Clinical Trial Results:
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.
Summary
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EudraCT number |
2012-004359-35 |
Trial protocol |
SE DE GB ES AT FR PL HR HU BG CZ |
Global end of trial date |
14 Mar 2019
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Results information
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Results version number |
v2(current) |
This version publication date |
22 Sep 2019
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First version publication date |
15 Jun 2017
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Other versions |
v1 |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
KF5503/65
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02081391 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
IND: 108134, Grünenthal: KF5503/65, Depomed: R331333PAI3037 | ||
Sponsors
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Sponsor organisation name |
Grünenthal GmbH
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Sponsor organisation address |
Zieglerstr. 6, Aachen, Germany, 52078
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Public contact |
Grünenthal Trial Information Desk, Grünenthal GmbH, +49 241569 3223, Clinical-Trials@grunenthal.com
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Scientific contact |
Grünenthal Trial Information Desk, Grünenthal GmbH, +49 241569 3223, Clinical-Trials@grunenthal.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000018-PIP01-07 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
28 Jul 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
14 Mar 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
14 Mar 2019
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
This trial was performed to meet requirements for pediatric development plans agreed with authorities in 2 regions (Paediatric Committee of the European Medicines Agency [EU PDCO] and United States Food and Drug Administration [US FDA]).
Main objectives of the trial for EU PDCO/US FDA:
Efficacy and safety of tapentadol oral solution in children and adolescents who had undergone surgery that, in the investigator’s opinion, would reliably produce moderate to severe pain requiring opioid treatment. Efficacy was analysed based on the total amount of supplemental opioid analgesic medication used over 24 hours (EU PDCO) and 12 hours (US FDA) following initiation of IMP.
Data for the EU part (in subjects aged 2 years to less than 18 years old) were presented in Version 1 of this record. Treatment of subjects aged less than 2 years old for the completion of the US part (subjects from birth to less than 17 years old) was completed in March 2019, results are added in Version 2 of the record.
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Protection of trial subjects |
The trial was conducted according to Good Clinical Practice guidelines, the applicable local laws, and in accordance with the ethical principles that have their origins in the Declaration of Helsinki.
The competent authorities approved the trial as required by national regulations.
Regulatory authorities were notified of the trial and amendments as required by national regulations.
An independent data monitoring committee was established to oversee subject’s safety in ongoing tapentadol trials in the pediatric population.
Subjects were carefully observed, especially during the first hour after the initiation of IMP.
Vital signs (respiratory rate, systolic and diastolic blood pressure, and pulse rate), sedation score, and oxygen saturation were measured before each dose of IMP was given.
Respiratory rate and heart rate had to be constantly monitored for 24 hours after first does of IMP and afterwards according local standard of care. Oxygen saturation had to be monitored constantly using pulse oximetry from before first dose of IMP until 4 hours after the last dose of IMP.
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Background therapy |
At some time after the surgery, the subject had started on nurse-controlled or patient-controlled analgesia (NCA/PCA) with morphine or hydromorphone according to the standard of care. Medications for the treatment of adverse events were allowed according to the investigator’s judgment and post-operative standard of care e.g., clinically relevant respiratory depression treated with naloxone, and nausea/vomiting treated with antiemetics, which may have been given prophylactically according to the standard of care. In exceptional cases, if a subject had unbearable pain despite using NCA/PCA, an additional bolus of morphine or hydromorphone was allowed using either the NCA/PCA pump system or by an intravenous bolus injection. | ||
Evidence for comparator |
N/A | ||
Actual start date of recruitment |
19 Feb 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 45
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Country: Number of subjects enrolled |
Spain: 13
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Country: Number of subjects enrolled |
United Kingdom: 2
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Country: Number of subjects enrolled |
Croatia: 12
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Country: Number of subjects enrolled |
Bulgaria: 15
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Country: Number of subjects enrolled |
Czech Republic: 13
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Country: Number of subjects enrolled |
France: 8
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Country: Number of subjects enrolled |
Germany: 6
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Country: Number of subjects enrolled |
Hungary: 9
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Country: Number of subjects enrolled |
United States: 93
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Worldwide total number of subjects |
216
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EEA total number of subjects |
123
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
6
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Infants and toddlers (28 days-23 months) |
17
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Children (2-11 years) |
95
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Adolescents (12-17 years) |
98
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
The trial started on 19 Feb 2015 with the enrollment of the first subject. Recruitment for the EU PDCO set (subjects aged 2 years to less than 18 years old) was completed on 05 Dec 2016 with the last subject out (LSO). Recruitment of the remaining subjects aged less than 2 years old for the US FDA population was completed on 14 Mar 2019 (LSO). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 216 subjects (or parents/caregivers) gave informed consent to participate in the trial, 180 of these subjects were allocated to study drug (investigational medicinal product = IMP) and 175 subjects received IMP (56 subjects on placebo and 119 subjects on tapentadol). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment period milestones
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Number of subjects started |
216 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Number of subjects completed |
180 [1] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Adverse event, non-fatal: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reason: Number of subjects |
Consent withdrawn by the parent(s) or subjects: 4 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reason: Number of subjects |
Inclusion criteria not met /exclusion criteria met: 28 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reason: Number of subjects |
Other not specified: 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [1] - The number of subjects reported to be in the pre-assignment period is not consistent with the number starting period 1. It is expected that the number completing the pre-assignment period are also present in the arms in period 1. Justification: A total of 180 subjects were allocated to IMP. Thereof, 5 subjects were allocated but not treated because after allocation, these were violating inclusion/exclusion criteria (2), consent was withdrawn (2) or for other reasons (1). A total of 175 subjects received IMP (56 subjects on placebo and 119 subjects on tapentadol). |
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Period 1
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Period 1 title |
12-h treatment period
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Blinding implementation details |
The trial was double-blinded to prevent bias.
The blind was broken for the EU PDCO set before recruitment of the <6 month-old subjects in the US FDA set was completed.
Subjects not belonging to the EU PDCO set (<2 years old) remained blinded (as independent randomization lists were used for subjects aged less than 2 years old) and were unblinded only after the data base was locked for all subjects from birth to less than 2 years old who were included in the US FDA <2 years population.
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Arms
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Are arms mutually exclusive |
No
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Arm title
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12-h treatment period - Overall (EU PDCO) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
All male and female subjects aged 2 years to less than 18 years who received at least 1 dose of IMP were considered for this arm. Subject had undergone surgery that, in the investigator’s opinion, would reliably produce moderate to severe pain requiring opioid treatment via nurse-controlled analgesia (NCA) or patient-controlled analgesia (PCA) . | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Overall | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Arm title
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12-h treatment period - Tapentadol (EU PDCO) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
This arm includes all subjects who received at least 1 dose of tapentadol oral solution. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Tapentadol oral solution
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Investigational medicinal product code |
CG5503
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Other name |
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Pharmaceutical forms |
Oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
The dose administered depended on the subject's body weight.
The dose to be administered was 1.25 mg/kg during the first 24 hours (the maximum individual dose of tapentadol was 100 mg).
The dosing interval was 4 hours (range ±15 minutes). If the subject was sleeping at the time of the scheduled dose, they were woken to take the IMP within a maximum of 6 hours after the previous dose. The dose of IMP was given as soon as possible after the subject was awake. The administration of IMP was based on the investigator’s judgment of the subject’s condition and sedation level.
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Arm title
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12-h treatment period - Placebo (EU PDCO) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
This arm includes all subjects who received at least 1 dose of placebo. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
The dose administered depended on the subject's body weight.
The dose to be administered was 1.25 mg/kg during the first 24 hours (equivalent to tapentadol).
The dosing interval was 4 hours (range ±15 minutes). If the subject was sleeping at the time of the scheduled dose, they were woken to take the IMP within a maximum of 6 hours after the previous dose. The dose of IMP was given as soon as possible after the subject was awake. The administration of IMP was based on the investigator’s judgment of the subject’s condition and sedation level.
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Arm title
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12-h treatment period - Overall (US FDA <2 years) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
All male and female subjects aged from birth (at least 37 weeks gestational age) to less than 2 years who received at least 1 dose of tapentadol OS or placebo were considered for this arm. Subjects had undergone surgery that, in the investigator's opinion, would reliably produce moderate to severe pain requiring opioid treatment via NCA. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
No intervention | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Arm title
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12-h treatment period - Tapentadol (US FDA <2 years) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
This arm includes all subjects from birth to less than 2 years of age who received at least 1 dose of tapentadol oral solution. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Tapentadol oral solution
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Investigational medicinal product code |
CG5503
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Other name |
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Pharmaceutical forms |
Oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
The dose administered depended on the subject's body weight.
The dose to be administered was 1.25 mg/kg during the first 24 hours (the maximum individual dose of tapentadol was 100 mg). Subjects aged 30 days to <6 months old were to be administered a dose of 0.5 mg/kg or placebo, neonates from birth to <30 days old a dose of 0.1 mg/kg during the first 24 hours.
The dosing interval was 4 hours (range ±15 minutes). If the subject was sleeping at the time of the scheduled dose, they were woken to take the IMP within a maximum of 6 hours after the previous dose. The dose of IMP was given as soon as possible after the subject was awake. The administration of IMP was based on the investigator’s judgment of the subject’s condition and sedation level.
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Arm title
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12-h treatment period - Placebo (US FDA <2 years) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
This arm includes all subjects from birth to less than 2 years of age who received at least one dose of placebo. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo oral solution
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
The dose administered depended on the subject's body weight.
The dose to be administered was 1.25 mg/kg during the first 24 hours (the maximum individual dose of tapentadol was 100 mg). Subjects aged 30 days to <6 months old were to be administered a dose of 0.5 mg/kg or placebo, neonates from birth to <30 days old a dose of 0.1 mg/kg during the first 24 hours.
The dosing interval was 4 hours (range ±15 minutes). If the subject was sleeping at the time of the scheduled dose, they were woken to take the IMP within a maximum of 6 hours after the previous dose. The dose of IMP was given as soon as possible after the subject was awake. The administration of IMP was based on the investigator’s judgment of the subject’s condition and sedation level.
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Period 2
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Period 2 title |
24-h treatment/trial completion
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Blinding implementation details |
The trial was double-blinded to prevent bias.
The blind was broken for the EU PDCO set before recruitment of the less than 2 year olds in the US FDA set was completed.
Subjects less than 2 years old in the US FDA set remained blinded (as independent randomization lists were used for subjects aged less than 2 years old), and were unblinded only after the database was locked for all subjects included in the US FDA <2 years set (subjects from birth to less than 2 years old).
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Arms
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Are arms mutually exclusive |
No
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Arm title
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24-h treatment/trial completion - Overall (EU PDCO) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
All male and female subjects aged 2 years to less than 18 years and received at least 1 dose of IMP and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Overall | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Arm title
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24-h treatment/trial completion - Tapentadol (EU PDCO) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
All male and female subjects aged 2 years to less than 18 years and received at least 1 dose of tapentadol oral solution and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Tapentadol oral solution
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Investigational medicinal product code |
CG5503
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Other name |
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Pharmaceutical forms |
Oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
The dose administered depended on the subject's body weight.
The dose to be administered was 1.25 mg/kg during the first 24 hours (the maximum individual dose of tapentadol was 100 mg).
The dosing interval was 4 hours (range ±15 minutes). If the subject was sleeping at the time of the scheduled dose, they were woken to take the IMP within a maximum of 6 hours after the previous dose. The dose of IMP was given as soon as possible after the subject was awake. The administration of IMP was based on the investigator’s judgment of the subject’s condition and sedation level.
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Arm title
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24-h treatment/trial completion - Placebo (EU PDCO) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
All male and female subjects aged 2 years to less than 18 years and received at least 1 dose of placebo and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
|
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Oral solution
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Routes of administration |
Oral use
|
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Dosage and administration details |
The dose administered depended on the subject's body weight.
The dose to be administered was 1.25 mg/kg during the first 24 hours (equivalent to tapentadol).
The dosing interval was 4 hours (range ±15 minutes). If the subject was sleeping at the time of the scheduled dose, they were woken to take the IMP within a maximum of 6 hours after the previous dose. The dose of IMP was given as soon as possible after the subject was awake. The administration of IMP was based on the investigator’s judgment of the subject’s condition and sedation level.
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Arm title
|
24-h treatment/trial completion - Overall (US FDA <2 years) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
All male and female subjects aged below 2 years who received at least 1 dose of IMP and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
No intervention | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Arm title
|
24-h treatment/trial completion - Tapentadol (US FDA <2 years) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
All male and female subjects aged below 2 years who received at least 1 dose of tapentadol and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Tapentadol oral solution
|
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Investigational medicinal product code |
CG5503
|
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Other name |
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Pharmaceutical forms |
Oral solution
|
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Routes of administration |
Oral use
|
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Dosage and administration details |
The dose administered depended on the subject's body weight.
The dose to be administered was 1.25 mg/kg during the first 24 hours (the maximum individual dose of tapentadol was 100 mg). Subjects aged 30 days to <6 months old were to be administered a dose of 0.5 mg/kg or placebo, neonates from birth to <30 days old a dose of 0.1 mg/kg during the first 24 hours.
The dosing interval was 4 hours (range ±15 minutes). If the subject was sleeping at the time of the scheduled dose, they were woken to take the IMP within a maximum of 6 hours after the previous dose. The dose of IMP was given as soon as possible after the subject was awake. The administration of IMP was based on the investigator’s judgment of the subject’s condition and sedation level.
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Arm title
|
24-h treatment/trial completion - Placebo (US FDA <2 years) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
All male and female subjects aged below 2 years who received at least 1 dose of placebo and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
|
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Oral solution
|
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Routes of administration |
Oral use
|
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Dosage and administration details |
The dose administered depended on the subject's body weight.
The dose to be administered was 1.25 mg/kg during the first 24 hours (equivalent to tapentadol). Subjects aged 30 days to <6 months old were to be administered a dose of 0.5 mg/kg or placebo, neonates from birth to <30 days old a dose of 0.1 mg/kg during the first 24 hours.
The dosing interval was 4 hours (range ±15 minutes). If the subject was sleeping at the time of the scheduled dose, they were woken to take the IMP within a maximum of 6 hours after the previous dose. The dose of IMP was given as soon as possible after the subject was awake. The administration of IMP was based on the investigator’s judgment of the subject’s condition and sedation level.
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Baseline characteristics reporting groups [1]
|
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Reporting group title |
12-h treatment period - Overall (EU PDCO)
|
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Reporting group description |
All male and female subjects aged 2 years to less than 18 years who received at least 1 dose of IMP were considered for this arm. Subject had undergone surgery that, in the investigator’s opinion, would reliably produce moderate to severe pain requiring opioid treatment via nurse-controlled analgesia (NCA) or patient-controlled analgesia (PCA) . | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
12-h treatment period - Tapentadol (EU PDCO)
|
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Reporting group description |
This arm includes all subjects who received at least 1 dose of tapentadol oral solution. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
12-h treatment period - Placebo (EU PDCO)
|
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Reporting group description |
This arm includes all subjects who received at least 1 dose of placebo. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
12-h treatment period - Overall (US FDA <2 years)
|
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Reporting group description |
All male and female subjects aged from birth (at least 37 weeks gestational age) to less than 2 years who received at least 1 dose of tapentadol OS or placebo were considered for this arm. Subjects had undergone surgery that, in the investigator's opinion, would reliably produce moderate to severe pain requiring opioid treatment via NCA. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
12-h treatment period - Tapentadol (US FDA <2 years)
|
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Reporting group description |
This arm includes all subjects from birth to less than 2 years of age who received at least 1 dose of tapentadol oral solution. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
12-h treatment period - Placebo (US FDA <2 years)
|
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Reporting group description |
This arm includes all subjects from birth to less than 2 years of age who received at least one dose of placebo. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same. Justification: Baseline characteristics are reported for all 175 treated subjects. Reporting is done separately for the Full Analysis Set for the EU PDCO (160 subjects aged 2 to less than 18 years) and for the US FDA <2 years group (15 subjects aged from birth to less than 2 years). |
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End points reporting groups
|
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Reporting group title |
12-h treatment period - Overall (EU PDCO)
|
||
Reporting group description |
All male and female subjects aged 2 years to less than 18 years who received at least 1 dose of IMP were considered for this arm. Subject had undergone surgery that, in the investigator’s opinion, would reliably produce moderate to severe pain requiring opioid treatment via nurse-controlled analgesia (NCA) or patient-controlled analgesia (PCA) . | ||
Reporting group title |
12-h treatment period - Tapentadol (EU PDCO)
|
||
Reporting group description |
This arm includes all subjects who received at least 1 dose of tapentadol oral solution. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours. | ||
Reporting group title |
12-h treatment period - Placebo (EU PDCO)
|
||
Reporting group description |
This arm includes all subjects who received at least 1 dose of placebo. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours. | ||
Reporting group title |
12-h treatment period - Overall (US FDA <2 years)
|
||
Reporting group description |
All male and female subjects aged from birth (at least 37 weeks gestational age) to less than 2 years who received at least 1 dose of tapentadol OS or placebo were considered for this arm. Subjects had undergone surgery that, in the investigator's opinion, would reliably produce moderate to severe pain requiring opioid treatment via NCA. | ||
Reporting group title |
12-h treatment period - Tapentadol (US FDA <2 years)
|
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Reporting group description |
This arm includes all subjects from birth to less than 2 years of age who received at least 1 dose of tapentadol oral solution. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours. | ||
Reporting group title |
12-h treatment period - Placebo (US FDA <2 years)
|
||
Reporting group description |
This arm includes all subjects from birth to less than 2 years of age who received at least one dose of placebo. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours. | ||
Reporting group title |
24-h treatment/trial completion - Overall (EU PDCO)
|
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Reporting group description |
All male and female subjects aged 2 years to less than 18 years and received at least 1 dose of IMP and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers). | ||
Reporting group title |
24-h treatment/trial completion - Tapentadol (EU PDCO)
|
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Reporting group description |
All male and female subjects aged 2 years to less than 18 years and received at least 1 dose of tapentadol oral solution and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers). | ||
Reporting group title |
24-h treatment/trial completion - Placebo (EU PDCO)
|
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Reporting group description |
All male and female subjects aged 2 years to less than 18 years and received at least 1 dose of placebo and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers). | ||
Reporting group title |
24-h treatment/trial completion - Overall (US FDA <2 years)
|
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Reporting group description |
All male and female subjects aged below 2 years who received at least 1 dose of IMP and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers). | ||
Reporting group title |
24-h treatment/trial completion - Tapentadol (US FDA <2 years)
|
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Reporting group description |
All male and female subjects aged below 2 years who received at least 1 dose of tapentadol and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers). | ||
Reporting group title |
24-h treatment/trial completion - Placebo (US FDA <2 years)
|
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Reporting group description |
All male and female subjects aged below 2 years who received at least 1 dose of placebo and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers). | ||
Subject analysis set title |
FAS-EU - Overall
|
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The Full Analysis Set included allocated and treated EU PDCO subjects aged 2 years to less than 18 years old.
If by error a subject did not receive the allocated medication, the subject was evaluated as allocated following the intention-to-treat principle.
|
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Subject analysis set title |
FAS-EU - Tapentadol
|
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
This subject analysis set included all EU PDCO subjects aged 2 years to less than 18 years old who were allocated to Tapentadol and received at least one dose of IMP.
If by error a subject did not receive the allocated medication, the subject was evaluated as allocated following the intention-to-treat principle.
|
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Subject analysis set title |
FAS-EU - Placebo
|
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
This subject analysis set included all EU PDCO subjects aged 2 years to less than 18 years old who were allocated to placebo and received at least one dose of IMP.
If by error a subject did not receive the allocated medication, the subject was evaluated as allocated following the intention-to-treat principle.
|
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Subject analysis set title |
SAF-EU - Tapentadol
|
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
This subject analysis set included all EU PDCO subjects aged 2 years to less than 18 years old who were allocated to Tapentadol and received at least one dose of IMP.
|
||
Subject analysis set title |
SAF-EU - Placebo
|
||
Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
This subject analysis set included subjects aged 2 years to less than 18 years old who were allocated to placebo and received at least one dose of IMP.
|
||
Subject analysis set title |
FAS-US <2 years - Overall
|
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The Full Analysis Set for the US FDA analysis in children below 2 years includes subjects less than 2 years old that are allocated and treated.
If by error a subject did not receive the allocated medication, the subject was evaluated as allocated following the intention-to-treat principle.
|
||
Subject analysis set title |
FAS-US <2 years - Tapentadol
|
||
Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The Full Analysis Set for the US FDA analysis in children below 2 years includes subjects less than 2 years old who were allocated to tapentadol oral solution and received at least one dose of treatment.
If by error a subject did not receive the allocated medication, the subject was evaluated as allocated following the intention-to-treat principle.
|
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Subject analysis set title |
FAS-US <2 years - Placebo
|
||
Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The Full Analysis Set for the US FDA analysis in children below 2 years includes subjects less than 2 years old who were allocated to placebo oral solution and received at least one dose of treatment.
If by error a subject did not receive the allocated medication, the subject was evaluated as allocated following the intention-to-treat principle.
|
||
Subject analysis set title |
SAF-US <2 years - Tapentadol
|
||
Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
This subject analysis set for the US FDA comprised subjects below 2 years of age who were allocated to tapentadol and received at least one dose of IMP.
|
||
Subject analysis set title |
SAF-US <2 years - Placebo
|
||
Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
This subject analysis set for the US FDA comprised subjects below 2 years of age who were allocated to placebo and received at least 1 dose of IMP.
|
|
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End point title |
Total amount of supplemental opioid analgesic medication used within 24 hours after first IMP | ||||||||||||
End point description |
The primary efficacy endpoint for the EU PDCO (and secondary endpoint for the US FDA) was the total amount of supplemental opioid analgesic medication (SOAM) used in the FAS-EU (from 2 years to <18 years old) within the first 24 hours after first IMP intake. Supplemental opioid analgesia was expressed in mg/kg of morphine i.v. equivalents.
|
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End point type |
Primary
|
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End point timeframe |
up to 24 hours
|
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|
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Statistical analysis title |
Difference Tapentadol –Placebo | ||||||||||||
Statistical analysis description |
The endpoint was analyzed using an analysis of variance model. This included treatment, baseline age group and the used supplemental opioid analgesic as factors. For subjects discontinuing treatment before 24 hours for any other reason than no further need of opioid analgesics or switch to exclusively oral opioid analgesics, cumulative supplemental opioid analgesia over the respective time period was based on the observed supplemental opioid use up to the time of the subject’s discontinuation.
|
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Comparison groups |
FAS-EU - Tapentadol v FAS-EU - Placebo
|
||||||||||||
Number of subjects included in analysis |
160
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0154 | ||||||||||||
Method |
ANOVA | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.1
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.18 | ||||||||||||
upper limit |
-0.02 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.04
|
|
|||||||||||||
End point title |
Total amount of supplemental opioid analgesic medication used within 12 hours after first IMP | ||||||||||||
End point description |
The primary efficacy endpoint for the US FDA (and secondary endpoint for the EU PDCO) was the total amount of supplemental opioid analgesic medication (SOAM) used in the FAS-EU (from 2 years to <18 years old) within the first 12 hours after first IMP intake. Supplemental opioid analgesia was expressed in mg/kg of morphine i.v. equivalents.
The overall SOAM use was low in subjects aged <2 years compared to older children.
Given the small sample size in the age groups <2 years, conclusions are limited and based on descriptive statistics. The average SOAM use was numerically higher for subjects treated with tapentadol compared to placebo during both 12 hours (0.03 compared to 0.01 mg/kg, respectively) and 24 hours (0.054 compared to 0.016 mg/kg, respectively) after first dose of IMP whereas the median use was lower with tapentadol compared to placebo for the 12-hour endpoint (0.00 mg/kg compared to 0.01 mg/kg).
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
up to 12 hours
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Difference Tapentadol - Placebo | ||||||||||||
Statistical analysis description |
The endpoint was analyzed using an analysis of variance model. This included treatment, baseline age group and the used supplemental opioid analgesic as factors. For subjects discontinuing treatment before 12 hours for any other reason than no further need of opioid analgesics or switch to exclusively oral opioid analgesics, cumulative supplemental opioid analgesia over the respective time period was based on the observed supplemental opioid use up to the time of the subject’s discontinuation.
|
||||||||||||
Comparison groups |
FAS-EU - Tapentadol v FAS-EU - Placebo
|
||||||||||||
Number of subjects included in analysis |
160
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0404 | ||||||||||||
Method |
ANOVA | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.05
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.09 | ||||||||||||
upper limit |
0 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.02
|
|
||||||||||||||||||||||||||||
End point title |
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 | |||||||||||||||||||||||||||
End point description |
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.
Supplemental opioid analgesia was expressed in mg/kg of morphine i.v. equivalents.
Data for subjects <2 years (FAS-US <2 years) are very limited only (1 subject per group) and are not presented separately: tapentadol 0.02, placebo 0.003 mg/kg from >24 hours to 36 hours and no use at all from >36 hours to 48 hours.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
24 to 96 hours after IMP
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||
End point title |
Changes from baseline in pain intensity using the FLACC scale in children from 2 years to less than 6 years | |||||||||||||||||||||||||||||||||||||||
End point description |
The Face, Legs, Activity, Cry, Consolability (FLACC) scale was used for children from 2 years to less than 6 years, or in older children who were not able to report their pain using the other scales.
It was developed by the Department of Anesthesiology, University of Michigan Medical School and Health Systems. It is a behavioral scale for scoring postoperative pain in young children. This tool includes five categories of pain behaviors, including facial expression, leg movement, activity, cry, and consolability. Each of the 5 categories F, L, A, C, and C is scored from 0-2, which results in a total score between 0 and 10.
The Pain intensity scores have been obtained before and after first dose of IMP, and before each subsequent dose of IMP, whenever possible.
Pain intensity scores and change from baseline values have been summarized descriptively for each time point.
|
|||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||
End point timeframe |
Change from baseline to first dose of IMP until the 8th dose of IMP and End of Treatment
|
|||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||
End point title |
Changes from baseline in pain intensity using the Faces Pain Scale in children aged 6 years to less than 12 years | |||||||||||||||||||||||||||||||||||||||
End point description |
For children aged 6 years (if possible) to less than 12 years, the pain intensity has been assessed by the use of the Faces Pain Scale-Revised (FPS-R).
The FPS-R is a validated self-report measure of pain intensity developed for children. 6 facial representations were used to indicate how much the pain hurts.
It was adapted from the Faces Pain Scale to make it possible to score the sensation of pain on the widely accepted 0-to-10 metric.
The Pain intensity scores have been obtained before and after first dose of IMP, and before each subsequent dose of IMP, whenever possible
Pain intensity scores and change from baseline values have been summarized descriptively for each time point
|
|||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||
End point timeframe |
Change from baseline to first dose of IMP until the 8th dose of IMP and End of Treatment
|
|||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||
End point title |
Changes from baseline in pain intensity using the Visual Analog Scale in children aged 12 years to less than 18 years | |||||||||||||||||||||||||||||||||||||||
End point description |
For children aged 12 years to less than 18 years, the pain intensity has been assessed by the use of a Visual analog scale (VAS).
The subject were asked to draw a single line to indicate the current level of pain intensity on a
100 mm line (visual analog scale - VAS) by marking a point on the line in response to: “My pain right now is”. The mark was scored between “no pain” and “pain as bad as it could be”. A value of 0 indicates "no pain". A value of 100 indicates "pain as bad as it could be".
The Pain intensity scores have been obtained before and after first dose of IMP, and before each subsequent dose of IMP, whenever possible.
Pain intensity scores and change from baseline values have been summarized descriptively for each time point.
|
|||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||
End point timeframe |
Change from baseline to first dose of IMP until the 8th dose of IMP and End of Treatment
|
|||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
CGIC by investigator/clinician after completion of the double-blind IMP treatment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The Clinical Global Impression of Change (CGIC) has been assessed at the End of Treatment Visit.
The investigator rated 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.
Results have been summarized descriptively.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
End of Treatment Visit
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
PGIC by subject/parent/legal guardian after completion of the double-blind IMP treatment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The Patient Global Impression of Change (PGIC) has been assessed at the End of Treatment Visit. Subjects verbally rated 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). If the subjects were not capable of completing the questionnaire the parent/legal guardian may have completed the questionnaire on behalf of the subject.
Results have been summarized descriptively.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
End of Treatment Visit
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Time to first and time to second NCA/PCA after the first dose of IMP | ||||||||||||||||||||||||||||||
End point description |
The time to first and time to second nurse-controlled/patient-controlled analgesia (NCA/PCA) after the first dose of IMP were summarized descriptively using time-to-event methods and displayed by relevant treatment groups. Subjects who completed the End of Treatment Visit before their first/second use of NCA/PCA or subjects who terminated treatment before their first/second use of NCA/PCA were censored at the End of Treatment Visit.
Time-to-event variables are reported using Kaplan-Meier analyses. Therefore, values might remain missing if the survival function does not reach a respective threshold. This is indicated by 9999.9.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
Time to first and second NCA/PCA administration
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
Notes [1] - 81 subjects with time to first NCA administration, 66 subjects with time to second administration. [2] - 46 subjects with time to first NCA administration, 37 subjects with time to second administration. [3] - 6 subjects with time to first NCA administration, 4 subjects with time to second administration. [4] - 3 subjects with time to first NCA administration, 1 subject with time to second administration. |
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||
End point title |
Time from first dose of IMP until IMP treatment discontinuation due to lack of efficacy | |||||||||||||||
End point description |
The distributions of the time from the first dose of IMP to treatment discontinuation due to lack of efficacy were summarized descriptively using time-to-event methods.
Subjects who reach the maximum duration of treatment (72 h) were censored at 72 h after first IMP intake. Subjects who discontinued during the Treatment Period for reasons other than lack of efficacy were censored at the time of the decision to discontinue treatment. Due to the low number of subjects with events, the median and the corresponding confidence interval could not be calculated. The time to treatment discontinuation due to lack of efficacy was longer in the tapentadol than in the placebo group. The hazard ratio (SE) of 2.15 (1.52) indicates that subjects on tapentadol discontinued later due to lack of efficacy than subjects on placebo (p = 0.2681 [Log-rank test]).
This analysis was not performed for subjects <2 years old. There was no subject with a premature IMP discontinuation due to lack of efficacy.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
up to 72 hours
|
|||||||||||||||
|
||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
End point title |
Palatability of the IMP after the first dose | |||||||||||||||||||||||||||
End point description |
Palatability of the study medication (IMP) after dosing in subjects aged 2 years to less than 18 years old was assessed using a 5-point verbal rating scale.
Palatability has been assessed by asking the following question “How does the medication taste?”. The categorical verbal rating ranged from really good, good, a bit good/a bit bad, bad, and really bad.
Responses were summarized. Missing values were not imputed.
Palatability was not planned to be analyzed in subjects <2 years old.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
After first dose of IMP
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
End point title |
Palatability of the IMP after the last dose | |||||||||||||||||||||||||||
End point description |
Palatability of the study medication (IMP) after dosing in subjects aged 2 years to less than 18 years old was assessed using a 5-point verbal rating scale.
Palatability has been assessed by asking the following question “How does the medication taste?”. The categorical verbal rating ranged from really good, good, a bit good/a bit bad, bad, and really bad.
Responses were summarized. Missing values were not imputed.
Palatability was not planned to be analyzed in subjects <2 years old.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
End of Treatment Visit
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
End point title |
Acceptability of the IMP after the first dose | |||||||||||||||||||||||||||
End point description |
The Acceptability of the study medication (IMP) after dosing in subjects aged 2 years to less than 18 years old was assessed using a 5-point verbal rating scale.
Acceptability has been assessed by asking the following question “Swallowing the medication is ...”. The categorical verbal rating ranged from was really easy, easy, a bit easy/a bit difficult, difficult, and really difficult.
Responses were summarized. Missing values were not imputed.
Acceptability was not planned to be analyzed in subjects <2 years old.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
After first dose of IMP
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
End point title |
Acceptability of the IMP after the last dose | |||||||||||||||||||||||||||
End point description |
The Acceptability of the study medication (IMP) after dosing in subjects aged 2 years to less than 18 years old was assessed using a 5-point verbal rating scale.
Acceptability has been assessed by asking the following question “Swallowing the medication is ...”. The categorical verbal rating ranged from was really easy, easy, a bit easy/a bit difficult, difficult, and really difficult.
Responses were summarized. Missing values were not imputed.
Acceptability was not planned to be analyzed in subjects <2 years old.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
End of Treatment Visit
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||
End point title |
Changes from baseline in pain intensity using the FLACC scale in children from birth to <2 years | |||||||||||||||||||||||||||||||||||||||
End point description |
The Face, Legs, Activity, Cry, Consolability (FLACC) scale was used for children from birth to less than 6 years, or in older children who were not able to report their pain using the other scales.
It was developed by the Department of Anesthesiology, University of Michigan Medical School and Health Systems. It is a behavioral scale for scoring postoperative pain in young children. This tool includes five categories of pain behaviors, including facial expression, leg movement, activity, cry, and consolability. Each of the 5 categories F, L, A, C, and C is scored from 0-2, which results in a total score between 0 and 10.
The Pain intensity scores have been obtained before and after first dose of IMP, and before each subsequent dose of IMP, whenever possible.
Pain intensity scores and change from baseline values were summarized descriptively for each time point. Standard deviations were not calculated for 4 or less subjects, as indicated by 9999.9.
|
|||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||
End point timeframe |
Change from baseline to first dose of IMP until the 8th dose of IMP and End of Treatment
|
|||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||
End point title |
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 | |||||||||||||||
End point description |
The assessment of suicidal ideation and behavior was a voluntary assessment to determine development of such behaviors after treatment of subjects with IMP. Suicidal ideation and behavior was assessed using the Columbia-Suicide Severity Rating Scale at baseline ("baseline" questionnaire) and at the end of treatment ("since last visit" questionnaire).
Results were presented in a subject data listing.
|
|||||||||||||||
End point type |
Other pre-specified
|
|||||||||||||||
End point timeframe |
Baseline and End of Treatment Visit
|
|||||||||||||||
|
||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Sedation scores using the University of Michigan Sedation Scale before first dose of IMP | ||||||||||||||||||||||||||||||||||||||||
End point description |
Sedation scores were obtained before each dose of IMP and summarized descriptively as a categorical variable.
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
before first dose of IMP
|
||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Sedation scores using the University of Michigan Sedation Scale before 8th administration of IMP | ||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Sedation scores were obtained before each dose of IMP and summarized descriptively as a categorical variable.
|
||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
before 8th administration of IMP
|
||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||
End point title |
Number of subjects discontinuing the trial due to TEAEs and drug-related adverse events | |||||||||||||||
End point description |
The number of subjects with at least 1 treatment emergent adverse event (TEAE) and drug-related TEAEs leading to discontinuation from the trial (i.e. TEAE with “countermeasures”: “trial discontinuation”) is provided.
|
|||||||||||||||
End point type |
Other pre-specified
|
|||||||||||||||
End point timeframe |
From first administration of IMP until the time of the subject-related end of trial.
|
|||||||||||||||
|
||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal vital signs – Diastolic Blood Pressure | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal vital signs – Systolic Blood Pressure | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal vital signs – Heart Rate | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal vital signs – Respiratory Rate | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Hemoglobin | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Mean Corpuscular Volume | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Hematocrit | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Mean Corpuscular Hemoglobin | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Red blood cell count | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Mean Corpuscular Hemoglobin Concentration | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Platelet count | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - White blood cell count | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Sodium | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Lipase | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Potassium | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Triglycerides | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Chloride | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Total Bilirubin | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Bicarbonate | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Alkaline Phosphatase | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Blood Urea Nitrogen | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Creatine kinase | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Creatinine | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Lactic Acid Dehydrogenase | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Uric acid | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Alanine aminotransferase | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Calcium | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Aspartate aminotransferase | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Phosphate | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Glucose | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Total Protein | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal laboratory parameter - Glomerular filtration rate | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
Notes [5] - No subject with data for end of treatment. [6] - No subject with data for end of treatment. |
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal 12-lead electrocardiogram (ECG) parameters - RR Duration | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal 12-lead electrocardiogram (ECG) parameters - PR Duration | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal 12-lead electrocardiogram (ECG) parameters - QRS Duration | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal 12-lead electrocardiogram (ECG) parameters - QT Duration | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal 12-lead electrocardiogram (ECG) parameters - QTcF | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of subjects who develop abnormal 12-lead electrocardiogram (ECG) parameters - Heart Rate | ||||||||||||||||||||||||||||||
End point description |
The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
|
||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||
End point timeframe |
until end of treatment
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Changes from baseline in vital signs parameters – Diastolic Blood Pressure | ||||||||||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to subsequent IMP administrations. The mean difference and standard deviation was calculated.
|
||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||
End point timeframe |
baseline to before the 8th dose of IMP
|
||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Changes from baseline in vital signs parameters – Systolic Blood Pressure | ||||||||||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to subsequent IMP administrations. The mean difference and standard deviation was calculated.
|
||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||
End point timeframe |
baseline to before the 8th dose of IMP
|
||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Changes from baseline in vital signs parameters – Heart Rate | ||||||||||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to subsequent IMP administrations. The mean difference and standard deviation was calculated.
|
||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||
End point timeframe |
baseline to before the 8th dose of IMP
|
||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Changes from baseline in vital signs parameters – Respiratory Rate | ||||||||||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to subsequent IMP administrations. The mean difference and standard deviation was calculated.
|
||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||
End point timeframe |
baseline to before the 8th dose of IMP
|
||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Hemoglobin | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Mean Corpuscular Volume | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Hematocrit | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Mean Corpuscular Hemoglobin | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Red blood cell count | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Mean Corpuscular Hemoglobin Concentration | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated based on central laboratory data.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Platelet count | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - White blood cell count | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Sodium | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Lipase | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Potassium | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Triglycerides | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Chloride | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Total Bilirubin | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Bicarbonate | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Alkaline Phosphatase | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Blood Urea Nitrogen | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Creatine kinase | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Creatinine | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Lactic Acid Dehydrogenase | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Uric acid | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Alanine transaminase | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Calcium | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Aspartate transaminase | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Phosphorus | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Glucose | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Total Protein | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Changes from baseline in safety laboratory parameters - Glomerular filtration rate | ||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
End point title |
Changes from baseline in 12-lead ECG parameters (2 years to <18 years) | |||||||||||||||||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
|||||||||||||||||||||||||||
End point type |
Other pre-specified
|
|||||||||||||||||||||||||||
End point timeframe |
baseline to end to treatment
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Changes from baseline in 12-lead ECG parameters - Heart Rate | ||||||||||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||
End point timeframe |
baseline to end to treatment
|
||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
End point title |
Changes from baseline in 12-lead ECG parameters (from birth to <2 years) | |||||||||||||||||||||||||||
End point description |
Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
|
|||||||||||||||||||||||||||
End point type |
Other pre-specified
|
|||||||||||||||||||||||||||
End point timeframe |
baseline to end of treatment
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Any Adverse Events (AE) that started at or after first administration of IMP or starting before the first dose of IMP and worsened in intensity after the first administration of IMP up to the end of the therapeutic reach of last administration of IMP.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
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.
Adverse events are listed by treatment and overall.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.1
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Overall (EU PDCO) – Safety Set
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
All subjects aged 2 years to below 18 years who received at least 1 dose of IMP. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Tapentadol (EU PDCO) - Safety Set
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
All subjects aged 2 years to below 18 years who received at least 1 dose of Tapentadol oral solution. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo (EU PDCO) - Safety Set
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
All subjects aged 2 years to below 18 years who received at least 1 dose of placebo. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Overall (US FDA <2 years) - Safety Set
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
All subjects from birth to below 2 years who received at least 1 dose of IMP. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Tapentadol (US FDA <2 years) - Safety Set
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
All subjects from birth to below 2 years who received at least 1 dose of tapentadol oral solution. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo (US FDA <2 years) - Safety Set
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
All subjects from birth to below 2 years who received at least 1 dose of placebo oral solution. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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27 Nov 2013 |
Amendment 01 was implemented to change the site of manufacture of the IMP for logistic reasons. |
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14 Oct 2014 |
Amendment 02 was implemented for clarification and to comply with US FDA requirements:
• The definition of completers has been amended.
• 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.
• The dose of tapentadol oral solution for subjects between 2 years and less than 6 years has now been defined.
• The list of prohibited medication taken within 14 days of allocation 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.
• The primary endpoint will also be evaluated using Bayesian statistics as a supportive analysis. The methodology will be described in the statistical analysis plan.
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16 Apr 2015 |
Amendment 03 was implemented to change 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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23 Jun 2015 |
Amendment 04 was implemented to:
• Clarify the definition for stopping IMP.
• Allow a clinician 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 to IMP until 4 hours after the last administration of IMP.
• Exclude continuous positive airway pressure or mechanical ventilation from time of allocation 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 body mass index (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 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.
• 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.
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27 Oct 2015 |
Amendment 05 was implemented 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.
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19 Aug 2016 |
Amendment 06 was implemented 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.
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24 Mar 2017 |
Amendment 07 was implemented 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
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Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
See primary endpoint for the US FDA. |