US FDA) have received tapentadol for at least 48 
hours.
Due to the overlapping age groups as per regulatory 
requirements, it is expected that approximately 168 
subjects will be treated with IMP in this trial.
The trial enrollment will then complete when the 
following 3 criteria are met:
...
• 100 subjects in the age range birth to less than 17 years 
of age on tapentadol for at least 2 doses (US FDA). 
Based on estimates from adult trials in acute pain, it is 
assumed that approximately 5% of subjects 
(approximately 8 subjects) may discontinue prior to 
receiving 2 doses of IMP, which is covered by the 
targeted sample size.
Due to the overlapping age groups as per regulatory 
requirements, it is expected that approximately 168 
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subjects will be treated with IMP in this trial.
An additional objective of the study is to meet a US FDA 
request to evaluate at least 25 subjects in the age range 
birth to less than 17 years of age who have been exposed 
to tapentadol for at least 48 hours. As medically 
appropriate, every effort will be made to enroll subjects 
in this trial to meet this objective.
Section 1: Protocol Synopsis – Blood sampling:
The total blood volume drawn per subject will not 
exceed approximately 15 mL during the trial (even when 
additional blood is drawn for a pharmacokinetic analysis 
when a serious adverse event occurs).
The total blood volume drawn per subject will not 
exceed approximately 15 mL for subjects aged 2 years 
and older or 2.4 mL/kg for subjects aged less than 
2 years during the trial (even when additional blood is 
drawn for a pharmacokinetic analysis if a serious adverse 
event occurs).
Section 1: Protocol Synopsis – Key data collected: Demographic data, background data, and other subject 
characteristics:
Section 12.1.1: Demographic data
...
(years for subjects aged 2 years and older, months for 
subjects aged 2 months to less than 2 years, and days for 
subjects aged less than 2 months – the day of birth is 
counted as day 1), race/ethnicity, height, and weight…
...
(years for subjects aged 2 years and older, months for 
subjects aged 2 months [i.e., 60 days] to less than 
2 years, and days for subjects aged less than 2 months 
[i.e., less than 60 days] – the day of birth is counted as 
day 1), race/ethnicity, height, and weight…
Section 1: Protocol Synopsis – Key data collected: Demographic data, background data, and other subject 
characteristics:
...
• The trade name, date, time, dose, and route of 
administration of opioid analgesic medication given 
post-operatively for pain before the first IMP dose. 
Recording limited to after surgery, for a period of 
(maximum) 24 hours before the first IMP dose.
...
• The indication, the type of surgical procedure, the date 
of surgery, the start time and completion time of surgery.
...
• The trade name, date, time, dose, and route of 
administration of opioid and non-opioid analgesic 
medication given post-operatively for pain before the 
first IMP dose. The detailed recording of these 
medications is limited to after surgery, for a period of 
(maximum) 24 hours before the first IMP dose.
...
• The indication, the type of surgical procedure, the date 
of surgery, the start time and completion time of surgery.
• Pain intensity scores (FLACC in subjects from birth to 
less than 6 years or in older children who are not able to 
report their pain using the other scales, FPS-R in 
subjects aged 6 years to less than 12 years old, and VAS 
in subjects aged 12 years to less than 18 years old) 
before each NCA/PCA activation, whenever possible, 
after the first dose of IMP.
Section 1: Protocol Synopsis – Key data collected: Efficacy:
...
• Trade name, dose, and time of each administration of 
NCA/PCA supplemental opioid analgesia from first dose 
of IMP until 4 hours after the last administration of IMP.
...
...
• Trade name, dose, and time of each administration of 
NCA/PCA supplemental opioid analgesia from first dose 
of IMP up to the End of Treatment Visit.
...
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• Acceptability and palatability of IMP in subjects aged 3 
years to less than 18 years old.
• Patient reported outcome for pain (FLACC in subjects 
from birth to less than 6 years or in older children who 
are not able to report their pain using the other scales, 
FPS-R in subjects aged 6 years to less than 12 years old, 
and VAS in subjects aged 12 years to less than 18 years 
old).
• The trade name, date, time, dose, dose unit, 
formulation, and route of administration of non-opioid 
analgesic medication. Recording is limited to after 
surgery (starting up to 24 hours before first IMP dose) 
until 4 hours after the last administration of IMP.
• Acceptability and palatability of IMP in subjects aged 2 
years to less than 18 years old.
• Pain intensity scores before and after first dose of IMP, 
before each subsequent dose of IMP, and at the End of 
Treatment Visit (FLACC in subjects from birth to less 
than 6 years or in older children who are not able to 
report their pain using the other scales, FPS-R in subjects 
aged 6 years to less than 12 years old, and VAS in 
subjects aged 12 years to less than 18 years old).
• The trade name, date, time, dose, dose unit, 
formulation, and route of administration of non-opioid 
analgesic medication. The detailed recording of these 
medications is limited to after surgery (starting up to 24 
hours before first IMP dose) up to the End of Treatment 
Visit.
Section 1: Protocol Synopsis – Key data collected: Safety:
Section 12.3: Collection of safety data
...
• C-SSRS score in subjects aged 6 years or older.
...
• C-SSRS score in subjects aged 6 years or older.
• University of Michigan Sedation Scale score.
Section 1: Statistical methods:
... Treatment effects will be estimated based on least-
squares means of the difference. The 95% confidence 
intervals and p-value will be presented for tapentadol 
compared with placebo. The test for the primary efficacy 
analysis will be 2-sided at a 0.05 level of significance.
...
Descriptive statistics, changes from baseline, frequency 
tabulations of abnormalities and subject listings will be 
provided for summarizing safety laboratory parameters, 
12-lead ECG, vital signs, and oxygen saturation across 
treatment group.
... Treatment effects will be estimated based on least-
squares means of the difference. The 95% confidence 
intervals and p-value will be presented for tapentadol 
compared with placebo. The test for the primary efficacy 
analysis will be 2-sided at a 0.05 level of significance.
Summary statistics for the primary efficacy endpoint will 
be provided by age group (birth to <30 days, 30 days to 
<6 months, 6 months to <2 years, 2 years to <6 years, 
6 years to <12 years, 12 years to <17 years, and 
17 years to <18 years) and by method of supplemental 
opioid administration (NCA vs. PCA) among other 
subgroup analyses.
...
Descriptive statistics, changes from baseline, frequency 
tabulations of abnormalities and subject listings will be 
provided for summarizing safety laboratory parameters, 
12-lead ECG, vital signs, and oxygen saturation across 
treatment group. Descriptive statistics will be provided 
for the sedation scores.
Section 1: Protocol synopsis - Statistical methods:
Section 14.2.6.1: Analysis of adverse events
...
The incidence, type, intensity, onset, duration,
relationship, treatment, and outcome of TEAEs will be 
listed and presented descriptively according to treatment 
group.
...
The incidence, type, intensity, onset, relationship, 
treatment, and outcome of TEAEs will be listed and 
presented descriptively according to treatment group.
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Section 1.2: Schedule of events
Record demographic data d
Record date of signing the informed consent/assent form, 
sex, race/ethnicity, and height.
[Added rows]
Record weight after surgery (can be measured before 
surgery if the surgery is not expected to notably change 
the weight). d
Record age at time of allocation/randomization. z
Record sedation score.
Record details of non-opioid analgesics
Detailed recording of analgesics
Record age at time of allocation/randomization 
Record vital signs
Record oxygen saturation
[Cross moved to column to coincide with allocation]
[Cross moved to column “After surgery”]
[Cross moved to column “After surgery”]
Record details of NCA/PCA and background infusion (if 
any).
Detailed recording of NCA/PCA and background 
infusion (if any) r [footnote r moved from cross, 
added <---> and “no background infusion” to columns 
first dose after and subsequent doses before and after]
Supplemental opioid analgesic medication by 
NCA/PCAt
[line deleted]
[Added row]
Record pain intensity before each NCA/PC activationu,t.
Section 1.2: Schedule of events: Footnotes
d) Demographic data to be collected and recorded for 
this trial includes date of signing the informed 
consent/assent form, sex, age at time of 
allocation/randomization (years for subjects aged 2 years 
and older, months for subjects aged 2 months to less than 
2 years, and days for subjects aged less than 2 months), 
race/ethnicity, height, and weight. The body mass index 
will be calculated automatically. The weight should be 
measured after surgery if the surgery notably changes the 
weight of the child.
h) Excluding anesthetics and medication used during the 
surgery.
i) Recording limited to after surgery (starting up to 24 
hours before first IMP dose) until 4 hours after the last 
administration of IMP.
j) In subjects aged 6 years or older. Any refusal to 
complete the questionnaire must be recorded with the 
reason.
d) The body mass index will be calculated automatically.
h) Record all medications, including opioid and non-
opioid analgesics but excluding anesthetics and 
medication used during the surgery (Section 12.1.2).
i) Recording of detailed information is limited to after 
surgery (starting up to 24 hours before first IMP dose) up 
to the End of Treatment Visit (Section 12.1.2.2).
j) In subjects aged 6 years or older. The administration of 
the C-SSRS “children’s baseline” must be performed 
after surgery. A refusal to answer the questions in the 
questionnaire that are appropriate for the subject must 
be recorded with the reason. The initials of the 
interviewer are to be recorded.
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m) Within 2 hours before allocation/randomization to 
IMP.
o) Using pulse oximetry. Record values under 92% for at 
least 60 seconds (excluding technical failures or 
artifacts).
r) Recording is limited to after surgery, for a period of 
(maximum) 24 hours before the first IMP dose.
s) IMP will be administered as an oral solution. The 
dosing interval is 4 hours (range ±15 minutes). Within 
the first 24 hours after the first dose of IMP, if the 
subject is sleeping at the time of the scheduled dose they 
must be woken to take the IMP within a maximum of 6 
hours after the previous dose. The reason for any delay 
in dosing beyond 4 hours 15 minutes needs to be 
documented. After 24 hours, the dosing interval may be 
lengthened up to a maximum of 10 hours, and the IMP 
dose may remain the same or may be decreased to 1.0 
mg/kg according to the investigator’s judgment of the 
subject’s reduced need for analgesia.
t) By NCA/PCA with morphine or hydromorphone in 
accordance with the standard of care at the site. Details 
of use will be recorded at times consistent with the 
memory of the NCA/PCA pump from first dose of IMP 
until 4 hours after the last administration of IMP. Details 
will be recorded of dosing of intravenous morphine or 
hydromorphone used if the NCA/PCA fails.
v) Between 30 minutes and 60 minutes after IMP, for 
which the subject may be woken if necessary.
w) In subjects aged 3 years to less than 18 years old.
[New footnote]
m) Directly before allocation/randomization to IMP.
o) Using pulse oximetry. Record values below 92% for at 
least 60 seconds (excluding technical failures or 
artifacts).
r) Recording of detailed information is limited to after 
surgery (starting up to 24 hours before first IMP dose) 
up to the End of Treatment Visit (Section 12.1.2.1). 
NCA/PCA is with morphine or hydromorphone in 
accordance with the standard of care at the site.
Detailed information on use will be recorded at times 
consistent with the memory of the NCA/PCA pump. 
Details will be recorded of dosing of intravenous 
morphine or hydromorphone used if the NCA/PCA fails.
s) The IMP will be administered as an oral solution. The 
dosing interval is 4 hours (range ±15 minutes). The 
reason for any delay in dosing beyond 4 hours 15 
minutes needs to be documented. If the subject is 
sleeping at the time of the scheduled dose they must be 
woken to take the IMP within a maximum of 6 hours 
after the previous dose. The dose of IMP must be taken 
as soon as possible after the subject is awake. After 24 
hours, the investigator may decrease the dose of IMP to 
1.0 mg/kg according to the investigator’s judgment of 
the subject’s reduced need for analgesia.
t) Footnote deleted and merged with footnote r.
New footnote inserted
t) Pain intensity scores should be obtained before each 
each NCA/PCA activation, whenever possible. However, 
the NCA/PCA activation should not be unduly delayed by 
the pain intensity assessment.
v) Between 30 minutes and 60 minutes after IMP. 
Subjects do not need to be woken for this assessment.
w) In subjects aged 2 years to less than 18 years old.
z) Years for subjects aged 2 years and older, months for 
subjects aged 2 months (i.e., 60 days) to less than 2 
years, and days for subjects aged less than 2 months 
(i.e., less than 60 days).
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Section 1.3.1: Inclusion criteria
Section 9.2.1: Inclusion criteria
5. Subject has undergone surgery (other than brain 
surgery or gastrointestinal surgery expected to affect the 
absorption of tapentadol [in the investigator’s judgment]) 
that, in the investigator’s opinion, would reliably 
produce moderate to severe pain requiring opioid 
treatment for at least 24 hours after 
allocation/randomization to IMP.
5. Subject has undergone surgery (other than brain 
surgery or gastrointestinal surgery expected to affect the 
absorption of tapentadol [in the investigator’s judgment]) 
that, in the investigator’s opinion, would reliably 
produce moderate to severe pain requiring opioid 
treatment for at least 24 hours after 
allocation/randomization to IMP. Subjects must remain 
hospitalized until the End of Treatment Visit.
Section 1.3.2: Exclusion criteria
Section 9.2.2: Exclusion criteria
...
10. Subject is not able to understand and comply with the 
protocol as appropriate for the age of the subject.
...
12. Subject is taking forbidden concomitant medication.
...
14. Subject has clinically relevant (in the investigator’s 
judgment) abnormal values for clinical chemistry or 
hematology (local laboratory sample taken after surgery). 
A subject is excluded if the: ...
• Glomerular filtration rate <60 mL/min (calculated 
according to a formula that is appropriate for the 
respective age group).
...
[New criteria]
...
10. 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.
...
12. Subject is taking prohibited concomitant medication. 
...
14. Subject has clinically relevant (in the investigator’s 
judgment) abnormal values for clinical chemistry or 
hematology (local laboratory sample taken after 
surgery). 
A subject is excluded if the: ...
• Glomerular filtration rate <60 mL/min (calculated 
according to Schwartz et al. 1984).
...
18. Female subject is breast-feeding a child.
Section 3: Abbreviations and definition of terms – Definition of terms
Abbreviations
IVRS/IWRS: Integrated voice/web response system
Definition of terms
Treatment completers: Treatment completers are treated 
subjects who completed all doses of scheduled IMP 
administration according to the protocol.
Trial completers: Treated subjects who have completed 
the trial according to the protocol.
Abbreviations
IVRS/IWRS: Interactive voice/web response system
Definition of terms
Treatment period completers: Two sets of treatment 
period completers will be defined for subjects in 
accordance with the time points of the primary endpoint, 
i.e., 12 hours and 24 hours.
Treatment period completers are defined for each of 
these sets as subjects who do not discontinue the 
treatment period before 12 hours and 24 hours, 
respectively.
Trial completers: Trial completers are defined as 
treatment period completers who have completed the 
Follow-up Visit. 
For purposes of compliance with a US FDA request, 
completers beyond 24 hours and up to 72 hours will be 
tracked and data reported.
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Section 4.2: Subject information and informed consent
...
As the inclusion of exclusively minors 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.
...
As the inclusion of exclusively minors 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, and an assent form signed 
as appropriate/applicable for the age of the subject.
Section 6.2: Relevant non-clinical and clinical data
Effects in humans
Tapentadol has been given to adults as an oral solution, 
intravenous solution, immediate-release (IR) tablets or 
capsules, and as prolonged-release (PR) tablets 
(including a tamper resistant formulation [TRF]). To 
date, tapentadol has been administered to children aged 3 
years to less than 18 years in the pediatric clinical 
program. The oral solution has been given to these 
children as a single dose in a pharmacokinetic trial.
...
Pharmacokinetics in children
A population pharmacokinetic model was developed by 
means of the non-linear mixed effect approach using the 
data available from 2 single-dose pharmacokinetic trials 
in children aged 6 years to less than 18 years 
(KF5503/68 and KF5503/59). A 1 compartment model 
was found to describe the data adequately. The 
pharmacokinetic parameters of the allometrically scaled 
base model were as follows: CL/F = 189 L.h-1, 
V/F = 783 L (the CL/F and V/F are typical estimates for 
a subject with a body weight of 50 kg), first order 
absorption rate constant (Ka) = 2.14 h-1, time delay 
between drug administration and beginning of absorption 
(TLAG) = 0.247 h. The modeled pharmacokinetic 
parameters in children aged 6 years to less than 18 years 
old are in line with the corresponding modeled 
pharmacokinetic parameters in adults. The coefficients of 
weight on CL/F and V/F were estimated to be 0.495 and 
0.726, respectively. The inter-individual variabilities on 
CL/F, V/F, and Ka were 20.1%, 10.2%, and 126.88%, 
respectively.
...
Safety in Phase II trials in children (tapentadol oral 
solution)
To date, in a single dose trial (KF5503/68) of 52 children 
having undergone dental, ear, nose, or throat surgery, 
there have been no deaths. There was 1 serious adverse 
event (post-operative bleeding after a tonsillectomy), and 
Effects in humans
Tapentadol has been given to adults as an oral solution, 
intravenous solution, immediate-release (IR) tablets or 
capsules, and as prolonged-release (PR) tablets 
(including a tamper resistant formulation [TRF]). To 
date, tapentadol has been administered to children aged 2 
years to less than 18 years in the pediatric clinical 
program. The oral solution has been given to these 
children as a single dose in 2 pharmacokinetic trials
(KF5503/68 and KF5503/59).
...
Pharmacokinetics in children
A population pharmacokinetic model was developed by 
means of the non-linear mixed effect approach using the 
data available from 2 single-dose pharmacokinetic trials 
in children aged 2 years to less than 18 years 
(KF5503/68 and KF5503/59). A 1 compartment model 
was found to describe the data adequately. The 
pharmacokinetic parameters of the allometrically scaled 
base model were as follows: CL/F = 172 L.h-1, 
V/F = 677 L (the CL/F and V/F are typical estimates for 
a subject with a body weight of 45 kg), first order 
absorption rate constant (Ka) = 2.01 h-1, time delay 
between drug administration and beginning of absorption 
(TLAG) = 0.247 h. The modeled pharmacokinetic 
parameters in children aged 2 years to less than 18 years 
old are in line with the corresponding modeled 
pharmacokinetic parameters in adults. The coefficients 
of weight on CL/F and V/F were estimated to be 0.635
and 0.853, respectively. The inter-individual variabilities 
on CL/F, V/F, and Ka were 22.4%, 17.3%, and 145.3%, 
respectively.
...
Safety in Phase II trials in children (tapentadol oral 
solution)
In a single dose trial (KF5503/68) of 66 children 
undergoing dental, ear, nose, or throat surgery, there 
were no deaths. There was 1 serious adverse event (post-
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6 subjects were discontinued due to an adverse event 
(vomiting, which was also considered a stopping 
criteria).
...
Safety experience from post-marketing data in adults
The total cumulative post-authorization patient exposure 
to tapentadol IR and tapentadol PR since the first launch 
in Jul 2008 up to Apr 2013 was 95 068 714 patient 
treatment days with an estimated average daily dose of 
280 mg. In the time period from first launch to 23 Apr 
2013, 4118 spontaneous, medically confirmed individual 
case safety reports (i.e., the physician confirmed the 
diagnosis) were received, reporting tapentadol either as 
the suspect, co-suspect, or suspect-interacting drug. 
Among the 4118 cases, there were 73 cases with a fatal 
outcome, 1265 serious nonfatal cases, and 2780 not 
serious cases. Age was reported in 1893 cases and 
ranged from 1 year to 96 years. The cases involved 1982
female patients and 1247 male patients (the sex was not 
reported or was reported as unknown in 889 cases). 
Overall, the most frequently reported preferred terms for 
these events were (in descending order of frequency) 
nausea, drug ineffective, dizziness, headache, 
hallucination, and vomiting.
operative bleeding 6 days after a tonsillectomy), and 6 
subjects were discontinued due to an adverse event 
(vomiting, which was also considered a stopping 
criteria).
...
Safety experience from post-marketing data in adults
The total cumulative post-authorization patient exposure 
to tapentadol (IR and PR) since the first launch in Jul 
2008 up to 20 May 2014 was 142 923 321 patient 
treatment days with an estimated average daily dose for 
tapentadol IR of 280 mg. In the time period from first 
launch to 20 May 2014, 5286 spontaneous, medically 
confirmed cases were received, reporting tapentadol 
either as the suspect, co-suspect, or suspect-interacting 
drug. Among the 5286 cases, there were 85 cases with a 
fatal outcome, 1607 serious nonfatal cases, and 3594 not 
serious cases. Age was reported in 2465 cases and 
ranged from <1 year to 100 years. The cases involved 
2552 female patients and 1557 male patients (the sex was 
not reported or was reported as unknown in 1177 cases). 
Overall, the most frequently reported preferred terms for 
these events were (in descending order of frequency) 
nausea, drug ineffective, dizziness, headache, 
hallucination, and vomiting.
Section 8.2: Trial rationale
Overall, there should be no difference in the intensity of 
pain measured between the 2 treatment groups. Hence, 
the opioid sparing effect (i.e., lower expected use of 
supplemental opioid analgesic in the tapentadol 
treatment group than in the placebo-treated group) can 
thus be considered a surrogate for more direct measures 
of analgesia, such as changes in pain intensity. The use 
of NCA/PCA will allow subjects on placebo to receive 
standard of care.
Overall, there should be no difference in the intensity of 
pain measured between the 2 treatment groups. Hence, 
the opioid sparing effect (i.e., lower expected use of 
supplemental opioid analgesic in the tapentadol 
treatment group than in the placebo-treated group) can be 
considered a surrogate for more direct measures of 
analgesia, such as changes in pain intensity. The use of 
NCA/PCA will allow subjects on placebo to receive 
analgesia.
Section 8.4: Discussion of the trial design
Choice of population and sites
The age ranges selected for the trial conform to the 
requirements for development of medicines in children 
(see Section 8.3). The types of surgery allowed are 
restricted to those that are expected to produce pain 
severe enough to require opioid analgesic treatment.
Choice of population and sites
The age ranges selected for the trial conform to the 
requirements for development of medicines in children 
(see Section 8.3). The types of surgery allowed are 
restricted to those that are expected to produce pain 
severe enough to require opioid analgesic treatment via
NCA/PCA.
Examples of surgeries suitable for this trial include, but 
are not limited to, spinal fusions, cleft palate repair, 
Nuss procedures, scoliosis repair, nephrectomy, 
pyeloplasty, and orthopedic procedures such as club foot 
repair, leg lengthening, open reduction and internal 
fixation of long bone fractures. Subjects must remain 
hospitalized until the End of Treatment Visit. 
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Comparator and use of NCA/PCA
...
Hence, due to the use of NCA/PCA as per usual routine, 
children will not be subjected to more pain than they 
would otherwise experience in the selected post-
operative setting.
...
A subject will be discontinued from the trial if there is
pain not controlled by the NCA/PCA pump requiring 
treatments other than those defined in the protocol.
Comparator and use of NCA/PCA
...
Hence, due to the use of NCA/PCA as per usual routine, 
children should not be subjected to more pain than they 
would otherwise experience in the selected post-
operative setting.
...
A subject will be discontinued from the trial if their pain 
is not controlled by the NCA/PCA pump, requiring 
treatments other than those defined in the protocol.
Dosing
...
Non-linear mixed effects modeling was performed to 
develop a population pharmacokinetic model in the 
pediatric population for tapentadol oral solution. The 
data from 2 dedicated single-dose pharmacokinetic trials 
(KF5503/68 and KF5503/59 [R33133PAI2005]) were 
used for the population pharmacokinetic model and 
served as a basis for dose selection in the current trial for 
children aged 6 years to less than 18 years old. The doses 
for children 2 years to less than 6 years of age are still to 
be predicted, but will be based on further data accruing 
from these trials. The doses for children aged from birth 
to 2 years will be predicted from additional 
pharmacokinetic sampling in children of the same age 
group.
Simulations were performed to identify tapentadol doses
that would produce total exposures (i.e., serum AUC for 
tapentadol) in pediatric subjects that are similar to those 
reported in adults. The approved adult therapeutic dose 
range that is generally associated with efficacy and good 
tolerability in adults, 50 mg to 100 mg, was used for 
comparison. These simulations showed that tapentadol 
doses of 1.25 mg/kg every 4 hours in subjects aged 6 
years to less than 18 years old are expected to produce 
exposures similar to those after administration of 50 mg 
to 100 mg every 4 hours, given as an immediate-release 
formulation in adults. The median steady state simulated 
AUCs after a 50 mg, 75 mg, and 100 mg dose in adults 
are 217 ng.h/mL, 325 ng.h/mL, and 433 ng.h/mL, 
respectively. In comparison, the median simulated steady 
state AUC in subjects aged 6 years to 17 years old 
receiving 1.25 mg/kg is 318 ng.h/mL.
Based on these results, a dose regimen of 1.25 mg/kg 
will be used for the first 24 hours of treatment in this trial 
in children aged 6 years to less than 18 years old. After 
24 hours after the start of IMP, and based on clinical 
judgment, the dose may either be continued at 
1.25 mg/kg or it may be decreased to 1.0 mg/kg. A 
decision to maintain or alter the dose will depend on the 
Dosing
...
Non-linear mixed effects modeling was performed to 
develop a population pharmacokinetic model in the 
pediatric population for tapentadol oral solution. The 
data from 2 dedicated single-dose pharmacokinetic trials 
(KF5503/68 and KF5503/59 [R33133PAI2005]) were 
used for the population pharmacokinetic model and 
served as a basis for dose selection in the current trial for 
children aged 2 years to less than 18 years old. The doses 
for children aged from birth to less than 2 years will be 
predicted from additional pharmacokinetic sampling in 
children of the same age group.
Simulations were performed to identify tapentadol doses 
that would produce total exposures (i.e., serum AUC for 
tapentadol) in pediatric subjects that are similar to those 
reported in adults. The approved adult therapeutic dose 
range that is generally associated with efficacy and good 
tolerability in adults, 50 mg to 100 mg, was used for 
comparison. These simulations showed that tapentadol 
doses of 1.25 mg/kg every 4 hours in subjects aged 2 
years to less than 18 years old are expected to produce 
exposures similar to those after administration of 50 mg 
to 100 mg every 4 hours, given as an immediate-release 
formulation in adults. The median steady state simulated 
AUCs after a 50 mg, 75 mg, and 100 mg dose in adults 
are 217 ng.h/mL, 325 ng.h/mL, and 433 ng.h/mL, 
respectively. In comparison, the median simulated steady 
state AUC in subjects aged 2 years to 17 years old 
receiving 1.25 mg/kg is 306 ng.h/mL.
Based on these results, a dose regimen of 1.25 mg/kg 
will be used for the first 24 hours of treatment in this trial 
in children aged 2 years to less than 18 years old. After 
24 hours after the start of IMP, and based on clinical 
judgment, the dose may either be continued at 
1.25 mg/kg or it may be decreased to 1.0 mg/kg. A 
decision to maintain or alter the dose will depend on the 
investigator’s judgment of the effectiveness of the 
analgesia and the adverse event profile observed in each 
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effectiveness of the analgesia and the adverse event 
profile observed in each child over the first 24 hour 
dosing period. The doses for subjects aged less than 6 
years old will be defined based on forthcoming 
pharmacokinetic data. Subjects less than 6 years old will 
not be recruited into the trial until the dose has been 
defined for them.
child over the first 24 hour dosing period. The doses for 
subjects aged less than 2 years old will be defined based 
on forthcoming pharmacokinetic data. Subjects less than 
2 years old will not be recruited into the trial until the 
dose has been defined for them.
Pain measurements
To measure pain intensity, 3 pain intensity scales will be 
used to cover the different age-related abilities to report 
pain. These assessments are discussed in Section 12.4.
Pain measurements
To measure pain intensity, 3 pain intensity scales will be 
used to cover the different age-related abilities to report 
pain. These assessments are discussed in Section 12.4. In 
addition, the investigator/delegate or subject will record 
a pain intensity score prior to each NCA/PCA activation, 
whenever possible (as requested by the US FDA). Pain 
intensity data collected for this purpose, i.e., directly 
before each NCA/PCA activation, will be used only for 
the purpose of exploratory descriptive analysis. 
Blood sampling
The total withdrawn blood volume in this trial will not 
exceed approximately 15 mL (even when additional 
blood is drawn for a pharmacokinetic analysis when a 
serious adverse event occurs), i.e., well within the 
maximum safe blood loss that is recommended in a 
pediatric population (e.g., EMEA ad hoc working party 
2008).
Blood sampling
The total withdrawn blood volume in this trial is given in 
Section 11.7, and this will not exceed the maximum safe 
blood loss that is recommended in a pediatric population 
(e.g., EMEA ad hoc working party 2008).
Section 8.5: Benefit/risk analysis
Safety - background procedures
All subjects will undergo a surgical procedure. The 
surgical procedure and anesthesia have inherent risks. 
However, these surgical procedures and the need for 
opioid treatment would be independent of participation 
in this trial.
Safety - background procedures
All subjects will undergo a surgical procedure. The 
surgical procedure and anesthesia have inherent risks. 
However, these surgical procedures and the need for 
opioid treatment are independent of participation in this 
trial.
Safety - selection of sites
The chosen investigative trial sites and the investigators 
will have experience in pediatric surgery and the trial 
sites will be properly prepared to conduct a clinical trial. 
The trial site staff will be trained in the use of the scales 
and instruments included in this trial to ensure that trial 
procedures and evaluations are carried out according to 
GCP, and in accordance with standard medical practice.
Safety - selection of sites
The chosen investigative trial sites and the investigators 
will have experience in the care of patients following
pediatric surgery and the trial sites will be properly 
prepared to conduct a clinical trial. The trial site staff 
will be trained in the use of the scales and instruments 
included in this trial to ensure that trial procedures and 
evaluations are carried out according to GCP, and in 
accordance with standard medical practice.
Section 9.3.1: Reasons for discontinuation of a subject
The investigator must discontinue subjects from the trial 
for the compulsory reasons given in Table 1. If the 
reason is given as optional, then the investigator may 
decide to stop the participation of the subject in the trial 
if the benefit/risk ratio is not favorable for the continued 
participation of the subject.
The investigator must discontinue subjects from the trial 
for the compulsory reasons given in Table 1. If the 
reason is given as optional, then the investigator may 
decide to stop the participation of the subject in the trial 
if the benefit/risk ratio is not favorable for the continued 
participation of the subject. The evaluation of optional 
reasons for discontinuation must be documented by the 
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...
Table 1: 
Protocol deviation. The subject is taking forbidden
medication (see Section 10.6.4).
...
A subject will be discontinued from IMP if they have not 
had a dose of IMP for 10 hours. Further trial procedures 
should be performed as scheduled including Visit 3 (End 
of Treatment Visit) and Visit 4 (Follow-up Visit).
investigator in the CRF.
...
Table 1: 
Protocol deviation. The subject is taking prohibited
medication (see Section 10.6.4).
...
Further trial procedures should be performed as 
scheduled including Visit 3 (End of Treatment Visit) and 
Visit 4 (Follow-up Visit).
Section 9.3.2: Procedure for the handling of prematurely discontinued subjects
The investigator must inform the sponsor within 24 
hours about any discontinuation of a subject and must 
document any discontinuation of a subject.
...
All efforts should be made to collect more data from 
subjects who are discontinued because of clinically 
relevant changes in liver parameters so that a valid 
causality assessment can be made.
The investigator must inform the sponsor within 24 
hours about any discontinuation of a subject.
...
All efforts should be made to collect data from subjects 
who are discontinued because of clinically relevant 
changes in liver parameters so that a valid causality 
assessment can be made.
Section 9.3.3: Premature termination or suspension of the trial
...
The party prematurely terminating or suspending the trial 
must promptly inform all other parties (i.e., the principal 
investigator(s), the relevant IEC/IRB, the regulatory 
authorities, the sponsor/the sponsor’s authorized 
delegate, or the DMC, as applicable).
...
The party prematurely terminating or suspending the trial 
must promptly inform all other parties (i.e., the principal 
investigator(s), the relevant IEC/IRB, the regulatory 
authorities, the sponsor/the sponsor’s authorized 
delegate, and the DMC, as applicable).
Section 9.3.3.1: Criteria to terminate or suspend the whole trial
...
A risk benefit committee organized by the operational 
lead will convene to decide on further action, which 
could include immediate stopping of the trial.
...
A risk benefit committee organized jointly by the 
operational lead and sponsor’s steering committee will 
convene to decide on further action, which could include 
immediate stopping of the trial.
Section 10: Treatments
10.6 Allowed and forbidden prior/concomitant 
medications.
10.6.4 Forbidden prior and concomitant medication
10.6 Allowed and prohibited prior/concomitant 
medications.
10.6.4 Prohibited prior and concomitant medication
Section 10.2.1: Dose
...
...
Volumes of 1 mL or less will be given using a 1 mL 
syringe with 0.05 mL graduations. Volumes of more than 
1 mL will be given using a 5 mL syringe with 0.1 mL 
graduations.
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Section 10.3: Method of assigning subjects to treatment groups (allocation/randomization)
...
Randomization numbers will be allocated in ascending 
order according to age group, starting with the oldest age 
group and progressing to the next younger age group.
...
Randomization numbers will be allocated in ascending 
order within each age group, and by ascending age 
group.
Section 10.4.1: Methods of blinding
Randomization and blinding will be done in accordance 
with the sponsor’s standard operating procedures 
(SOPs).
Randomization and blinding will be done in accordance 
with the operational lead’s standard operating 
procedures (SOPs).
Section 10.4.2: Methods of unblinding
The investigator, the responsible department of the 
sponsor, and the responsible drug safety department and 
contract research organization will receive appropriate 
methods for unblinding of single cases, i.e., IVRS/IWRS 
access to unblinding functionality.
Personnel in the sponsor’s departments of clinical trials 
supply will be unblinded during the trial according to the 
sponsor’s SOPs for randomization and unblinding during 
the trial. The qualified person for pharmacovigilance 
may be unblinded at any time during the trial.
Persons involved in the conduct (including subjects and 
investigators), data management, and analysis of the trial 
will remain blinded until unblinding is performed after 
database lock at the end of the trial. Unblinding will be 
initiated by the sponsor’s department of biostatistics 
according to the sponsor’s SOPs for randomization and 
unblinding.
The investigator, the responsible department of the 
operational lead, and the responsible drug safety 
department and contract research organization will 
receive appropriate methods for unblinding of single 
cases, i.e., via the IVRS/IWRS.
Personnel in the operational lead’s departments of 
clinical trials supply will be unblinded during the trial 
according to the operational lead’s SOPs for 
randomization and unblinding during the trial. The 
qualified person for pharmacovigilance may be 
unblinded at any time during the trial.
Persons involved in the conduct (including subjects and 
investigators), data management, and analysis of the trial 
will remain blinded until unblinding is performed after 
database lock at the end of the trial. Unblinding will be 
initiated by the operational lead’s department of 
biostatistics according to the operational lead’s SOPs for 
randomization and unblinding.
Section 10.5.1: Supplemental opioid analgesic medication
...
After the first dose of IMP (see table below), NCA/PCA 
will be continued with the same opioid as used 
previously (i.e., morphine or hydromorphone, defined as 
supplemental opioid analgesia), according to investigator 
judgment and standard of care.
...
After the first dose of IMP (see Table 2), NCA/PCA will 
be continued with the same opioid as used previously 
(i.e., morphine or hydromorphone, defined as 
supplemental opioid analgesia), according to investigator 
judgment and standard of care.
Section 10.6.2: Concomitant medications
If, in the interests of the subject’s safety, the 
administration of forbidden concomitant medications is 
required, the sponsor should be informed in advance (or 
promptly after the instance).
If, in the interests of the subject’s safety, the 
administration of prohibited concomitant medications is 
required, the sponsor should be informed in advance (or 
promptly after the instance).
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Section 11.1: Course of the trial
The trial consists of an Enrollment Period starting up to 
28 days before allocation/randomization to IMP and 
lasting up to the time of allocation/randomization to 
IMP, whereby subjects may be enrolled in the trial either 
pre- or post-operatively; a Treatment and Evaluation 
Period (up to 48 hours); and a Follow-Up Period (10 
days to 14 days after the first dose of IMP).
The trial consists of an Enrollment Period starting up to 
28 days before allocation/randomization to IMP and 
lasting up to the time of allocation/randomization to 
IMP, whereby subjects may be enrolled in the trial either 
pre- or post-operatively; a Treatment and Evaluation 
Period (up to 96 hours); and a Follow-Up Period (10 
days to 14 days after the first dose of IMP).
Section 11.1.1: Enrollment Period (Visit 1)
The following evaluations will be performed during this 
period:
...
• Record demographic data: date of signing the informed 
consent/assent form, sex, age at time of 
allocation/randomization (years for subjects aged 2 years 
and older, months for subjects aged 2 months to less than 
2 years, and days for subjects aged less than 2 months –
the day of birth is counted as day 1), race/ethnicity, 
height, and weight. The BMI will be calculated 
automatically. The data may be extracted from the 
hospital charts if already available according to the 
standard of care. The weight should be measured after 
surgery if the surgery notably changes the weight of the 
child.
...
• Complete the C-SSRS “children’s baseline” 
questionnaire if the subject is aged 6 years or older. Any
refusal to complete the questionnaire must be recorded 
with the reason. This must be performed after surgery.
...
• Record vital signs (respiratory rate, systolic and 
diastolic blood pressure, and pulse rate) within 2 hours
before allocation/randomization to IMP.
• Record oxygen saturation within 2 hours before 
allocation/randomization to IMP.
...
[New]
The following evaluations will be performed during this 
period:
...
• Record date of signing the informed consent/assent 
form, sex, race/ethnicity, and height. 
The data may be extracted from the hospital charts if 
already available according to the standard of care. 
• Record weight after surgery (can be measured before 
surgery if the surgery is not expected to notably change 
the weight). The BMI will be calculated automatically.
...
• Complete the C-SSRS “children’s baseline” 
questionnaire if the subject is aged 6 years or older. The 
C-SSRS will be explained and shown to the parents/legal 
guardian at the time of the informed consent procedure.
The administration of the C-SSRS must be performed 
after surgery. A refusal to answer the questions in the 
questionnaire that are appropriate for the subject must 
be recorded with the reason. Referrals to mental health 
professionals will be made as determined by the 
investigator. Record the initials of the interviewer.
...
• Record vital signs (respiratory rate, systolic and 
diastolic blood pressure, and pulse rate) after surgery
directly before allocation/randomization to IMP.
• Record oxygen saturation after surgery directly before 
allocation/randomization to IMP.
...
• Record age at time of allocation/randomization (years 
for subjects aged 2 years and older, months for subjects 
aged 2 months (i.e., 60 days) to less than 2 years, and 
days for subjects aged less than 2 months ( i.e., less than 
60 days) – the day of birth is counted as day 1).
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Section 11.1.2.1: Visit 2
Before first dose of investigational medicinal product
• Record the following details about opioid analgesic 
medication ...
− The times of starting and stopping the background 
infusion.
• Record the trade name, date, time, dose, dose unit, 
formulation, and route of administration of non-opioid 
analgesic medication given to the subject after surgery 
(starting up to 24 hours before first IMP dose).
...
• Record the following directly before (i.e., within 10 
minutes) administration of IMP:
− Vital signs (respiratory rate, systolic and diastolic 
blood pressure, and pulse rate).
...
Record values under 92% for at least 60 seconds 
(excluding technical failures or artifacts).
Before first dose of investigational medicinal product
• Record the following details about opioid analgesic 
medication ...
− The times of starting and stopping the background 
infusion.
− The lockout time.
• Record the trade name, date, time, dose, dose unit, 
formulation, and route of administration of opioid and
non-opioid analgesic medication given to the subject for 
the time period indicated in the schedule of events for 
analgesic medication (Section 1.2).
...
• Record the following directly before (i.e., within 10 
minutes) administration of IMP:
− Vital signs (respiratory rate, systolic and diastolic 
blood pressure, and pulse rate).
− Sedation score (see Section 12.3.10).
...
Record values below 92% for at least 60 seconds 
(excluding technical failures or artifacts).
Administration of first dose of investigational 
medicinal product (Day 1)
Dosing with IMP will be stopped when opioid analgesic 
medication is no longer needed, or after a maximum of
48 hours.
Administration of first dose of investigational 
medicinal product (Day 1)
The subject will only receive IMP if the SpO2 does not 
drop below 92% for a period of 60 seconds in the 
10 minutes before IMP administration.
Dosing with IMP will be stopped when opioid analgesic 
medication is no longer needed, or after 72 hours after 
first IMP administration.
After the first dose of investigational medicinal 
product
...
• Administer supplemental opioid analgesic medication 
as required (by NCA/PCA, see Section 10.5.1). Record 
the following at times consistent with the memory of the 
NCA/PCA pump from first dose of IMP until 4 hours 
after the last administration of IMP:
...
− The doses of each administration.
…
After the first dose of investigational medicinal 
product
...
• Administer supplemental opioid analgesic medication 
as required (by NCA/PCA, see Section 10.5.1). Record 
the following at times consistent with the memory of the 
NCA/PCA pump for the time period indicated in the 
schedule of events (Section 1.2):
...
− The doses of each administration.
− The lockout time.
…
• Pain intensity scores should be obtained before each 
NCA/PCA activation, whenever possible. However, the 
NCA/PCA activation should not be unduly delayed by the 
pain intensity assessment.
• Record pain intensity within 30 minutes to 60 minutes 
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• Record pain intensity within 30 minutes to 60 minutes 
after the first dose of IMP only (see Section 12.2.5), for 
which the subject may be woken if necessary. 
…
• Record the palatability and acceptability of the oral 
solution after the first dose of IMP in subjects aged 3 
years to less than 18 years old.
...
• Record the trade name, date, time, dose, dose unit, 
formulation, and route of administration of non-opioid 
analgesic medication given to the subject until 4 hours 
after the last administration of IMP.
after the first dose of IMP only (see Section 12.2.5). 
Subjects do not need to be woken for this assessment.
…
• Record the palatability and acceptability of the oral 
solution after the first dose of IMP in subjects aged 2 
years to less than 18 years old.
...
• Record the trade name, date, time, dose, dose unit, 
formulation, and route of administration of non-opioid 
analgesic medication given to the subject for the time 
period indicated in the schedule of events (Section 1.2). 
The same details of any additional opioid medication 
used inadvertently must be collected.
Before subsequent doses of investigational medicinal 
product
...
• Record the following directly before (i.e., within 10 
minutes) administration of IMP:
...
• Record the following details about the use of 
supplemental opioid analgesic medication (by 
NCA/PCA) at times consistent with the memory of the 
NCA/PCA pump from first dose of IMP until 4 hours 
after the last administration of IMP:
…
− The doses of each administration.
…
• Record the trade name, date, time, dose, dose unit, 
formulation, and route of administration of non-opioid 
analgesic medication given to the subject until 4 hours 
after the last administration of IMP.
Before subsequent doses of investigational medicinal 
product
The subject will only receive IMP if the SpO2 does not 
drop below 92% for a period of 60 seconds in the 
10 minutes before IMP administration.
...
• Record the following directly before (i.e., within 10 
minutes) administration of IMP:
− Sedation score (see Section 12.3.10).
...
• Record the following details about the use of 
supplemental opioid analgesic medication (by 
NCA/PCA) at times consistent with the memory of the 
NCA/PCA pump for the time period indicated in the 
schedule of events (Section 1.2):
…
− The doses of each administration.
− The lockout time.
…
• Pain intensity scores should be obtained before each 
NCA/PCA activation, whenever possible. However, the 
NCA/PCA activation should not be unduly delayed by the 
pain intensity assessment.
…
• Record the trade name, date, time, dose, dose unit, 
formulation, and route of administration of non-opioid 
analgesic medication given to the subject for the time 
period indicated in the schedule of events (Section 1.2). 
The same details of any additional opioid medication 
used inadvertently must be collected.
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Section 11.1.2.3: Visit 3 (End of Treatment Visit)
...
• Record the trade name, date, time, dose, dose unit, 
formulation, and route of administration of non-opioid 
analgesic medication given to the subject until 4 hours 
after the last administration of IMP.
...
• Complete the C-SSRS questionnaire “children’s since 
last visit” if the subject is aged 6 years or older. Any
refusal to complete the questionnaire must be recorded 
with the reason.
...
• Record pain intensity (see Section 12.2.5).
• Record the palatability and acceptability of the oral 
solution in subjects aged 3 years to less than 18 years 
old.
...
• Record the trade name, date, time, dose, dose unit, 
formulation, and route of administration of non-opioid 
analgesic medication given to the subject for the time 
period indicated in the schedule of events (Section 1.2).
The same details of any additional opioid medication 
used inadvertently must be collected.
...
• Complete the C-SSRS questionnaire “children’s since 
last visit” if the subject is aged 6 years or older. A refusal 
to answer the questions in the questionnaire that are 
appropriate for the subject must be recorded with the 
reason. Record the initials of the interviewer.
...
• Record pain intensity (see Section 12.2.5). Pain 
intensity scores should be obtained before each 
NCA/PCA activation, whenever possible. However, the 
NCA/PCA activation should not be unduly delayed by the 
pain intensity assessment.
• Record the palatability and acceptability of the oral 
solution in subjects aged 2 years to less than 18 years 
old.
Section 11.7: Overview of blood sampling in this trial
...
The approximate amount of blood drawn for this trial is 
given in Table 3. Repeat or unscheduled samples may be 
taken for safety reasons. For details of steps taken to 
reduce the risk to the subjects regarding blood sampling, 
please see Section 8.5.
Table 3: Approximate volume of blood to be collected 
from each subject
The total blood volume drawn per subject will not 
exceed approximately 15 mL during the trial (even when
additional blood is drawn for a pharmacokinetic analysis 
when a serious adverse event occurs) (Table 3), therefore 
subjects who participate in the trial will not exceed the 
recommended limits for blood drawn (Section 8.4).
... 
Repeat or unscheduled samples may be taken for safety 
reasons. For details of steps taken to reduce the risk to 
the subjects regarding blood sampling, please see Section 
8.5.
For subjects aged 2 years and older, the approximate 
amount of blood drawn for this trial is given in Table 3. 
Table 3: Approximate volume of blood to be collected 
from each subject aged 2 years and older
For subjects aged 2 years and older, the total blood 
volume drawn per subject will not exceed approximately 
15 mL during the trial (even if additional blood is drawn 
for a pharmacokinetic analysis if a serious adverse event 
occurs) (Table 3).
For subjects aged less than 2 years old, blood sampling 
for clinical chemistry and hematology should be 
performed such that blood volumes taken do not exceed 
0.8 mL/kg body weight for each sampling time point, and 
2.4 mL/kg in total (EMEA ad hoc working party 2008).
The volume of blood drawn from subjects who 
participate in the trial will not exceed the recommended 
limits (Section 8.4).
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Section 12.1.2: Prior and concomitant medications
...
Section 12.1.2.1 Opioid analgesic medication given by 
NCA/PCA and background infusion before first dose of 
investigational medicinal product
...
Section 12.1.2.1: Opioid analgesic medication given by 
NCA/PCA and background infusion
Section 12.1.2.1: Opioid analgesic medication given by NCA/PCA and background infusion
The following details about opioid analgesic medication 
given by NCA/PCA and by background infusion (if any) 
after surgery will be recorded. The recording is for a 
maximum of 24 hours before the first IMP dose:
• The trade names of the opioid analgesic medications 
used.
...
• The times of starting and stopping the background 
infusion.
The following details about opioid analgesic medication 
given by NCA/PCA and by background infusion (if any) 
after surgery will be recorded. The recording is from up 
to 24 hours before first dose of IMP until the End of 
Treatment Visit:
• The trade names of the opioid analgesic medications 
used.
...
• The times of starting and stopping the background 
infusion.
• The lockout time.
See Section 12.1.3 for medication used outside of this 
timeframe.
Section 12.1.2.2: Detailed information for other analgesic (opioid and non-opioid) medication [New section]
...
The trade name, date, time, dose, dose unit, formulation, 
and route of administration of analgesic medication will 
be recorded, irrespective of the indication. The detailed 
recording of these medications is limited to after surgery 
(starting up to 24 hours before first IMP dose) until the 
End of Treatment Visit, as indicated in the schedule of 
events (see Section 1.2). 
See Section 12.1.3 for medication used outside of this 
timeframe.
Section 12.1.3: Prior and concomitant therapies
All therapies used within 28 days before 
allocation/randomization to IMP and up to the end of the 
trial must be recorded.
All therapies, excluding anesthetics and medication used 
during the surgery, used within 28 days before 
allocation/randomization to IMP and up to the end of the 
trial must be recorded.
Section 12.1.6: Other data
The times of starting and stopping the continuous 
monitoring of pulse oximetry, respiration rate, and heart 
rate will be recorded. If the IMP is given via a 
nasogastric tube, this will be documented.
The times of starting and stopping the continuous 
monitoring of pulse oximetry, respiration rate, and heart 
rate will be recorded. If the IMP is given via a 
nasogastric tube, this will be documented.
Pain intensity scores (see Section 12.2.5 for a 
description of the pain intensity scales) will be collected 
before each NCA/PCA activation, whenever possible.
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Section 12.2.1: Amount of supplemental opioid used
The details of the supplemental opioid analgesic 
medication used will be recorded at times consistent with 
the memory of the NCA/PCA pump from the first dose 
of IMP until 4 hours after the last administration of IMP
as indicated in the schedule of events (see Section 1.2).
The following details will be recorded:
• The trade names of the supplemental opioid analgesic 
medications used.
• The doses of each administration.
• The times of each administration.
Details of intravenous morphine or hydromorphone used
if the NCA/PCA line fails will also be recorded.
The details of the supplemental opioid analgesic 
medication used (see Section 12.1.2.1) will be recorded 
at times consistent with the memory of the NCA/PCA 
pump from the first dose of IMP, as indicated in the 
schedule of events (see Section 1.2).
Details of intravenous morphine or hydromorphone used 
if the NCA/PCA line fails will also be recorded.
Section 12.2.2: Amount of non-opioid analgesic medication used
The trade name, date, time, dose, dose unit, formulation, 
and route of administration of non-opioid analgesic 
medication will be recorded, irrespective of the 
indication. Recording is limited to after surgery (starting 
up to 24 hours before first IMP dose) until 4 hours after 
the last administration of IMP, as indicated in the 
schedule of events (see Section 1.2).
Detail of the administration of non-opioid analgesic 
medication will be recorded as given in Section 12.1.2.2, 
irrespective of the indication. 
Section 12.2.3.2: Clinical Global Impression of Change
The CGIC (Schneider et al. 1997) was chosen as a 
complementary assessment of analgesic efficacy.
The CGIC (Schneider et al. 1997) was chosen as a 
complementary assessment of analgesic efficacy.
Inter-rater reliability will be assessed for the CGIC as 
part of site training.
Section 12.2.4: Palatability and acceptability of IMP
Responses for palatability and acceptability will be 
evaluated in subjects aged 3 years to less than 18 years 
old on 5-point hedonic scales in combination with a 
verbal rating and documented (Guinard 2001), unless the 
subject is administered the IMP by a nasogastric tube.
Responses for palatability and acceptability will be 
evaluated in subjects aged 2 years to less than 18 years 
old on 5-point hedonic scales in combination with a 
verbal rating and documented (Guinard 2001), unless the 
subject is administered the IMP by a nasogastric tube.
Section 12.2.5.1: Face, Legs, Activity, Cry, and Consolability scale
...
The investigator will record the results of these 
measurements in the subject’s medical file before 
recording the data.
...
The investigator will record the results of these 
measurements in the subject’s questionnaire before 
recording the data in the CRF. The total score will not be 
captured by the CRF but will be calculated during the 
analysis of the trial. Inter-rater reliability will be 
evaluated for the FLACC as part of site training.
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Section 12.3.2: Safety laboratory
White blood cell (WBC) count with differential count if 
abnormal
Lipase
Clinical chemistry and hematology – central 
laboratory
...
The creatinine clearance (CLCR) will be calculated using 
a central laboratory standard age appropriate formula.
[table of parameters moved to here]
White blood cell (WBC) count with differential count 
Lipase (not required for the local laboratory assessment)
Clinical chemistry and hematology – central 
laboratory
...
The creatinine clearance (CLCR) will be calculated 
according to Schwartz et al. 1984.
If the red or white blood cell analyses are clinically 
relevantly abnormal, the red or white cell morphologies 
must be reported, respectively.
Section 12.3.4: Twelve-lead electrocardiogram
Twelve-lead ECGs will be recorded after surgery prior to 
allocation/randomization to IMP and at End of 
Treatment. The measured ECG intervals will be RR, PR, 
QRS, and QT; the corrected [Fridericia] QTcF will be 
calculated. Cardiologists at a central ECG laboratory will 
read all 12-lead ECGs. The investigator will review the 
12-lead ECG for clinically relevant abnormalities prior 
to dosing subjects. Specific 12-lead ECG procedures will 
be provided in a separate manual. The investigator will 
document all abnormal 12-lead ECG results, with a 
judgment whether the abnormality is clinically relevant.
Twelve-lead ECGs will be recorded after surgery prior to 
allocation/randomization to IMP and at End of 
Treatment. The measured ECG intervals will be RR, PR, 
QRS, and QT; the corrected [Fridericia] QTcF will be 
calculated. The investigator will review the 12-lead ECG 
for clinically relevant abnormalities prior to dosing 
subjects. The investigator will document all abnormal 
12-lead ECG results, with a judgment whether the
abnormality is clinically relevant.
Section 12.3.5: Vital signs (respiratory rate, systolic and diastolic blood pressure, and heart rate) and oxygen 
saturation
Vital signs (respiratory rate, systolic and diastolic blood 
pressure, and pulse rate) and oxygen saturation (by pulse 
oximetry) will be measured as per standard of care and 
recorded at the times specified in the schedule of events 
(see Section 1.2) and recorded.
Vital signs (respiratory rate, systolic and diastolic blood 
pressure, and pulse rate) and oxygen saturation (by pulse 
oximetry) will be measured as per standard of care and 
recorded at the times specified in the schedule of events 
(see Section 1.2).
Section 12.3.7: Continuous monitoring of oxygen saturation
If the saturation falls below 92% for more than
60 seconds (excluding technical failures or artifacts), the 
lowest value, the length of time the saturation is below 
92%, and vital signs are to be recorded.
If the oxygen saturation falls below 92% for at least
60 seconds (excluding technical failures or artifacts), the 
lowest value, the length of time the oxygen saturation is 
below 92%, and vital signs are to be recorded.
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Section 12.3.9: Columbia–suicide severity rating scale
...
Any refusal to complete the questionnaire must be 
recorded with the reason.
...
The C-SSRS will be administered by a clinician who has 
been certified to administer the C-SSRS.
...
A refusal to answer the questions in the questionnaire 
that are appropriate for the subject must be recorded 
with the reason.
...
The C-SSRS will be administered by a clinician who has 
been certified to administer the C-SSRS. 
The C-SSRS will be explained and shown to the 
parents/legal guardians prior to use.
Section 12.3.10: University of Michigan Sedation Scale
[new section]
The University of Michigan Sedation Scale (Section 
19.11) is a validated (Malviya et al. 2002) observational 
pediatric 5-point sedation scale. It will be used to assist 
in accurately assessing the depth of sedation before the 
administration of IMP. The investigator will record the 
sedation score at the times specified in the schedule of 
events (see Section 1.2).
Section 13.4: Source data
In certain circumstances, data may only be recorded in 
the trial-specific CRF and not in other documents. When 
this occurs, the CRF is considered to be the source 
document. Data expected to be only recorded in the CRF 
are: race/ethnic group.
In certain circumstances, data may only be recorded in 
the trial-specific CRF and not in other documents. When 
this occurs, the CRF is considered to be the source 
document. Data expected to be only recorded in the CRF 
are: race/ethnic group, and the result of the calculation of 
creatinine clearance (CLCR) according to Schwartz et al. 
1984.
Section 14: Statistical methods and sample size determination
There are different requirements for the EU PDCO and 
US FDA including the age range of the patient 
population (EU PDCO: 2 years to <18 years of age, US 
FDA: birth to <17 years of age) and the timing of the
primary efficacy endpoint (EU PDCO: 24 hours, US 
FDA: 12 hours) that impact the statistical methods and 
are reflected in the following sections.
There are different requirements for the EU PDCO and 
US FDA including the age range of the patient 
population (EU PDCO: 2 years to <18 years of age, US 
FDA: birth to <17 years of age) and the timing of the 
primary efficacy endpoint (EU PDCO: 24 hours, US 
FDA: 12 hours) that impact the statistical methods and 
are reflected in the following sections.
As applicable and appropriate for the individual 
endpoint, the endpoints will be analyzed in the age 
ranges for the EU PDCO and for the US FDA.
Section 14.1: Sample size rationale
...
To meet US FDA requirements, enrollment will 
continue, if necessary, until a minimum of 100 subjects 
have received at least 2 doses of tapentadol and 25 
subjects have received tapentadol for at least 48 hours. 
Based on estimates from adult trials in acute pain, it is 
assumed that approximately 5% of subjects 
(approximately 8 subjects) may discontinue prior to 
receiving 2 doses of IMP, which is covered by the 
...
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targeted sample size (i.e., approximately 168 subjects).
...
The trial enrollment will then complete when the 
following 4 criteria are met:
...
• 100 subjects in the age range birth to less than 17 years 
of age on tapentadol for at least 2 doses. 
• 25 subjects in the age range birth to less than 17 years 
of age (US FDA) have received tapentadol for at least 48 
hours.
Due to the overlapping age groups as per regulatory 
requirements, it is expected that approximately 168 
subjects will be treated with IMP in this trial.
...
The sample size calculation was performed using the 
Procedure MTT0-1 for the two group t-test, assuming 
equal group means and variance, and unequal group sizes 
using the sample size program nQuery v7.0 (Dixon and 
Massey 1983, O’Brien and Muller 1993).
...
The trial enrollment will then complete when the 
following 3 criteria are met:
...
• 100 subjects in the age range birth to less than 17 years 
of age on tapentadol for at least 2 doses (US FDA). 
Based on estimates from adult trials in acute pain, it is 
assumed that approximately 5% of subjects 
(approximately 8 subjects) may discontinue prior to 
receiving 2 doses of IMP, which is covered by the 
targeted sample size.
Due to the overlapping age groups as per regulatory 
requirements, it is expected that approximately 168 
subjects will be treated with IMP in this trial.
An additional objective of the study is to meet a US FDA 
request to evaluate at least 25 subjects in the age range 
birth to less than 17 years of age who have been exposed 
to tapentadol for at least 48 hours. As medically 
appropriate, every effort will be made to enroll subjects 
in this trial to meet this objective.
...
The sample size calculation was performed using the 
sample size program nQuery v7.0 (Dixon and Massey 
1983, O’Brien and Muller 1993) for unequal group sizes 
and the above assumptions regarding the effect size and 
the allocation ratio of 2:1 (tapentadol:placebo).
Section 14.2: Analysis of the trial – statistical analysis
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.
The statistical analysis of this trial will be performed as 
summarized in this protocol and given in detail in the 
statistical analysis plan. The statistical analysis plan will 
be prepared before the database is released (locked and 
unblinded).
The statistical analysis of this trial will be planned, 
performed, and reported by operational lead personnel 
or by authorized operational lead delegates, in 
accordance with operational lead’s SOPs.
The statistical analysis of this trial will be performed as 
summarized in this protocol and given in detail in the 
statistical analysis plan. The statistical analysis plan will 
be finalized before the first subject in.
Section 14.2.3: Analysis of subject characteristics data
...
...
Pain intensity scores collected before each NCA/PCA 
activation will be analyzed descriptively by treatment 
group.
Section 14.2.5.1: Primary efficacy endpoint
...
For subjects who withdraw from the trial prior to the 12-
hour or 24-hour time point, cumulative supplemental 
opioid analgesia over the respective time period will be 
based on the observed supplemental opioid use up to the 
...
For subjects who withdraw from the trial prior to the 12-
hour or 24-hour time point due to any other reason than 
no further need of opioid analgesic medication, 
cumulative supplemental opioid analgesia over the 
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time of the subject’s discontinuation. If a subject used a 
total of X mg/kg of supplemental opioid through Hour T 
(24 hours), cumulative use over 24 hours will be 
estimated as (X/T)*24 mg/kg. If T is <12 hours, 
cumulative use over 12 hours will be estimated as 
(X/T)*12. This extrapolation assumes a constant use (in 
mg/kg per hour) of supplemental opioid over 24 hours. 
Other imputation methods will be used for sensitivity 
analyses. These will be described in detail in the 
statistical analysis plan.
...
A sensitivity analysis will be performed using the 
respective Per Protocol Set and analyzed using the same 
ANOVA model.
respective time period will be based on the observed 
supplemental opioid use up to the time of the subject’s 
discontinuation. If a subject used a total of X mg/kg of 
supplemental opioid through Hour T (24 hours), 
cumulative use over 24 hours will be estimated as 
(X/T)*24 mg/kg. If T is <12 hours, cumulative use over 
12 hours will be estimated as (X/T)*12. This 
extrapolation assumes a constant use (in mg/kg per hour) 
of supplemental opioid over 24 hours. For subjects who 
withdraw from the trial due to no further need of opioid 
analgesic medication, the cumulative use of 
supplemental opioid will equal the total amount of 
supplemental opioid used up to the time of withdrawal. 
Other imputation methods will be used for sensitivity 
analyses. These will be described in detail in the 
statistical analysis plan.
...
A sensitivity analysis will be performed using the 
respective Per Protocol Set and analyzed using the same 
ANOVA model.
The primary endpoint will also be evaluated using 
Bayesian statistics as a supportive analysis (EU PDCO).
The methodology will be described in the statistical 
analysis plan.
Section 14.2.5.2: Secondary endpoints and subgroup analyses
...
The amount of supplemental opioid analgesic medication 
(morphine equivalents in mg/kg body weight) used 
within the first 12 hours or 24 hours after first IMP 
intake will be a secondary efficacy endpoint for the EU 
PDCO or US FDA, respectively.
...
The analysis will also be repeated for the total amount of 
supplemental opioid analgesic medication received 
during treatment with IMP within 72 hours after the first 
dose of IMP.
...
The total amounts of non-opioid analgesic medications 
used (irrespective of the indication) within the first 12 
hours and 24 hours after first IMP intake will be grouped 
...
The amount of supplemental opioid analgesic medication 
(morphine equivalents in mg/kg body weight) used 
within the first 12 hours or 24 hours after first IMP 
intake will be a secondary efficacy endpoint for the EU 
PDCO or US FDA, respectively.
...
In addition, the total amount of supplemental opioid 
analgesic medication received, assessed in 12 hour 
intervals from 24 hours to 96 hours, will be summarized 
descriptively. The intervals will be >24 to 36 hours, >36 
to 48 hours, >48 to 60 hours, >60 to 72 hours, >72 to 84 
hours, and >84 to 96 hours. For each interval, only 
subjects who have their End of Treatment Visit after the 
start of the interval will be included. If a subject has 
their End of Treatment Visit during a given interval, the 
missing data for the remainder of the given interval will 
be imputed using a similar methodology as for the 
primary efficacy endpoint, but using only data from 
within the given interval. The subject will then not be 
included in the subsequent intervals.
...
The total amounts of non-opioid analgesic medications 
used (irrespective of the indication) within the first 12 
hours and 24 hours after first IMP intake will be grouped 
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according to ingredient and route of administration, and 
descriptively summarized by treatment group and 
presented in tables.
...
Pain intensity scores and change from baseline values 
will be summarized descriptively over time by treatment 
group and age categories (respective age-defined pain 
scale), as well as being listed. Figures will also be 
produced, where required.
according the Anatomical Therapeutic Chemical 
Classification System (World Health Organization Drug 
Dictionary coding) and route of administration, and 
descriptively summarized by treatment group and 
presented in tables.
...
Pain intensity scores recorded relative to IMP intake, 
and at the End of Treatment Visit, with changes from 
baseline values, will be summarized descriptively over 
time by treatment group and age categories (respective 
age-defined pain scale), as well as being listed. Figures 
will also be produced, where required.
...
Subgroup analyses
Summary statistics for the primary efficacy endpoint will 
be provided by age group (birth to <30 days, 30 days to 
<6 months, 6 months to <2 years, 2 years to <6 years, 6 
years to <12 years, 12 years to <17 years, and 17 years 
to <18 years) and by method of supplemental opioid 
administration (NCA vs. PCA) among other subgroup 
analyses.
Section 14.2.6.7: Analysis of sedation scores
[new section]
Descriptive statistics of sedation scores will be provided 
at each scheduled time point as described in Section 1.2.
Section 14.3: Ad hoc meta-analyses
[section deleted]
Section 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 will be publically disclosed in 
accordance with the sponsor’s disclosure policy (e.g., on 
ClinicalTrials.gov) and operational lead’s disclosure 
policy (e.g., according to the European Federation of 
Pharmaceutical Industries and Associations (EFPIA) 
Principles for Responsible Clinical Trial Data Sharing) 
and applicable regulatory guidance. The operational lead 
will post clinical trial information in a lay person 
understandable form in a freely accessible operational 
lead’s internet portal.
Section 17: References
[New citations]
Malviya S, Voepel-Lewis T, Tait AR, Merkel S, Tremper 
K, Naughton N. Depth of sedation in children 
undergoing computed tomography: validity and 
reliability of the University of Michigan Sedation Scale 
(UMSS). Br J Anaesth 2002; 88(2): 241–5.
Schwartz GJ, Feld LG, Langford DJ. A simple estimate 
of glomerular filtration rate in full-term infants during 
the first year of life. J Pediatr 1984; 104(6): 849–54.
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Section 19.2: Face, Legs, Activity, Cry, Consolability scale
[Scale updated with latest version]
Instructions for use:
1. Rate patient in each of the five measurement 
categories.
2. Add the scores together.
3. Document the total pain score.
Section 19.3: Faces pain scale - Revised
[scale has been updated (attribution was moved from 
bottom to top of page)]
Section 19.6: Palatability and acceptability questionnaire
a little bit bad/a little bit good
a little bit difficult/a little bit easy
a bit bad/a bit good
a bit difficult/a bit easy
[reference given]
Section 19.10.3: Procedure
• Fill S-Monovette® with 1 mL of blood.
• Fill S-Monovette® with 0.5 mL of blood.
Section 19.10.5: Contact
Contact person
Dr 
 
Contact person
Dr 
Deputy: 
E-mail address
Operational lead
@grunenthal.com
Bioanalytical laboratory
@grunenthal.com
E-mail address
Operational lead
@grunenthal.com
Bioanalytical laboratory
@grunenthal.com
@grunenthal.com
Phone
Operational lead
+49 (0) 241-569-
Bioanalytical laboratory
+49 (0) 241-569-
Phone
Operational lead
+49 (0) 241-569-
Bioanalytical laboratory
+49 (0) 241-569-
+49 (0) 241-569
Section 19.11: University of Michigan Sedation Scale
[scale has been added]
18.3
Protocol Amendment 03
Amendment rationale
This amendment has been enacted to reflect a change in the sponsor from Janssen Research & 
Development, LLC to Grünenthal GmbH. As a consequence, the functions of the sponsor and the 
operational lead were merged.
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Title page: 
Tapentadol (code numbers CG5503 and R331333, 
respectively) is being developed under a Licensing 
agreement between Ortho-McNeil Pharmaceutical Inc., 
Janssen Research & Development, L.L.C., and 
Grünenthal GmbH that was executed in February 2003.
Tapentadol (code numbers CG5503 and R331333, 
respectively) is being developed under a Licensing 
agreement between Ortho-McNeil Pharmaceutical Inc., 
Janssen Research & Development, L.L.C., and 
Grünenthal GmbH that was executed in February 2003, 
the rights to which were subsequently acquired by 
Depomed, Inc. in April 2015.
Trial numbers:
KF5503/65 (Grünenthal)
R331333PAI3037 (Janssen)
Trial number:
KF5503/65
R331333PAI3037
IND number:
108134 (Janssen Research & Development).
IND number:
108134
Sponsor: 
Janssen Research & Development LLC, Titusville, 
United States.
Sponsor: 
Grünenthal GmbH, 52099 Aachen, Germany.
Operational lead
Grünenthal GmbH, 52099 Aachen, Germany.
[deleted]
Sponsor’s medically qualified person:
Dr 
, Clinical Leader, 
Janssen Research & Development, LLC
Phone: +1 609-730-
@ITS.JNJ.com a
Sponsor’s medically qualified person:
Dr 
, Head Global Clinical 
Development Strategy,
Grünenthal GmbH
Phone: +49 241-569-
@grunenthal.com a
Sponsor’s signatory:
Dr 
, Clinical Leader
Janssen Research & Development, LLC
Sponsor’s signatory:
Dr 
, Head Global Clinical 
Development Strategy,
Grünenthal GmbH
Operational lead’s medically qualified person:
Dr 
, Head Global Clinical 
Development Strategy,
Grünenthal GmbH
Phone: +49 241-569-
@grunenthal.com
[deleted]
Operational lead’s signatory:
Dr 
, Head Global Clinical 
Development Strategy,
Grünenthal GmbH
[deleted]
[New section]
Collaborator: Depomed, Newark, California
[New section]
Collaborator’s signatory:
, Chief 
Medical Officer & Senior Vice President, 
 
, Senior Director, Clinical Operations,
Depomed, Inc, Newark, California
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Section 1: Protocol synopsis: Statistical methods:
...
Adverse events will be coded using the most current 
version of the Medical Dictionary for Regulatory 
Activities (MedDRA) used by the operational lead.
...
Adverse events will be coded using the most current 
version of the Medical Dictionary for Regulatory 
Activities (MedDRA) used by the sponsor.
Section 3: Abbreviations and definition of terms
By definition, the Enrollment Period as used by the 
operational lead company (Grünenthal GmbH) is 
synonymous with the Screening Period as used by the 
sponsor company (Janssen Research & Development), 
and allocation as used by the operational lead company
is synonymous with randomization as used by the 
sponsor company.
By definition, Enrollment Period is synonymous with 
Screening Period, and allocation is synonymous with 
randomization.
Section 5.3: The sponsor and sponsor’s personnel
Janssen Research & Development accepts the 
responsibility to be the sponsor of this clinical trial.
Grünenthal GmbH, 52099 Aachen, Germany is the 
sponsor’s designee and accepts the responsibility of the 
operational lead for the trial.
The sponsor can delegate tasks to the operational lead. 
The extent of the delegation will be documented.
The sponsor/operational lead 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/operational lead 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.
Grünenthal GmbH, 52099 Aachen, accepts the 
responsibility to be the sponsor of this clinical trial.
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.
Section 5.4: Data monitoring committee
...
The DMC members will neither be employees of the 
sponsor/operational lead nor be directly involved in the 
ongoing pediatric trials with tapentadol. Further details 
describing the data to be assessed and operational aspects 
of the DMC will be given in a charter which will be 
issued before the first subject is enrolled in this trial. 
Based on the reviewed data, the DMC may recommend 
the implementation of additional measures or dose 
changes. The final decision on how to further proceed 
with the trial will be made by the sponsor/operational 
lead on the basis of the DMC recommendation.
...
The DMC members will neither be employees of the 
sponsor or collaborator nor be directly involved in the 
ongoing pediatric trials with tapentadol. Further details 
describing the data to be assessed and operational aspects 
of the DMC will be given in a charter which will be 
issued before the first subject is enrolled in this trial. 
Based on the reviewed data, the DMC may recommend 
the implementation of additional measures or dose 
changes. The final decision on how to further proceed 
with the trial will be made by the sponsor or 
collaborator on the basis of the DMC recommendation.
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Section 9.3.3.1: Criteria to terminate or suspend the whole trial
...
A risk benefit committee organized jointly by the 
operational lead and sponsor’s steering committee will 
convene to decide on further action, which could include 
immediate stopping of the trial.
The DMC may recommend stopping the trial, but the 
final decision will rest jointly with the sponsor and
operational lead.
The trial may be restarted following a thorough 
evaluation by the sponsor and operational lead.
...
A risk benefit committee organized by the sponsor will 
convene to decide on further action, which could include 
immediate stopping of the trial.
The DMC may recommend stopping the trial, but the 
final decision will rest with the sponsor and 
collaborator.
The trial may be restarted following a thorough 
evaluation by the sponsor and collaborator.
Section 10.1.1: Identity and composition – tapentadol oral solution (test)
Section 10.1.2: Identity and composition – placebo (comparator)
...
Manufacturer:
Janssen Pharmaceutica NV, Beerse, Belgium.
...
Manufacturer:
Grünenthal GmbH, Aachen, Germany.
Section 10.4.1: Methods of blinding
...
Randomization and blinding will be done in accordance 
with the operational lead’s standard operating procedures 
(SOPs).
...
Randomization and blinding will be done in accordance 
with the sponsor’s standard operating procedures 
(SOPs).
Section 10.4.2: Methods of unblinding
...
The investigator, the responsible department of the 
operational lead, and the responsible drug safety 
department and contract research organization will 
receive appropriate methods for unblinding of single 
cases, i.e., via the IVRS/IWRS.
Personnel in the operational lead’s departments of 
clinical trials supply will be unblinded during the trial 
according to the operational lead’s SOPs for 
randomization and unblinding during the trial. The 
qualified person for pharmacovigilance may be 
unblinded at any time during the trial.
Persons involved in the conduct (including subjects and 
investigators), data management, and analysis of the trial 
will remain blinded until unblinding is performed after 
database lock at the end of the trial. Unblinding will be 
initiated by the operational lead’s department of 
biostatistics according to the operational lead’s SOPs for 
randomization and unblinding.
...
The investigator, the responsible department of the 
sponsor, the responsible drug safety department, and 
contract research organization will receive appropriate 
methods for unblinding of single cases, i.e., via the 
IVRS/IWRS.
Personnel in the sponsor’s departments of clinical trials 
supply will be unblinded during the trial according to the 
sponsor’s SOPs for randomization and unblinding during 
the trial. The qualified person for pharmacovigilance 
may be unblinded at any time during the trial.
Persons involved in the conduct (including subjects and 
investigators), data management, and analysis of the trial 
will remain blinded until unblinding is performed after 
database lock at the end of the trial. Unblinding will be 
initiated by the sponsor’s department of biostatistics 
according to the sponsor’s SOPs for randomization and 
unblinding.
Section 10.5.1: Supplemental opioid analgesic medication
...
The supplemental opioid analgesic medication must be 
purchased by the trial site unless otherwise agreed upon 
with the sponsor/operational lead.
...
The supplemental opioid analgesic medication must be 
purchased by the trial site unless otherwise agreed upon 
with the sponsor.
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Section 10.7: Documentation of drug accountability
...
Before the unused and residual IMPs and other 
medications supplied to the investigator are returned or 
destroyed, the investigator must allow the operational 
lead’s representative to perform drug reconciliation.
...
Before the unused and residual IMPs and other 
medications supplied to the investigator are returned or 
destroyed, the investigator must allow the sponsor’s
representative to perform drug reconciliation.
Section 12.3.2.1: Serum concentrations of tapentadol
...
Serum samples will be analyzed to determine 
concentrations of tapentadol and, optionally, tapentadol-
O-glucuronide using a validated liquid chromatography-
tandem mass spectrometry bioanalytical assay under the 
supervision of the department of pharmacokinetics at the 
operational lead.
...
Serum samples will be analyzed to determine 
concentrations of tapentadol and, optionally, tapentadol-
O-glucuronide using a validated liquid chromatography-
tandem mass spectrometry bioanalytical assay under the 
supervision of the department of pharmacokinetics at the 
sponsor.
Section 13.3: Data management: Coding
Medication names will be coded using the World Health 
Organization-Drug Dictionary. Medical history terms 
and adverse events will be coded using MedDRA. As 
required by the operational lead’s SOPs, the version 
most recently implemented by the operational lead will 
be used at the time of database lock. Coding will be 
reviewed by the operational lead’s personnel according 
to standard procedures.
Medication names will be coded using the World Health 
Organization-Drug Dictionary. Medical history terms 
and adverse events will be coded using MedDRA. As 
required by the sponsor’s SOPs, the version 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.
Section 13.4: Source data
...
During trial conduct, vendors are responsible for data 
security with oversight from the operational lead. 
All data captured from all subjects will be sent to the 
sponsor/operational lead in human readable form on a 
read-only compact disc for filing/archiving according to 
sponsor/operational lead SOPs.
...
During trial conduct, vendors are responsible for data 
security with oversight from the sponsor. 
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.
Section 13.5: Investigator’s site file and the trial master file
...
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 clinic/hospital policy, but 
at least until informed by the sponsor/operational lead
that the trial-related records are no longer required.
...
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 clinic/hospital policy, but 
at least until informed by the sponsor that the trial-
related records are no longer required.
Section 14.2: Analysis of the trial – statistical analysis
The statistical analysis of this trial will be planned, 
performed, and reported by operational lead personnel or 
by authorized operational lead delegates, in accordance 
with operational lead’s SOPs.
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.
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Section 14.2.6.1: Analysis of adverse events
The original terms used in the CRFs by investigators to 
identify adverse events will be coded using the most 
recent version of MedDRA used by the operational lead.
The original terms used in the CRFs by investigators to 
identify adverse events will be coded using the most 
recent version of MedDRA used by the sponsor.
Section 15.1: Quality system
The sponsor/operational lead is responsible for 
implementing and maintaining quality assurance and 
quality control systems with written SOPs.
The sponsor is responsible for implementing and 
maintaining quality assurance and quality control 
systems with written SOPs.
Section 15.2: Data quality assurance
The accuracy and reliability of the trial data will be 
assured by careful clinical research 
organization/investigator selection and oversight by the 
performance of a combination of trial site visits, training, 
monitoring visits, remote verification by the 
sponsor/operational lead of appropriate use of electronic 
tools by the site, data cleaning, and audits.
The accuracy and reliability of the trial data will be 
assured by careful clinical 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 the site, data 
cleaning, and audits.
Section 15.2.2: Trial site monitoring
Trial site monitoring as defined in GCP will be 
performed by sponsor/operational lead personnel or by 
authorized sponsor delegates at pre-defined intervals 
depending on the progress of the trial.
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.
Section 15.2.3: Audits
Audits as defined by GCP will be performed for this 
trial. The investigator will permit sponsor/operational 
lead personnel or authorized delegates to audit the trial 
facilities and documentation at agreed times.
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.
Section 15.3: Inspections
The investigator, the sponsor, the operational lead, 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, at the operational lead, or at other 
establishments. 
The investigator or personnel at other establishments 
should notify the sponsor/operational lead as soon as 
possible about any upcoming regulatory authority 
inspection.
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.
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Section 16.1: Insurance
If insurance for subjects is required by applicable 
regulatory requirements in the participating countries, 
the sponsor/operation lead 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 changes to the trial are implemented after the initial 
insurance was arranged, e.g., due to protocol 
amendments, the sponsor/operational lead will notify the 
insurance company of these changes in accordance with 
the insurance conditions. If changes to insurance arise, 
the sponsor/operational lead will inform the investigators 
who will then inform their subjects/parents/legal 
guardians about relevant changes, if required.
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 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, if required.
Section 16.2: Legal regulations
...
Before initiating the trial, if required by the applicable 
regulatory requirements, the sponsor/operation lead 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.
...
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.
Section 16.3: Contracts
Specific contracts between the relevant parties, i.e., 
between the investigator/other parties at the trial site(s) 
and the sponsor/operational lead or its local offices or 
contract research organization or its affiliates authorized 
by the sponsor/operational lead, 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/operational lead, if applicable.
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.
Section 16.4: Subject data and data protection
...
The investigator is required to ensure that any documents 
or data given to the sponsor/operational lead or its 
representatives do not contain information that would 
affect the anonymity of the subjects.
...
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.
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Section 16.5: Publication policy
The results of this trial will be publically disclosed in 
accordance with the sponsor’s disclosure policy (e.g., on 
ClinicalTrials.gov) and operational lead’s disclosure 
policy (e.g., according to the European Federation of 
Pharmaceutical Industries and Associations (EFPIA) 
Principles for Responsible Clinical Trial Data Sharing)
and applicable regulatory guidance. The operational lead
will post clinical trial information in a lay person 
understandable form in a freely accessible operational 
lead’s internet portal.
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 and operational lead reserve 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, operational 
lead, or the coordinating investigator) has the right to 
prohibit publication or public disclosure unless it can be 
shown to affect possible patent rights.
The results of this trial will be publically disclosed in 
accordance with the sponsor’s disclosure policy (e.g., on 
ClinicalTrials.gov), according to the European 
Federation of Pharmaceutical Industries and 
Associations (EFPIA) Principles for Responsible 
Clinical Trial Data Sharing, and applicable regulatory 
guidance. The sponsor will post clinical trial information 
in a lay person understandable form in a freely accessible 
sponsor internet portal.
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, the coordinating investigator) 
has the right to prohibit publication or public disclosure 
unless it can be shown to affect possible patent rights.
Section 16.6: Final report
A final report integrating clinical and statistical results 
will be prepared by the sponsor/operational lead. The 
coordinating investigator will approve the final report on 
behalf of the participating investigators. 
The sponsor/operational lead will provide the competent 
authority and relevant IEC/IRB with a summary of the 
final report in accordance with applicable regulatory 
requirements.
A final report integrating clinical and statistical results 
will be prepared by the sponsor. The coordinating 
investigator will approve the final report on behalf of the 
participating investigators. 
The sponsor will provide the competent authority and 
relevant IEC/IRB with a summary of the final report in 
accordance with applicable regulatory requirements.
Section 16.7: Approval
16.7.1 Sponsor and operational lead
This protocol has been approved in accordance with 
sponsor and operational lead SOPs.
16.7.1 Sponsor 
This protocol has been approved in accordance with 
sponsor SOPs.
Section 19.10.2: Devices
...
Other devices may be used if equivalent after approval 
by the operational lead.
...
Other devices may be used if equivalent after approval 
by the sponsor.
Section 19.10.4: Shipment
...
• Send the samples by premium courier door-to-door 
delivery to the bioanalytical laboratory (address given in 
Section 19.10.5). Choice of courier has to be approved 
by the operational lead.
...
• Send the samples by premium courier door-to-door 
delivery to the bioanalytical laboratory (address given in 
Section 19.10.5). Choice of courier has to be approved 
by the sponsor.
Section 19.10.5: Contact
Operational lead ... Bioanalytical laboratory
Sponsor ... Bioanalytical laboratory
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18.4
Protocol Amendment 04
Amendment rationale
This amendment has been enacted to:
•
Clarify the definition for stopping IMP.
•
Allow dosing with morphine or hydromorphone for technical reasons if an NCA/PCA dose 
cannot be given.
•
Allow a clinician bolus or intravenous bolus of morphine or hydromorphone if the subject 
had unbearable pain in exceptional cases. This has been enacted to ensure that the subjects 
are not exposed to more pain than would normally be the case.
•
Add peri- or post-operative analgesia supplied by a continuous regional technique (e.g., 
nerve block, wound infiltration catheter) or subject controlled epidural analgesia to the 
prohibited medication from 6 hours prior to time of allocation/randomization to IMP until 
4 hours after the last administration of IMP.
•
Exclude continuous positive airway pressure or mechanical ventilation from time of 
allocation/randomization to IMP until 4 hours after the last administration of IMP.
•
Modify 2 exclusion criteria to:
−
8. Subject is obese in the investigator’s judgment. Obesity can be determined based on 
appropriate BMI charts or tables; e.g., a BMI above the 97th percentile for children 
based on the World Health Organization growth charts (see Section 19.9).
−
16. Peri- or post-operative analgesia supplied by a continuous regional technique (e.g., 
nerve block, wound infiltration catheter) or subject controlled epidural analgesia that 
was terminated less than 6 hours before allocation/randomization to IMP.
•
Add an exclusion criteria of: Subject requires continuous positive airway pressure or 
mechanical ventilation, at the time of allocation to IMP.
•
Allow the use of non-sponsor supplied dosing syringes. This has been enacted for logistical 
reasons and does not affect the outcome parameters.
•
Specify that the administration of IMP must not be repeated if the subject vomits or 
regurgitates a complete dose. If only part of the dose is vomited or regurgitated, the 
remainder of the dose may be administered at the investigator’s discretion.
•
Allow the pregnancy test to be done on either a urine sample or a serum sample.
•
Restrict CGIC and PGIC data to a descriptive analysis in the final report.
•
Only list physical examination findings in the final report.
In addition, a number of clarifications have been made, and discrepancies and inconsistencies have 
been corrected.
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.
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Title page: 
Tapentadol (code numbers CG5503 and R331333, 
respectively) is being developed under a Licensing 
agreement between Ortho-McNeil Pharmaceutical Inc., 
Janssen Research & Development, L.L.C., and 
Grünenthal GmbH that was executed in February 2003, 
the rights to which were subsequently acquired by 
Depomed, Inc. in April 2015.
Tapentadol (code numbers CG5503 and R331333, 
respectively) is being developed under a Licensing 
agreement between Ortho-McNeil Pharmaceutical Inc., 
Janssen Research & Development, L.L.C., and 
Grünenthal GmbH that was executed in February 2003, 
the United States rights to which were subsequently 
acquired by Depomed, Inc. in April 2015. Subsequent to 
investigational new drug (IND) and new drug 
application (NDA) acquisition, Depomed Inc. has further 
transferred sponsor regulatory obligations for this trial 
to Grünenthal.
Trial design: This is a Phase III, randomized, multi-site, 
double-blind, placebo-controlled, parallel group, 
multiple oral dose trial of tapentadol (Nucynta/Palexia).
Trial design: This is a Phase III, randomized, multi-site, 
double-blind, placebo-controlled, parallel group, 
multiple oral dose trial of tapentadol oral solution.
Sponsor’s medically qualified person:
Dr 
, Head Global Clinical 
Development Strategy,
Grünenthal GmbH
Sponsor’s medically qualified person:
Dr 
, Senior International Clinical 
Lead,
Grünenthal GmbH
Sponsor’s signatory:
Dr 
, Head Global Clinical 
Development Strategy,
Grünenthal GmbH
Sponsor’s signatory:
Dr 
, Senior International Clinical 
Lead,
Grünenthal GmbH
Collaborator’s signatory:
Collaborator’s signatories:
Section 1: Protocol synopsis: Trial design
Section 8: Trial design
Section 8.4: Discussion of the trial design
This is a Phase III, randomized, multi-site, double-blind, 
placebo-controlled, parallel group, multiple oral dose 
trial of tapentadol (Nucynta/Palexia).
This is a Phase III, randomized, multi-site, double-blind, 
placebo-controlled, parallel group, multiple oral dose 
trial of tapentadol oral solution.
Section 1: Protocol synopsis: Trial population 
Section 9.1: Subject enrollment procedure
...
The trial enrollment will be initiated in a staggered 
approach, starting with enrollment of an older age group 
until pharmacokinetic data are available in younger age 
groups.
...
The trial enrollment will be initiated in a staggered 
approach, starting with enrollment of an older age group 
until pharmacokinetic data are available in younger age 
groups from other trials in the pediatric clinical 
development program of tapentadol.
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Section 1: Protocol synopsis: Trial treatments
Section 10.2.2: Total dosing time and dosing interval
Section 11.1.2.1: Visit 2: Administration of first dose of investigational medicinal product (Day 1)
...
Dosing with IMP will be stopped when opioid analgesic 
medication is no longer needed, or 72 hours after first 
IMP administration.
...
Dosing with IMP will be stopped if:
• A switch to exclusively oral opioid analgesic 
medication is indicated according to the local standard 
of care.
• Opioid analgesic medication is no longer needed. 
• IMP has been administered for 72 hours.
Section 1: Protocol synopsis: Concomitant medications/therapies
Section 10.6.3: Allowed prior and concomitant medication
...
If the NCA/PCA intravenous line fails for any reason, it 
should be restarted/repaired immediately. During the 
interim, morphine or hydromorphone may be 
administered intravenously. 
...
If the NCA/PCA intravenous line fails for any reason, it 
should be restarted/repaired immediately. During the 
interim, morphine or hydromorphone may be 
administered intravenously.
In exceptional cases, if a subject has unbearable pain 
despite using NCA/PCA, an additional bolus (defined as 
a clinician bolus) of morphine or hydromorphone may be 
administered. The clinician bolus can be given either 
using the NCA/PCA pump system or by an intravenous 
bolus injection.
The opioid given as a clinician bolus or if the NCA/PCA 
intravenous line fails must be the same as that used in 
the NCA/PCA pump system.
Section 1: Protocol synopsis: Concomitant medications/therapies
Section 10.6.4: Prohibited prior and concomitant medication/therapy
Prohibited medication from 6 hours prior to time of 
allocation/randomization to IMP until 4 hours after the 
last administration of IMP
• Long-acting opioids. 
• Medication used for sedation (as noted above, 
benzodiazepines may be used to treat muscle spasms or 
anxiety).
Prohibited medication from time of 
allocation/randomization to IMP until 4 hours after the 
last administration of IMP
• Opioids (other than morphine, hydromorphone, or 
IMP).
Prohibited medication from 6 hours prior to time of 
allocation/randomization to IMP until 4 hours after the 
last administration of IMP
• Long-acting opioids. 
• Medication used for sedation (as noted above, 
benzodiazepines may be used to treat muscle spasms or 
anxiety).
• Peri- or post-operative analgesia supplied by a 
continuous regional technique (e.g., nerve block, wound 
infiltration catheter) or subject controlled epidural 
analgesia.
Prohibited medication/therapy from time of 
allocation/randomization to IMP until 4 hours after the 
last administration of IMP
• Opioids (other than protocol defined morphine, 
hydromorphone, or IMP).
• Continuous positive airway pressure or mechanical 
ventilation.
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Section 1: Protocol synopsis: Key data collected
Efficacy
• Trade name, dose, and time of each administration of 
intravenous morphine or hydromorphone given if the 
NCA/PCA line fails.
...
Safety
...
• Pregnancy test (urine) for female subjects aged 12 
years or older, or post-menarchal, or sexually active.
Efficacy
• Trade name, dose, and time of each administration of 
intravenous morphine or hydromorphone given if the 
NCA/PCA line fails, or a clinician bolus is given.
...
Safety
...
• Pregnancy test for female subjects aged 12 years or 
older, or post-menarchal, or sexually active.
Section 1: Protocol synopsis: Statistical methods
...
Changes in physical examination findings compared to 
Visit 1 will be summarized by body system and results
will be listed.
...
The physical examination findings will be listed per time 
point.
Section 1.2: Schedule of events
...
Perform a urine pregnancy test
...
[Footnotes]
j) In subjects aged 6 years or older. The administration of 
the C-SSRS “children’s baseline” must be performed 
after surgery. A refusal to answer the questions in the 
questionnaire that are appropriate for the subject must be 
recorded with the reason. The initials of the interviewer 
are to be recorded.
q) For female subjects if aged 12 years or older, or post-
menarchal, or sexually active, a urine sample will be
provided by the subject within 48 hours prior to 
allocation/randomization to IMP.
r) Recording of detailed information is limited to after 
surgery (starting up to 24 hours before first IMP dose) up 
to the End of Treatment Visit (Section 12.1.2.1). 
NCA/PCA is with morphine or hydromorphone in 
accordance with the standard of care at the site. Detailed 
information on use will be recorded at times consistent 
with the memory of the NCA/PCA pump. Details will be 
recorded of dosing of intravenous morphine or 
hydromorphone used if the NCA/PCA fails.
...
Perform a pregnancy test
...
[Footnotes]
j) In subjects aged 6 years or older. The administration of 
the C-SSRS “children’s baseline” must be performed 
after surgery. A refusal to answer the questions in the 
questionnaire that are appropriate for the subject must be 
recorded with the reason. The initials of the interviewer 
are to be recorded. The C-SSRS will only be used at a 
trial site if its use has not been rejected by the 
responsible ethics committee.
q) For female subjects if aged 12 years or older, or post-
menarchal, or sexually active. Within 48 hours prior to 
allocation/randomization to IMP.
r) Recording of detailed information is limited to after 
surgery (starting up to 24 hours before first IMP dose) up 
to the End of Treatment Visit (Section 12.1.2.1). 
NCA/PCA is with morphine or hydromorphone in 
accordance with the standard of care at the site. Detailed 
information on use will be recorded at times consistent 
with the memory of the NCA/PCA pump. Details will be 
recorded of dosing of intravenous morphine or 
hydromorphone used if the NCA/PCA fails, or a 
clinician bolus is given.
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t) Pain intensity scores should be obtained before each 
NCA/PCA activation, whenever possible. However, the 
NCA/PCA activation should not be unduly delayed by 
the pain intensity assessment. 
t) Pain intensity scores should be obtained before each 
NCA/PCA activation, whenever possible. However, the 
NCA/PCA activation should not be unduly delayed by 
the pain intensity assessment. Pain intensity scores 
should also be obtained if intravenous morphine or 
hydromorphone is given if the NCA/PCA line fails, or if 
a clinician bolus is given.
Section 1.3.1: Inclusion criteria
Section 9.2.1: Inclusion criteria
4. A female subject must have a negative urine
pregnancy test if aged 12 years or older, or is post-
menarchal, or is sexually active.
5. Subject has undergone surgery (other than brain 
surgery or gastrointestinal surgery expected to affect the 
absorption of tapentadol [in the investigator’s judgment]) 
that, in the investigator’s opinion, would reliably 
produce moderate to severe pain requiring opioid 
treatment for at least 24 hours after 
allocation/randomization to IMP. Subjects must remain 
hospitalized until the End of Treatment Visit.
4. A female subject must have a negative pregnancy test 
if aged 12 years or older, or is post-menarchal, or is 
sexually active.
5. Subject has undergone surgery (other than brain 
surgery or gastrointestinal surgery expected to affect the 
absorption of tapentadol [in the investigator’s judgment]) 
that, in the investigator’s opinion, would reliably 
produce moderate to severe pain requiring opioid 
treatment for at least 24 hours after first dose of IMP. 
Subjects must remain hospitalized until the End of 
Treatment Visit.
Section 1.3.2: Exclusion criteria
Section 9.2.2: Exclusion criteria
8. Subject is obese, e.g., BMI above the 97th percentile 
for children based on the World Health Organization 
growth charts (see Section 19.9).
16. Peri- or post-operative analgesia supplied by a 
continuous regional technique (i.e., nerve block) or 
subject controlled epidural analgesia that was terminated 
less than 6 hours before allocation/randomization to 
IMP.
[New exclusion criterion]
8. Subject is obese in the investigator’s judgment.
Obesity can be determined based on appropriate BMI 
charts or tables; e.g., a BMI above the 97th percentile 
for children based on the World Health Organization 
growth charts (see Section 19.9).
16. Peri- or post-operative analgesia supplied by a 
continuous regional technique (e.g., nerve block, wound 
infiltration catheter) or subject controlled epidural 
analgesia that was terminated less than 6 hours before 
allocation/randomization to IMP.
Subject requires continuous positive airway pressure or 
mechanical ventilation, at the time of allocation to IMP. 
[Rationale] Safety
Section 3: Abbreviations and definition of terms: Definition of terms
...
[New]
...
Enrolled subjects: Informed consent given according to 
local regulations, and subject given a subject 
identification number by the IVRS/IWRS.
...
Clinician bolus: An additional bolus of morphine or 
hydromorphone given either using the NCA/PCA pump 
system or by an intravenous bolus injection. The 
clinician bolus can only be given in exceptional cases if 
a subject suffers unbearable pain despite using 
NCA/PCA.
...
Enrolled subjects: Informed consent/assent given 
according to local regulations, and subject given a 
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...
Treated subjects: Allocated subjects with at least 1 
administration of IMP.
subject identification number by the IVRS/IWRS.
...
Treated subjects: Subjects with at least 1 administration 
of IMP.
Section 8.4: Discussion of the trial design
Comparator and use of NCA/PCA
...
A subject will be discontinued from the trial if their pain 
is not controlled by the NCA/PCA pump, requiring 
treatments other than those defined in the protocol.
Comparator and use of NCA/PCA
...
A subject will be discontinued from the trial if their pain 
is not controlled by the IMP plus NCA/PCA, requiring 
treatments other than those defined in the protocol.
Section 9.3.1: Reasons for discontinuation of a subject: Table 1
Protocol deviation
...
• The subject is taking prohibited medication (see 
Section 10.6.4).
Protocol deviation
...
• The subject is taking prohibited medication/therapy
(see Section 10.6.4).
Section 10.1.3: Preparation
...
The IMP will be supplied as a liquid in 100 mL bottles 
intended for multiple use per subject. A dosing syringe 
for oral use will be provided with the IMP and must be 
used for IMP administration.
...
The IMP will be supplied as a liquid in 100 mL bottles 
intended for multiple use per subject. A dosing syringe 
for oral use (either a syringe supplied by the sponsor or 
a suitable sponsor-approved alternative, as defined in 
Section 10.2.1 and in the Investigational Product 
Preparation Instructions supplied by the sponsor) must 
be used for IMP administration.
Section 10.2.1: Dose
...
[New text]
...
Dosing charts will be provided by the sponsor.
Section 10.2.3: Administration
...
[New text]
...
The administration must not be repeated if the subject 
vomits or regurgitates a complete dose. If only part of 
the dose is swallowed before vomiting or regurgitation, 
the remainder of the dose may be administered at the 
investigator’s discretion. Vomiting and/or regurgitation 
must be recorded as an adverse event.
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Section 10.5.1: Supplemental opioid analgesic medication
...
[New text]
...
If the NCA/PCA intravenous line fails for any reason, it 
should be restarted/repaired immediately. During the 
interim, morphine or hydromorphone may be 
administered intravenously.
In exceptional cases, if a subject has unbearable pain 
despite using NCA/PCA, an additional bolus (defined as 
a clinician bolus) of morphine or hydromorphone may be 
administered. The clinician bolus can be given either 
using the NCA/PCA pump system or by an intravenous 
bolus injection.
Section 10.7: Documentation of drug accountability
...
The bottles of oral solution (tapentadol or placebo) will 
be weighed to determine the amount used. The 
instructions for weighing will be given separately. The 
weighing scales used must be appropriately calibrated 
and verified.
...
The bottles of oral solution (tapentadol or placebo) will 
be weighed to determine the amount used. The 
instructions for weighing will be given separately. The 
weighing scales used must be appropriately calibrated 
and verified. Instructions for drug accountability will be 
given in the drug accountability log.
Section 11.1.1: Enrollment Period (Visit 1)
...
• Complete the C-SSRS “children’s baseline” 
questionnaire if the subject is aged 6 years or older. The 
C-SSRS will be explained and shown to the parents/legal 
guardian at the time of the informed consent procedure
...
• Take a urine sample and perform a urine pregnancy test 
in female subjects if aged 12 years or older, or post-
menarchal, or sexually active, within 48 hours prior to 
allocation/randomization to IMP.
...
• Complete the C-SSRS “children’s baseline” 
questionnaire if the subject is aged 6 years or older. The 
C-SSRS will be explained and demonstrated at the time 
of the informed consent procedure.
...
• Perform a pregnancy test in female subjects if aged 12 
years or older, or post-menarchal, or sexually active, 
within 48 hours prior to allocation/randomization to 
IMP.
Section 11.1.2.1: Visit 2
Administration of first dose of investigational medicinal 
product (Day 1)
...
The first dose of IMP is given when IMP is available on 
the ward and the investigator determines it is medically 
appropriate for the subject to receive the IMP.
At the time of the first IMP administration, the 
background opioid infusion (if any) will be discontinued.
The IMP will be administered as an oral solution as 
described in Section 10.2. Dosing with IMP will be 
stopped when opioid analgesic medication is no longer 
needed, or after 72 hours after first IMP administration.
Administration of first dose of investigational medicinal 
product (Day 1)
...
The first dose of IMP is given when IMP is available on 
the ward and the investigator determines it is medically 
appropriate for the subject to receive the IMP. The time 
between allocation to IMP and first administration 
should be kept as short as possible.
At the time of the first IMP administration, the 
background opioid infusion (if any) will be discontinued.
The IMP will be administered as an oral solution as 
described in Section 10.2. 
After the first dose of investigational medicinal product
...
• Administer supplemental opioid analgesic medication 
After the first dose of investigational medicinal product
...
• Administer supplemental opioid analgesic medication 
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as required (by NCA/PCA, see Section 10.5.1). Record 
the following at times consistent with the memory of the 
NCA/PCA pump for the time period indicated in the 
schedule of events (Section 1.2):
...
− The trade name of intravenous morphine or 
hydromorphone, dose, and time of dosing if the 
NCA/PCA fails.
• Pain intensity scores should be obtained before each 
NCA/PCA activation, whenever possible. However, the 
NCA/PCA activation should not be unduly delayed by 
the pain intensity assessment.
as required (by NCA/PCA, see Section 10.5.1). Record 
the following at times consistent with the memory of the 
NCA/PCA pump for the time period indicated in the 
schedule of events (Section 1.2):
...
− The trade name of intravenous morphine or 
hydromorphone, dose, and time of dosing if the 
NCA/PCA fails, or a clinician bolus is given.
• Pain intensity scores should be obtained before each 
NCA/PCA activation, whenever possible. However, the 
NCA/PCA activation should not be unduly delayed by 
the pain intensity assessment. Pain intensity scores 
should also be obtained if intravenous morphine or 
hydromorphone is given if the NCA/PCA line fails, or if 
a clinician bolus is given.
Before subsequent doses of investigational medicinal 
product
...
• Record the following details about the use of 
supplemental opioid analgesic medication (by 
NCA/PCA) at times consistent with the memory of the 
NCA/PCA pump for the time period indicated in the 
schedule of events (Section 1.2):
...
− The trade name of intravenous morphine or 
hydromorphone, dose, and time of dosing if the 
NCA/PCA fails.
• Pain intensity scores should be obtained before each 
NCA/PCA activation, whenever possible. However, the 
NCA/PCA activation should not be unduly delayed by 
the pain intensity assessment.
Before subsequent doses of investigational medicinal 
product
...
• Record the following details about the use of 
supplemental opioid analgesic medication (by 
NCA/PCA) at times consistent with the memory of the 
NCA/PCA pump for the time period indicated in the 
schedule of events (Section 1.2):
...
−The trade name of intravenous morphine or 
hydromorphone, dose, and time of dosing if the 
NCA/PCA fails, or a clinician bolus is given.
• Pain intensity scores should be obtained before each 
NCA/PCA activation, whenever possible. However, the 
NCA/PCA activation should not be unduly delayed by 
the pain intensity assessment. Pain intensity scores 
should also be obtained if intravenous morphine or 
hydromorphone is given if the NCA/PCA line fails, or if 
a clinician bolus is given.
Section 11.1.2.3: Visit 3 (End of Treatment Visit)
...
• Record pain intensity (see Section 12.2.5). Pain 
intensity scores should be obtained before each 
NCA/PCA activation, whenever possible. However, the 
NCA/PCA activation should not be unduly delayed by 
the pain intensity assessment.
...
• Record pain intensity (see Section 12.2.5). Pain 
intensity scores should be obtained before each 
NCA/PCA activation, whenever possible. However, the 
NCA/PCA activation should not be unduly delayed by 
the pain intensity assessment. Pain intensity scores 
should also be obtained if intravenous morphine or 
hydromorphone is given if the NCA/PCA line fails, or if 
a clinician bolus is given.
Section 12.2.1: Amount of supplemental opioid used
Details of intravenous morphine or hydromorphone used
if the NCA/PCA line fails will also be recorded.
Details of intravenous morphine or hydromorphone used 
if the NCA/PCA line fails, or a clinician bolus is given
will also be recorded.
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Section 12.3: Collection of safety data
• Pregnancy test (urine) for female subjects aged 12 
years or older, or post-menarchal, or sexually active.
• Pregnancy test for female subjects aged 12 years or 
older, or post-menarchal, or sexually active.
Section 12.3.2: Safety laboratory
The creatinine clearance (CLCR) will be calculated
according to Schwartz et al. 1984.
The glomerular filtration rate will be estimated
according to Schwartz et al. 1984.
Section 12.3.3: Pregnancy test
For female subjects if aged 12 years or older, or post-
menarchal, or sexually active, a dipstick test will be 
performed on a urine sample provided within 48 hours 
prior to allocation/randomization to IMP.
For female subjects if aged 12 years or older, or post-
menarchal, or sexually active, a pregnancy test will be 
performed within 48 hours prior to 
allocation/randomization to IMP. This may be done on a 
serum sample according to local routine, or using a 
urine dipstick test (either supplied by the sponsor or a 
local test capable of detecting human chorionic 
gonadotropin levels of 25 mIU/mL or greater and a 
sensitivity/specificity of >99%).
Section 12.3.7: Continuous monitoring of oxygen saturation
Oxygen saturation will be monitored continuously using 
pulse oximetry from after surgery until 4 hours after the 
last administration of IMP.
Oxygen saturation will be monitored continuously using 
pulse oximetry from before allocation/randomization to 
IMP (but after surgery) until 4 hours after the last 
administration of IMP.
Section 12.3.9: Columbia–suicide severity rating scale
...
The C-SSRS will be explained and shown to the 
parents/legal guardians prior to use.
...
The C-SSRS will be explained and shown to the 
parents/legal guardians prior to use.
The C-SSRS will only be used at a trial site if its use has 
not been rejected by the responsible ethics committee.
Section 13.4: Source data
Data expected to be only recorded in the CRF are: 
race/ethnic group, and the result of the calculation of 
creatinine clearance (CLCR) according to Schwartz et al. 
1984.
Data expected to be only recorded in the CRF are: 
race/ethnic group, and the result of the estimation of the
glomerular filtration rate according to Schwartz et al. 
1984.
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Section 14.2.5.2: Secondary endpoints and subgroup analyses
...
The CGIC and PGIC, both using a 7-point rating scale at 
the End of Treatment Visit (Visit 3), will be tabulated by 
treatment group and analyzed using the Cochran–
Mantel–Haenszel (CMH) test, controlling for baseline 
age group and supplemental opioid analgesic used.
...
The time to first and time to second NCA/PCA after the 
first dose of IMP will be summarized descriptively and 
displayed by treatment group and by treatment group and 
age categories. Figures will also be produced, where 
required.
...
The CGIC and PGIC, both using a 7-point rating scale at 
the End of Treatment Visit (Visit 3), will be described 
descriptively.
...
The time to first and time to second NCA/PCA after the 
first dose of IMP will be summarized descriptively and 
displayed by treatment group and by treatment group and 
age categories. Figures will also be produced, where 
required. Any supplemental opioid analgesic medication 
given intravenously if the NCA/PCA pump fails and any 
clinician bolus will be included in this analysis.
Section 14.2.6.5: Analysis of physical examination data
Changes in physical examination findings compared to 
Visit 1 will be summarized by body system. Results will 
also be listed.
The physical examination findings will be listed per time 
point as described in Section 1.2.
18.5
Protocol Amendment 05
Amendment rationale
This amendment has been enacted to:
•
Define the dosing for subjects aged 6 months to <2 years old.
•
Provide restrictions for the medication that can be taken by mothers of a newborn or 
breastfeeding mother.
•
Allow the safety laboratory blood sample analysis to be performed at a local laboratory for 
subjects <2 years old to limit the amount of blood taken.
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.
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Section 1: Protocol synopsis: Trial treatments: Investigational medicinal products: Table of dosing regimen
Section 10.2.1: Dose: Table 2: Determination of tapentadol dose and oral solution concentration
2 years to 18 years old
6 months to 18 years old
Birth to 2 years old
Birth to 6 months old
a) The doses for subjects aged less than 2 years old (as 
determined at the time of allocation to IMP) will be 
defined based on forthcoming pharmacokinetic data. 
Recruitment of this age group will commence when the 
dose has been defined.
a) The doses for subjects aged less than 6 months old (as 
determined at the time of allocation to IMP) will be 
defined based on forthcoming pharmacokinetic data. 
Recruitment of this age group will commence when the 
dose has been defined.
Section 1: Protocol synopsis: Concomitant medications/therapies:
Section 10.6.4: Prohibited prior and concomitant medications/therapy
Prohibited medication from 6 hours prior to time of
allocation/randomization  to IMP until 4 hours after the 
last administration of IMP
…
[New text]
Prohibited medication from 6 hours before 
allocation/randomization  to IMP until 4 hours after the 
last administration of IMP
…
Restrictions for the mother of a newborn or 
breastfeeding mother
• For monoamine oxidase inhibitors, neuroleptics, 
anticonvulsants, antiparkinsonian drugs, methadone, 
and all serotonergic drugs including selective 
serotonin/norepinephrine reuptake inhibitors, tricyclic 
antidepressants, linezolid, and triptans:
− Prepartum intake by a mother of a newborn subject is 
prohibited in the 14 days prior to the subject’s 
allocation/randomization to IMP.
− The intake of these medications by the breastfeeding 
mother of a subject is prohibited from 14 days prior to 
the subject’s allocation/randomization to IMP until the 
end of treatment with the IMP.
• For opioid medication (including tapentadol 
formulations) and medication used for sedation:
− The intake of opioid medication (including tapentadol 
formulations) and medication used for sedation by the 
breastfeeding mother of a subject is prohibited from 48 
hours prior to the subject’s allocation/randomization to 
IMP until the end of treatment with the IMP. 
− The intake of opioid medication (including tapentadol 
formulations) and medication used for sedation taken 
prepartum by the mother of a newborn subject is 
prohibited from 48 hours prior to the subject’s 
allocation/randomization to IMP.
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Section 1: Protocol synopsis: Statistical methods:
…
Descriptive statistics, changes from baseline, frequency 
tabulations of abnormalities and subject listings will be 
provided for summarizing safety laboratory parameters, 
12-lead ECG, vital signs, and oxygen saturation across 
treatment group.
…
Descriptive statistics, changes from baseline, frequency 
tabulations of abnormalities and subject listings will be 
provided for summarizing safety laboratory parameters 
(only for blood samples analyzed at the central 
laboratory), 12-lead ECG, vital signs, and oxygen 
saturation across treatment group.
Section 1.2: Schedule of events: footnote
h) Record all medications, including opioid and non-
opioid analgesics but excluding anesthetics and 
medication used during the surgery (Section 12.1.2). 
h) Record all medications, including opioid and non-
opioid analgesics but excluding anesthetics and 
medication used during the surgery (Section 12.1.2). This 
includes the recording of prohibited medication used by 
breastfeeding mothers and prohibited prior medication 
used by mothers of a newborn subject.
Section 1.3.2: Exclusion criteria
Section 9.2.2: Exclusion criteria
[New text]
20. The mother of a newborn subject or the breastfeeding 
mother of a subject was administered a prohibited 
medication (see Restrictions for the mother of a newborn 
or breastfeeding mother).
Standardization of trial population.
Section 6.2: Relevant non-clinical and clinical data: Pharmacokinetics in children
A population pharmacokinetic model was developed ....
A population pharmacokinetic model was developed ...
The addition of data from children aged 1 month to less 
than 2 years (KF5503/72) resulted in minor changes in 
the model and was best described by incorporation of an 
Emax type maturation function. The pharmacometric 
parameters changed to: CL/F = 160 L.h-1, V/F = 546 L 
(the CL/F and V/F are typical estimates for a subject 
with a body weight of 34 kg), Ka = 2.21 h-1, 
TLAG = 0.267 h, with the coefficients of weight on CL/F 
and V/F being estimated as 0.551 and 0.829, 
respectively. The maturation function, which describes 
the age at which half the maximum CL/F within the data 
set is reached, was estimated as 46 weeks. The inter-
individual variabilities on CL/F and V/F remained the 
same with only the variability on Ka increasing to 148%.
Section 8.4: Discussion of the trial design: Dosing
Non-linear mixed effects modeling was performed to 
develop a population pharmacokinetic model in the 
pediatric population for tapentadol oral solution. The 
data from 2 dedicated single-dose pharmacokinetic trials 
(KF5503/68 and KF5503/59 [R33133PAI2005]) were 
used for the population pharmacokinetic model and 
served as a basis for dose selection in the current trial for 
children aged 2 years to less than 18 years old. The doses 
for children aged from birth to less than 2 years will be
Non-linear mixed effects modeling was performed to 
develop a population pharmacokinetic model in the 
pediatric population for tapentadol oral solution. The 
data from 2 dedicated single-dose pharmacokinetic trials 
(KF5503/68 and KF5503/59 [R33133PAI2005]) were 
used for the population pharmacokinetic model and 
served as a basis for dose selection in the current trial for 
children aged 2 years to less than 18 years old. The doses 
for children aged from birth to less than 2 years are
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predicted from additional pharmacokinetic sampling in 
children of the same age group.
…
[New paragraph]
Based on these results, a dose regimen of 1.25 mg/kg 
will be used for the first 24 hours of treatment in this trial 
in children aged 2 years to less than 18 years old. After 
24 hours after the start of IMP, and based on clinical 
judgment, the dose may either be continued at 1.25 
mg/kg or it may be decreased to 1.0 mg/kg. A decision to 
maintain or alter the dose will depend on the 
investigator’s judgment of the effectiveness of the 
analgesia and the adverse event profile observed in each 
child over the first 24 hour dosing period. The doses for 
subjects aged less than 2 years old will be defined based 
on forthcoming pharmacokinetic data. Subjects less than 
2 years old will not be recruited into the trial until the 
dose has been defined for them.
predicted from additional pharmacokinetic sampling in 
children of the same age group.
…
The population pharmacokinetic model used for the 
pediatric dose simulations was updated with exposure 
data obtained from children aged 1 month to less than 2 
years (KF5503/72), the simulations were then redone to 
determine the appropriate dose for the age group 6 
months to less than 2 years. The simulations specified 
that the dose of 1.25 mg/kg would give similar exposures 
as that observed in the age group 2 years to less than 18 
years.
Based on these results, a dose regimen of 1.25 mg/kg 
will be used for the first 24 hours of treatment in this trial 
in children aged 6 months to less than 18 years old. After 
24 hours after the start of IMP, and based on clinical 
judgment, the dose may either be continued at 1.25 
mg/kg or it may be decreased to 1.0 mg/kg. A decision to 
maintain or alter the dose will depend on the 
investigator’s judgment of the effectiveness of the 
analgesia and the adverse event profile observed in each 
child over the first 24 hour dosing period. The doses for 
younger subjects aged less than 6 months will be defined 
based on forthcoming pharmacokinetic data. Younger 
subjects will not be recruited into the trial until the dose 
has been defined for them.
Section 9.1: Subject enrollment procedure
…
The trial enrollment will be initiated in a staggered 
approach, starting with enrollment of an older age group 
until pharmacokinetic data are available in younger age 
groups from other trials in the pediatric clinical 
development program of tapentadol. Initially, subjects 
aged 2 years to less than 18 years will be recruited. 
Subjects from birth to less than 2 years of age will be 
recruited after pharmacokinetic and safety data are 
obtained and the dose selection has been defined for 
younger age groups. Allocation/randomization to IMP 
will be stratified by 7 age groups and by use of morphine 
or hydromorphone as supplemental opioid analgesia 
(Section 10.3).
…
The trial enrollment will be initiated in a staggered 
approach. Enrollment starts with an older age group until 
pharmacokinetic data are available in younger age 
groups from other trials in the pediatric clinical 
development program of tapentadol. Initially, subjects 
aged 2 years to less than 18 years are to be recruited. The 
recruitment of subjects aged 6 months to less than 
2 years is allowed following Amendment 05, based on 
pharmacokinetic and safety data gathered from a 
separate trial in the same age group. Subjects from birth 
to less than 6 months of age will be recruited after 
pharmacokinetic and safety data are obtained and the 
dose selection has been defined for younger age groups. 
Allocation/randomization to IMP will be stratified by 7 
age groups and by use of morphine or hydromorphone as 
supplemental opioid analgesia (Section 10.3).
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Section 9.3.1: Reasons for discontinuation of a subject: Table 1: Reasons for compulsory and optional 
discontinuation of subjects from trial participation (discontinuation criteria)
Protocol deviation:
...
The subject is taking prohibited medication/therapy (see 
Section 10.6.4).
Protocol deviation:
...
The subject or mother of a newborn or breastfeeding 
mother has taken prohibited medication/therapy (see 
Section 10.6.4).
Section 11.1.1: Enrollment Period (Visit 1)
The following evaluations will be performed during this 
period:
…
• Record prior medication and therapies, as appropriate 
(excluding anesthetics and medication used during the 
surgery). 
...
• Take blood for both local and central safety laboratory 
(clinical chemistry and hematology) investigations when 
the subject is considered clinically stable after surgery. 
The values of the local laboratory will be used for 
verification of exclusion criteria.
The following procedures will be performed during this 
period:
…
• Record prior medication and therapies, as appropriate 
(excluding anesthetics and medication used during the 
surgery). This includes the recording of prohibited 
medication used by breastfeeding mothers and 
prohibited prior medication used by mothers of a 
newborn subject.
...
• Take blood for both local and central (children aged 
2 years or older) or local (children younger than 2 years 
old) safety laboratory (clinical chemistry and 
hematology) investigations when the subject is 
considered clinically stable after surgery. The values of 
the local laboratory will be used for verification of 
exclusion criteria.
Section 11.1.2.1: Visit 2
Before first dose of investigational medicinal product
…
• Record intake of other concomitant medication and use 
of therapies as appropriate (the use of concomitant 
medication and therapies is to be recorded when they are 
started, stopped, or the dose changed), excluding 
anesthetics and medication used during the surgery.
…
After the first dose of investigational medicinal product
…
• Record intake of concomitant medication and use of 
therapies as appropriate (the use of concomitant 
medication and therapies is to be recorded when they are 
started, stopped, or the dose changed).
…
Before subsequent doses of investigational medicinal 
product
…
• Record intake of concomitant medication and use of 
therapies as appropriate (the use of concomitant 
Before first dose of investigational medicinal product
…
• Record intake of other concomitant medication and use 
of therapies as appropriate (the use of concomitant 
medication and therapies is to be recorded when they are 
started, stopped, or the dose changed), excluding 
anesthetics and medication used during the surgery. This 
includes the recording of prohibited medication used by 
breastfeeding mothers.
…
After the first dose of investigational medicinal product
…
• Record intake of concomitant medication and use of 
therapies as appropriate (the use of concomitant 
medication and therapies is to be recorded when they are 
started, stopped, or the dose changed). This includes the 
recording of prohibited medication used by 
breastfeeding mothers.
…
Before subsequent doses of investigational medicinal
product
…
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medication and therapies is to be recorded when they are 
started, stopped, or the dose changed).
• Record intake of concomitant medication and use of 
therapies as appropriate (the use of concomitant 
medication and therapies is to be recorded when they are 
started, stopped, or the dose changed). This includes the 
recording of prohibited medication used by 
breastfeeding mothers.
Section 11.1.2.3: Visit 3 (End of Treatment Visit)
The following evaluations will be performed during this 
period:
…
• Record intake of concomitant medication and use of 
therapies as appropriate (the use of concomitant 
medication and therapies is to be recorded when they are 
started, stopped, or the dose changed).
...
• Take blood for safety laboratory (to be sent to the 
central laboratory).
The following procedures will be performed during this 
period:
…
• Record intake of concomitant medication and use of 
therapies as appropriate (the use of concomitant 
medication and therapies is to be recorded when they are 
started, stopped, or the dose changed). This includes the 
recording of prohibited medication used by
breastfeeding mothers.
...
• Take blood for safety laboratory (to be sent to the 
central laboratory for children aged 2 years or older or 
local laboratory for children younger than 2 years old).
Section 11.7: Overview of blood sampling in this trial
For subjects aged 2 years and older, the approximate 
amount of blood drawn for this trial is given in Table 3. 
The approximate amount of blood drawn for this trial is 
given in Table 3. Local laboratories can use 
microsampling, especially for subjects aged <2 years 
old, so these blood volumes may be lower.
Table 3: Approximate volume of blood to be collected 
from each subject aged 2 years and older
Table 3: Approximate volume of blood to be collected 
from each subject 
Number of samples
Clinical chemistry: 2 for central, 1 for local
Hematology:          2 for central, 1 for local
Number of samples 
                              2 years to <18 years
<2 years
Clinical chemistry: 2 for central, 1 for local 2 for local
Hematology:          2 for central, 1 for local 2 for local
Approximate total blood volume per test
Clinical chemistry: 6 mL
Hematology:          6 mL
Total:                    12 mL
Approximate total blood volume per test
                         2 years to <18 years
<2 years
Clinical chemistry: 6 mL
4 mL
Hematology:          6 mL
4 mL
Total:                    12 mL
8 mL
Section 12.1.2: Prior and concomitant medications
…
Trade names should be given in preference to generic 
names when recording medication. The generic name 
may be used if the trade name is not available.
…
Trade names should be given in preference to generic 
names when recording medication. The generic name 
may be used if the trade name is not available.
Prohibited medication used by the mother of a newborn 
or breastfeeding mother will be recorded.
Section 12.3.1: Adverse events: Special procedures for serious adverse events
If possible, after all serious adverse events, a blood 
sample for the quantitation of systemic exposure of 
If possible, after all serious adverse events, a blood 
sample for the central laboratory quantitation of 
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tapentadol and tapentadol-O-glucuronide should be 
drawn in close temporal relationship to the serious 
adverse event.
systemic exposure of tapentadol and tapentadol-O-
glucuronide should be drawn in close temporal 
relationship to the serious adverse event.
Section 12.3.2: Safety laboratory
…
Clinical chemistry and hematology – central laboratory
…
Clinical chemistry and hematology – local laboratory
Blood samples for clinical chemistry and hematology for 
the local laboratory will be taken at the same time as the 
blood sample for the central laboratory before 
allocation/randomization to IMP. 
The results of blood analyzed in a local laboratory for 
clinical chemistry and hematology will be used for 
verification of the exclusion criteria. The results of the 
tests must be available for review before a subject is 
allocated to IMP. Parameters specified in the exclusion 
criteria need to be reviewed. This does not preclude the 
need to take a sample for central laboratory analysis.
…
Clinical chemistry and hematology – central laboratory 
(for subjects aged 2 years to less than 18 years)
…
Clinical chemistry and hematology – local laboratory (all 
subjects)
Blood samples for clinical chemistry and hematology for 
the local laboratory will be taken at the same time as the 
blood sample for the central laboratory before 
allocation/randomization to IMP for subjects aged 2 
years to less than 18 years. For subjects less than 2 
years old, only the blood sample for local analysis will 
be taken.
The results of blood analyzed in a local laboratory for 
clinical chemistry and hematology will be used for 
verification of the exclusion criteria. The results of the 
tests must be available for review before a subject is 
allocated to IMP. Parameters specified in the exclusion 
criteria need to be reviewed. This does not preclude the 
need to take a sample for central laboratory analysis for 
subjects aged 2 years to less than 18 years.
Section 14.2.3: Analysis of subject characteristics data
… 
Pain intensity scores collected before each NCA/PCA 
activation will be analyzed descriptively by treatment 
group.
… 
Pain intensity scores collected before each NCA/PCA 
activation will be analyzed descriptively by treatment 
group.
Prohibited medication used by the mother of a newborn 
or breastfeeding mother will be listed by subject.
Section 14.2.6.2: Analysis of safety laboratory data
…
Descriptive statistics will be calculated for each safety 
laboratory parameter at baseline and at each scheduled 
time point as described in Section 1.2.
…
Descriptive statistics (only for blood samples analyzed at 
the central laboratory) will be calculated for each safety 
laboratory parameter at baseline and at each scheduled 
time point as described in Section 1.2.
Section 19.10.5: Contact
Sponsor                       Bioanalytical laboratory
Grünenthal GmbH      Grünenthal GmbH
Deputy: 
@grunenthal.com
@grunenthal.com
+49 (0) 241-569-
Dr 
@grunenthal.com
+49 (0) 241-569-
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+49 (0) 241-569-
+49 (0) 241-569-
18.6
Protocol Amendment 06
Amendment rationale
This amendment has been enacted to:
•
Enable the EU PDCO data set to be analyzed for regulatory requirements prior to 
completion of the US FDA data set.
•
Remove the analysis of non-opioid analgesic medication as a secondary endpoint for 
logistical reasons.
•
Clarify an inconsistency with regard to the start of continuous oxygen saturation 
monitoring.
•
Update information on post-marketing experience.
•
Update the collaborator's signatories.
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: 
Title page
Collaborator’s signatories: 
, Chief Medical Officer & Senior Vice 
President,
, Senior Director, Clinical Operations,
Depomed, Inc, Newark, California
Collaborator’s signatories: 
Dr
, Chief Medical Officer & Senior 
Vice President,
Dr 
, Vice President, Clinical Affairs,
Depomed, Inc, Newark, California
Title page
Sponsor’s medically qualified person: 
Phone: +49 241-569-
  
Sponsor’s medically qualified person: 
Phone: +1 (908) 745-
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Section 1: Protocol synopsis: Definition of endpoints: The secondary efficacy endpoints are:
Section 8.1: Definition of endpoints: The secondary efficacy endpoints are:
• The total amount of supplemental opioid analgesic 
medication received, assessed in 12 hour intervals from 
24 hours to 96 hours after the first dose of IMP.
• The total amount of non-opioid analgesics used 
(irrespective of the indication, e.g., acetaminophen, 
which can also be given as antipyretic medication) 
during the treatment period within the first 24 hours (EU 
PDCO) or within the first 12 hours (US FDA) after the 
first dose of IMP.
• Palatability and acceptability of the IMP after the first 
and last doses of IMP in subjects aged 2 years to less 
than 18 years old (EU PDCO).
• The total amount of supplemental opioid analgesic 
medication received, assessed in 12 hour intervals from 
24 hours to 96 hours after the first dose of IMP.
• Palatability and acceptability of the IMP after the first 
and last doses of IMP in subjects aged 2 years to less 
than 18 years old (EU PDCO).
Section 1: Protocol synopsis: Sample size rationale:
Section 14.1: Sample size rationale
...
The trial enrollment will then complete when the 
following 3 criteria are met:
• At least 159 treated subjects in the age range 2 years to 
less than 18 years of age (EU PDCO).
• At least 159 treated subjects in the age range birth to 
less than 17 years of age (US FDA).
• 100 subjects in the age range birth to less than 17 years 
of age on tapentadol for at least 2 doses (US FDA).
Based on estimates from adult trials in acute pain, it is 
assumed that approximately 5% of subjects 
(approximately 8 subjects) may discontinue prior to 
receiving 2 doses of IMP, which is covered by the 
targeted sample size.
Due to the overlapping age groups as per regulatory 
requirements, it is expected that approximately 
168 subjects will be treated with IMP in this trial.
...
Due to the overlapping age groups as per regulatory 
requirements, it is expected that approximately 
168 subjects will be treated with IMP in this trial.
Completion of trial enrollment
The trial enrollment for the EU PDCO set (see 
Section 14.2.1 for the definition of the analysis 
populations) will complete when the following criterion 
is met:
• At least 159 treated subjects in the age range 2 years to 
less than 18 years of age (EU PDCO).
The trial enrollment for the US FDA set will complete 
when the following 2 criteria are met:
• At least 159 treated subjects in the age range birth to 
less than 17 years of age (US FDA).
• 100 subjects in the age range birth to less than 17 years 
of age on tapentadol for at least 2 doses (US FDA).
Based on estimates from adult trials in acute pain, it is 
assumed that approximately 5% of subjects 
(approximately 8 subjects) may discontinue prior to 
receiving 2 doses of IMP, which is covered by the 
targeted sample size.
Section 1: Protocol synopsis: Sample size rationale:
...
Reporting
Two reports will be prepared for the trial. The first 
report will be prepared after the date of the last contact 
with the last subject according to the protocol for the EU 
PDCO set (last subject out - EU PDCO). The second 
report will be prepared after the date of the last contact 
with the last subject according to the protocol for the US 
FDA set (last subject out - US FDA).
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Section 1: Protocol synopsis: Statistical methods:
...
Summary statistics for the primary efficacy endpoint will 
be provided by age group (birth to <30 days, 30 days to 
<6 months, 6 months to <2 years, 2 years to <6 years, 
6 years to <12 years, 12 years to <17 years, and 17 years 
to <18 years) and by method of supplemental opioid 
administration (NCA vs. PCA) among other subgroup 
analyses.
...
Summary statistics for the primary efficacy endpoint will 
be provided by age group (birth to <30 days, 30 days to 
<6 months, 6 months to <2 years, 2 years to <6 years, 
6 years to <12 years, 12 years to <17 years, and 17 years 
to <18 years, as applicable for the EU PDCO set and US 
FDA set) and by method of supplemental opioid 
administration (NCA vs. PCA) among other subgroup 
analyses.
Section 3: Abbreviations and definition of terms: Definition of terms
...
Last subject out: Date of last contact with the last subject 
according to the protocol.
...
Last subject out - EU PDCO: Date of last contact with 
the last subject according to the protocol for the EU 
PDCO set.
Last subject out - US FDA: Date of last contact with the 
last subject according to the protocol for the US FDA 
set.
Section 6.2: Relevant non-clinical and clinical data: Safety experience from post-marketing data in adults
The total cumulative post-authorization patient exposure 
to tapentadol (IR and PR) since the first launch in 
Jul 2008 up to 20 May 2014 was 142 923 321 patient 
treatment days with an estimated average daily dose for 
tapentadol IR of 280 mg. In the time period from first 
launch to 20 May 2014, 5286 spontaneous, medically 
confirmed cases were received, reporting tapentadol 
either as the suspect, co-suspect, or suspect-interacting 
drug. Among the 5286 cases, there were 85 cases with a 
fatal outcome, 1607 serious nonfatal cases, and 3594 not 
serious cases. Age was reported in 2465 cases and 
ranged from <1 year to 100 years. The cases involved 
2552 female patients and 1557 male patients (the sex 
was not reported or was reported as unknown in 
1177 cases). Overall, the most frequently reported 
preferred terms for these events were (in descending 
order of frequency) nausea, drug ineffective, dizziness, 
headache, hallucination, and vomiting.
The total cumulative post-authorization patient exposure 
to tapentadol (IR and PR) since the first launch in 
Jul 2008 up to 20 May 2016 was 314 million patient 
treatment days with an estimated average daily dose for 
tapentadol IR of 280 mg. In the time period from first 
launch to 20 May 2016, 7556 spontaneous, medically 
confirmed cases were received, reporting tapentadol 
either as the suspect, co-suspect, or suspect-interacting 
drug. Among the 7556 cases, there were 188 cases with a 
fatal outcome, 2195 serious nonfatal cases, and 5173 not 
serious cases. Age was reported in 3687 cases and 
ranged from 0 years to 100 years. The cases involved 
3690 female patients and 2243 male patients (the sex 
was not reported or was reported as unknown in 
1623 cases). Overall, the most frequently reported 
preferred terms for these events were (in descending 
order of frequency) nausea, drug ineffective, dizziness, 
somnolence, vomiting, and headache.
Section 7: Trial objectives
The primary efficacy objective (either 12 hours or 
24 hours) for 1 region is considered as the secondary 
efficacy objective in the other, for the different age 
range, as described below.
Subjects can be treated for up to 72 hours, and efficacy 
and safety information will also be collected throughout 
this time period.
The primary efficacy objective (either 12 hours or 
24 hours) for 1 region is considered as the secondary 
efficacy objective in the other, for the different age 
range, as described below.
Two reports will be prepared for the trial. The first 
report will be prepared after the last subject out of the 
EU PDCO set. The second report will be prepared after 
the last subject out of the US FDA set.
Subjects can be treated for up to 72 hours, and efficacy 
and safety information will also be collected throughout 
this time period.
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Section 8.4: Discussion of the trial design: Blinding
The trial is double-blinded to prevent bias.
The trial is double-blinded to prevent bias. The EU 
PDCO set will be locked and unblinded before 
recruitment of the under 2 year olds in the US FDA set is 
completed. All subjects in the EU PDCO set (which 
includes completed subjects aged 2 years or older in the 
US FDA set) will remain locked after the analysis of the 
first report. Subjects under 2 years old in the US FDA set 
will remain blinded, as independent randomization lists 
are used for subjects aged less than 2 years old.
Section 10.4.1: Methods of blinding
Randomization and blinding will be done in accordance 
with the sponsor’s standard operating procedures 
(SOPs).
Randomization and blinding will be done in accordance 
with the sponsor’s standard operating procedures 
(SOPs).
There are 4 randomization lists for this trial; 
1 randomization list for each of the 3 youngest age 
groups (birth to <30 days, 30 days to <6 months, 
6 months to <2 years), each stratified by supplemental 
opioid used (morphine versus hydromorphone), and 
1 randomization list for the older age groups stratified 
by age group (2 years to <6 years, 6 years to <12 years, 
12 years to <17 years, 17 years to <18 years) and 
supplemental opioid use. Unblinding can be performed 
for 1 or more of these lists individually.
Section 10.4.2: Methods of unblinding
Personnel in the sponsor’s departments of clinical trials 
supply will be unblinded during the trial according to the 
sponsor’s SOPs for randomization and unblinding during 
the trial. The qualified person for pharmacovigilance 
may be unblinded at any time during the trial.
Persons involved in the conduct (including subjects and 
investigators), data management, and analysis of the trial 
will remain blinded until unblinding is performed after 
database lock at the end of the trial. Unblinding will be 
initiated by the sponsor’s department of biostatistics 
according to the sponsor’s SOPs for randomization and 
unblinding. 
Personnel in the sponsor’s department of clinical trials 
supply will be unblinded during the trial according to the 
sponsor’s SOPs for randomization and unblinding during 
the trial. Once the EU PDCO set has completed 
recruitment and data for these subjects is locked, 
unblinding will be performed for those subjects aged 
2 years and older. The additional age groups under 
2 years old will be unblinded at the end of the trial. The 
qualified person for pharmacovigilance may be 
unblinded at any time during the trial.
Persons involved in the conduct (including subjects and 
investigators), data management, and analysis of the trial 
will remain blinded until unblinding is performed after 
data is locked. Unblinding will be initiated by the 
sponsor’s department of biostatistics according to the 
sponsor’s SOPs for randomization and unblinding. 
Section 12.1.2.1: Opioid analgesic medication given by NCA/PCA and background infusion
Section 12.1.2.2: Detailed information for other analgesic (opioid and non-opioid) medication
See Section 12.1.3 for medication used outside of this 
timeframe.
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Section 12.1.3: Prior and concomitant therapies
All therapies, excluding anesthetics and medication used
during the surgery, used within 28 days before 
allocation/randomization to IMP and up to the end of the 
trial must be recorded. 
All therapies used within 28 days before 
allocation/randomization to IMP and up to the end of the 
trial must be recorded. 
Section 12.3.7
Continuous monitoring of oxygen saturation
Oxygen saturation will be monitored continuously using 
pulse oximetry before allocation/randomization to IMP 
(but after surgery) until 4 hours after the last 
administration of IMP.
Oxygen saturation will be monitored continuously using 
pulse oximetry from before the first dose of IMP until 
4 hours after the last administration of IMP.
Section 13.3: Data management: External data
...
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.
... 
At the end of the trial, the contract research 
organization(s) providing these data will provide the data 
management center with a final data transfer.
Section 13.3: Data management: Database lock
When all data have been received and entered, all data 
checks and quality control checks have been performed, 
and all queries are resolved, the trial database will be 
considered clean and can be locked.
There will be 2 data locks for this trial. For the first 
report, only data for the EU PDCO set will be locked 
within the electronic CRF, the CRF will not be shut 
down. Any potential subsequent unlocking of this set of 
data will be performed according to the sponsor’s SOPs 
for database unlock. The subjects’ data will be locked as 
soon as all data for the EU PDCO set are considered 
clean (i.e., all data have been received and entered, all 
data checks and quality control checks on these data 
have been performed, and all queries for these data are 
resolved). The same procedure will apply for the final 
data lock at the end of the trial.
Section 14: Statistical methods and sample size determination
As applicable and appropriate for the individual 
endpoint, the endpoints will be analyzed in the age 
ranges for the EU PDCO and for the US FDA.
As applicable and appropriate for the individual 
endpoint, the endpoints will be analyzed in the age 
ranges for the EU PDCO and for the US FDA.
Two reports will be prepared for the trial. The first 
report will be prepared after the last subject out of the 
EU PDCO set. The second report will be prepared after 
the last subject out of the US FDA set. Further details on 
the reports are given in Section 16.6.
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Section 14.2.1: Analysis populations (analysis sets): Safety Set
The Safety Set comprises all treated subjects in the 
required age range for the EU PDCO and US FDA. For
the EU PDCO, this will include subjects 2 years to less 
than 18 years of age; for the US FDA, this will include 
subjects from birth to less than 17 years of age.
The Safety Set comprises all treated subjects in the 
required age ranges for the EU PDCO and US FDA. The 
overall Safety Set will include all treated subjects in the 
trial. The EU PDCO Safety Set will include subjects 
2 years to less than 18 years of age; the US FDA Safety 
Set will include subjects from birth to less than 17 years 
of age. A subject will be considered as treated if 
administered any amount of IMP.
If by error a subject does not receive the allocated 
medication, the subject will be evaluated according to 
the received IMP.
Section 14.2.1: Analysis populations (analysis sets): Full Analysis Set
The Full Analysis Set is identical to the respective Safety 
Set.
The overall Full Analysis Set includes all subjects that 
are allocated and treated. The EU PDCO Full Analysis 
Set will include allocated and treated subjects aged 
2 years to less than 18 years old; the US FDA Full 
Analysis Set will include allocated and treated subjects 
from birth to less than 17 years of age. 
If by error a subject does not receive the allocated 
medication, the subject will be evaluated as allocated 
within the Full Analysis Set following the intention-to-
treat principle.
Section 14.2.1: Analysis populations (analysis sets): Per Protocol Set
The Per Protocol Set is a subset of the respective Full 
Analysis Set, excluding subjects with protocol deviations 
that may have an impact on the results of the primary 
efficacy analyses. Further details of the Per Protocol Set 
definition will be specified in the statistical analysis plan.
The EU PDCO or US FDA Per Protocol Set is a subset 
of the respective Full Analysis Set, excluding subjects 
with protocol deviations that may have an impact on the 
results of the primary efficacy analyses. Further details 
of the Per Protocol Set definition will be specified in the 
statistical analysis plan.
Section 14.2.5.1: Primary efficacy endpoint
...
For subjects who withdraw from the trial prior to the 12-
hour or 24-hour time point due to any other reason than 
no further need of opioid analgesic medication, 
cumulative supplemental opioid analgesia over the 
respective time period will be based on the observed 
supplemental opioid use up to the time of the subject’s 
discontinuation. If a subject used a total of X mg/kg of 
supplemental opioid through Hour T (24 hours), 
cumulative use over 24 hours will be estimated as 
(X/T)*24 mg/kg. If T is <12 hours, cumulative use over 
12 hours will be estimated as (X/T)*12. This 
extrapolation assumes a constant use (in mg/kg per hour) 
of supplemental opioid over 24 hours. For subjects who 
withdraw from the trial due to no further need of opioid 
analgesic medication, the cumulative use of 
supplemental opioid will equal the total amount of 
supplemental opioid used up to the time of withdrawal. 
Other imputation methods will be used for sensitivity 
analyses. These will be described in detail in the 
statistical analysis plan.
...
For subjects who withdraw from the trial prior to the 12-
hour or 24-hour time point due to any other reason than 
no further need of opioid analgesic medication or switch 
to exclusively oral opioid analgesic medication, 
cumulative supplemental opioid analgesia over the 
respective time period will be based on the observed 
supplemental opioid use up to the time of the subject’s 
discontinuation. If a subject used a total of X mg/kg of 
supplemental opioid through Hour T (24 hours), 
cumulative use over 24 hours will be estimated as 
(X/T)*24 mg/kg. If T is <12 hours, cumulative use over 
12 hours will be estimated as (X/T)*12. This 
extrapolation assumes a constant use (in mg/kg per hour) 
of supplemental opioid over 24 hours. For subjects who 
withdraw from the trial due to no further need of opioid 
analgesic medication or switch to exclusively oral opioid 
analgesic medication, the cumulative use of 
supplemental opioid will equal the total amount of 
supplemental opioid used up to the time of withdrawal. 
Other imputation methods will be used for sensitivity 
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analyses. These will be described in detail in the 
statistical analysis plan.
Section 14.2.5.2: Secondary endpoints and subgroup analyses
...
The total amounts of non-opioid analgesic medications
used (irrespective of the indication) within the first 
12 hours and 24 hours after first IMP intake will be 
grouped according the Anatomical Therapeutic Chemical 
Classification System (World Health Organization Drug 
Dictionary coding) and route of administration, and 
descriptively summarized by treatment group and 
presented in tables.
...
The number and proportion of subjects taking non-
opioid analgesic medications (irrespective of the 
indication) within the first 12 hours and 24 hours after 
first IMP intake will be grouped according to the 
Anatomical Therapeutic Chemical Classification System 
(World Health Organization Drug Dictionary coding),
and presented in tables by treatment group.
Section 14.2.5.2: Secondary endpoints and subgroup analyses: Subgroup analyses
Summary statistics for the primary efficacy endpoint will 
be provided by age group (birth to <30 days, 30 days to 
<6 months, 6 months to <2 years, 2 years to <6 years, 
6 years to <12 years, 12 years to <17 years, and 17 years 
to <18 years) and by method of supplemental opioid 
administration (NCA vs. PCA) among other subgroup 
analyses.
Summary statistics for the primary efficacy endpoint will 
be provided by age group (birth to <30 days, 30 days to 
<6 months, 6 months to <2 years, 2 years to <6 years, 
6 years to <12 years, 12 years to <17 years, and 17 years 
to <18 years, as applicable for the EU PDCO set and US 
FDA set) and by method of supplemental opioid 
administration (NCA vs. PCA) among other subgroup 
analyses.
Section 14.2.6: Analysis of safety data
The analysis of safety data will be performed for the 
respective Safety Set.
The analysis of safety data will be performed for the EU 
PDCO Safety Set for the EU PDCO report and for the 
overall Safety Set for the US FDA report.
Section 16.5: Publication policy
The results of this trial will be publically disclosed in 
accordance with the sponsor’s disclosure policy (e.g., on 
ClinicalTrials.gov), according to the European 
Federation of Pharmaceutical Industries and 
Associations (EFPIA) Principles for Responsible 
Clinical Trial Data Sharing, and applicable regulatory 
guidance. The sponsor will post clinical trial information 
in a lay person understandable form in a freely accessible 
sponsor internet portal.
The results of this trial will be publically disclosed in 
accordance with the sponsor’s disclosure policy (e.g., on 
ClinicalTrials.gov), according to the European 
Federation of Pharmaceutical Industries and 
Associations (EFPIA) Principles for Responsible 
Clinical Trial Data Sharing, and applicable regulatory 
guidance. The sponsor will post clinical trial information 
in a lay person understandable form in a freely accessible 
sponsor internet portal. Due to the preparation of 
2 reports, the data presented in the databases may differ.
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Section 16.6: Final report
A final report integrating clinical and statistical results 
will be prepared by the sponsor. The coordinating 
investigator will approve the final report on behalf of the 
participating investigators. 
The sponsor will provide the competent authority and 
relevant IEC/IRB with a summary of the final report in 
accordance with applicable regulatory requirements. 
The coordinating investigator will be provided with a 
summary of the final report. 
Two reports for the trial, integrating clinical and 
statistical results, will be prepared by the sponsor. The 
first report will be prepared after the last subject out of 
the EU PDCO set. For the first report the efficacy and 
safety data will be reported for the EU PDCO set, the 
subgroup of subjects aged 2 years to less than 18 years 
old.
The second report will be prepared after the last subject 
out of the US FDA set. For the second report the safety 
data will be reported for all subjects in the study; that is 
the subjects reported in the first report combined with 
subjects aged less than 2 years old. The second report 
will include 2 sets of efficacy results; the previously 
reported results for the EU PDCO set and the efficacy 
results for the US FDA set.
The coordinating investigator will approve the reports on 
behalf of the participating investigators. 
The sponsor will provide the competent authority and 
relevant IEC/IRB with summaries of the reports in 
accordance with applicable regulatory requirements. 
The coordinating investigator will be provided with 
summaries of the reports. 
18.7
Protocol Amendment 07
Amendment rationale
This amendment has been enacted to:
•
Specify the doses of tapentadol oral solution to give to subjects less than 6 months old.
•
Limit the safety laboratory blood sampling for subjects with a low body weight to a subset 
of clinical chemistry evaluations only.
•
Update the contact details of the international coordinating investigator.
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: 
Title page: International coordinating investigator:
Prof 
Children’s National Medical Center, Pharmacology & 
Physiology, George Washington University School of 
Medicine and Health Sciences, 111 Michigan Avenue, 
N.W. Washington, D.C. 20010. United States of 
America. a
Prof 
Division of Clinical Pharmacology, Children’s National 
Health System, 111 Michigan Avenue, N.W. 
Washington, D.C. 20010, United States of America. a
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Changes to this protocol include:
Formerly read:
Now reads: 
Section 1: Protocol synopsis: Trial treatments: Investigational medicinal products
Age of 
subject
Dose for 
the first 
24 hours
Dose after 
the first 
24 hours 
Body 
weight
Tapentadol 
oral 
solution or 
placebo
6 months to 
18 years old
1.25 mg/
kg
1.25 mg/kg 
or 
1.0 mg/kg
20 k
g
4 mg/mL
20 k
g
20 mg/mL
Birth to 
6 months 
old
To be 
defined a
20 k
g
4 mg/mL
20 k
g
20 mg/mL
a) The doses for subjects aged less than 6 months old (as 
determined at the time of allocation to IMP) will be 
defined based on forthcoming pharmacokinetic data. 
Recruitment of this age group will commence when the 
dose has been defined.
Age of 
subject
Dose for 
the first 
24 hours
Dose after
the first 
24 hours 
Body 
weight
Tapentadol 
oral 
solution or 
placebo
6 months 
to 
18 years 
old
1.25
mg/kg
1.25 mg/kg 
or 1.0 mg/kg
20 kg
4 mg/mL
20 kg
20 mg/mL
30 days to 
6 months 
old
0.5 mg/kg
0.5 mg/kg or 
0.3 mg/kg
-
4 mg/mL
Birth to 
<30 days 
old
0.1 mg/kg
0.1 mg/kg or 
0.075 mg/kg
-
4 mg/mL
Formerly read:
Now reads: 
Section 1: Protocol synopsis: Trial treatments: Investigational medicinal products
...
The administration of IMP is based on the investigator’s 
judgment of the subject’s condition and sedation level.
After 24 hours, the investigator may decrease the dose of 
IMP to 1.0 mg/kg according to the investigator’s 
judgment of the subject’s reduced need for analgesia.
...
The administration of IMP is based on the investigator’s 
judgment of the subject’s condition and sedation level.
Dose reduction after 24 hours
The dose of IMP may be reduced after 24 hours if there 
is a reduced need for analgesia according to the 
investigator’s judgment, as follows:
• Age 6 months or more: 1.0 mg/kg.  
• Age 30 days to less than 6 months: 0.3 mg/kg.
• Age birth to less than 30 days old: 0.075 mg/kg.
Section 1: Protocol synopsis: Key data collected: Safety
• Adverse events.
• Safety laboratory (clinical chemistry and hematology).
• Pregnancy test for female subjects aged 12 years or 
older, or post-menarchal, or sexually active.
• Adverse events.
• Safety laboratory.
• Pregnancy test for female subjects aged 12 years or 
older, or post-menarchal, or sexually active.
Section 1.2: Schedule of events
Take blood for safety laboratory (clinical chemistry and 
hematology)
Take blood for safety laboratory
Section 1.3.1: Inclusion criteria
Section 9.2.1: Inclusion criteria
2. Male or female subject aged from birth to less than 
18 years.
2. Male or female subject aged from birth (37 weeks 
gestational age) to less than 18 years.
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Section 1.3.2: Exclusion criteria
Section 9.2.2: Exclusion criteria
8. Subject is obese in the investigator’s judgment. 
Obesity can be determined based on appropriate BMI 
charts or tables; e.g., a BMI above the 97th percentile for 
children based on the World Health Organization growth 
charts (see Section 19.9).
...
14. Subject has clinically relevant (in the investigator’s 
judgment) abnormal values for clinical chemistry or 
hematology (local laboratory sample taken after surgery). 
A subject is excluded if the:
• Aspartate transaminase or alanine transaminase is >3-
times upper limit of normal.
• Total bilirubin is >2-times upper limit of normal 
(except if the cause is due to Gilbert’s syndrome). 
• Glomerular filtration rate <60 mL/min (calculated 
according to Schwartz et al. 1984).
8. Subject is obese in the investigator’s judgment. 
Obesity can be determined based on appropriate BMI 
charts or tables; e.g., a BMI above the 97th percentile for 
children based on the World Health Organization growth 
charts (see Section 19.9).
or
Subject weight is less than 2500 gm.
...
14. Subject has clinically relevant (in the investigator’s 
judgment) abnormal values for clinical chemistry or 
hematology (local laboratory sample taken after surgery). 
A subject aged 6 months to less than 18 years old is 
excluded if the:
• Aspartate transaminase or alanine transaminase is >3-
times upper limit of normal.
• Total bilirubin is >2-times upper limit of normal 
(except if the cause is due to Gilbert’s syndrome). 
• Glomerular filtration rate <60 mL/min (calculated 
according to Schwartz et al. 1984).
A subject aged from birth to less than 6 months old is 
excluded if:
• Aspartate transaminase or alanine transaminase is >3-
times upper limit of normal.
• There is pathological jaundice in the opinion of the 
investigator.
• Glomerular filtration rate (calculated according to 
Schwartz et al. 1984) is: 
−<20 mL/min/1.73 m2 for subjects <1 week post-
partum.
−<30 mL/min/1.73 m2 for subjects 1 week to 8 weeks 
post-partum.
−<50 mL/min/1.73 m2 for subjects >8 weeks post-
partum to <6 months old.
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Section 6.2: Relevant non-clinical and clinical data: Pharmacokinetics in children
...
The addition of data from children aged 1 month to less 
than 2 years (KF5503/72) resulted in minor changes in
the model and was best described by incorporation of an 
Emax type maturation function. The pharmacometric 
parameters changed to: CL/F = 160 L.h-1, V/F = 546 L 
(the CL/F and V/F are typical estimates for a subject 
with a body weight of 34 kg), Ka = 2.21 h-1, 
TLAG = 0.267 h, with the coefficients of weight on CL/F 
and V/F being estimated as 0.551 and 0.829, 
respectively. The maturation function, which describes 
the age at which half the maximum CL/F in the data set 
was estimated as 46 weeks. The inter-individual 
variabilities on CL/F and V/F remained the same with 
only the variability on Ka increasing to 148%.
...
The addition of data from KF5503/72, i.e., adding data 
from children aged birth to less than 2 years, resulted in 
minor changes to the model (comprising children from 
birth to 18 years old) and was best described by 
incorporation of an Emax type maturation function. The 
pharmacometric parameters changed to: CL/F = 155 L.h-
1, V/F = 533 L (the CL/F and V/F are typical estimates 
for a subject with a body weight of 32.6 kg), Ka = 2.44 h-
1, TLAG = 0.267 h, with the coefficients of weight on 
CL/F and V/F being estimated as 0.562 and 0.827, 
respectively. The maturation function, which describes 
the age at which half the maximum CL/F in the data set 
was estimated as 39 weeks. The inter-individual 
variabilities on CL/F, V/F, and Ka remained virtually the 
same. 
Section 8.4: Discussion of the trial design: Dosing
... 
The population pharmacokinetic model used for the 
pediatric dose simulations was updated with exposure 
data obtained from children aged 1 month to less than 
2 years (KF5503/72), the simulations were then redone 
to determine the appropriate dose for the age group 
6 months to less than 2 years. The simulations specified 
that the dose of 1.25 mg/kg would give similar exposures 
as that observed in the age group 2 years to less than 
18 years.
Based on these results, a dose regimen of 1.25 mg/kg 
will be used for the first 24 hours of treatment in this trial 
in children aged 6 months to less than 18 years old. After 
24 hours after the start of IMP, and based on clinical 
judgment, the dose may either be continued at 
1.25 mg/kg or it may be decreased to 1.0 mg/kg. A 
decision to maintain or alter the dose will depend on the 
investigator’s judgment of the effectiveness of the 
analgesia and the adverse event profile observed in each 
child over the first 24 hour dosing period. The doses for 
younger subjects aged less than 6 months will be defined 
based on forthcoming pharmacokinetic data. Younger 
subjects will not be recruited into the trial until the dose 
has been defined for them.
... 
The population pharmacokinetic model used for the 
pediatric dose simulations was updated with exposure 
data obtained from children aged birth to less than 
2 years (KF5503/72), the simulations were then redone 
to determine the appropriate dose for the age group 
6 months to less than 2 years. The simulations specified 
that the dose of 1.25 mg/kg would give similar exposures 
as that observed in the age group 2 years to less than 
18 years. For the younger groups, a lower dose is 
required.
Based on these results, a dose regimen of 1.25 mg/kg 
will be used for the first 24 hours of treatment in this trial 
in children aged 6 months to less than 18 years old. After 
24 hours after the start of IMP, and based on clinical 
judgment, the dose may either be continued at 
1.25 mg/kg or it may be decreased to 1.0 mg/kg. A 
decision to maintain or alter the dose will depend on the 
investigator’s judgment of the effectiveness of the 
analgesia and the adverse event profile observed in each 
child over the first 24 hour dosing period. For children 
aged 1 month to less than 6 months, and birth to less 
than 1 month old, doses of 0.5 mg/kg and 0.1 mg/kg, 
respectively, are expected to produce similar exposures 
as that observed in the age group 6 months to less than 
18 years.
Section 9.1: Subject enrollment procedure
…
The trial enrollment will be initiated in a staggered 
approach. Enrollment starts with an older age group until 
pharmacokinetic data are available in younger age 
…
The trial enrollment will be initiated in a staggered 
approach. Enrollment starts with an older age group until 
pharmacokinetic data are available in younger age 
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groups from other trials in the pediatric clinical 
development program of tapentadol. Initially, subjects 
aged 2 years to less than 18 years are to be recruited. The 
recruitment of subjects aged 6 months to less than 
2 years is allowed following Amendment 05, based on 
pharmacokinetic and safety data gathered from a separate 
trial in the same age group. Subjects from birth to less 
than 6 months of age will be recruited after 
pharmacokinetic and safety data are obtained and the 
dose selection has been defined for younger age groups. 
Allocation/randomization to IMP will be stratified by 7 
age groups and by use of morphine or hydromorphone as 
supplemental opioid analgesia (Section 10.3).
groups from other trials in the pediatric clinical 
development program of tapentadol. Initially, subjects 
aged 2 years to less than 18 years are to be recruited. The 
recruitment of subjects aged 6 months to less than 
2 years is allowed following Amendment 05 and the 
recruitment of subjects aged from birth to less than 6 
months of age is allowed following Amendment 07, based 
on pharmacokinetic and safety data gathered from a 
separate trial in the same age group. Subjects from birth 
to less than 6 months of age will be recruited after 
pharmacokinetic and safety data are obtained and the 
dose selection has been defined for younger age groups. 
Allocation/randomization to IMP will be stratified by 7 
age groups and by use of morphine or hydromorphone as 
supplemental opioid analgesia (Section 10.3).
Section 10.1.3: Preparation
..
The IMP does not require preparation. 
The IMP will be supplied as a liquid in 100 mL bottles 
intended for multiple use per subject. 
..
The IMP will be supplied as a liquid in 100 mL bottles 
intended for multiple use per subject.
Section 10.2.1: Dose
Table 2: Determination of tapentadol dose and oral 
solution concentration
Age of 
subject
Dose for 
the first 
24 hours
Dose after 
the first 
24 hours 
Body 
weight
Tapentadol 
oral 
solution or 
placebo
6 months to 
18 years old
1.25 mg/
kg
1.25 mg/k
g or 
1.0 mg/kg
20 kg
4 mg/mL
20 kg
20 mg/mL
Birth to 
6 months old
To be 
defined a
20 kg
4 mg/mL
20 kg
20 mg/mL
a) The doses for subjects aged less than 6 months old (as 
determined at the time of allocation to IMP) will be 
defined based on forthcoming pharmacokinetic data. 
Recruitment of this age group will commence when the 
dose has been defined.
Volumes of 1 mL or less will be given using a 1 mL 
syringe with 0.05 mL graduations. Volumes of more than 
1 mL will be given using a 5 mL syringe with 0.1 mL 
graduations.
Table 2: Determination of tapentadol dose and oral 
solution concentration
Age of 
subject
Dose for 
the first 
24 hours
Dose after 
the first 
24 hours 
Body 
weight
Tapentadol 
oral 
solution or 
placebo
6 months 
to 
18 years 
old
1.25 
mg/kg
1.25 mg/kg 
or 
1.0 mg/kg
20 kg
4 mg/mL
20 kg
20 mg/mL
30 days to 
6 months 
old
0.5 mg/kg
0.5 mg/kg 
or 
0.3 mg/kg
-
4 mg/mL
Birth to 
<30 days 
old
0.1 mg/kg
0.1 mg/kg 
or 
0.075 mg/k
g
-
4 mg/mL
The IMP does not require preparation unless very small 
volumes would need to be administered, in which case 
the IMP may be suitably diluted. This may be necessary, 
for example, for subjects less than 6 months old. The 
investigators will be supplied with instruction sheets for 
the preparation of the IMP.
Volumes of 1 mL or less will be given using a 1 mL 
syringe with 0.05 mL graduations. Volumes of more than 
1 mL will be given using a 5 mL syringe with 0.1 mL 
graduations.
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Section 10.2.2: Total dosing time and dosing interval
...
The administration of IMP is based on the investigator’s 
judgment of the subject’s condition and sedation level.
After 24 hours, the investigator may decrease the dose of 
IMP to 1.0 mg/kg according to the investigator’s 
judgment of the subject’s reduced need for analgesia.
...
The administration of IMP is based on the investigator’s 
judgment of the subject’s condition and sedation level.
The dose of IMP may be reduced after 24 hours if there 
is a reduced need for analgesia according to the 
investigator’s judgment, as follows:
• Age 6 months or more: 1.0 mg/kg.  
• Age 30 days to less than 6 months: 0.3 mg/kg.
• Age birth to less than 30 days old: 0.075 mg/kg.
Section 11.1.1: Enrollment Period (Visit 1)
...
The following procedures will be performed during this 
period:
...
• Record a 12-lead ECG. This must be performed after 
surgery.
• Take blood for both local and central (children aged 
2 years or older) or local (children younger than 2 years 
old) safety laboratory (clinical chemistry and 
hematology) investigations when the subject is 
considered clinically stable after surgery. The values of 
the local laboratory will be used for verification of 
exclusion criteria.
...
The following procedures will be performed during this 
period:
...
• Record a 12-lead ECG. This must be performed after 
surgery.
• Take blood for both local and central (children aged 
2 years or older) or local (children younger than 2 years 
old) safety laboratory investigations when the subject is 
considered clinically stable after surgery. The values of 
the local laboratory will be used for verification of 
exclusion criteria.
Section 11.2: Examination hierarchy and time windows
Non-invasive procedures (including completion of 
questionnaires) should generally be performed first. 
Blood samples for safety laboratory should be taken after 
all non-invasive procedures have been completed. The 
exact order that procedures are performed may deviate 
due to local circumstances and do not constitute, per se, a 
protocol deviation.
Non-invasive procedures (including completion of 
questionnaires) should generally be performed first. 
Blood samples for safety laboratory should be taken after 
all non-invasive procedures have been completed. The 
order that procedures are performed may deviate due to 
local circumstances and a change in the order does not 
constitute, per se, a protocol deviation.
Section 11.7: Overview of blood sampling in this trial
...
Table 5: Approximate volume of blood to be collected 
from each subject 
Assessment
Approx-
imate 
blood 
volume 
per 
sample
Number of 
samples
Approximate total 
blood volume per 
test a
2 years 
to <18
years
<2
years
2 years 
to <18
years
<2
years
Clinical 
chemistry
2 mL
2 for 
central, 
1 for 
local
2 for 
local
6 mL
4 mL
...
Table 6: Approximate volume of blood to be collected 
from each subject 
Assessment
Approx
-imate 
blood 
volume 
per 
sample
Number of 
samples
Approximate 
total blood 
volume per test a
2 years to
<18 years
<2
years
b
2 years 
to <18
years
<2
years
Clinical 
chemistry
2 mL
2 for 
central, 1 
for local
2 for 
local
6 mL
4 mL
Hematolog
y
2 mL
2 for 
central, 1 
for local
2 for 
local
6 mL
4 mL
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Hematology
2 mL
2 for 
central, 
1 for 
local
2 for 
local
6 mL
4 mL
Total
12 mL
8 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.
For subjects aged 2 years and older, the total blood 
volume drawn per subject will not exceed approximately 
15 mL during the trial (even if additional blood is drawn 
for a pharmacokinetic analysis if a serious adverse event 
occurs) (Table 3). 
For subjects aged less than 2 years old, blood sampling 
for clinical chemistry and hematology should be 
performed such that blood volumes taken do not exceed 
0.8 mL/kg body weight for each sampling time point, 
and 2.4 mL/kg in total (EMEA ad hoc working party 
2008). 
The volume of blood drawn from subjects who 
participate in the trial will not exceed the recommended 
limits (Section 8.4).
Total
12 mL
8 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.
b) For subjects with a low body weight, blood sampling 
for clinical chemistry and hematology may be limited to 
a subset of clinical chemistry evaluations only to keep 
the total blood volume drawn low.
The volume of blood drawn from subjects who 
participate in the trial will not exceed the recommended 
limits (Section 8.4).
For subjects aged 2 years and older, the total blood 
volume drawn per subject will not exceed approximately 
15 mL during the trial (even if additional blood is drawn 
for a pharmacokinetic analysis if a serious adverse event 
occurs) (Table 3). 
For subjects aged less than 2 years old, blood sampling 
for clinical chemistry and hematology should be 
performed such that blood volumes taken do not exceed 
0.8 mL/kg body weight for each sampling time point, 
and 2.4 mL/kg in total (EMEA ad hoc working party 
2008). 
For subjects less than 6 months old with a low body 
weight, such that the drawing of sufficient blood sample 
volumes for both clinical chemistry and hematology are 
precluded, the tests may be limited to a subset of clinical 
chemistry evaluations only (the tests to be performed are 
alanine transaminase and aspartate transaminase, 
alkaline phosphatase, and creatinine [with calculation of 
the glomerular filtration rate]). Local site-specific 
guidelines must also be adhered to. Other chemistry and 
hematology values from samples taken for the standard 
of care may be used to supplement the safety laboratory 
profile.
Section 12.3: Collection of safety data
The following safety data will be collected:
• Adverse events.
• Safety laboratory (clinical chemistry and hematology).
• Pregnancy test for female subjects aged 12 years or 
older, or post-menarchal, or sexually active.
The following safety data will be collected:
• Adverse events.
• Safety laboratory.
• Pregnancy test for female subjects aged 12 years or 
older, or post-menarchal, or sexually active.
Section 12.3.2: Safety laboratory
...
The following tests will be performed:
...
The following tests will be performed unless the weight 
of the subject precludes full blood sampling, in which 
case the tests may be limited (see Section 11.7):
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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 disorder
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
Ileus 
Intestinal ischaemia 
Intestinal perforation 
Melaena 
Mesenteric occlusion 
Mesenteric vein thrombosis
Pancreatitis
Peritonitis
General disorders and administration site conditions
Malignant hyperthermia
Hepato-biliary disorders
Hepatic failure
Hepatitis fulminant
Hepatic necrosis
Hepatorenal syndrome
Portal hypertension
Reye’s syndrome
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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 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
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 haemorrhage
Priapism
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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).
Dated Jul 2012
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19.2
Face, Legs, Activity, Cry, Consolability scale
This is an example and the version used may differ.
Source: Merkel et al. 1997.
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FLACC Behavioral Scale
Categories
Scoring
0
1
2
FaCe
No particular expression or
smile
Occasional grimace or
frown, withdrawn,
disinterested
Frequent to constant frown,
clenched jaw, quivering chin
Leas
Normal position or relaxed
Uneasy, restless. tense
Kicking, or legs drawn up
Activity
Lying quietly. normal
position. moves easily
Squirming, shifting back and
forth, tense
Arched. rigid. or jerking
Cry
No cry (awake or asleep)
Moans or whimpers.
occasional complaint
Crying steadily. screams or
sobs. frequent complaints
Consolability
Content. relaxed
Reassured by occasional
touching. hugging.
or being talked to,
distractable
Difficult to console or
comfort
Each of the five categories (F) Face; (L) Legs: (A) Activity; (C) Cry; (C) Consolability is scored from 0-2.
which results in a total score between zero and ten.
O 2002. The Regents of the University of Michigan. All Rights Reserved.


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19.3
Faces pain scale – Revised
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1078581 FPS-R_AU2 0_vgLAon.doc
Faces Pain Scale - Revised (FPS-R)
In the following instructions, say "hurt" or 'pain" whichever seems right for a particular child.
"These faces show how much something can hurt. This face (point to left-most face] shows no pain. The faces show more and more pain [point to each from left
to right] up to this one [point to right-most face] - it shows very much pain. Point to the face that shows how much you hurt [right now]."
Score the chosen face 0, Z 
4, 6, 8, or 10, counting left to right, so "0" = "no pain" and "10" = "very much pain". Do not use words like "happy" and "sad". This scale is
intended to measure how children feel inside, not how their face looks.
Permission for Use. Copyright of the FPS-R is held by the International Association for the Study of Pain (IASP) ©2001. This material may be photocopied for non-commercial clinical, educational, and
research use. For reproduction of the FPS-R in a journal, book, or web page, or for any commercial use of the scale, request permission from IASP online at www.iasp-pain.org/FPS-R.
Sources. Hicks CL, von Baeyer CL, Spafford P, van Korlaar I, Goodenough B. The Faces Pain Scale — Revised: Toward a common metric in pediatric pain measurement. Pain 2001;93:173-183. Bieri D,
Reeve R, Champion GD, Addicoat 4 
Ziegler J. The Faces Pain Scale for the self-assessment of the severity of pain experienced by children: Development, initial validation and preliminary investigation
for ratio scale properties. Pain 1990;41:139-150.
(fold along dotted line)
10 
8 
6 
4 
2 
0
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19.4
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
The line will be 100 mm in length. The subject will be instructed to make a mark on the line to 
indicate the pain intensity.
Using a standard ruler, 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 millimeter (0-100) from the bottom of the scale to the subject’s mark and record this 
distance in the CRF.
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19.5
Columbia–Suicide Severity Rating Scale
Source: http://www.cssrs.columbia.edu/scales_cssrs.html
19.5.1
Columbia–Suicide Severity Rating Scale – children’s baseline
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(C-SSRS)
Children's Baseline
Version 6/23/10
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.;
Burke, A.; Oquendo, M.; Mann, J.
Disclaimer:
This scale is intended to be used by individuals who have received training in its administration. The questions contained
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of
suicidal ideation or behavior depends on the judgment of the individual administering the scale.
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History
Form developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A.,
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.)
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside
Drive, New York, New York, 10032; inquiries and training requirements contact posnerk@childpsydr.columbia.edu
© 2008 The Research Foundation for Mental Hygiene, Inc.


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1010567
GRUNENTHAL
SUICIDAL IDEATION
Ask questions 1 and 2 If both are negative, proceed to "Suicidal Behavior" section. If the answer to question 2 
is "yes",
ask questions 3, 4 and 5. If the answer to question 1 and/or 2 
is 'yes': complete `Intensity of 
Ideation" section below.
Lifetime
1. Wish to be Dead
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.
Have you thought about being dead or what it would be lilleto be dead?
Have you wished you were dead or wished you could go to sleep and never wake up?
Do you ever wish you weren't alive anymore?
If yes, describe:
Yes 
No
0
2. Non-Specific Active Suicidal Thoughts
General, non-specific thoughts of wanting to end one's life/commit suicide (e.g., "I've thought about kiting myself') without thoughts of ways to kill
oneself/associated methods, intent, or plan.
Have you thought about doing something to make yourself not alive anymore?
Have you had any thoughts about killing yours«?
If yes. describe:
Yes 
No
K 
K
3. Active Suicidal ideation with Any Methods (Not Plan) without intent to Act
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time,
place or method details worked out (eg.. thought of method to kill self but not a specific plan). Includes person who would say. 'I thought about taking an
overdose but l never made a specific plan as to when, where or how I would actually do it... and I would never go through with it."
Have you thought about how you would do that or how you would make yourself not alive anymore (kill yourself)? What did you think about?
If yes, describe:
Yes 
No
o
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts. as opposed to "I have the thoughts but I
Yes 
No
ID 
ID
definitely will not do anything about them."
When you thought about making yourself not alive anymore (or kitting yourself), did you think that this was something you might actually do?
This is different from (as opposed to) having the thoughts but knowing you wouldn't do anything about it.
Wye, 
describe:
5. Active Suicidal Ideation with Specific Plan and Intent
Thoughts of killing oneself with details of plan hilly or partially worked out and subject has some intent to carry it out.
Have you ever decided how or when you would make yourself not alive anymore/kill yourser Have you ever planned out (worked out the details on
how you would do a?
What was your plan?
Alien you made this plan (or worked out these details), was any part of you thinking about actually doing a?
If yes, describe:
Vi, NO
L. 
L.
INTENSITY OF IDEATION
The following feature should be rated with respect to the most severe type ofideation (t e., 1-5 from above, with 1 being the least severe
and 5 being the most severe).
Most Severe Ideation:
Most
Severe
Type # 
(I-5) 
Description of Ideation
Frequency
How entity times have you had these thoughts? 
Write response
(1) Only one time (2) A few times (3) A lot (4) All the time (0) Don't know/Not applicable
Version 6/23/10


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SUICIDAL BEHAVIOR
(Check all that apply, so long as these are separate events; must ask about ail types)
lilt` 110f
Actual Attempt:
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent
does not have to be 100%. If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not
have to be any injury or harm. 
just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results,
this is considered an attempt.
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example. a highly lethal
act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head jumping from window of a high floor/story). Also, if
someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.
Did you ever do anything to try to kill yourself or make yourself not alive anymore? What did you do?
" 
\''
L L
Total # of
Attempts
Did you ever hurt yourself on purpose? Why did you do that?
Did you 
as a way to end your hfe?
Did you want to die (even a little) when you 
?
Were you trying to make yourself not alive anymore when you 
?
Or did you think it was possible you could have died from 
?
Yes No
U LI
Yes No
K 
U
Or did you do it purely for other reasons, not at all to end your life or kill yourself 
(like to make yourself 
feel better, or get
something else to happen)? (Self-Injurious Behavior without suicidal intent)
If yes. describe:
Has subject engaged in Non-Suicidal Self-Injurious Behavior?
Has subject engaged in Self-Injurious Behavior, intent unknown?
Interrupted Attempt:
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have
occurres().
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an attempt rather than an interrupted attempt.
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger,
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around
neck but has not yet started to hang - is stopped from doing so.
Has there been a time when you started to do something to make yourself not alive anymore (end your life or kill yourself) but
someone or something stopped you before you actually did anything? What did you do?
If yes, describe:
Yes No
0 0
Total N of
interrupted
Aborted Attempt:
When person begins to take steps toward staking a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior.
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else.
Has there been a time when you started to do something to make yourself not alive anynwre (end your life or kill yourself) but
you changed your mind (stopped yourself) before you actually did anything? What did you do?
If yes, describe:
ye, No
L L
total ,. of
aborted
Preparatory Acts or Behavior:
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, well as assembling a .specific
method (e.g., buying pills, purchasing a gun) or preparing for one's death by suicide (e.g.. giving things away, writing a suicide note).
Have you done anything to get ready to snake yourself not alive anymore (to end your life or kill yourseg)- like giving things
away, writing a goodbye note, getting things you need to kill yourself?
If yes, describe:
.'a 
\o
L L
Suicidal Behavior:
Suicidal behavior was present during the assessment period?
Yes 
No
K 
K
Answer for Actual Attempts Only
Most Recent
Attempt
Date:
Most Lethal
Attempt
Date:
Initial/First
Attempt
Date:
Actual Lethality/Medical Damage:
0. No physical damage or very minor physical damage (eg., surface scratches).
1. Minor physical damage (e.g., lethargic speech; first-degree bums; mild bleeding; sprains).
2. Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree
burns; bleeding of major vessel).
3. Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with
reflexes intact; third-degree burns less than 20% of body, extensive blood loss but can recover; major fractures).
4. Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes third-
degree burns over 20% of body, extensive blood loss with unstable vital signs, major damage to a vital area).
5. Death
E,,/,,.(',/,
Enter Code
Enter Code
Potential Lethality: Only Answer if Actual LethalitywO
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had
potential for very serious lethality: put gurt in mouth and pulled the trigger but gun fails to fire so no medical damage; laying
on train tracks with oncoming train but pulled away before run over).
0 = Behavior not likely to result in injury
1 = 
Behavior likely to result in injury but not likely to cause death
2 = 
Behavior likely to result in death despite available medical care
Enter Code
Enter Code
Enter Code


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19.5.2
Columbia–Suicide Severity Rating Scale – children’s since last visit
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COLUMBIA-SUICIDE SEVERITY
RATING SCALE
(C-SSRS)
Children's Since Last Visit
Version 6/23/10
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.;
Burke, A.; Oquendo, M.; Mann, J.
Disclaimer:
This scale is intended to be used by individuals who have received training in its administration. The questions contained
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of
suicidal ideation or behavior depends on the judgment of the individual administering the scale.
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History
Form developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York NY, 10032. (Oquendo M. A.,
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103-130, 2003.)
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside
Drive, New York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu
© 2008 The Research Foundation for Mental Hygiene, Inc.


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SUICIDAL IDEATION
Ask questions I and 2. If both are negative, proceed to "Suicidal Behavior" section. If the answer to question 2 
is `yes';
ask questions 3, 4 and 5. If the answer to question I and/or 2 
is "yes", complete "Intensity of 
Ideation" section below.
Since Last
Visit
1. Wish to be Dead
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.
Have you thought about being dead or what It would be like to be dead?
Have you wished you were dead or wished you could go to sleep and never wake up?
Do you wish you weren't alive anymore?
If yes, describe:
Yes 
No
O O
2. Nonspecific Active Suicidal Thoughts
General, non-specific thoughts of wanting to end one's life/commit suicide (e.g., "I've ;bought about telling mysef) without thoughts of ways to kill
oneself/associated methods, intent, or plan during the assessment period.
Have you thought about doing something to make yourself not alive anymore?
Have you had any thoughts about killing purser
If yes. describe:
Yes 
No
O O
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time,
place or method details worked out (e.g.. thought of method to kill self but not a specific plan). Includes person who would say. "I thought about taldng an
overdose but I never made a specific plan as to when, where or how 1 would actually do h...and I would never go through with it."
Have you thought about how you would do that or how you would make yourself not alive anymore (kill yourself)? What did you think about?
If yes, describe:
Yes 
No
O D
4. Active Suicidal Ideation with Some intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts as opposed to "I have the thoughts but I
Yes 
No
0
definitely will not do anything about them."
When you thought about making yourself not alive anymore (or killing yourself), did you think that mi.s was something you might actually do?
This is different from (as opposed to) having the thoughts but knowing you wouldn't do anything about it
If yes, describe:
5. Active Suicidal Ideation with Specific Plan and intent
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out.
Have you decided how or when you would make purser not alive anymore/kill yourse f? Have you planned out (worked out the details of) how you
would do It?
ghat was your plan?
When you made this plan (or worked out these details). was any part of you thinking about actually doing h?
If yes, describe:
Yes 
No
0
INTENSITY OF IDEATION
The following feature should be rated with respect to the most severe type of ideation (i.e., I -S from above, with I being the least severe
and 5 being the most severe).
Most Severe Ideation:
Most
Severe
Type # 
(1-5) 
Description of Ideation
Frequency
How Hearty times have you had these thoughts? 
Write response
(1) Only one time (2) A few times (3) A lot (4) All the time (0) Don't know/Not applicable
Version 6/23/10


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SUICIDAL BEHAVIOR
(Check all that apply, so long as these are separate events; must ask about all types)
since Last
Visit
Actual Attempt:
A potentially self-injurious act committed with at least some wish to die, asa result ofact. Behavior was in part thought of as method to kill oneself. Intent
does not have to be 100%. if there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not
have to be any injury or harm, 
just the potential for injury or hare. If person pulls trigger while gun is in mouth but gun is broken so no injury results,
this is considered an attempt.
Inferring Intent: Even if an individual deities intenthvish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly lethal
act that is clearly not an accident so tto other intent but suicide can be inferred (e.g.. gunshot to head, jumping from window of a high floor/story). Also, if
someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.
Did you do a:vthine to try to kill yourself or make yourself not alive anymore? What did you do?
Yes No
D 0
Total # of
Attempts
Did you hurt yourself on purpose? Why did you do that?
Did you 
as a way to end your life?
Did you want to die (even a little) when you?
Were you trying to stake yourself not alive anymore when you 
?
Or did you think it was possible you could have died from 
?
Yes No
0 0
Yes No
D 0
Or did you do it purely for otter reasons, not at all to end your life or kill yourself 
(like to make yourself 
feel better, or get
something else to happen)? (Self-Injurious Behavior without suicidal intent)
if yes, describe:
Has subject engaged in Non-Suicidal Self-Injurious Behavior?
Has subject engaged in Self-Injurious Behavior, intent unknown?
Interrupted Attempt;
When the person is inlerupted (by an outside circumstance) front starting the potentially self-injurious act of not for that, actual attempt would have
occurred).
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an attempt rather than an interrupted attempt.
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger.
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump. is grabbed and taken down from ledge. Hanging: Person has noose around neck
but has not yet started to hang - is stopped from doing so.
Has there been a time when you started to do something to make yourself not alive anymore (end your life or kill yourself) hut
someone or something stopped you before you actually did anything? What did you do?
If yes, describe:
Ses 
No
L U
Total n of
intcn opted
Aborted Attempt or Self-Interrupted Attempt:
When person begins to take steps toward shaking a ahicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior.
Examples are similar to interrupted attempts, except that the individual stops himlhersclf, instead of being stopped by something else.
Has there been a time when you started to do something to make yourself not alive anymore (end your life or kill yourself) but you
changed your mind (stopped yourself) before you actually did anything? What did you do?
If yes, describe:
Yes 
No
L K
Total a of
aborted
or self-
interrupted
Preparatory Acts or Behavior:
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a specific
method (eg., buying pills, purchasing a gun) or preparing for one's death by suicide (eg., giving things away, writing a suicide note).
Have you done anything to get ready to make yourself not alive anymore (to end your life or kill yourself)- like giving things away,
writing a goodbye note, getting things you need to kill yourself?
if yes, describe:
t r` \s
u u
Suicidal Behavior:
Suicidal behavior was present during the assessment period?
Yes No
K 
K
Suicide:
Yes No
K K
Answer for Actual Attempts Only
Most Lethal
Attempt
Date:
Actual Lethality/Medical Damage:
0. No physical damage or very minor physical damage (e.g.. surface scratches).
1. Minor physical damage (e.g.. lethargic speech: first-degree bunts: mild bleeding: sprains).
2. Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree bums bleeding of major vessel).
3. Moderately severe physical damage medical hospitalization and likely intensive care required (e.g., comatose with reflexes intact; third-degree bums less
than 20% of body; extensive blood loss but can recover; major fractures).
4. Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree bums over 20% of body;
extensive blood loss with unstable vital signs major damage to a vital area).
5. Death
Liter code
Potential Lethality: Only Answer if Actual Lethality
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for very serious
lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train but pulled away before
run over).
0 = 
Behavior not likely to result in injury
1 = 
Behavior likely to result in injury but not likely to cause death
2 = Behavior likely to result in death despite available medical care
Enter Code


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19.6
Palatability and acceptability questionnaire
Source: Guinard 2011.
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Questions on palatability and acceptability
• How does the medication taste?
really 
bad
bad
• Swallowing the medication is
really
difficult
difficult
II •
a bit bad/
a bit good
a bit
difficult!
a bit easy
good
really
good
easy 
really
easy
Literature: Guinard JX. Sensory and consumer testing with children. Trends in Food Science &
Technology 2001; 11: 273-283.
PAQ (UK-English) 19MAR2013 FINAL


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19.7
Algorithm to detect potential severe cases of drug-induced liver 
injury
Check laboratory values at the times specified in the trial protocol for increases of alanine 
transaminase, aspartate transaminase, and total 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 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 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 local laboratory tests as listed in Table 7.
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Table 7:
Local 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 
Hemachromatosis 
Ferritin 
Hepatocellular cancer 
α –fetoprotein
Ag = antigen; ANA = anti-nuclear antibody; HB = hemoglobin; Ig = immune globulin; P-ANCA = perinuclear anti-
neutrophil cytoplasmic antibodies; PCR = polymerase chain reaction; RNA = ribonucleic acid; SMA = smooth muscle 
antibody; V = virus; VCA = viral capsid antigen.
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19.8
Global impression of change
Clinical Global Impression of Change (CGIC)
Rate total improvement whether or not, in your judgment, it is due entirely to drug 
treatment.
Compared to his condition at admission to the project, how much has he changed?
[1] 
Very much improved
[5] Minimally worse
[2] 
Much improved
[6] Much worse
[3] 
Minimally improved
[7] Very much worse
[4] 
No change
[0] Not assessed
Source: National Institute of Mental Health (NIMH)
Patient (or parent/legal guardian) Global (overall) Impression of Change (PGIC)
Please select the number that best describes how you feel.
Since the start of the study, my overall status is:
one box only:
[1] 
Very Much Improved
[2] 
Much Improved
[3] 
Minimally Improved
[4] 
No Change
[5] 
Minimally Worse
[6] 
Much Worse
[7] 
Very Much Worse
(US/English)
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19.9
World Health Organization body mass index growth charts
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BMI-for-age GIRL
Birth to 2 years (percentiles)
World ~~
Months
71
zo
19
12
14
13
11
11
10
97th
85th
50th
15th
3rd
Birth
1 year
Age (completed months and years
2 
years
'19
'17
.16
.14
to
WHO Child G owth Standards


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BMI-for-age GIRLS
2 to 5 years (percentiles)
Örld 
 na izä~tiön
19
19
14
,97th
— = 
85th
 50th
' 15th
3rd
Months 12
2 years
3years` 
- 
4 years
Age (completed months and years
in
18
16
15
11
I3
10 
11
5 years
BMI-for-age GIRLS
5 
to 19 years (percentiles)
WHO Child G owth Standards
World Health
Organization
28
26
24
M
5 20
m
18
16
14
Months 12 3 5 9 
3 6 8 
3 8 9 
3 6 9 
3 6 9 
3 8 9 
3 6 9 
3 6 9 
3 6 9 
3 6 9 
3 6 9 
3 6 9 
3 8 9 
3 6 9
Years 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19
Age (completed months and years)
28
18
16
14
12
2007 1.N1O Reference


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BMI-for-age BOYS
Birth to 2 years (percentiles)
world Health
nj 
organization
5th
Oth
3rd
Eldie
t year
Age (completed months and years)
years
21
20
BMI-for-age BOYS
2 to 5 years (percentiles)
WXOrnIm Growth Standards
*World~
19
la
wrath t'
years
97th
851h
50th
3rd
3 years 
4yurs
Age (completed months and years)
16
14
WHO Child Growth Standards


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BMI-for-age BOYS
5 to 19 years (percent les)
World Health
Organization
30
28
26
_4
E 2_
20
18
16
14
L_
Months 72 3 6 9 3 6 9 
3 6 9 
3 6 9 
3 6 9 
3 6 9 
3 6 9 
3 6 9 
3 6 9 
3 6 9 
3 6 8 
3 6 9 
3 6 9 
3 6 9
Years 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19
Age (completed months and years)
30
28
26
24
22
16
Ic
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19.10
Collecting, handling and shipment of pharmacokinetic serum samples
19.10.1
Labeling
The labels should include the following information:
•
Trial number.
•
Subject number.
•
Time and date of sample.
•
Nominal sampling time after the last administered dose of IMP.
19.10.2
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.
19.10.3
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 30 minutes.
•
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.
19.10.4
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 
(address given in Section 19.10.5). 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.
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19.10.5
Contact
Contact person
Dr 
Dr 
E-mail address
@grunenthal.com
@grunenthal.com
Phone
+49 (0) 241-569-
+49 (0) 241-569-
Postal address
Zieglerstraße 6
52078 Aachen
Germany
Fax
+49 (0) 241-569-
19.11
University of Michigan Sedation Scale
0
Awake and alert
1
Minimally sedated: tired/sleepy, appropriate response to verbal conversation and/or sound
2 
Moderately sedated: somnolent/sleeping, easily aroused with light tactile stimulation or a simple verbal 
command
3 
Deeply sedated: deep sleep, arousable only with significant physical stimulation
4 
Unarousable
Source: Malviya et al. 2002.
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GRUN E
.
Confidential
SDR-SAP-TRIAL-02
STATISTICAL ANALYSIS PLAN
Trial number: 
KF5503/65 (Grünenthal)
R331333PA13037 (Janssen)
Title of trial: 
An evaluation of the efficacy and safety of tapentadol oral solution
in the treatment of post-operative acute pain requiring opioid
treatment in pediatric subjects aged from birth to less than 18 years
old.
EudraCT number: 
2012-004359-35
Development phase: 
Phase III
Investigational medicinal 
Tapentadol oral solution.
products (IMPs): 
Placebo.
Version 
Date
Original 
10 Dec 2014
Amendment 01 
09 Sep 2016
Amendment 02 
06 Jul 2018
Trial Biostatistician (Grünenthal)
Clinical Scientist (Grinenthal)
(Depomed)
DMS version number
1.0
2.0
3.0
Signature 
Date
se
U..
Date
-§-iMmi
CONFIDENTIAL
No part of this document may be passed on, reproduced or published without written
permission of Grünenthal
NCT02081391


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TABLE OF CONTENTS
TABLE OF CONTENTS
2
LIST OF TABLES
4
LIST OF FIGURES
4
LIST OF ABBREVIATIONS
6
DEFINITIONS OF TERMS
8
1
INTRODUCTION
9
2
TRIAL OBJECTIVES
9
3
TRIAL DESIGN
10
3.1
Overall trial design and plan
10
3.2
Sample size
13
3.3
Randomization
15
4
OVERVIEW OF PLANNED ANALYSES
15
4.1
Final analyses
15
4.2
Interim analyses
16
5
DOCUMENT AND CHANGE HISTORY
16
5.1
Changes in analysis compared to the trial protocol
16
5.2
SAP amendment rationale
16
5.2.1
Amendment 01
16
5.2.2
Amendment 02
17
6
SUBJECT POPULATIONS
18
6.1
Enrolled Set
18
6.2
Allocated Set
18
6.3
Safety Set
18
6.4
Full Analysis Set
19
6.5
Per Protocol Set
19
7
ANALYSIS CONVENTIONS
19
7.1
General principles
19
7.2
Definitions
21
7.3
Definition of subgroups
21
7.4
Further definitions
23
8
DISPOSITION
23
8.1
Subject disposition
23
8.2
Time to discontinuation
24
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8.3
Protocol deviations
24
9
DEMOGRAPHICS AND OTHER SUBJECT CHARACTERISTICS
25
9.1
Subject demographics
25
9.2
Baseline characteristics
26
9.3
Subject medical history
27
9.4
Prior and concomitant medication
27
9.5
Pain intensity related to NCA/PCA
28
10
EXPOSURE AND COMPLIANCE
28
10.1
Exposure
28
10.2
Compliance
29
11
EFFICACY ANALYSES
29
11.1
Primary endpoint
29
11.1.1
Primary analyses
30
11.1.2
Sensitivity analyses
31
11.1.3
Other analysis
34
11.2
Secondary endpoints
35
11.2.1
Supplemental opioid analgesic medication
35
11.2.2
Clinical Global Impression of Change (CGIC)
36
11.2.3
Patient Global Impression of Change (PGIC)
36
11.2.4
Palatability and Acceptability
36
11.2.5
Pain intensity related to administration of IMP and 
End of Treatment Visit
37
11.2.6
Supplemental non-opioid analgesic medication
39
11.2.7
Time to first and time to second NCA/PCA after first IMP
39
11.2.8
Time to treatment discontinuation due to lack of efficacy
39
12
ANALYSIS OF PHARMACOKINETIC AND 
PHARMACODYNAMICS PARAMETERS
39
13
SAFETY ANALYSES
39
13.1
Adverse events
40
13.2
Laboratory parameters
42
13.3
Electrocardiogram
43
13.4
Vital signs and oxygen saturation
45
13.5
Additional safety parameters
46
13.5.1
Physical examination
46
13.5.2
Columbia-Suicide Severity Rating Scale
47
13.5.3
Sedation score
47
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14
REFERENCES
47
15
SAP AMENDMENTS
47
15.1
SAP Amendment 01
47
15.2
SAP Amendment 02
48
16
APPENDIX
48
16.1
Programming specifications
48
16.1.1
Percentages and decimal places
48
16.1.2
Presentation of descriptive statistics
48
16.1.3
Precision of time variables
48
16.1.4
Treatment Period
49
16.1.5
Bayesian analysis for the EU PDCO population
49
16.1.6
Analyses of medication intake regarding different trial phases
51
16.1.7
Treatment period and trial completer
52
16.1.8
Time to treatment discontinuation
53
16.1.9
Determination of FLACC total score
53
16.1.10
Multiple assessments of pain intensity, vital signs and oxygen saturation
53
16.1.11
TEAE assignment of AEs in case of (partially) missing dates
53
16.1.12
Compliance algorithm
54
16.2
Sponsor defined alert ranges for laboratory parameters
56
16.3
List of statistical output documentation
58
LIST OF TABLES
Table 1:
Schedule of events
12
Table 2:
Differences in amount of supplemental opioid use in previously 
conducted trials in post-surgical pediatric subjects
13
Table 3:
Classification of abnormal ECG parameters
44
Table 4:
Classification of abnormal QTcF values
44
Table 5:
Normal ranges of vital signs and oxygen saturation
46
Table 6:
Sponsor defined alert values for vital signs and oxygen saturation
46
Table 7:
Parameters to be calculated for continuous variables
48
Table 8:
Sponsor defined alert ranges for laboratory parameters
56
LIST OF FIGURES
Figure 1:
Immediate post-operative timeline
11
Figure 2:
Depictions of regulatory-required age ranges
14
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Figure 3:
Average amount of supplemental opioid analgesia used after first IMP 
intake
33
Figure 4:
Area under the pain curve
38
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LIST OF ABBREVIATIONS
Abbreviation
Explanation
AE
Adverse event
ALT
Alanine transaminase
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
AST
Aspartate transaminase
ATC
Anatomical Therapeutic Chemical
AUPC
Area under the pain curve
BMI
Body mass index
BUN
Blood urea nitrogen
CGIC
Clinical Global Impression of Change
CI
Confidence interval
C-SSRS
Columbia-Suicide Severity Rating Scale
DBP
Diastolic blood pressure
DMC
Data monitoring committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EU
European Union
EU PDCO
Pediatric Committee (of the European Medicines Agency)
FAS
Full Analysis Set
FLACC
Face, Legs, Activity, Cry, Consolability (scale)
FPS-R
Faces Pain Scale–Revised
HR
Heart rate
IMP
Investigational medicinal product(s)
IV
Intravenous
IVRS/IWRS
Interactive voice/web response system
LDH
Lactic acid dehydrogenase
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCMC
Markov chain Monte Carlo
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
NCA
Nurse controlled analgesia
PCA
Patient controlled analgesia
PGIC
Patient Global (overall) Impression of Change
PPS
Per Protocol Set
Q1
First quartile
Q3
Third quartile
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QTcF
Corrected QT interval using the Fridericia correction (ECG)
RBC
Red blood cell
SAE
Serious adverse event
SAF
Safety Set
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SD
Standard deviation
SOAM
Supplemental opioid analgesic medication
SOP
Standard operating procedure(s)
TEAE
Treatment emergent adverse event
US
United States
US FDA
Food and Drug Administration of the United States of America
VAS
Visual analog scale
WBC
White blood cell
WHO-DD
World Health Organization Drug Dictionary
Système International d’Unités units, vital signs, electrocardiogram and laboratory parameters are not included in this 
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DEFINITIONS OF TERMS
Term
Definition
Allocated subjects
Enrolled subjects who are allocated (randomized) to IMP.
Clinician bolus
An additional bolus of morphine or hydromorphone given either using the nurse 
controlled analgesia (NCA)/patient controlled analgesia (PCA) pump system or by an 
intravenous bolus injection. The clinician bolus can only be given in exceptional cases if 
a subject suffers unbearable pain despite using NCA/PCA.
Discontinuation
The act of concluding the participation of an enrolled subject in a trial prior to 
completion of all activities required by the protocol.
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/assent given according to local regulations, and subject given a subject 
identification number by the interactive voice/web response system (IVRS/IWRS).
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 (IMP)
A generic term describing the preparations under investigation in this trial, i.e., 
tapentadol oral solution and placebo.
Last subject out - EU 
PDCO
Date of last contact with the last subject according to the protocol for the EU PDCO
(Pediatric Committee [of the European Medicines Agency]) set. 
Last subject out - US 
FDA
Date of last contact with the last subject according to the protocol for the US FDA (Food 
and Drug Administration of the United States of America) set. 
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 period 
completers
Two sets of treatment period completers will be defined for subjects in accordance with 
the time points of the primary endpoint, i.e., 12 hours and 24 hours.
Treatment period completers are defined for each of these sets as subjects who do not 
discontinue the treatment period before 12 hours and 24 hours, respectively.
Trial completers
Trial completers are defined as treatment period completers who have completed the 
Follow-up Visit.
For purposes of compliance with a US FDA request, completers beyond 24 hours and up 
to 72 hours will be tracked and data reported.
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1
INTRODUCTION
This statistical analysis plan (SAP) includes all definitions and details for the analysis of the trial 
KF5503/65 – R331333PAI3037. The analysis will be performed in the Department of Biostatistics 
at 
 in accordance with this SAP.
The original SAP corresponds to the trial protocol of KF5503/65 – R331333PAI3037 including 
protocol amendment 02 dated 14 Oct 2014. 
The SAP amendment 01 corresponds to the Trial Protocol of KF5503/65 – R331333PAI3037 
including protocol amendment 06 dated 19 Aug 2016. 
This SAP amendment 02 aligned the SAP to the Trial Protocol of KF5503/65 – R331333PAI3037 
including protocol amendment 07 dated 24 Mar 2017. 
2
TRIAL OBJECTIVES
Trial KF5503/65 – R331333PAI3037 is part of a pediatric development program that fulfills 
differing requirements of the EU PDCO and the US FDA. For the EU PDCO, to assess the efficacy 
and safety of tapentadol in the treatment of acute pain, subjects between 2 years and less than 
18 years old will be evaluated. For the US FDA, subjects between birth and less than 17 years old 
will be evaluated.
The clinical hypothesis of this trial is that tapentadol oral solution reduces the total amount of 
supplemental opioid analgesic medication used over 12 hours (primary objective for US FDA) or 
24 hours (primary objective for EU PDCO) following initiation of IMP, compared to placebo, in 
children and adolescents who have undergone surgery that, in the investigator’s opinion, would 
reliably produce moderate to severe pain requiring opioid treatment.
The primary efficacy objective (either 12 hours or 24 hours) for 1 region is considered as the 
secondary efficacy objective in the other, for the different age range, as described below.
Two reports will be prepared for the trial. The first report will be prepared after the last subject out 
of the EU PDCO set. The second report will be prepared after the last subject out of the US FDA 
set.
Subjects can be treated for up to 72 hours, and efficacy and safety information will also be collected 
throughout this time period.
Primary objectives:
For EU PDCO: To evaluate the efficacy of tapentadol oral solution, based on the total amount of 
supplemental opioid analgesic medication used over 24 hours following initiation of IMP, in 
children and adolescents aged 2 years to less than 18 years who have undergone surgery that, in the 
investigator’s opinion, would reliably produce moderate to severe pain requiring opioid treatment.
For US FDA: To evaluate the efficacy of tapentadol oral solution, based on the total amount of 
supplemental opioid analgesic medication used over 12 hours following initiation of IMP, in 
children and adolescents aged from birth to less than 17 years who have undergone surgery that, in 
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the investigator’s opinion, would reliably produce moderate to severe pain requiring opioid 
treatment.
For both EU PDCO and US FDA: To evaluate the safety of tapentadol oral solution in children and 
adolescents aged 2 years to less than 18 years (EU PDCO) and children and adolescents aged from
birth to less than 17 years (US FDA) who have undergone surgery that, in the investigator’s 
opinion, would reliably produce moderate to severe pain requiring opioid treatment.
Secondary objectives:
To assess the efficacy of tapentadol oral solution using multiple subjective and objective measures 
of the subject’s response to treatment (see Section 11.2).
3
TRIAL DESIGN
3.1
Overall trial design and plan
This is a Phase III, randomized, multi-site, double-blind, placebo-controlled, parallel group, 
multiple oral dose trial of tapentadol in male and female subjects aged from birth to less than 
18 years old who have undergone surgery that, in the investigator’s opinion, would reliably produce 
moderate to severe pain requiring opioid treatment via either NCA or PCA. 
A target number of 159 randomized subjects will be treated with IMP in the EU PDCO age range 
(2 years to less than 18 years of age) and in the US FDA age range (birth to less than 17 years of 
age). Due to the overlapping age groups as per regulatory requirements, it is expected that 
approximately 168 subjects will be treated with IMP in this trial. 
Subjects will be randomly assigned to 1 of the 2 treatment arms in a 2:1 tapentadol oral solution to 
placebo ratio. Permuted block randomization will be stratified by predefined age groups and 
supplemental opioid used.
For each subject, the trial will include the following periods:
Enrollment Period (Visit 1; Day -28 to Day -1)
The duration of this period will be as per standard of care for the concerned surgery, but the start of 
enrollment is not to exceed 28 days before allocation/randomization to IMP, which constitutes the 
end of the enrollment period. Subjects may start enrollment before or after surgery. The 
inclusion/exclusion criteria will be assessed after surgery in order to confirm the eligibility of the 
subject for randomization. To qualify for randomization, after the surgery the subject must have 
been started on NCA/PCA with morphine or hydromorphone, with or without a background 
infusion. This includes subjects receiving morphine or hydromorphone via background infusion 
who did not actively utilize NCA/PCA. The background infusion (if any) must be with a low dose 
infusion of the same opioid as that used for the NCA/PCA.
Treatment and Evaluation Period (Visit 2 and Visit 3)
Visit 2 starts once the subject has been allocated to IMP. At the time of first IMP administration, the 
background opioid infusion (if any) will be discontinued. The IMP will be administered as an oral 
solution. The dosing interval is 4 hours (range ±15 minutes). If the subject is sleeping at the time of 
the scheduled dose, they must be woken to take the IMP within a maximum of 6 hours after the 
previous dose. This dose must be taken as soon as possible after the subject is awake. Within the 
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first 24 hours the dose will be 1.25 mg/kg (6 months to <18 years; the dose is still to be determined 
for subjects aged from birth to <6 months old). After 24 hours, the investigator may decrease the 
dose of IMP to 1.0 mg/kg according to the investigator’s judgment of the subject’s reduced need for 
analgesia. Dosing with IMP will be stopped when opioid analgesic medication is no longer needed,
a switch to exclusively oral opioid analgesic medication takes place, or 72 hours after first IMP 
administration.
Visit 3 will be performed between 4 hours and 24 hours after the last administration of IMP, or if 
the subject is prematurely discontinued from the trial. The visit must be performed before discharge 
from the hospital.
Follow-up Visit (Visit 4; Day 10 to Day 14)
Only adverse events (AEs) and intake of concomitant medication and therapies will be assessed at 
this visit, which may be performed by telephone.
For a summary of the trial as a flow diagram, see Figure 1; for the schedule of events see Table 1.
NCA = nurse controlled analgesia; PCA = patient controlled analgesia; IMP = investigational medicinal product.
Figure 1:
Immediate post-operative timeline
Background infusion (if any) 
according to standard of care
NCA/PCA with morphine or hydromorphone
Verify subject 
eligibility.
Complete 
enrollment.
Allocation/
randomization to IMP
Per investigator judgment:

Start IMP dosing (tapentadol 
oral solution or placebo).

Continue NCA/PCA without 
background infusion (if any).
IMP (tapentadol oral solution or placebo)
Careful safety monitoring of the subject
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Table 1:
Schedule of events
Period:
Visit:
Enrollment
Treatment and evaluation
Follow
-up
1
2
3
4 
Time:
28 days before 
allocation/
randomization 
First dose
Day 1 
Subsequent 
doses
End of 
Treat-
ment
Day 10 
to 
Day 14
Before
After
Before
After
Any 
time
After 
surgery
Obtain informed consent/assent 
X
Record date of signing the informed 
consent/assent form, sex, race/ethnicity, 
and height.
X 
Record weight after surgery (can be 
measured before surgery if the surgery is 
not expected to notably change the 
weight) 
X
Record age at time of 
allocation/randomization 
X
Record clinically relevant medical/surgical 
history
X
Record details about the surgery
X
Perform a physical examination
X 
X 
Record intake of prior/concomitant 
medication and therapies, as appropriate
X
X
<------------------------------------>
X
Detailed recording of analgesics 
X
X
X
X
Record C-SSRS 
X
X
Continuous heart- and respiratory-rate 
recording for 24 hours after first IMP 
     <---------------------------->
Record vital signs 
X 
X
X
X
Record sedation score
X
X
Continuous oxygen saturation 
measurement until 4 hours after the last 
administration of IMP
    <------------------------------->
Record oxygen saturation
X 
X
X
X
Record 12-lead electrocardiogram
X
X
Take blood for safety laboratory (clinical 
chemistry and hematology)
X
X
Perform a pregnancy test
X
Check inclusion/exclusion criteria
X
Allocate subject to IMP
X
Stop background infusion (if any) of 
opioids at time of first IMP dose
X
Detailed recording of NCA/PCA and 
background infusion (if any) 
X
<---------------------------------->
no background infusion
Administer IMP (record time and dose) 
X
X
Record pain intensity 
X
X
X
X
Record pain intensity before each 
NCA/PCA activation
<---------------------------------->
Record palatability and acceptability 
X
X
Global impression of change 
X
Perform and document drug accountability
X
Assess and record adverse events 
<-------------------------------------------------------------------------->
Assess discontinuation criteria
X
X
X
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Period:
Visit:
Enrollment
Treatment and evaluation
Follow
-up
1
2
3
4 
Time:
28 days before 
allocation/
randomization 
First dose
Day 1 
Subsequent 
doses
End of 
Treat-
ment
Day 10 
to 
Day 14
Before
After
Before
After
Dispense subject trial card
X
C-SSRS = Columbia-Suicide Severity Rating Scale; IMP = investigational medicinal product; NCA = nurse controlled 
analgesia; PCA = patient controlled analgesia.
3.2
Sample size
The sample size determination was based on the primary efficacy endpoint variable for the 
respective Full Analysis Sets (FASs). A linear relationship is assumed between the 12 hour and 
24 hour supplemental opioid analgesic use for the purposes of the sample size calculation and the 
final analyses. 
The sample size calculation was based on results, summarized in Table 2, from previously 
conducted trials in post-surgical pediatric subjects where supplemental opioid use was measured.
Table 2:
Differences in amount of supplemental opioid use in previously conducted trials in 
post-surgical pediatric subjects
Reference
Supplemental opioid use (morphine or 
morphine-equivalent) in original units
Converted to cumulative 
use over 24 hours (mg/kg)
Treatment group 
difference based on 
cumulative use over 
24/12 hours (mg/kg)
Rusy et al. 
2010
Placebo: 0.055 ± 0.017 mg/kg per h
Gabapentin: 0.046 ± 0.016 mg/kg per h
Placebo: 1.32 ± 0.408
Gabapentin: 1.10 ± 0.384
0.22/0.11
Rugyte 
and Kokki 
2007
Placebo: 0.028 ± 0.0083 mg/kg per h
Ketoprofen: 0.020 ± 0.0100 mg/kg per h
Placebo: 0.67 ± 0.20
Ketoprofen: 0.49 ± 0.24
0.18/0.09
For the current trial, a value of 0.20 mg/kg in 24 hours (0.10 mg/kg in 12 hours) for the between-
treatment group difference and a more conservative value of 0.42 mg/kg in 24 hours (0.21 mg/kg in 
12 hours) for the standard deviation (SD) were considered adequate assumptions. The standardized 
effect size based on these values (0.20/0.42 = 0.48) is more conservative than the standardized 
effect sizes observed in Rusy et al. 2010 (approximately 0.55) or Rugyte and Kokki 2007
(approximately 0.80). A smaller effect size was chosen to account for additional variability in the 
trial due to local standards of care. 
Assuming α = 0.05 (2-sided), 80% power (β = 0.2), and a randomization ratio of 2:1 (tapentadol to 
placebo) results in a sample size of 106 tapentadol-treated subjects and 53 placebo-treated subjects. 
Since there is only 1 primary endpoint for each regulatory authority (EU PDCO/US FDA), no 
multiplicity adjustment will be performed.
The target is to have approximately 159 randomized (allocated) subjects treated with IMP in the EU 
PDCO age range (2 years to less than 18 years of age) and in the age range (birth to less than 
17 years of age) (Figure 2). 
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FDA = Food and Drug Administration of the United States of America; PDCO = Pediatric Committee (of the European 
Medicines Agency); N = target number of treated subjects.
Figure 2:
Depictions of regulatory-required age ranges
The treatment of at least 159 subjects with IMP in the EU PDCO age range and US FDA age range 
is the target for the minimum required number of subjects to meet the statistical power calculation 
for the primary efficacy endpoints of the trial and regulatory requirements. 
Due to the overlapping age groups as per regulatory requirements, it is expected that approximately 
168 subjects will be treated with IMP in this trial. 
The trial enrollment for the EU PDCO set (see Section 6 for the definition of the analysis 
populations) will complete when the following criterion is met:
•
At least 159 treated subjects in the age range 2 years to less than 18 years of age (EU 
PDCO).
The trial enrollment for the US FDA set will complete when the following 2 criteria are met:
•
At least 159 treated subjects in the age range birth to less than 17 years of age (US FDA).
•
100 subjects in the age range birth to less than 17 years of age on tapentadol for at least 
2 doses (US FDA). Based on estimates from adult trials in acute pain, it is assumed that 
approximately 5% of subjects (approximately 8 subjects) may discontinue prior to 
receiving 2 doses of IMP, which is covered by the targeted sample size.
An additional objective of the trial is to meet a US FDA request to evaluate at least 25 subjects in 
the age range birth to less than 17 years of age who have been exposed to tapentadol for at least 
48 hours. As medically appropriate, every effort will be made to enroll subjects in this trial to meet 
this objective. A combination of blinded and unblinded monitoring will ensure the 3 above criteria 
as well as a minimum target of randomized subjects within all cohorts are met. The respective
processes are described in a separate document. 
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The sample size calculation was performed using the sample size program nQuery v7.0 (Dixon and 
Massey 1983, O’Brien and Muller 1993) for unequal group sizes and the above assumptions 
regarding the effect size and the allocation ratio of 2:1 (tapentadol:placebo).
3.3
Randomization 
Randomization and blinding will be done in accordance with the sponsor’s standard operating 
procedures (SOPs).
Randomization will be outsourced to a Central Randomization Center (
 
) which will develop an IVRS/IWRS. The IVRS/IWRS will be used to assign a subject 
number at the Enrollment Visit (Visit 1) as well as a randomization number and medication kit 
number at randomization. The IVRS/IWRS will also be used to support the drug supply chain 
management processes of distribution and return. 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 
in a 2:1 tapentadol oral solution to placebo ratio. 
Computer-generated randomization will be implemented by using permuted blocks of treatments 
and stratified by predefined age groups (birth to <30 days, 30 days to <6 months, 6 months to 
<2 years, 2 years to <6 years, 6 years to <12 years, 12 years to <17 years, 17 years to <18 years) 
and supplemental opioid used (morphine versus hydromorphone).
There are 4 randomization lists for this trial; 1 randomization list for each of the 3 youngest age 
groups each stratified by supplemental opioid used (morphine versus hydromorphone), and 
1 randomization list for the older age groups stratified by age group (2 years to <6 years, 6 years to 
<12 years, 12 years to <17 years, 17 years to <18 years) and supplemental opioid use. Unblinding 
can be performed for 1 or more of these lists individually.
Once the EU PDCO set has completed recruitment and data for these subjects is locked, unblinding 
will be performed for those subjects aged 2 years and older. The additional age groups under 
2 years old will be unblinded at the end of the trial.
4
OVERVIEW OF PLANNED ANALYSES 
4.1
Final analyses
The EU final analysis will be performed after all subjects in the EU PDCO set have completed the 
trial, the data for the EU PDCO set was locked and subjects aged over 2 years were unblinded. The 
second final analysis will be performed after all subjects (EU PDCO set and US FDA set) have 
completed the trial, the database was locked, and subjects aged under 2 years were unblinded (the 
EU PDCO set being already locked and unblinded).
For information on the final reporting for EU PDCO and US FDA see Section 16.6 of the protocol 
amendment 06.
The final reporting for US FDA will be based on the EU PDCO reporting and extended by a 
descriptive analysis of all subjects less than 2 years old. Further details are provided in 
Section 5.2.2.
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4.2
Interim analyses
No formal interim analysis of efficacy is planned in the trial.
An independent data monitoring committee (DMC) will be established to perform, on a regular 
basis, an independent and objective review of the safety data, and to provide recommendations 
about continuing or terminating the trial or about any other modification to the trial protocol or trial 
conduct as described in the DMC charter.
All analyses performed for the DMC will be described in a separate document. Results of the 
analyses performed for the DMC will not be included in the final study reports.
5
DOCUMENT AND CHANGE HISTORY
5.1
Changes in analysis compared to the trial protocol
Not applicable.
5.2
SAP amendment rationale
5.2.1
Amendment 01
The amendment 01 to the final SAP was prepared to include changes of protocol amendment 04, 
23rd June 2015 to protocol amendment 06, 19th Aug 2016. Hence it is mainly supposed to reflect the 
analysis of the EU PDCO data set for regulatory requirements prior to completion of the US FDA 
data set. Furthermore, the following additional changes have been embedded. 
•
Reflect adaptations to populations as per protocol amendments and introduction of 
“Allocated Set” to cope for subjects that have been allocated but were not treated.
•
Prior and concomitant medication section was adapted for consistency to standard wording.
•
Removal of the analysis of non-opioid analgesic medication as a secondary endpoint for 
logistical reasons.
•
Compliance calculation algorithm was adapted and updated.
•
Embed analysis of clinician bolus or intravenous bolus of morphine or hydromorphone if 
the subject had unbearable pain in exceptional cases.
•
Removal of analysis reducing primary endpoint analysis to subjects who received at least 2 
doses of IMP.
•
For global impression of change questionnaires Cochran-Mantel-Haenszel testing was 
removed.
•
For subjects younger than 2 years only local laboratory analyses are performed, and 
therefore for these age groups laboratory values will not be part of summary statistics.
•
Physical examination derived 2 times during trial will only be presented in subject data 
listing.
•
Treatment period start date/time was changed to data/time of first IMP intake instead of 
allocation date/time.
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•
Adaptations and additions were made to the derivation of the amount of morphine or 
hydromorphone from different electronic case report form (eCRF) pages and how to handle 
missing information.
Some adaptations adding clarifications to individual analyses or done for sake of consistency are 
not specified here.
Minor editorial changes, such as the correction of typing errors or format changes, are not 
specifically listed. 
5.2.2
Amendment 02
This amendment has been enacted after the database for the EU analysis (all subjects 2 years to less 
than 18 years old) has been fully locked and the EU analysis has been performed, in order to further 
describe how the original US objective of analyzing subjects aged between birth and less than 
17 years will now be implemented.

US primary endpoint analysis: The primary and sensitivity analyses for the primary 
endpoint (ANOVA) will now be performed on the FAS-EU data set. For subjects less than 2 
years old the primary endpoint will be analyzed descriptively (FAS-US <2). For details 
please refer to Section 11.1.

Secondary efficacy endpoints: Subjects aged 2 years and above (FAS-EU) have already been 
covered in the analysis performed for EU reporting. This analysis will be complemented 
with a descriptive analysis of subjects less than 2 years old (FAS-US <2) in order to achieve 
complete reporting for the age range required by US FDA. For details please refer to 
Section 11.2. 

Safety analysis: Subjects aged 2 years and above (SAF-EU) have already been covered in 
the analysis performed for EU reporting. The main safety analyses will be complemented 
with a descriptive analysis of subjects less than 2 years old (SAF-US <2) in order to achieve 
complete reporting for the age range required by US FDA. For details please refer to 
Section 13.
By this approach the analysis for the US endpoints includes subjects aged 17 years old. These 
subjects were originally not required to be analyzed and reported for the US endpoints based on a 
Written Request for tapentadol agreed with the FDA. However, there is strong evidence that 
adolescents aged 17 years old and younger adolescents show a comparable physiological response 
to exposure with tapentadol (with regards to efficacy, safety and tolerability). These subjects will 
add further value and reliability to the analysis, and is not expected to, based upon currently 
available scientific information, bias the study outcomes. It therefore was decided to include these 
subjects in the evaluation of US endpoints as well.
On the other hand subjects less than 2 years old are analyzed separately. This does not effect 
secondary endpoint and safety analysis as the relevant data complement the already reported data. 
Also for the primary endpoint, the analysis will unlikely be impacted considerably given the limited 
number of 15 subjects planned in this age range.
Furthermore, the imputation strategy for the sensitivity analyses for the US FDA primary endpoint 
is adapted within this amendment based on a request by the FDA (see Section 11.1.2). 
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Except for disposition displays no combined display of subjects below and above 2 years will be 
done. 
6
SUBJECT POPULATIONS
Most analyses planned on the US or overall population for the final report will be limited to
subjects less than 2 years old. Those will be denoted with the extention <2, e.g., analyses on
subjects less than 2 years old and on the FAS-US will be denoted by FAS-US <2 and on the SAF-US
will be denoted by SAF-US <2.
6.1
Enrolled Set
The Enrolled Set will include all enrolled subjects (as defined in the protocol) of the trial. In the 
following sections, this set will be denoted by Enroll-All.
For the EU PDCO, the Enrolled Set will include all enrolled subjects (as defined in the protocol) 
from 2 years to less than 18 years of age and be denoted by Enroll-EU; for the US FDA, the 
Enrolled Set (Enroll-US) will include all enrolled subjects (as defined in the protocol) from birth to 
less than 17 years of age. The latter will be reported by presentation of the Enrolled-EU
complemented by the Enrolled-US <2, which denotes those subjects less than 2 years old and is 
identical to the Enrolled-All <2.
6.2
Allocated Set
The overall Allocated Set will include all enrolled subjects that are allocated (randomized) to IMP. 
This set will be denoted by Allocated-All.
For the EU PDCO, the Allocated Set will include allocated subjects 2 years to less than 18 years of 
age and will be denoted by Allocated-EU; for the US FDA, the Allocated Set (Allocated-US) will 
include allocated subjects from birth to less than 17 years of age. The latter will be reported by 
presentation of the Allocated-EU complemented by the Allocated-US <2, which denotes those 
subjects less than 2 years old and is identical to the Allocated-All <2.
6.3
Safety Set
The Safety Set (SAF) comprises all treated subjects in the required age ranges for the EU PDCO 
and US FDA. The overall Safety Set will include all treated subjects of the trial. This set will be 
denoted by SAF-All. The EU PDCO Safety Set will include subjects 2 years to less than 18 years of 
age and will be denoted by SAF-EU; the US FDA Safety Set (SAF-US) will include subjects from 
birth to less than 17 years of age. The latter will be reported by presentation of the SAF-EU
complemented by the SAF-US <2, which denotes those subjects less than 2 years old and is 
identical to the SAF-All <2. A subject will be considered as treated if administered any amount of 
IMP.
If by error a subject does not receive the allocated medication, the subject will be evaluated 
according to the received IMP.
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6.4
Full Analysis Set
The overall FAS includes all subjects that are allocated and treated. This set will be denoted by 
FAS-All. The EU PDCO FAS will include allocated and treated subjects aged 2 years to less than 
18 years old and will be denoted by FAS-EU; the US FDA FAS (FAS-US) will include allocated 
and treated subjects from birth to less than 17 years of age. The latter will be reported by 
presentation of the FAS-EU complemented by the FAS-US <2, which denotes those subjects less 
than 2 years old and is identical to the FAS-All <2. 
If by error a subject does not receive the medication to which she/he was allocated, the subject will 
be evaluated as allocated within the FAS following the intention-to-treat principle.
6.5
Per Protocol Set
The EU PDCO or US FDA Per Protocol Sets (PPSs) define subsets of the subjects in the FASs
without any major protocol deviations affecting the primary efficacy endpoint. The major protocol 
deviations which will lead to the exclusion of a subject from the PPS(s) will be decided during 
blinded data review meetings which will be held before locking and unblinding the data for the EU 
PDCO set and before database lock and unblinding for subjects aged less than 2 years. 
Corresponding to the FAS-EU and FAS-US, the PPSs will be denoted by PPS-EU and PPS-US, with 
PPS-EU excluding those subjects from the FAS-EU with major protocol deviations for the EU 
primary endpoint (24 hours) and PPS-US excluding those subjects from the FAS-US with major 
protocol deviations affecting the US primary endpoint (12 hours). Furthermore, PPS-EU-12h will 
denote the analysis set covering the EU PDCO age range (2 years to less than 18 years old) without 
any major protocol deviations affecting the US primary efficacy endpoint (12-hour time frame). 
7
ANALYSIS CONVENTIONS
7.1
General principles
If an analysis defined in the SAP is specified to be conducted in 2 (or more) analysis sets and the 
analysis sets represent the same group of subjects, presentations will only be prepared once. 
Programming specifications for this SAP are described in Section 16.1, giving more information 
about technical details of SAP text.
Unless stated otherwise, all data collected in this trial will at least be summarized by descriptive 
methods (see Section 16.1.1 and Section 16.1.2), based on the nature of the variable:
•
For continuous variables, descriptive statistics will include the number of observations, 
number of missing observations, arithmetic mean, SD, minimum, first quartile (Q1), 
median, third quartile (Q3), and maximum. If there are fewer than 5 non-missing values, 
only a subset of these statistics, depending on the number of non-missing observations, will 
be displayed.
•
For categorical variables, frequency counts and percentages will be used to summarize the 
results. The number of non-missing values will be used as denominator in percentage 
calculations.
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•
For time-to-event variables, descriptive statistics will include the number of observations, 
minimum, first quartile (Q1), median, third quartile (Q3), and maximum. Furthermore,
Kaplan-Meier estimates and graphs will be provided. The Kaplan-Meier graph will
additionally provide the respective number at risk and the Kaplan-Meier estimates at 
6 hours, 12 hours, 18 hours, 24 hours, 48 hours and 72 hours. Additionally, the Kaplan-
Meier graph will include the median time-to-event and its 95% confidence interval (CI) for 
both treatment groups. Censoring mechanisms depend on the specific endpoint and will be
described in the respective section.
For statistical analyses, pain intensity scores assessed by all 3 age-dependent measurements will be 
regarded as a continuous variable. Other ordinal variables will be analyzed as categorical variables. 
The main analysis will focus on the treatment, thus all summaries and graphical presentations will 
be displayed by assigned treatment group.
Unless specified otherwise, statistical tests and CIs are 2-sided and use a significance level of 
 =0.05.
Subject data will be presented in subject data listings.
Unscheduled measurements will generally be presented only in the subject data listing and will not 
be included in summary statistics. However, there are 3 exceptions to this rule:
1.
In case of unscheduled baseline measurements (see Section 9.2) between the last scheduled 
measurement before first administration of IMP and administration of first IMP, the latest of 
these unscheduled measurements replaces the scheduled baseline measurement.
2.
Values outside of sponsor defined alert ranges (potentially clinically important values) for vital 
signs, oxygen saturation, and laboratory parameters resulting from unscheduled assessments 
will be included with scheduled measurements in the respective analyses. Furthermore,
abnormal electrocardiogram (ECG) values based on measurement from the ECG central reader 
and clinically relevant abnormal values assessed by the investigator resulting from unscheduled 
assessments will be included in the respective analyses.
3.
For unscheduled and thus multiple assessments of vital signs, oxygen saturation, and pain 
intensity (excluding pain intensities measured related to NCA/PCA) between 2 doses of IMP, 
the latest occurring assessment before the subsequent dose will be used for statistical analyses.
The remaining records, unless they yield values outside the sponsor defined alert ranges
(potentially clinically important values, see above), will only be included in the subject data 
listing.
All medications will be coded according to the World Health Organization Drug Dictionary (WHO-
DD). 
All investigator-reported terms for medical history in the eCRF and all original terms used by the 
investigators in the eCRFs to identify AEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA).
For the final analysis, the latest version of the WHO-DD/MedDRA at the time of coding for final 
evaluation will be used. Coding for the DMC analyses is addressed separately in the SAP for the 
DMC. For the EU final analysis (first database lock) the latest version at that time point will be 
used. Recoding will be performed for the final analysis if applicable and changes to EU analysis 
might be possible.
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Two reports will be prepared for the trial. Further details on the reports are given in Section 16.6 of 
the protocol.
If not otherwise specified analysis of subjects less than 2 years old will be descriptive and presented 
separately. Most analyses planned on the FAS-US or FAS-All will be conducted for the FAS-US <2
population only and most analyses planned on the SAF-US or SAF-All will be conducted for the 
SAF-US <2. Further details are provided in the respective sections. 
7.2
Definitions
For all differences between tapentadol and placebo, tapentadol will constitute the minuend and 
placebo the subtrahend of the difference.
In this trial, baseline is defined as the last non-missing assessment before first IMP intake. 
Depending on the parameter, this is either the assessment at the Enrollment Visit (before or after 
surgery), the assessment done at Visit 2 before first administration of IMP, or an unscheduled 
measurement between the last scheduled measurement before first administration of IMP and 
administration of first IMP. 
7.3
Definition of subgroups
Subgroup analyses, e.g., according to age categories or supplemental opioid used, may also be 
explored as appropriate. 
If stated in this SAP that a summary will be displayed for relevant age groups, it means the 
following:
•
For the EU PDCO (analysis sets ending in -EU): 
−
2 years to less than 6 years
−
6 years to less than 12 years
−
12 years to less than 18 years
•
For the US FDA (analysis sets ending in -US):
−
Birth to less than 30 days
−
30 days to less than 6 months
−
6 months to less than 2 years
−
2 years to less than 6 years
−
6 years to less than 12 years
−
12 years to less than 17 years
•
For the overall trial population (analysis sets ending in -All):
−
Birth to less than 30 days
−
30 days to less than 6 months
−
6 months to less than 2 years 
−
2 years to less than 6 years
−
6 years to less than 12 years
−
12 years to less than 17 years
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−
17 years to less than 18 years
For inferential analyses which include age group as a factor, age groups might be pooled if there are 
insufficient numbers of subjects, i.e. less than 6 subjects, in any of the age groups. If for an analysis 
it is stated in this SAP that age groups will be pooled, the following pooling algorithm applies 
separately to the 3 age groups of subjects less than 2 years old and the remaining 3 age groups of 
subjects older than or equal to 2 years:
1.
The age subgroup with fewest subjects is pooled with the adjacent age group with the smaller 
number of subjects. 
a.
If the threshold of 6 subjects is not reached, the pooled subgroup is pooled with the 
remaining age group and the algorithm terminates.
b.
If the threshold of 6 subjects is reached, the algorithm proceeds with step 2.
2.
Check if the remaining subgroup consists of fewer than 6 subjects. 
c.
If the remaining subgroup consists of fewer than 6 subjects, it will be pooled with 
the pooled age group of step 1 and the algorithm terminates.
d. If the remaining subgroup consists of at least 6 subjects, the algorithm terminates.
In case of discrepancies between the IVRS/IWRS recording and the eCRF for age group and/or 
supplemental analgesia used for NCA/PCA (morphine/hydromorphone), the entry in the eCRF will 
be used for all analyses unless explicitly stated otherwise.
Geographical regions are the following: 
•
Europe
•
USA
Type of administration of supplemental opioid analgesia: 
•
PCA
•
NCA
Supplemental opioid analgesia used: 
•
Hydromorphone
•
Morphine
Race:
•
American Indian or Alaska Native
•
Asian
•
Black or African American
•
Native Hawaiian or other Pacific Islander
•
White
•
Other
Sex:
•
Female
•
Male
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For analysis of subjects less than 2 years old, no subgroup analysis will be performed apart from 
age group analyses due to the low number of subjects.
7.4
Further definitions
Supplemental opioid analgesic medication is defined as morphine or hydromorphone that is 
administered via intravenous NCA/PCA or intravenous bolus in case of NCA/PCA pump failure or 
clinician bolus or any other intravenious administered opioid after first administration of IMP up to
the End of Treatment Visit and will be evaluated as morphine IV equivalents. Details regarding the 
relationship to the eCRF can be found in Section 16.1.6. 
8
DISPOSITION
Unless stated otherwise subject disposition will be displayed for the following analysis sets:
•
Enroll-All
•
Enroll-EU
•
Enroll-US <2
Time to discontinuation and protocol deviations will be displayed for the following analysis sets:
•
FAS-EU
•
FAS-US <2 ( only protocol deviations)
8.1
Subject disposition
Subject disposition will be descriptively summarized (per treatment group and overall) in terms of 
the number (N) and percentage (%) for the following populations:
•
Subjects enrolled (only N, only overall)
•
Subjects enrolled but not allocated and reason for non-allocation (only overall)
•
Subjects allocated
•
SAF
•
FAS
•
PPS
•
Treatment period completers and treatment period discontinuations at 12 hours and
24 hours after first IMP intake. For the derivation of treatment period completion status at 
both time points, see Section 16.1.7.
•
Trial completers and trial discontinuations at 12 hours and 24 hours after first IMP intake. 
For the derivation of trial completion status at both time points, see Section 16.1.7.
For subjects enrolled but not allocated and for the reasons for not being allocated, the percentage 
denominator will be the number of enrolled subjects. For the SAF, FAS, and the PPS the percentage 
denominator will be the number of allocated subjects.
For the summaries of treatment period and trial completion/discontinuation, 2 analyses will be 
performed. For the first analysis, the percentage denominator will be the number of subjects in the
FAS and if a subject discontinues treatment, the subject will be considered a discontinuation for all 
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subsequent time points as well. As an additional analysis, the percentage denominator will be the 
number of subjects in the FAS who are “at risk” for discontinuation at the given time point: For the 
12-hour time point, this will be the number of subjects in the FAS. For the 24-hour time point, this 
will be the number of subjects in the FAS who completed the 12-hour time point.
For the Enroll-All set (and Enroll-EU for EU PDCO), the above information will also be displayed
per each relevant age group (1 table), per each type of supplemental opioid analgesic medication 
used (1 table), and per each country (1 table).
The reasons for treatment and trial discontinuations will be summarized for all allocated subjects, 
overall and separately for allocated subjects discontinuing
•
Before first IMP (trial discontinuations only)
•
After first IMP but before or at 12 hours after first IMP
•
After 12 hours but before or at 24 hours after first IMP
•
After 24 hours after first IMP
Percentage denominator will be the number of subjects discontinuing in the respective category. 
The details for “other reasons” will be presented in a listing, if applicable.
8.2
Time to discontinuation
The distribution of the time from first IMP intake to discontinuation from treatment (see 
Section 16.1.8 for details) before 72 hours after first IMP will be summarized using time-to-event 
methods. For subjects who reach the maximum duration of treatment (72 hours, see Section 16.1.4), 
the time to discontinuation will be censored at 72 hours after first IMP intake.
Time to discontinuation due to lack of efficacy will be evaluated as described in Section 11.2.8.
Time to discontinuation due to an AE will be evaluated as described in Section 13.1.
8.3
Protocol deviations
Major protocol deviations will be summarized by FAS-EU and FAS-US <2 and grouped into 
different categories such as
•
Violation of inclusion/ exclusion criteria
•
Time schedule deviations
•
Non-compliance regarding intake of IMP/supplemental analgesia
•
Missing essential data
•
Subject not discontinued as per protocol of trial
•
Other non-compliance
Multiple deviations can occur in the same subject and thus a subject can be counted in more than 
1 deviation category.
Subject listings of major protocol deviations will be sorted by country and site.
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9
DEMOGRAPHICS AND OTHER SUBJECT CHARACTERISTICS
No statistical tests for comparison of demographic and baseline data will be performed.
Unless stated otherwise demographic and baseline data will be displayed for the following analysis 
sets:
•
FAS-All
•
FAS-EU
•
FAS-US <2
Medical history and previous and concomitant medication will be displayed for the following 
analysis sets:
•
SAF-EU
•
SAF-US <2
Pain intensity related to NCA/PCA will be displayed for the following analysis sets:
•
FAS-EU
•
FAS-US
9.1
Subject demographics
Subjects demographics are age [years], weight [kg], height [cm], body mass index (BMI) [kg/m2], 
sex, race, ethnicity, and trial-relevant age group. Further additional age groups will also be 
considered: birth to <28 days, 28 days to <2 years, 2 years to <12 years, 12 years to <16 years and 
12 years to <18 years . 
All data as recorded in the eCRF are used for the analyses of subject demographics. 
•
Regarding age, the age at the time of allocation is recorded in the eCRF. 
−
For age recorded in months for subjects aged 60 days to less than 2 years, the following 
conversion rule is used:
−
For age recorded in days for subjects aged less than 60 days, the following conversion 
rule is used:
 [
]
365.25 


=  []
−
For age converted from days/months to years, the resulting value is rounded to 
3 decimal places.
Subject demographics will be summarized with descriptive statistics for each treatment group and 
overall. For the FAS-All and FAS-EU, subject demographics will be summarized with descriptive 
statistics for each trial-relevant age group (no display of age group) and for FAS-EU also by type of 
supplemental opioid analgesic medication used.
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Age groups as recorded in the IVRS/IWRS will be summarized with descriptive statistics.
Both values, age (eCRF) and age (IVRS/IWRS), will be displayed in the subject data listing. The 
listings will also include the ages of eCRF and IVRS/IWRS converted into years.
9.2
Baseline characteristics
Baseline characteristics will be descriptively summarized for each treatment group and overall. For
the FAS-All and FAS-EU, baseline characteristics will be summarized with descriptive statistics for 
each trial-relevant age group.
Continuous baseline characteristics are: 
•
Amount of (post-operative) morphine or hydromorphone taken within 24 hours prior to first 
IMP administration (mg/kg of morphine equivalent). See Section 16.1.6 for details.
•
Amount of (post-operative) non-opioid analgesic medication taken within 24 hours prior to 
first IMP administration, grouped by WHO-DD coding and route of administration. See 
Section 11.2.6 for a description of how standardized dose amounts are calculated. See 
Section 16.1.6 and Section 16.1.7 for further details. 
•
Duration of surgery (in minutes).
•
Time between end of surgery and administration of first IMP.
Categorical baseline characteristics are: 
•
Type of surgery.
•
Type of opioid analgesia used (hydromorphone/morphine).
•
Type of administration (NCA/PCA) and additionally
−
Opioid analgesia used (hydromorphone/morphine) for NCA. The percentage 
denominator will be the total number of subjects on NCA in the respective treatment 
groups.
−
Opioid analgesia used (hydromorphone/morphine) for PCA. The percentage 
denominator will be the total number of subjects on PCA in the respective treatment 
groups.
•
Application of background infusion (yes/no) and additionally
−
Opioid analgesia used (hydromorphone/morphine) for background infusion. The 
percentage denominator will be the total number of subjects with background infusion
in the respective treatment groups.
•
Results of pregnancy test.
Furthermore, type of opioid analgesia used (hydromorphone/morphine) as recorded per 
IVRS/IWRS will be summarized with descriptive statistics. Both information (type of opioid 
analgesia used based on IVRS/IWRS and based on eCRF) will be displayed in the subject data 
listing. 
For the following parameters, collected on more than 1 occasion during the trial including baseline, 
assessment at baseline will be presented with assessments later on in the trial and not separately for 
baseline: 
•
Pain intensity
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−
Face, Legs, Activity, Cry, Consolability scale (FLACC) for children who are less than 
6 years or in older children who are not able to report their pain using the other scales
−
Faces Pain Scale-Revised (FPS-R) for children between 6 years and less than 12 years
−
Visual analog scale (VAS) for children between 12 years and less than 18 years.
•
Physical examination 
•
Vital signs 
•
Oxygen saturation before first IMP intake
•
Safety laboratory parameters 
•
12-lead ECG 
•
Sedation score
Further subject characteristic data collected according to the protocol, i.e. date of signing the 
informed consent/assent form, date, start and completion time of surgery, the indication, and further 
information collected on opioid analgesic medication given before first dose of IMP (as per 
protocol) will be included in the subject data listing only. 
9.3
Subject medical history
The assessment of a disease being previous or concomitant is entered directly in the eCRF by the 
investigator and will be evaluated as documented on the relevant medical history page of the eCRF. 
•
Previous diseases:
−
A table will summarize the number of subjects with (at least 1) previous disease(s) and 
the number of subjects per each previous disease, sorted alphabetically by primary 
System Organ Class and Preferred Term.
•
Concomitant diseases:
−
A table will summarize the number of subjects with (at least 1) concomitant disease(s)
and the number of subjects per each concomitant disease, sorted alphabetically by 
primary System Organ Class and Preferred Term.
9.4
Prior and concomitant medication
This section covers all prior and concomitant medication as per Section 16.1.6 received and 
additional therapies and treatments performed within 28 days prior to randomization to IMP up to 
the end of the trial (excluding anesthetics and medication used during the surgery).
The terms prior and concomitant are defined as follows:
•
Prior is all medication stopped prior to the first dose of IMP, regardless of its start date
•
Concomitant is any medication not stopped before the first dose of IMP, regardless of its 
start date
Medication will be summarized and sorted alphabetically separately for prior and concomitant 
medication by Anatomical Therapeutic Chemical (ATC) categories (Level 2: pharmacological or 
therapeutic subgroup and Level 3: chemical or therapeutic or pharmacological subgroup). 
For each medication the number of subjects will be displayed. In addition, the number of subjects 
with medication started after last dose of IMP will be displayed. 
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Medication or therapy started after last dose of IMP will be flagged in the subject data listing.
•
Details of the WHO-DD Preferred Name and the reason for use will also be given in the 
listings together with the MedDRA coding of the indication, the regimen, route, start, and 
stop date and time. The listings will differentiate between prior and concomitant 
medications.
9.5
Pain intensity related to NCA/PCA
Pain intensity scores related to NCA/PCA (including IV administration in case of NCA/PCA failure 
or clinician bolus) will be assessed, when possible, prior to each administration of supplemental 
opioid analgesia by NCA/PCA. These pain intensities are recorded on the pain intensity page of the 
eCRF with “Time-point” equal “before NCA/PCA”. 
For each subject, all non-missing pain intensity scores obtained prior to NCA/PCA will be grouped 
in 5 time intervals: [0 h, 12 h], (12 h, 24 h], (24 h, 48 h], (48 h, 72 h] and (72 h, 96 h] after first IMP 
intake. The date/time of the pain assessment, as per eCRF, will determine the corresponding time 
interval, not the date/time of the subsequent NCA/PCA administration. For each subject and each of 
the 5 time intervals, all non-missing pain intensity scores will be averaged. For each time interval, 
these averages will be summarized descriptively. 
10
EXPOSURE AND COMPLIANCE
Exposure data will be displayed for the following analysis sets:
•
SAF-US <2
•
SAF-EU
Compliance data will be displayed for the following analysis sets:
•
FAS-EU
•
FAS-US <2
10.1
Exposure
Extent of exposure will be summarized with descriptive statistics
For the Treatment Period, the amount of IMP (in mg/kg) and the number of IMP intakes will be 
summarized descriptively, separately for the intervals:
•
[0 h, 12 h] 
•
(12 h, 24 h]
•
(24 h, 48 h)
•
[48 h, 72 h]
and over the entire 24-, 48-, and 72-hours periods ([0 h, 24 h], [0 h, 48 h] , [0 h, 72 h]). 
The calculation of amount of IMP (in mg/kg) per administration will be calculated based on the 
following formula using the values provided in the eCRF “Administration of IMP” page:
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The duration of exposure will also be summarized using descriptive statistics. Furthermore, the 
number of subjects with at least 12 hours and at least 24 hours duration of exposure will be 
summarized. The duration of exposure is defined as the time between the first IMP intake and the 
last intake of IMP.
In addition, the number of subjects with the last intake of IMP at least 44 hours after the first IMP 
intake will be presented to address the US FDA request to evaluate at least 25 subjects in the age 
range birth to less than 17 years of age exposed to tapentadol for at least 48 hours.
Subject listings of exposure will be presented for all treated subjects.
10.2
Compliance
Dosing compliance for a subject will be calculated based on the specifications in Section 16.1.12. 
Compliance will be summarized as 12-h and 24-h compliance by age group and treatment using 
descriptive statistics on the FAS-EU and the FAS-All.
Subject listings of complicance will be presented for all treated subjects.
11
EFFICACY ANALYSES
Unless stated otherwise, all efficacy analyses with the exception of Palatability and Acceptability
and the results of the Bayesian analysis will be displayed for the following analysis sets:
•
FAS-EU
•
FAS-US <2
The Palatability and Acceptability questionnaire as well as results of the Bayesian analysis will be 
displayed only for the following analysis set:
•
FAS-EU 
Summary statistics for all efficacy endpoints will be provided. Furthermore, for the primary 
efficacy endpoint, summary statistics will additionally be displayed for each of the conducted 
sensitivity analyses.
11.1
Primary endpoint
The primary efficacy endpoints for the US FDA and EU PDCO are the amount of supplemental
opioid analgesic medication used within the first 12 hours and 24 hours after first IMP intake, 
respectively. Supplemental opioid analgesia will be expressed in mg/kg of morphine IV 
equivalents. The primary efficacy endpoints will be analyzed as described in the following section
on all subjects aged 2 years to <18 years (FAS-EU) for both US FDA and EU PDCO. The primary 
efficacy endpoint for US FDA for subjects less than 2 years old will be descriptively summarized
using summary statistics for continuous variables as outlined in Section 7.1.
Hydromorphone doses will be multiplied by 5 to obtain the morphine equivalent.
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11.1.1
Primary analyses
Let ,, , be defined as
, :
Expected value of supplemental opioid analgesic medication (SOAM) used in the 
tapentadol group
within the first T hours after first IMP intake
, :
Expected value of SOAM used in the placebo group 
within the first T hours after first IMP intake
The primary null hypothesis to be tested for the EU PDCO is that , is equal to ,. The 
alternative hypothesis is that , is different from ,. I.e:
 : , −, = 0 vs &: , −, ≠0.
The primary null hypothesis to be tested for the US FDA is that ,& is equal to ,&. The 
alternative hypothesis is that ,& is different from ,&. I.e:
 : ,& −,& = 0 vs &: ,& −,& ≠0.
The primary null hypotheses for each region will be tested using an analysis of variance (ANOVA) 
which includes treatment, baseline age group, and the supplemental opioid analgesic used 
(morphine versus hydromorphone) as factors. 
In case of fewer than 6 subjects in an age group, age groups will be pooled according to the rules 
described in Section 7.3. If fewer than 6 subjects received hydromorphone or if fewer than 
6 subjects received morphine, the factor supplemental opioid analgesia used will not be included in 
the ANOVA model.
Treatment effects will be estimated based on least squares means of the difference. The 95% CI and 
p-value will be presented for the difference in least squares means. Additionally descriptive 
95% CIs will be presented for the individual least squares means of both treatments.
Two scatter plots, 1 for T=12 and 1 for T=24 will be provided, illustrating the pairs ()*, *
), where 
)* denotes the weight of subject i and *
 the total amount of supplemental opioid analgesia
(morphine equivalents in mg/kg body weight) used within the first T=12 or T=24 hours after first 
IMP intake.
For subjects who discontinue from the treatment prior to 24 hours after first IMP intake, the 
following imputation rule will be used for the primary endpoint:
•
Let t be the time difference between first IMP intake and time of discontinuation, as per 
eCRF.
•
Let X be the cumulative sum of the amounts of supplemental opioid analgesia (mg/kg) of 
all NCA/PCA usages before discontinuation. 
•
Discontinuation due to any other reason than “opioid analgesic medication is no longer 
needed” or “switch to exclusively oral opioid analgesic medication”:
−
Time of discontinuation prior to 12 hours after first IMP intake (t<12 h):
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
12 h endpoint: Cumulative use over 12 hours will be estimated as 
(X/t)*12 mg/kg

24 h endpoint: Cumulative use over 24 hours will be estimated as 
(X/t)*24 mg/kg
−
Time of discontinuation between 12 hours and 24 hours after first IMP intake 
(12 h≤t<24 h):

12 h endpoint: For cumulative use over 12 hours the exact value is used.

24 h endpoint: Cumulative use over 24 hours will be estimated as 
(X/t)*24 mg/kg
This extrapolation assumes a uniform use (in mg/kg per hour) of supplemental opioid over 
24 hours.
•
Discontinuation due to reason “opioid analgesic medication is no longer needed” or “switch 
to exclusively oral opioid analgesic medication”:
−
Time of discontinuation prior to 12 hours after first IMP intake (t<12 h):

12 h endpoint: Cumulative use over 12 hours will be estimated as X mg/kg

24 h endpoint: Cumulative use over 24 hours will be estimated as X mg/kg
−
Time of discontinuation between 12 hours and 24 hours after first IMP intake 
(12 h≤t<24 h):

12 h endpoint: For cumulative use over 12 hours the exact value is used.

24 h endpoint: Cumulative use over 24 hours will be estimated as X mg/kg
Further detail on respective eCRF pages used for the calculation of amount of supplemental opioid 
analgesic medication per subject is given in Section 16.1.6. Also, further information on calculation 
of amounts of supplemental opioid analgesia (mg/kg) for subjects with missing NCA/PCA 
information is given.
11.1.2
Sensitivity analyses
The following sensitivity analyses will be performed for the primary endpoint of both regions. 
The analyses of the primary endpoints will be repeated for the PPS. This means that the analyses of 
the primary endpoints will be repeated for the following analysis sets:
•
PPS-EU for the EU primary endpoint (24 hours)
•
PPS-EU-12h for the US primary endpoint (12 hours).
Furthermore, 2 different imputation rules, not relying on a uniform use of supplemental opioid over 
24 hours (EU PDCO primary endpoint) / 12 hours (US FDA primary endpoint), will be used for 
subjects discontinuing treatment due to any other reason than “opioid analgesic medication is no 
longer needed” or “switch to exclusively oral opioid analgesic medication”. For subjects 
discontinuing treatment due to the reason “opioid analgesic medication is no longer needed” or 
“switch to exclusively oral opioid analgesic medication” the same imputation method as for the 
primary analysis will be used for these sensitivity analyses.
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1.) Placebo mean imputation rule:
The placebo mean imputation rule will use only information of subjects receiving placebo to impute 
the unknown amount of supplemental opioid analgesia between the time of discontinuation and 
12/24 hours after first IMP intake for subjects in both treatment arms. Assuming that placebo 
subjects will require more supplemental opioid analgesia, this approach is conservative, but reflects 
the increased need of supplemental opioid analgesia after terminating treatment with tapentadol.
Let X be the set of all amounts of supplemental opioid analgesia (morphine equivalents, mg/kg) 
used by all placebo subjects after first IMP intake. 
Each ,*-. corresponds to a time of NCA/PCA-activation (hours after first IMP intake), denoted by 
/*and a number 0* of placebo subjects still on treatment at time /*, constituting a triple (/*, ,*, 0*).
Without loss of generality, these triples will be sorted by time /*, i.e. for (/*, ,*, 0*), 1/2, ,2, 023, 4 <
6, it holds /* ≤/2. For / ∈[0,24], let m denote the integer for which /: ≤/ < /:;&.
The average cumulative use of supplemental analgesia in the placebo group up to time t will be 
calculated by
<(/) = =
,*
0*
:
*>&
For subjects terminating treatment prematurely after / < T, ? - {12, 24}, hours after first IMP 
intake with an amount of , mg/kg of supplemental opioid analgesia (morphine equivalents) used 
up to / , amount of supplemental opioid analgesia up to T hours will be imputed by
, + F(T) −F(/ )
For an illustration of this procedure, see Figure 3.
2.) Treatment mean imputation rule:
The treatment mean imputation rule will use information of the subject’s treatment group to impute 
the unknown amount of supplemental opioid analgesia between the time of discontinuation and 
12/24 hours after first IMP intake for subjects in both treatment arms. This approach more closely 
reflects the actual expected amount of supplemental opioid analgesia needed by the subject, if the 
subject did not prematurely terminate the particular treatment.
Let . be the set of all amounts of supplemental opioid analgesia (morphine equivalents, mg/kg) 
used by all placebo subjects after first IMP intake. 
Let . be the set of all amounts of supplemental opioid analgesia (morphine equivalents, mg/kg) 
used by all tapentadol subjects after first IMP intake. 
The above procedure for 1.) Placebo mean imputation rule will be applied to both sets . and 
., yielding the average cumulative use of supplemental analgesia functions < and <, 
respectively.
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For subjects terminating treatment prematurely after / < T, ? - {12, 24}, hours after first IMP 
intake with an amount of , mg/kg of supplemental opioid analgesia (morphine equivalents) used 
up to / , amount of supplemental opioid analgesia up to T hours will be imputed according to the 
function of the corresponding treatment group, i.e.
, + <(T) −<(/ ), for subjects on placebo
, + <(T) −<(/ ), for subjects on tapentadol
IMP = investigational medicinal product.
Figure 3:
Average amount of supplemental opioid analgesia used after first IMP intake
For the US FDA primary endpoint, the following sensitivity analyses will be performed in addition
as requested by the FDA. 
The primary analysis of the primary endpoint and the respective PPS analysis will be repeated with 
subjects who “switch to exclusively oral opioid analgesic medication” not handled in the same way 
as subjects who discontinue due to reason “opioid analgesic medication is no longer needed” but as 
all others, i.e. assuming a uniform use of supplemental opioid over 12 hours. 
The analyses of the US FDA primary endpoint using the placebo mean imputation rule and the 
treatment mean imputation rule will be repeated, applying those 2 imputation rules also for subjects 
discontinuing treatment due to “switch to exclusively oral opioid analgesic medication”.
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F{24}
F(to)
Amount of supplemental opioid analgesia
d °
average amount of supplemental analgesiae-~-°~—
ß¢
used between to and 24 hours 
o-
~
Po-
'
xo+F(24)-F{to}
~o
-o-
f -o- /ham 1.Wr~~I`
d
°i,
„
oa 
et
iter
0
6
12 to
hours after first IMP intake
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11.1.3
Other analysis
There will be no multiplicity adjustments for any of these analyses, thus all of them will be 
conducted at a significance level of  = 0.05 and regarded as exploratory.
11.1.3.1
ANCOVA including pain intensity at baseline (based on each age-defined pain 
scale) as a covariate
The following analysis will be done for the 24-hour endpoint in subjects 2 years and above (FAS-
EU) only. 
An analysis of covariance (ANCOVA) including treatment and the supplemental opioid analgesic 
used (morphine versus hydromorphone) as factors and age at baseline and pain intensity at baseline 
as covariates will be conducted. Since different pain scales were used for different age groups, the 
analysis will be performed on the following 3 subgroups:
1.
Children less than 6 years and older children who were not able to report their pain using the 
other scales and used the FLACC, including the FLACC score at baseline as covariate
2.
Children between 6 years and less than 12 years old, including the FPS-R score at baseline as 
covariate
3.
Children between 12 years and less than 18 years old, including the VAS score at baseline as 
covariate
Estimation of least squares means, determination of the p-value and CIs, and application of the 
missing data imputation method will be done as described in Section 11.1.1 for the primary 
analysis.
11.1.3.2
ANCOVA including amount of opioid analgesia (morphine or 
hydromorphone) used prior to IMP as a covariate
The following analysis will be done for the 24-hour endpoint in subjects 2 years and above (FAS-
EU) only. 
An ANCOVA including treatment, baseline age group (pooled, if applicable), and the opioid 
analgesic medication used (morphine versus hydromorphone) as factors and the amount (mg/kg of 
morphine equivalents) of morphine/hydromorphone used 24 hours prior to IMP intake as a 
covariate will be conducted. Estimation of least squares means and CIs and application of the
missing data imputation method will be done as described in Section 11.1.1 for the primary 
analysis.
11.1.3.3
Subgroup analyses
The following analysis will be done for subjects 2 years and above (FAS-EU) only. 
Summary statistics for the primary endpoint will be provided for each level of the following factors:
•
Relevant age groups (12-hour and 24-hour endpoint)
•
Sex (only 24-hour endpoint)
•
Race (only 24-hour endpoint)
•
Geographical region (only 24-hour endpoint)
•
Type of administration of supplemental opioid analgesia: NCA/PCA (12-hour and 24-hour 
endpoint)
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•
Supplemental opioid analgesia used: Hydromorphone/morphine (only 24-hour endpoint)
Furthermore, for factor levels that include at least 15% of overall data, the difference in least 
squares means between tapentadol and placebo and their CI will be provided and illustrated in
forest plots for the 24-hour endpoint. Basis for the least squares means will be an ANOVA
including treatment, baseline age group and the supplemental opioid analgesic used (morphine 
versus hydromorphone) as factors (pooled if applicable). For the subgroup investigations of relevant 
age groups and supplemental opioid analgesia used, the respective factor will be excluded from the 
model.
11.1.3.4
Bayesian analysis for the EU PDCO population only
For the EU PDCO, for the primary endpoint, a Bayesian ANOVA that includes treatment, baseline 
age group, and the supplemental opioid analgesic used (morphine versus hydromorphone) as factors 
will be conducted. The Bayesian framework allows the incorporation of prior information gathered 
on tapentadol in earlier trials in the analysis. Prior information that was obtained from trials in 
adults will be incorporated into the analysis using a conditional power prior approach (see, e.g.,
Neelon and O’Malley 2010), which allows down-weighting of the prior information in the final 
analysis. A detailed description of this analysis can be found in Section 16.1.5.
11.2
Secondary endpoints
All non-descriptive analyses of secondary endpoints will be conducted at a significance level of 
 = 0.05 and regarded as exploratory. No adjustment for multiplicity for any of the analyses of the 
secondary endpoints will be made. If not stated differently subjects less than 2 years old will be 
separately analyzed using the FAS-US <2.
11.2.1
Supplemental opioid analgesic medication 
The primary endpoint for the US FDA evaluated on the FAS-EU will be used as a secondary 
endpoint for the EU PDCO. The same ANOVA model as defined above for the primary efficacy 
endpoints will be used to assess treatment differences. Summary statistics will also be provided for 
each relevant age group. The primary analysis on the FAS-EU for the primary efficacy endpoint for 
the EU PDCO, the amount of supplemental opioid analgesic medication used within the first 
24 hours after first IMP intake, will be considered as a secondary endpoint for the US FDA.
Furthermore, the primary efficacy endpoint for the EU PDCO will be descriptively summarized for 
the FAS-US<2 and the respective age groups.
In addition, the total amount of supplemental opioid analgesic medication received, assessed in 
12-hour intervals from 24 hours to 96 hours (see Section 16.1.6 for details), will be summarized 
descriptively for the FAS-EU and FAS-US <2. 
The intervals will be:
•
(24 hours, 36 hours]
•
(36 hours, 48 hours]
•
(48 hours, 60 hours]
•
(60 hours, 72 hours]
•
(72 hours, 84 hours]
•
(84 hours, 96 hours]
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For each interval, only subjects who have their End of Treatment Visit after the start of the interval 
will be included. 
If a subject has their End of Treatment Visit at time / during a given interval (/*, /*;&], the subject 
will not be included in subsequent intervals and the missing data for the remainder of the given 
interval will be imputed:
•
Let t:= / −/* be the time difference between the lower bound of the given interval and the
time of the End of Treatment Visit, as per eCRF.
•
Let X be the cumulative sum of the amounts of supplemental opioid analgesia (mg/kg) of 
all NCA/PCA usages within the given interval (/*, /*;&], i.e. between /* and / .
•
Discontinuation due to any other reason than “opioid analgesic medication is no longer 
needed” or “switch to exclusively oral opioid analgesic medication”:
Cumulative use within the given interval (/*, /*;&] will be estimated as (X/t)*12 mg/kg.
•
Discontinuation due to reason “opioid analgesic medication is no longer needed” or “switch 
to exclusively oral opioid analgesic medication”:
Cumulative use within the given interval (/*, /*;&] will be estimated as X mg/kg.
11.2.2
Clinical Global Impression of Change (CGIC)
At the End of Treatment Visit, the response of the CGIC questionnaire is measured on an ordinal, 
7-category scale. Results will be summarized descriptively. 
Furthermore, the categories “very much improved” and “much improved”, as well as the remaining 
5 categories will be pooled and the resulting binary variable will be summarized descriptively. 
Descriptive results of the 7-categorical and the binary variable will be displayed in a single table.
11.2.3
Patient Global Impression of Change (PGIC)
At the End of Treatment Visit, the PGIC questionnaire will be completed by the subject, parent, or 
legal guardian. The response of the PGIC is measured on an ordinal, 7-category scale. Results will 
be summarized descriptively.
Furthermore, the categories “very much improved” and “much improved”, as well as the remaining 
5 categories will be pooled and the resulting binary variable will be summarized descriptively. 
Descriptive results of the 7-categorical and the binary variable will be displayed in a single table.
11.2.4
Palatability and Acceptability
The palatability and acceptability questionnaire consists of 2 dimensions (taste/swallowing). The 
response to each dimension is measured on an ordinal, 5-category scale. Assessments are performed 
after first dose of IMP and at the End of Treatment Visit in subjects aged 2 years to less than 
18 years old. Missing values will not be imputed.
For each of the 2 time points and each of the 2 dimensions, responses will be summarized with 
descriptive statistics. The change between the 2 visits will be displayed for each dimension in a shift 
table. The summary statistics will be repeated for each age subgroup in the EU PDCO population.
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11.2.5
Pain intensity related to administration of IMP and 
End of Treatment Visit
Pain assessments related to administration of IMP and the End of Treatment Visit will occur at the 
following times during the course of the Treatment Period:
•
Before first dose of IMP (baseline)
•
Between 30 minutes and 60 minutes after first dose of IMP
•
Before each succeeding dose of IMP
•
End of Treatment Visit
Pain intensity scores and change from baseline values will be summarized descriptively for each 
time point by age-defined pain scale (i.e. FLACC/FPS-R/VAS). The summary will also contain the 
CIs of each treatment group. For the FAS-US <2 only the FLACC summary will be used.
A figure illustrating the means ± CI for both treatments at each assessment prior dosing will be 
provided for each age-defined pain scale.
Furthermore the area under the pain curve (AUPC) up to 12 hours and 24 hours will be calculated:
For each pain assessment i, each subject j yields a tuple (/*,2, F*,2), where /*,2 is the time (hours after 
first IMP intake) of the pain assessment i of subject j and F*,2 is the pain intensity difference 
between baseline and assessment i of subject j. Baseline assessments will be denoted by i=0. 
According to the study design, subjects will have a different number of pain assessments (denoted 
by mj). According to the different age groups F*,2 will be assessed by 1 of the 3 different pain 
intensity instruments: 
•
F*,2 = FLACC0,j – FLACCi,j or
•
F*,2 = FPS-R0,j – FPS-Ri,j or
•
F*,2 = VAS0,j – VASi,j
For each j, tupels (/*,2, F*,2), 4 = 1, … , H2 will be linearly interpolated (see Figure 4) and the area 
under the curve will be determined summing the resulting trapezoids (Ai,j, i=1,…mj) up to 12 hours 
(AUPC12) and 24 hours (AUPC24). For an illustration, see Figure 4.
AUPCT:
1.
For all i ∈{1, … , H2} with /*,2 ≤?: 
*,2 =
1F*,2 + F*I&,23 ∗(/*2 −/*I&,2)
2
2.
If applicable, for i ∈{1, … , H2} with /*I&,2 < ? < /*,2:
*,2 =
1F*I&,2 + 1? −/*I&,23 ∗1F*,2 −F*I&,23/(/*,2 −/*I&,2) + F*I&,23 ∗(? −/*I&,2)
2
3.
For each subject j completing treatment for T hours, let iT be the index i with /*I&,2 < ? ≤/*,2:
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LMN2 = = *,2
*O
*>&
For subjects j who prematurely discontinue the treatment at time /̃ < ?, the following formula 
will be applied:
LMN2 = ?
/̃ = *,2
:Q
*>&
Intermediate missing pain values will not be imputed. Missing pain values at the 
End of Treatment Visit will be imputed by the mean of non-missing pain scores assessed by the 
age-defined pain scale in the respective treatment group at the End of Treatment Visits.
The larger the AUPCT, the higher the pain improvement of the particular treatment group. Note that 
areas below the x-axis, caused by pain values larger than baseline pain, will proportionally decrease 
the value of the particular 2 and thus the value of AUPCT.
IMP = investigational medicinal product.
Figure 4:
Area under the pain curve
The AUPCT for 12 hours (AUPC12) and 24 hours (AUPC24) will be descriptively summarized for 
each treatment group and age-defined pain scale.
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difference in pain intense 
CV
0 
4 
8 
12 14 
20 
24 
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11.2.6
Supplemental non-opioid analgesic medication 
The number and proportion of subjects taking non-opioid analgesic medications (irrespective of the 
indication) within the first 12 hours and 24 hours after first IMP intake (see Section 16.1.6 and
Section 16.1.7 for details) will be grouped according to WHO-DD coding and will be summarized 
descriptively by treatment group.
11.2.7
Time to first and time to second NCA/PCA after first IMP
The time to first and time to second NCA/PCA (including IV administration in case of NCA/PCA 
failure or clinician bolus) after the first dose of IMP will be summarized descriptively using time-
to-event methods and displayed overall. Additionally treatment groups will be compared using the 
log-rank test for the overall population. The hazard ratio of the 2 treatment groups will be provided. 
Subjects who complete the End of Treatment Visit (Visit 3) before their first/second use of 
NCA/PCA or subjects who terminate treatment before their first/second use of NCA/PCA will be 
censored at the End of Treatment Visit. Kaplan-Meier graphs will be provided. 
11.2.8
Time to treatment discontinuation due to lack of efficacy
In case of more than a total of 9 treatment discontinuations due to lack of efficacy, for the FAS-All 
the distributions of the time from the first dose of IMP to treatment discontinuation (see 
Section 16.1.8 for details) due to lack of efficacy will be summarized descriptively using time-to-
event methods and compared between the treatment groups using the log-rank test. The hazard ratio 
of the 2 treatment groups will be provided. Subjects who reach the maximum duration of treatment 
(72 hours, see Section 16.1.4) will be censored at 72 hours after first IMP intake. Subjects who 
discontinue during the Treatment Period for reasons other than lack of efficacy will be censored at 
the time of the decision to discontinue treatment.
This analysis will not be done for the FAS-US <2 due to the small number of subjects.
12
ANALYSIS OF PHARMACOKINETIC AND 
PHARMACODYNAMICS PARAMETERS
Not applicable.
13
SAFETY ANALYSES
The analysis of safety data will be performed for the EU PDCO Safety Set for the EU PDCO report 
and for the EU PDCO Safety Set and US FDA Safety Set for subjects less than 2 years for the final
report. 
All data regarding adverse events, laboratory parameters, vital signs, oxygen saturation, ECG, 
physical examination, Columbia-Suicide Severity Rating Scale (C-SSRS), and the sedation score
will be displayed on the EU PDCO Safety Set (SAF-EU) for the EU PDCO report. For the final
report the EU PDCO report will be amended with data of subjects less than 2 years old using the 
SAF-US <2 if not indicated differently.
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13.1
Adverse events
Any AE that occurs at or after first administration of IMP and up to the end of the therapeutic reach
of last administration of IMP is considered as treatment emergent AE (TEAE). The therapeutic 
reach is the time after IMP intake that a subject is still considered to be potentially affected by a 
study drug. For tapentadol oral solution, the therapeutic reach is defined as 48 hours after (last) IMP 
intake. An AE starting before the first dose of IMP and worsened in intensity between the first 
administration of IMP and the end of the therapeutic reach of last administration of IMP will also 
qualify as a TEAE. Handling rules for (partially) missing dates and times of AEs are described in
Section 16.1.11.
Pre-existing diseases or conditions occurring before enrollment are considered to be medical history 
and should be recorded as AEs only if they worsen (untoward change in intensity, frequency, or 
quality) after enrollment.
For AEs where the intensity changes over time, the maximum intensity observed during the whole 
duration of the AE will be documented and captured in the database. If the AE stopped and 
reoccurred with a different or the same intensity, it will be entered as new AE in the eCRF.
All AEs with start date/time after enrollment but before first administration of IMP and that do not 
worsen after IMP intake, and all AEs with start date/time after the therapeutic reach of last IMP will 
be regarded as non-TEAE.
Related TEAEs are TEAEs that are at least possibly related to the IMP as documented in the eCRF
(possible, probable/likely, certain).
The following 3 overview tables will be generated by treatment group and overall for the SAF-EU.
The first and the second table will also be summarized for the SAF-EU for each relevant age group. 
Information of the first table for the SAF-EU will also be provided for each geographical region, 
sex, race and ethnicity.
1.
Summary of the number of subjects with 
•
At least 1 TEAE 
•
At least 1 non-serious TEAE
•
At least 1 serious TEAE
•
At least 1 related serious TEAE
•
At least 1 related TEAE
•
At least 1 TEAE leading to discontinuation from the treatment (i.e. TEAE with “Action 
taken with IMP”: “drug withdrawn”)
•
At least 1 TEAE leading to discontinuation from the trial (i.e. TEAE with 
“Countermeasures”: “trial discontinuation”)
•
A TEAE with a fatal outcome 
2.
Summary of the number of subjects 
•
Categorized by number of TEAEs per subject (0, 1, 2, 3, 4, 5, and >5)
3.
Summary of the number of subjects with
•
At least 1 non-TEAE
•
At least 1 serious non-TEAE
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For subjects less than 2 years old the first overview table as outlined above will be provided for the 
SAF-US <2.
Unless stated otherwise, the following TEAE summaries will be presented by treatment group as 
well as for relevant age groups: 
By Preferred Term (sorted by decreasing incidence in the tapentadol group), the number of subjects
will be summarized per each TEAE occurring in at least 5% of subjects in at least 1 treatment arm
(only SAF-EU).
By System Organ Class and Preferred Term (sorted alphabetically), the number of subjects will be 
summarized per each
•
TEAE
•
Serious TEAE (only overall, not for relevant age groups)
•
TEAE leading to discontinuation from the treatment (for SAF-US <2 only for relevant age 
groups)
The following TEAE summaries will be presented by treatment group only:
Number of subjects by System Organ Class and Preferred Term and 1 of the following TEAE 
descriptors:
•
Intensity (mild, moderate, severe)
For multiple occurrences of a TEAE in a subject the worst intensity, i.e. the most to the 
right in parentheses above, is used for the summary table.
•
Relationship to the IMP (not related, not assessable/unclassifiable, conditional/unclassified,
unlikely, possible, probable/likely, certain)
For multiple occurrences of a TEAE in a subject the most related, i.e. the most to the right 
in parentheses above, is used for the summary table.
•
Outcome (unknown, recovered/resolved, recovering/resolving, not recovered/not resolved, 
resolved with sequelae, fatal) (only SAF-EU)
For multiple occurrences of a TEAE in a subject the worst outcome, i.e. the most to the 
right in parentheses above, is used for the summary table.
•
Action taken with IMP (not applicable, unknown, dose not changed, dose reduced, drug 
withdrawn)
For multiple occurrences of a TEAE in a subject the most dramatic action taken with IMP, 
i.e. the most to the right in parentheses above, is used for the summary table. (only SAF-
EU)
•
Countermeasures (none, others, newly started medication, trial discontinuation)
For multiple occurrences of a TEAE in a subject the most dramatic countermeasure, i.e. the 
most to the right in parentheses above, is used for the summary table. (only SAF-EU)
•
Time to onset after first IMP intake (categories: ≤1 h, >1-≤4 h, >4-≤12 h, >12-≤24 h, 
>24-≤48 h, >48-≤72 h, >72 h) (only SAF-EU)
All AEs will be listed together with information on onset, duration, intensity, seriousness, 
relationship to IMP, outcome, and countermeasure(s) taken.
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Additionally, the following listings will be produced for enrolled subjects: 
•
All deaths
•
All serious AEs
•
All AEs that lead to discontinuation from the treatment
•
All AEs that lead to discontinuation from the trial
Adverse event summaries will only include events up to the Follow-up Visit, i.e. 14 days after first 
IMP intake. Serious AEs (SAEs) occurring after the Follow-up Visit will be added to the safety 
database and will be described in the integrated clinical trial report but not considered in any 
statistical analysis. 
The distributions of the time from the first dose of IMP to treatment discontinuation (see 
Section 16.1.8 for details) due to AE will be summarized descriptively using time-to-event methods
(only SAF-EU). Subjects who reach the maximum duration of treatment (72 hours, see 
Section 16.1.4) will be censored at 72 hours after first IMP intake. Subjects who discontinue during 
the Treatment Period for reasons other than AE will be censored at the time of the decision to 
discontinue treatment.
13.2
Laboratory parameters
For subjects aged at least 2 years, laboratory parameters are assessed by a local and central 
laboratory at baseline. Blood samples taken at the End of Treatment Visit will only be analyzed by a 
central laboratory. For subjects aged less than 2 years, only the local laboratory analysis will be 
performed. For summary statistics (SAF-EU), only values obtained from the central laboratory will 
be used. Laboratory data of subjects <2 years (SAF-US<2) will be summarized based on respective 
reference ranges as provided by the local laboratory.
All laboratory parameters collected in this trial are continuous variables:
Hematology panel
Hemoglobin 
Mean corpuscular volume (MCV)
Hematocrit 
Mean corpuscular hemoglobin (MCH)
Red blood cell (RBC) count 
Mean corpuscular hemoglobin concentration (MCHC)
Platelet count
White blood cell (WBC) count with differential count
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Clinical chemistry panel
Sodium
Creatinine
Lipase (not required for the local laboratory assessment)
Lactic acid dehydrogenase (LDH)
Potassium
Uric acid
Triglycerides
Alanine transaminase (ALT)
Chloride
Calcium
Total bilirubin
Aspartate transaminase (AST)
Bicarbonate
Phosphorus
Alkaline phosphatase
Glucose
Blood urea nitrogen (BUN)
Total protein
Creatine kinase
The glomerular filtration rate will be estimated according to Schwartz et al. 1984.
Descriptive statistics will be calculated for each safety laboratory parameter and glomerular 
filtration rate at baseline, at the End of Treatment Visit, and for the changes from baseline to the 
End of Treatment Visit. Descriptive statistics will be done for laboratory values from the central 
laboratory only.
A shift table (changes from normal to abnormal [high, low] and vice versa) will be provided for the 
changes with respect to the reference range for the laboratory parameters. 
Values outside sponsor defined alert ranges (potentially clinically important values) for the 
laboratory parameters will be assessed based on the classification in Table 8. This applies for all 
laboratory values recorded. The number of subjects with at least 1 value outside the sponsor defined 
alert ranges (potentially clinically important values) will be summarized descriptively. A listing of 
subjects with values outside the sponsor defined alert ranges (potentially clinically important 
values) will be generated.
13.3
Electrocardiogram
Twelve-lead ECGs will be recorded at baseline and the End of Treatment Visit. The parameters 
assessed in the ECG are the RR interval, PR interval, QRS interval and QT interval. The corrected 
QTcF (Fridericia) interval will be calculated as QTcF = QT/(RR)⅓. Normal and abnormal ECG 
parameters are assessed according to the classification in Table 3 and Table 4. Furthermore, the 
investigator will provide an ECG overall interpretation at the Enrollment Visit and the 
End of Treatment Visit (“normal”, “abnormal, clinically not relevant” and “abnormal, clinically 
relevant”).
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Table 3:
Classification of abnormal ECG parameters
Parameter (unit)
Age class
Abnormally low
Abnormally high
PR (msec)
0-<1 months
<100
>150
1-<6 months
<100
>150
7-<12 months
<100
>150
1-<2 years
<100
>150
2-<3 years
<100
>150
3-<12 years
<100
>180
12-<18 years
<100
>200
QRS (msec)
0-<1 months
<40
>79
1-<6 months
<40
>79
7-<12 months
<40
>79
1-<2 years
<40
>79
2-<3 years
<40
>79
3-<12 years
<50
>89
12-<18 years
<60
>99
QT (msec)
0-<1 month
<320
>450 
1-<6 months
<320
>450
7-<12 months
<320
>450
1-<2 years
<320
>450
2-<18 years
<320
>450
RR (msec)
0-<3 months
<333
>750
3-<6 months
<400
>860
7-<12 months
<400
>860
1-<2 years
<430
>1000
2-<18 years 
<600
>1200
The ECG parameters are based on standard criteria of the ECG provider ERT.
ECG = electrocardiogram.
Table 4:
Classification of abnormal QTcF values
Parameter (unit)
Classification
Criterion
QTcF_MN (msec)
Normal
≤450
Prolonged
>450
The QTcF_MN (_MN: mean of all beats) values are based on standard criteria of the ECG provider ERT.
QTcF = Corrected QT interval using the Fridericia correction (ECG).
Descriptive statistics of the ECG parameters at baseline, at End of Treatment Visit, and for changes 
from baseline to End of Treatment Visit will be generated based on measurement from the ECG 
central reader. Moreover, the classification of abnormal QTcF values (normal, prolonged) and other 
abnormal ECG parameters (“normal”, “abnormally low/high”) by visit will be summarized 
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descriptively for each relevant age group. Shift tables will summarize the changes between 
measurements at the baseline and End of Treatment Visit based on the classification of parameters. 
The overall interpretation on ECG findings (“normal”, “abnormal, clinically not relevant”, and 
“abnormal, clinically relevant”) assessed by the investigator will be summarized by visit and 
relevant age group. 
13.4
Vital signs and oxygen saturation
Vital signs measured in the trial are diastolic and systolic blood pressure (DBP and SBP; mmHg), 
heart rate (HR; beats per minute), and respiration rate (breaths per minute). Furthermore, oxygen 
saturation will be measured. Vital signs and oxygen saturation are assessed at the Enrollment Visit, 
before every administration of IMP and at the End of Treatment Visit. For the analyses the baseline 
value will be the assessment defined for baseline in Section 7.2.
Descriptive statistics of vital signs and oxygen saturation by time point and also for the changes 
from baseline to each time point measured will be provided. A shift table with respect to the normal 
ranges presented in Table 5 will be provided.
Values outside the sponsor defined alert ranges (potentially clinically important values) are assessed 
according to the classifications in Table 6 depending on the subject’s age. A listing of subjects with 
values outside these ranges will be generated. The number of subjects regarding values outside the 
sponsor defined alert range (alert low, non-alert, alert high) will be summarized descriptively and 
the display will be repeated by age group. Furthermore, the display by individual parameter is 
repeated separately for subjects with a baseline value or the respective parameter within or outside 
the normal range.
Furthermore, for subjects with oxygen saturation below 92% for at least 60 seconds, the time that 
oxygen saturation fell below 92%, the lowest oxygen saturation as well as the corresponding
systolic blood pressure, diastolic blood pressure, respiratory rate, and HR will be included in the 
subject listing.
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Table 5:
Normal ranges of vital signs and oxygen saturation
Parameter 
(unit)
Age class
0-<3
months
3-<6
months
6-<12
months
1-<3
years
3-<6
years
6-<9
years
9-<12
years
12-<16
years
16-<18 
years
Diastolic 
BP (mmHg)
45-55
50-65
55-65
55-70
50-75
57-71
60-75
64-78
65-81
Systolic BP 
(mmHg)
65-85
70-90
80-100
90-105
90-105
95-110
101-116
108-121
109-127
Heart rate 
HR (bpm)
100-150
90-120
80-120
70-110
86-117
74-111
67-103
62-96
58-92
Respiration 
rate 
35-55
30-45
25-40
20-30
21-27
18-24
16-22
15-21
13-19
Oxygen 
saturation 
SpO2 (%) 
≥96
≥96
≥96
≥96
≥96
≥96
≥96
≥96
≥96
The ranges of vital signs are based on Fleming et al. 2011 and NIH pediatric blood pressure charts.
BP = blood pressure; NIH = National Institute of Health.
Table 6:
Sponsor defined alert values for vital signs and oxygen saturation
Parameter 
(unit)
Age class
0-<3 
months
3-<12 
months
1-<3
years
3-<6 
years
6-<9
years
9-<12
years
12-<16 
years
16-<18
years
Diastolic BP 
(mmHg)
abnormally low
<35
<40
<40
<45
<42
<45
<49
<50
abnormally high
>65
>85
>90
>80
>86
>89
>93
>95
Systolic BP 
(mmHg)
abnormally low
<60
<60
<75
<80
<80
<86
<93
<95
abnormally high
>110
>110
>120
>110
>125
>130
>135
>140
Heart rate 
HR (bpm)
abnormally low
<80
<70
<60
<80
<74
<67
<62
<58
abnormally high
>180
>150
>140
>120
>111
>103
>96
>92
Respiration 
rate 
abnormally low
<25
<20
<18
<17
<12
<12
<12
<12
abnormally high
>70
>60
>50
>30
>24
>24
>24
>24
Oxygen 
saturation 
SpO2 (%) 
abnormally low
<92
<92
<92
<92
<92
<92
<92
<92
BP = blood pressure.
13.5
Additional safety parameters
13.5.1
Physical examination
A general physical examination will be done at the Enrollment Visit by rating each body system as 
normal or abnormal. An update of the physical status is recorded at the End of Treatment Visit
(changed/unchanged). 
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Results of all physical examinations will be presented in a subject data listing, including the 
descriptions of abnormalities. 
13.5.2
Columbia-Suicide Severity Rating Scale
For the C-SSRS, results of each asked question for suicidal ideation and for suicidal behavior, at 
children’s baseline (questionnaire at Enrollment Visit, but after surgery) as well as since last visit 
(questionnaire at End of Treatment Visit), will be presented in a subject data listing. 
13.5.3
Sedation score
Sedation scores will be summarized descriptively as a categorical variable for each time point 
indicated in Table 1. 
14
REFERENCES
Dixon WJ, Massey FJ Jr. Introduction to statistical analysis. 4th ed. McGraw-Hill; 1983.
Fleming S, Thompson M, Stevens R, Heneghan C, Plüddemann A, Maconochie I, et al. Normal 
ranges of heart rate and respiratory rate in children from birth to 18 years of age: a systematic 
review of observational studies. Lancet 2011; 377 (9770): 1011-8. Published online including 
webappendix (doi:10.1016/S0140-6736(10)62226-X).
Neelon B, O’Malley JA. Bayesian analysis using power priors with application to pediatric quality 
of care. J Biom Biostat 2010; 1: 103.
O’Brien RG, Muller KE. Unified power analysis for t-Tests through multivariate hypotheses. In: 
Applied Analysis of Variance in Behavioral Science. Marcel Dekker, New York; 1993. pp. 297-
344.
Rusy LM, Hainsworth KR, Nelson TJ, Czarnecki ML, Tassone JC, Thometz JG, et al. Gabapentin 
use in pediatric spinal fusion patients: a randomized, double-blind, controlled trial. Anesth Analg 
2010; 110 (5): 1393-8. 
Rugyte D, Kokki H. Intravenous ketoprofen as an adjunct to patient-controlled analgesia morphine 
in adolescents with thoracic surgery: a placebo controlled double-blinded study. Eur J Pain 2007; 11 
(6): 694-9.
Schwartz GJ, Feld LG, Langford DJ. A simple estimate of glomerular filtration rate in full-term 
infants during the first year of life. J Pediatr 1984; 104 (6): 849-54.
Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, et al. New equations to 
estimate GFR in children with CKD. J Am Soc Nephrol 2009; 20 (3): 629-37.
15
SAP AMENDMENTS
15.1
SAP Amendment 01
This amendment was prepared to include changes of protocol amendment 04, 23rd June 2015 to 
protocol amendment 06, 19th Aug 2016.
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A detailed description of all changes made in amendment 01 of this SAP can be found in 
Section 5.2.1.
15.2
SAP Amendment 02
This amendment was prepared to further describe how the US objective of analyzing subjects aged 
between birth and less than 17 years will be implemented.
A detailed description of all changes made in amendment 02 of this SAP can be found in 
Section 5.2.2.
16
APPENDIX
16.1
Programming specifications
16.1.1
Percentages and decimal places
•
Percentages have to be presented to 1 decimal point. 
•
Percentages equal to 0 or 100 have to be presented as such without any decimal point. 
•
For descriptive summary statistics, the same number of decimal places as in the raw data 
should be presented when reporting minimum and maximum values, 1 more decimal place 
when reporting mean, quartiles and 95% CI and SD.
•
P-values will be displayed up to the fourth decimal place.
−
P-values rounded to 0.0000 will be displayed as “<0.0001”
−
P-values rounded to 1.0000 will be displayed as “>0.9999”
16.1.2
Presentation of descriptive statistics
For descriptive statistics of a continuous variable and less than 5 non-missing values the rules of
Table 7 apply.
Table 7:
Parameters to be calculated for continuous variables
Number of non-
missing values
n
missing n
mean
SD
min
Q1
median
Q3
max
0
+
+
-
-
-
-
-
-
-
1.2.3.4
+
+
+
-
+
-
+
-
+
5
+
+
+
+
+
+
+
+
+
+ = summary statistic will be presented; - = summary statistic will not be presented.
n = number of values; min = minimum; max = maximum; SD = standard deviation; Q1 = first quartile; Q3 = third 
quartile.
16.1.3
Precision of time variables
The precision of time assessments captured in the eCRF is minutes, which will be utilized in all 
calculations. Unless stated otherwise, when summary statistics are applied on time variables, results 
are illustrated in hours with 2 decimal places. The conversion of minutes to hours is:
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16.1.4
Treatment Period 
The Treatment Period start date/time is the date/time of first IMP intake as documented on the 
eCRF.
The Treatment Period end date/time is assessed by the following formula from eCRF data:
end date/time = min{72 hours after first IMP intake,
date/time captured on End of Treatment page}
Subjects reaching the maximum duration of treatment (72 hours) are identified by the main reason 
to discontinue treatment on the “End of Treatment” page in the eCRF:
•
“Maximum duration of treatment (72 hours) reached”
16.1.5
Bayesian analysis for the EU PDCO population
The primary endpoint for the EU PDCO will also be analyzed within the Bayesian framework, 
using prior information for the treatment effect from a clinical trial for acute pain in adults 
. This prior information will be incorporated into the analysis using a conditional 
power prior approach (see, e.g., Neelon and O’Malley 2010), which allows to control the weight of 
the prior information in the final analysis.
For the EU PDCO, for the primary endpoint, a Bayesian ANOVA that includes treatment, baseline 
age group, and the supplemental opioid analgesic used (morphine versus hydromorphone) as factors 
will be conducted. In case of fewer than 6 subjects in an age group, age groups will be pooled 
according to the rules described in Section 7.3. If fewer than 6 subjects received hydromorphone or 
if fewer than 6 subjects received morphine, the factor supplemental opioid analgesia used will not 
be included in the ANOVA model.
Non-informative Normal prior distributions with mean 0 and variance 1000 will be assigned to the 
intercept and the regression coefficients for baseline age group and opioid analgesic used. The prior 
for the treatment effect will be a Normal distribution with mean equal to the treatment effect 
derived from the trial in adults (−0.463, see below) and variance equal to the variance of the 
treatment effect derived from the trial in adults (0.06762, see below) divided by δ, where δ ∈[0,1]
represents the down-weighting factor of the information from adults; when δ = 0 the prior variance 
equals infinity and hence an improper flat prior distribution is considered, and when δ = 1 the 
variance equals that derived from the adults. Finally a non-informative Gamma distribution with 
parameters shape = 0.001 and rate = 0.001 will be assumed for the residual precision 1 S
⁄
(i.e. the 
inverse of the residual variance). 
A value of δ = 0.1 will be considered for the down-weighting factor. This corresponds to down-
weighting the information obtained from the trial in adults by 90%.
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The posterior distribution has no analytical closed expression. Therefore Markov chain Monte Carlo 
(MCMC) simulation techniques will be used to obtain a sample of the posterior distribution of all 
model parameters. This will be done using the SAS Proc MCMC as implemented in SAS v9.3 or 
later. To this end, a chain of 110 000 iterations will be run, discarding the first 10 000 as burn-in 
and keeping every 10th. The resulting thinned sample of size 10 000 will be used to summarize the 
posterior distribution of all the model parameters. 
The posterior distribution of the treatment effect will be plotted (density function) and numerically 
summarized using the mean, quartiles, SD, and 95% credibility interval. In addition the posterior 
probability for the treatment effect to be below 0 will be presented. 
Superiority of tapentadol versus placebo will be considered if the upper limit of the 95% credibility 
interval is below 0.
Bayesian model details
Let YV be the amount of supplemental opioid analgesic medication taken by subject i within the first 
24 hours after first IMP intake, TV the treatment group (0 = placebo, 1 = tapentadol), AV the age 
group (categories coded from 1 to K) and OV the type of opioid analgesic used (0 = hydromorphone, 
1 = morphine). Then the Bayesian model is as follows:
YV~Normal(μV, σ)
μV = β + = β&^I(`a>^)
b
c>&
+ βOV + βdTV
β , β&&, … β&e, β~Normal(0,1000)
βd~Normal fm`, s`

δ h
1/σ~ Gamma(0.001,0.001)
where m` = −0.463 and s`
 = 0.0676 are respectively the expected value and the variance of the 
treatment effect βd derived from 
 (see next section for further details).
Elicitation of the prior distribution for the treatment effect
In 
, four different types of rescue medication were used: acetaminophen (1st line), 
ibuprofen (2
line), ketorolac (2nd line) and Lortab (3rd line). Given the lack of equivalence between 
these and morphine, it is not feasible to assess the total amount of rescue medication taken in 
morphine equivalent. However, the combined number of intakes is to some extent informative of 
the amount of supplemental analgesia used. For subjects in the FAS, the mean (SD) of the number 
of doses taken of all types of rescue medication combined on Day 2 (the first 24 hours after surgery) 
was 4.2 (2.2) in the placebo group, 2.3 (1.9) in the tapentadol 58 mg group (HCL salt, 
corresponding to 50 mg free base as used in the rest of the document) and 1.6 (1.8) in the tapentadol 
116 mg group (HCL salt, corresponding to 100 mg free base as used in the rest of the document) 
based on 67, 67, and 68 subjects, respectively (integrated clinical trial report
, 
Section
, Table 
).
Adopting a conservative approach, we focus on the difference between placebo and tapentadol 
58 mg (the lowest dose of tapentadol). The relative difference between placebo and tapentadol in 
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the mean number intakes can be roughly estimated as (4.2-2.3)/4.2 = 0.452. That is, subjects in the 
tapentadol 58 mg group used 45.2% less supplemental analgesia than those in the placebo group. 
This estimation can be slightly refined using simulation. If we assume that the number of intakes is 
approximately normally distributed according to Normal(4.2, 2.22) for placebo and Normal(2.3, 
1.92) for tapentadol, both truncated to the interval [0, +∞], then we can draw n = 67 values from 
each distribution and compute the relative difference between the sample means. If we repeat this 
process a large number of times, say 1 000 000, then we get an empirical estimate of the mean and 
SD for the relative difference of 0.429 and 0.0616, respectively.
Rusy et al (2010) observed a mean (SD) supplemental use of opioid of 1.32 (0.408) mg/kg over 
24 hours based on 30 subjects in the placebo group. Rugyte et al (2007) observed in their placebo 
group a mean (SD) supplemental use of opioid of 0.67 (0.20) mg/kg over 24 hours based on 
17 subjects. The pooled mean (SD) of supplemental opioid analgesia for the placebo group in both 
studies is 1.08 (0.349) mg/kg over 24 hours.
With the distribution of the relative difference between placebo and tapentadol in the intake of 
rescue medication in adults, a Normal(0.429, 0.06162), and the mean amount of supplemental 
opioid analgesia in pediatric population (1.08 mg/kg), we can derive the prior distribution for the 
treatment effect (tapentadol – placebo) as Normal(−0.429*1.08, (0.0626*1.08) 2)=Normal(-0.463, 
0.06762). Therefore the conditional prior given a down-weighting factor δ is Normal(−0.463, 
0.06762/ δ).
16.1.6
Analyses of medication intake regarding different trial phases
Baseline characteristics:
The amount of morphine or hydromorphone taken within 24 hours prior to first IMP administration 
and after surgery will be derived from the following eCRF pages:
•
Opioid Background Infusion
•
Opioid Analgesics administered by NCA/PCA
•
Additional IV Bolus Administration of Opioid Analgesics (clinician bolus, or in case of 
NCA/PCA failure)
•
Other Analgesic Medication (only opioid analgesic medication and only before first IMP 
intake and after surgery)
The total amounts of non-opioid analgesic medications used within 24 hours prior to first IMP 
administration and after surgery will be derived from the following eCRF pages:
•
Other Analgesic Medication (only non-opioid analgesic medication and only before first 
IMP intake and after surgery)
•
Prior / concomitant medication
Efficacy endpoints:
The amount of supplemental opioid analgesic medication used within the first 12 hours, within the 
first 24 hours and between 24 hours and 96 hours after first IMP intake will be derived from the 
following eCRF pages:
•
Opioid Analgesics administered by NCA/PCA
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•
Additional IV Bolus Administration of Opioid Analgesics (clinician bolus, or in case of 
NCA/PCA failure) 
•
Other Analgesic Medication (all intraveneous opioid used, added as morphine equivalents 
(1st IMP to 12h/24h/decision to stop treatment); morphine equivalents of IV opioids will be 
calculated with respective conversion factors)
The number of subjects taking non-opioid analgesic medications within the first 12 hours and 
24 hours after first IMP intake will be derived from the following eCRF pages:
•
Other Analgesic Medication (only non-opioid analgesic medication and only after first IMP 
intake)
•
Prior / concomitant medication
Handling of missing/partial information on NCA/PCA administered opioid analgesics
For some subjects the time on the NCA/PCA page was not always related to a push, in some cases 
the nurse entered the time and the dose administered since the nurse last checked. This means the 
date/time of the eCRF entry will be used as the end time of an interval over which the recorded dose 
was given. The start time will be the last NCA/PCA entry before. The dose will be distributed 
evenly over the time interval. The subjects to be handled this way will be identified using a specific 
protocol deviation code.
In case only a total dose is available respective start and stop times should be entered into the eCRF
(the start time should be associated with a zero dose entry and the end time with the dose) and then 
the total dose will be analyzed as interval dose.
Subjects who were given oral morphine/hydromorphone instead of using NCA/PCA are handled as 
zero NCA/PCA dose to be consistent with handling of patients switching to exclusively oral opioid 
analgesic medication as per protocol amendment 04.
Handling of the individual subjects with missing or only partial information will in addition be 
described in the final statistical review report.
Prior and concomitant medications:
Analyses of prior and concomitant medication will be based on information of the following eCRF 
pages:
•
Prior / concomitant medication
•
Additional therapies / treatments
•
Other Analgesic Medication 
•
Opioid Background Infusion
•
Opioid Analgesics administered by NCA/PCA
•
Additional IV Bolus Administration of Opioid Analgesics (clinician bolus, or in case of 
NCA/PCA failure)
16.1.7
Treatment period and trial completer
There are 2 sets of treatment period completers, completing 12 hours and 24 hours of treatment.
For the 12 hours treatment period completer: 
•
Decision to discontinue treatment is later than 12 hours after first IMP intake
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For the 24 hours treatment period completer: 
•
Decision to discontinue treatment is later than 24 hours after first IMP intake
The time of first IMP intake will be assessed from the “Administration of IMP page” in the eCRF.
The time of the decision to discontinue treatment will be assessed from the “End of Treatment”
page in the eCRF. If the decision occurs prior to last dose of IMP then the date/time of last IMP 
dose will be used instead. If the decision is more than 6 hours after the last dose of IMP then the 
date/time of last dose of IMP + 6 hours will be used instead.
There are 2 sets of trial completers, i.e. 12 hours and 24 hours trial completer.
An X-hours trial completer is an X-hours treatment period completer that completed the 
Follow-up Visit, i.e. Visit 4. 
16.1.8
Time to treatment discontinuation
For all time to treatment discontinuation analyses, the time to treatment discontinuation will be 
calculated in hours using the following formula:

/
/4H kl 
m44k0 /k /kF //H0/ k0 n0
 kl ?/H0/ F −
/
/4H 1/ opM 40/q
16.1.9
Determination of FLACC total score
Regarding the FLACC questionnaire, the individual values of the 5 categories as per eCRF will be 
used to calculate the total score for statistical evaluation. If at least 1 of the 5 categories is missing, 
the total score will be set to missing as well.
16.1.10
Multiple assessments of pain intensity, vital signs and oxygen saturation
Pain intensity, vital signs and oxygen saturation are assessedbefore each administration of IMP:
•
For all these parameters, the corresponding number of IMP administration is captured in the 
eCRF and will be used for analyses by time point (i.e. administration of IMP) or to identify 
specific time points.
•
Pain intensity is additionally assessed after the first dose and at the End of Treatment visit, 
which will also be selectable time-points on the eCRF-page for pain intensity.
•
Additionally vital signs and oxygen saturation are assessed at the Enrollment visit and End 
of Treatment visit on different eCRF-pages, enabling clear distinction from assessments 
prior each administration of IMP for these parameters.
16.1.11
TEAE assignment of AEs in case of (partially) missing dates
Handling of missing or partial missing dates for AEs:
•
Let dTS : hTS : mTS denote the date : hour : minute of first IMP intake
•
Let dTE : hTE : mTE denote the date : hour : minute of the end of the therapeutic reach of the 
last IMP administration (derived variable, not directly assessable from eCRF data)
•
Let dAS : hAS : mAS denote the date : hour : minute of the start of the AE
•
Let dAE : hAE : mAE denote the date : hour : minute of the end of the AE
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1.
dAS : hAS : mAS non-missing
a.
dAS : hAS : mAS ∈[dTS : hTS : mTS , dTE : hTE : mTE] TEAE
b. dAS : hAS : mAS ∉[dTS : hTS : mTS , dTE : hTE : mTE] non-TEAE
2.
dAS : hAS available, mAS missing
c.
dAS : hAS ∈[dTS : hTS , dTE : hTE ] TEAE
d. dAS : hAS ∉[dTS : hTS , dTE : hTE ] non-TEAE
3.
dAS available, hAS missing, mAS availability irrelevant
e.
dAS  ∈[dTS , dTE ] TEAE
f.
dAS ∉[dTS , dTE ] non-TEAE
4.
dAS missing, hAS , mAS availability irrelevant
g. dAE : hAE : mAE non-missing
i. dAE : hAE : mAE ≥dTS : hTS : mTS TEAE
ii. dAE : hAE : mAE < dTS : hTS : mTS non-TEAE
h. dAE : hAE available, mAE missing
i. dAE : hAE ≥dTS : hTS TEAE
ii. dAE : hAE < dTS : hTS  non-TEAE
i.
dAE available, hAE missing, mAE availability irrelevant
i. dAE ≥dTS TEAE
ii. dAE < dTS  non-TEAE
j.
dAE missing, hAE, mAE availability irrelevant  TEAE
16.1.12
Compliance algorithm
All information is based on the “Administration of IMP” page of the eCRF.
•
Let / , … , /: be the times of administration of IMP
•
Let &, … , : be the sleeping indicator respective to /&, … , /: with
•
* = 1 if “subject sleeping” is ticked
•
* = 0 otherwise (i.e. if no entry or “other” is ticked)
•
Let T be the time of decision to discontinue the treatment on the “End of Treatment” page
•
For information on time calculation will be done in hours (x.xx h) and for dosing 
information unit is milligram (x.xx mg)
For the 24-hour compliance
Let ?t the sleep adjusted treatment time (hours) be defined as
?t = min{? −/ , 24} [h] −= * w* x{yzIy{|}[h]
:
*>&
With the delay of treatment (hours) as
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w* = min{/* −/*I& −4.25, 1.75} [h]
Cj the compliance of subject j as percent of actual intake is defined as:
•
N2 =
}~y *yc [:]
(⌊t .
⁄
⌋;&)∗min&.∗Q,&   [:] ∗100%,
if actual intake < floor
t
. + 1 ∗min1.25 ∗)2, 100
•
N2 = 100%,
•
if floor
t
. + 1 ∗min1.25 ∗)2, 100 < actual intake < floor
t
d. + 1 ∗min1.25 ∗
)6, 100
•
N2 =
}~y *yc [:]
(⌊t d.
⁄
⌋;&)∗min&.∗Q,&   [:] ∗100%,
•
if actual intake > floor
t
d. + 1 ∗min1.25 ∗)2, 100
Where )2 is the weight of subject in kg j and “actual intake” is the actual intake of IMP of subject j
(mg). Note that the maximum single dose a patient is permitted to receive is 100 mg and the dose 
for the first 24 hours is 1.25 mg/kg. The dosing interval is 4 hours with a range of ±0.25 hours. The 
floor function returns the largest integer that is less than or equal to the argument.
12-hour compliance
Repeat the above algorithm by substituting “24” by “12” in the above definition of ?t.
Actual intake derivation
For actual intake of IMP of subject j, use the sum of the amount of IMP of each administration of 
IMP of subject j up to the time of discontinuation/ at 12 hours/ at 24 hours (inclusive). 
For each administration of IMP use the following calculation procedure to obtain the amount of 
IMP intake:
Check if “Was dose completely administered” is ticked “Yes” or “No”
a.
If “Yes”: Use the value in “Total dose planned for administration” [mg]
b.
If “No”: take the entry in “approximate volume administered” [ml] and multiply by “dose 
strength”, i.e. either by 4 if “4 mg/ml” is ticked or by 20 if “20 mg/ml” is ticked
Compliance for subjects below 6 month will be based on dosing recommendations as per protocol 
amendment 07 but will be done according to same algorithm.
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16.2
Sponsor defined alert ranges for laboratory parameters
Table 8:
Sponsor defined alert ranges for laboratory parameters
Parameter
Age class 
(years)
Abnormally low
Abnormally 
high
Comment
Chemistry
ALT
2-10
-/-
>2.0 ULN
>10-<18
>3.0 ULN
AST
2-7
-/-
>2.0 ULN
>7-<18
>3.0 ULN
AP
2-<18
-/-
>2.0 ULN
Total bilirubin
2-<18
-/-
>1.5 ULN
Total protein 
2-<18
<0.5 LLN
>1.1 ULN
Bicarbonate
2-<4
<12 mmol/l
>28 mmol/l
4-<18
<17 mmol/l
>30.6 mmol/l
Estimated GFR 
based on serum 
creatinine as 
offered by central 
lab (see also 
Schwartz et al. 
2009)
2-<18
GFR 
<90 ml/min/1.7 m2
-/-
Triglycerides 
(male)
0-<10
<0.34 mmol/l
>1.13 mmol/l
10-<15
<0.36 mmol/l
>1.41 mmol/l
15-<18
<0.42 mmol/l
>1.67 mmol/l
Triglycerides 
(female)
0-<10
<0.4 mmol/l
>1.24 mmol/l
10-<15
<0.42 mmol/l
>1.48 mmol/l
15-<18
<0.44 mmol/l
>1.40 mmol/l
Chloride
0-<18
<94 mmol/l
>112 mmol/l
Urea
2-<18
-/-
>2.0 ULN
Sodium
2-<18
<0.95 LLN
>1.05 ULN
Potassium
2-<18
<0.9 LLN
>1.1 ULN
Calcium
2-<18
<0.8 LLN
>1.2 ULN
Phosphorous
2-<18
<0.8 LLN
>1.2 ULN
Glucose (random)
2-<18
<0.8 LLN
>2.5 ULN
Uric Acid
2-<18
-/-
>1.5 ULN
Creatinine
2-<18
-/-
>1.5 ULN
CK
2-7
-/-
>6 ULN
>7-10
>2.5 ULN
Female
>10-<18
>5 ULN
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Parameter
Age class 
(years)
Abnormally low
Abnormally 
high
Comment
Male
>10-<18
>2.5 ULN
LDH
2-<18
-/-
>2.0 ULN
Lipase
2-<18
-/-
>2.0 ULN
Hematology
Haematocrit
2-<18
<30%
>55%
Haemoglobin 
(female)
2-<6
<100 g/l
>160 g/l
6-<18
<110 g/l
>180 g/l
Haemoglobin 
(male)
2-<6
<100 g/l
>160 g/l
6-<18
<110 g/l
>190 g/l
MCV
2-<6
<74 fl
6-<18
<76 fl
>98 fl
MCH (male)
2-<3
<25 pg
>29 pg
3-<6
<25 pg
>30 pg
6-<12
<24 pg
>34 pg
12-<18
<26 pg
>34 pg
MCH (female)
2-<3
<25 pg
>28 pg
3-<6
<25 pg
>30 pg
6-<12
<24 pg
>34 pg
12-<18
<26 pg
>34 pg
MCHC
0-<18
<310 g/l
>380 g/l
WBC
2-<18
<3000/µl
>15 000/µl
RBC (male)
2-<3
<4.1/µl
>5.1/µl
3-<6
<4.1/µl
>5.3/µl
6-<12
<3.7/µl
>6.0/µl
12-<18
<4.5/µl
>6.4/µl
RBC (female)
2-<3
<4.4/µl
>5.0/µl
3-<6
<4.1/µl
>5.2/µl
6-<12
<3.7/µl
>6.0/µl
12-<18
<4.1/µl
>5.6/µl
Platelets
2-<18
<110*109/l
>600*109/l
The values are still to be determined for subjects aged from birth to <2 years old.
-/- = No sponsor-defined alert ranges defined.
ALT = alanine transaminase; AST = aspartate transaminase; AP = alkaline phosphatase; GFR = glomerular filtration 
rate; CK = creatine kinase; LDH = lactic acid dehydrogenase; LLN = lower limit normal; MCH = mean corpuscular 
hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; RBC = red 
blood cell; ULN = upper limit normal; WBC = white blood cell.
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16.3
List of statistical output documentation
The statistical output documentation to be included integrated clinical trial report Section 16.1.9 
will contain the original SAS output for the analyses (including sensitivity analyses) of the primary 
endpoint.
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