Trial Outcomes & Findings for A Study to Look at Tapentadol Tablets in Children and Adolescents in Pain (NCT NCT02151682)

Last Updated: 2019-09-12

Results Overview

The proportion of participants classified as responders was assessed and compared between the treatment groups. A participant was defined as responder if both of the following criteria were met: * Completion of the 14-day Treatment Period (Part 1). * One of the following calculated from the scheduled pain assessments ("pain right now") documented during the last 3 days of the Treatment Period: * Average pain less than 50 on a visual analog scale (VAS, range 0 \[no pain\] to 100 \[pain as bad as it could be\]) for participants aged 12 years to less than 18 years; or less than 5 on the Faces Pain Scale-revised (FPS-R, range 0 \[no pain\] and 10 \[very much pain\]) for participants aged 6 years to less than 12 years. * Average reduction from baseline of pain greater than or equal to 20 on a VAS for participants aged 12 years to less than 18 years; or greater than or equal to 2 on the FPS-R for participants aged 6 years to less than 12 years.

Recruitment status

COMPLETED

Study phase

PHASE2/PHASE3

Target enrollment

73 participants

Primary outcome timeframe

From Day 1 up to Day 14 (End of Part 1)

Results posted on

2019-09-12

Participant Flow

The first participant was enrolled for Part 1 on 29 April 2015.

73 participants signed an informed consent form (assented). 1 participant withdrew consent and 2 did not meet in-/exclusion criteria. 70 participants were allocated to investigational medicinal product (IMP). 1 of the allocated participants was not treated, resulting in 69 participants who were dosed in Part 1.

Participant milestones

Participant milestones
Measure	Morphine Prolonged-release (Part 1) 10 milligram (mg) or 30 mg tablets were taken orally twice daily. Starting doses varied from 10 to 40 mg morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.	Tapentadol Prolonged-release (Part 1) 25 mg or 100 mg tablets were taken orally twice daily. Starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.	Tapentadol in Part 2 After Tapentadol or Morphine in Part 1 26 Participants on tapentadol PR in Part 1 continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. 10 Participants on morphine PR in Part 1 were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily. Treatment with tapentadol was up to 12 months in Part 2.	Observation Period After Tapentadol in Part 1 14 Participants who completed tapentadol PR in Part 1 of the study and 4 of 5 participants who discontinued tapentadol treatment early in Part 1 continued directly in the observation period in Part 2 for up to 12 months (with standard-of-care treatment if needed). One subject who withdrew consent in Part 1 did not enter the observation period.	Observation Period After Morphine in Part 1 12 Participants who completed morphine PR treatment in Part 1 of the study and 2 participants who discontinued early from morphine treatment in Part 1 continued directly in the observation period in Part 2 (with standard-of-care treatment if needed).	Observation Period After Tapentadol in Part 2 19 Participants who completed tapentadol treatment in Part 1 and discontinued from tapentadol treatment in Part 2 and 7 participants who completed morphine treatment in Part 1 and discontinued from tapentadol in Part 2 entered the Observation Period for up to 12 months (with standard-of-care treatment if needed).
Part 1: 14 Days Morphine or Tapentadol STARTED	24	45	0	0	0	0
Part 1: 14 Days Morphine or Tapentadol COMPLETED	22	40	0	0	0	0
Part 1: 14 Days Morphine or Tapentadol NOT COMPLETED	2	5	0	0	0	0
Part 2: Tapent. Extension or Observation STARTED	0	0	36	18	14	0
Part 2: Tapent. Extension or Observation COMPLETED	0	0	8	14	14	0
Part 2: Tapent. Extension or Observation NOT COMPLETED	0	0	28	4	0	0
Part 2: Observ. Aft. Tapent. Extension STARTED	0	0	0	0	0	26
Part 2: Observ. Aft. Tapent. Extension COMPLETED	0	0	0	0	0	19
Part 2: Observ. Aft. Tapent. Extension NOT COMPLETED	0	0	0	0	0	7

Reasons for withdrawal

Reasons for withdrawal
Measure	Morphine Prolonged-release (Part 1) 10 milligram (mg) or 30 mg tablets were taken orally twice daily. Starting doses varied from 10 to 40 mg morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.	Tapentadol Prolonged-release (Part 1) 25 mg or 100 mg tablets were taken orally twice daily. Starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.	Tapentadol in Part 2 After Tapentadol or Morphine in Part 1 26 Participants on tapentadol PR in Part 1 continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. 10 Participants on morphine PR in Part 1 were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily. Treatment with tapentadol was up to 12 months in Part 2.	Observation Period After Tapentadol in Part 1 14 Participants who completed tapentadol PR in Part 1 of the study and 4 of 5 participants who discontinued tapentadol treatment early in Part 1 continued directly in the observation period in Part 2 for up to 12 months (with standard-of-care treatment if needed). One subject who withdrew consent in Part 1 did not enter the observation period.	Observation Period After Tapentadol in Part 2 19 Participants who completed tapentadol treatment in Part 1 and discontinued from tapentadol treatment in Part 2 and 7 participants who completed morphine treatment in Part 1 and discontinued from tapentadol in Part 2 entered the Observation Period for up to 12 months (with standard-of-care treatment if needed).
Part 1: 14 Days Morphine or Tapentadol Adverse Event	0	2	0	0	0
Part 1: 14 Days Morphine or Tapentadol Withdrawal by Subject	0	1	0	0	0
Part 1: 14 Days Morphine or Tapentadol Technical problems	0	1	0	0	0
Part 1: 14 Days Morphine or Tapentadol No need for opioid	1	1	0	0	0
Part 1: 14 Days Morphine or Tapentadol Missing	1	0	0	0	0
Part 2: Tapent. Extension or Observation Adverse Event	0	0	3	0	0
Part 2: Tapent. Extension or Observation Death	0	0	0	2	0
Part 2: Tapent. Extension or Observation Withdrawal by Subject	0	0	1	1	0
Part 2: Tapent. Extension or Observation Lack of Efficacy	0	0	3	0	0
Part 2: Tapent. Extension or Observation Protocol Violation	0	0	1	0	0
Part 2: Tapent. Extension or Observation No need for opioid	0	0	13	0	0
Part 2: Tapent. Extension or Observation Missing	0	0	0	1	0
Part 2: Tapent. Extension or Observation Various other	0	0	6	0	0
Part 2: Tapent. Extension or Observation Final post-treatment visit not performed	0	0	1	0	0
Part 2: Observ. Aft. Tapent. Extension Withdrawal by Subject	0	0	0	0	1
Part 2: Observ. Aft. Tapent. Extension Death	0	0	0	0	1
Part 2: Observ. Aft. Tapent. Extension Missing	0	0	0	0	3
Part 2: Observ. Aft. Tapent. Extension Various other	0	0	0	0	2

Baseline Characteristics

Height is presented by age group.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Morphine Prolonged-release (Part 1) n=24 Participants The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.	Tapentadol Prolonged-release (Part 1) n=45 Participants The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.	Total n=69 Participants Total of all reporting groups
Age, Continuous All participants	13.2 years STANDARD_DEVIATION 2.8 • n=24 Participants	13.2 years STANDARD_DEVIATION 2.8 • n=45 Participants	13.2 years STANDARD_DEVIATION 2.8 • n=69 Participants
Sex: Female, Male Female	10 Participants n=24 Participants	22 Participants n=45 Participants	32 Participants n=69 Participants
Sex: Female, Male Male	14 Participants n=24 Participants	23 Participants n=45 Participants	37 Participants n=69 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants n=24 Participants	7 Participants n=45 Participants	11 Participants n=69 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	20 Participants n=24 Participants	36 Participants n=45 Participants	56 Participants n=69 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=24 Participants	2 Participants n=45 Participants	2 Participants n=69 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=24 Participants	0 Participants n=45 Participants	0 Participants n=69 Participants
Race (NIH/OMB) Asian	0 Participants n=24 Participants	0 Participants n=45 Participants	0 Participants n=69 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=24 Participants	1 Participants n=45 Participants	1 Participants n=69 Participants
Race (NIH/OMB) Black or African American	0 Participants n=24 Participants	0 Participants n=45 Participants	0 Participants n=69 Participants
Race (NIH/OMB) White	24 Participants n=24 Participants	44 Participants n=45 Participants	68 Participants n=69 Participants
Race (NIH/OMB) More than one race	0 Participants n=24 Participants	0 Participants n=45 Participants	0 Participants n=69 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=24 Participants	0 Participants n=45 Participants	0 Participants n=69 Participants
Age, customized 6 years to less than 12 years	7 Participants n=24 Participants	12 Participants n=45 Participants	19 Participants n=69 Participants
Age, customized 12 years to less than 18 years	17 Participants n=24 Participants	33 Participants n=45 Participants	50 Participants n=69 Participants
Height 6 years to less than 12 years	138.9 centimeters STANDARD_DEVIATION 13.4 • n=7 Participants • Height is presented by age group.	136.0 centimeters STANDARD_DEVIATION 12.5 • n=12 Participants • Height is presented by age group.	137.1 centimeters STANDARD_DEVIATION 12.5 • n=19 Participants • Height is presented by age group.
Height 12 years to less than 18 years	165.8 centimeters STANDARD_DEVIATION 11.2 • n=17 Participants • Height is presented by age group.	162.9 centimeters STANDARD_DEVIATION 11.3 • n=33 Participants • Height is presented by age group.	163.9 centimeters STANDARD_DEVIATION 11.2 • n=50 Participants • Height is presented by age group.
Weight 6 years to less than 12 years	34.17 kilograms STANDARD_DEVIATION 14.08 • n=7 Participants • Weight is presented by age group.	32.37 kilograms STANDARD_DEVIATION 11.39 • n=12 Participants • Weight is presented by age group.	33.03 kilograms STANDARD_DEVIATION 12.09 • n=19 Participants • Weight is presented by age group.
Weight 12 years to less than 18 years	56.69 kilograms STANDARD_DEVIATION 9.52 • n=17 Participants • Weight is presented by age group.	56.35 kilograms STANDARD_DEVIATION 13.92 • n=33 Participants • Weight is presented by age group.	56.47 kilograms STANDARD_DEVIATION 12.50 • n=50 Participants • Weight is presented by age group.
Body Mass Index 6 years to less than 12 years	17.28 kg/m^2 STANDARD_DEVIATION 5.69 • n=7 Participants • Body Mass Index is presented by age group.	17.08 kg/m^2 STANDARD_DEVIATION 3.38 • n=12 Participants • Body Mass Index is presented by age group.	17.16 kg/m^2 STANDARD_DEVIATION 4.22 • n=19 Participants • Body Mass Index is presented by age group.
Body Mass Index 12 years to less than 18 years	20.59 kg/m^2 STANDARD_DEVIATION 2.98 • n=17 Participants • Body Mass Index is presented by age group.	21.15 kg/m^2 STANDARD_DEVIATION 4.66 • n=33 Participants • Body Mass Index is presented by age group.	20.96 kg/m^2 STANDARD_DEVIATION 4.14 • n=50 Participants • Body Mass Index is presented by age group.
Pain cause Cancer-related pain · 6 years to less than 12 years	1 Participants n=5 Participants • As a parameter of special interest, pain cause (cancer-related pain, non-cancer-related pain) was presented by age group.	0 Participants n=9 Participants • As a parameter of special interest, pain cause (cancer-related pain, non-cancer-related pain) was presented by age group.	1 Participants n=14 Participants • As a parameter of special interest, pain cause (cancer-related pain, non-cancer-related pain) was presented by age group.
Pain cause Cancer-related pain · 12 years to less than 18 years	4 Participants n=5 Participants • As a parameter of special interest, pain cause (cancer-related pain, non-cancer-related pain) was presented by age group.	9 Participants n=9 Participants • As a parameter of special interest, pain cause (cancer-related pain, non-cancer-related pain) was presented by age group.	13 Participants n=14 Participants • As a parameter of special interest, pain cause (cancer-related pain, non-cancer-related pain) was presented by age group.
Pain cause Non-cancer-related pain · 6 years to less than 12 years	6 Participants n=19 Participants • As a parameter of special interest, pain cause (cancer-related pain, non-cancer-related pain) was presented by age group.	12 Participants n=36 Participants • As a parameter of special interest, pain cause (cancer-related pain, non-cancer-related pain) was presented by age group.	18 Participants n=55 Participants • As a parameter of special interest, pain cause (cancer-related pain, non-cancer-related pain) was presented by age group.
Pain cause Non-cancer-related pain · 12 years to less than 18 years	13 Participants n=19 Participants • As a parameter of special interest, pain cause (cancer-related pain, non-cancer-related pain) was presented by age group.	24 Participants n=36 Participants • As a parameter of special interest, pain cause (cancer-related pain, non-cancer-related pain) was presented by age group.	37 Participants n=55 Participants • As a parameter of special interest, pain cause (cancer-related pain, non-cancer-related pain) was presented by age group.
Type of pain Neuropathic	4 Participants n=24 Participants	9 Participants n=45 Participants	13 Participants n=69 Participants
Type of pain Nociceptive/somatic	13 Participants n=24 Participants	28 Participants n=45 Participants	41 Participants n=69 Participants
Type of pain Nociceptive/visceral	0 Participants n=24 Participants	0 Participants n=45 Participants	0 Participants n=69 Participants
Type of pain Neuropathic and nociceptive/somatic	6 Participants n=24 Participants	6 Participants n=45 Participants	12 Participants n=69 Participants
Type of pain Neuropathic and nociceptive/visceral	0 Participants n=24 Participants	0 Participants n=45 Participants	0 Participants n=69 Participants
Type of pain Nociceptive/somatic and nociceptive/visceral	1 Participants n=24 Participants	1 Participants n=45 Participants	2 Participants n=69 Participants
Type of pain All of the pain types	0 Participants n=24 Participants	1 Participants n=45 Participants	1 Participants n=69 Participants
Pain intensity (FPS-R) 6 years to less than 12 years	6.7 units on a scale STANDARD_DEVIATION 2.1 • n=6 Participants • FPS-R data at baseline were available for 32 participants on tapentadol PR and for 19 participants on morphine PR (51 of 69 participants overall).	5.8 units on a scale STANDARD_DEVIATION 3.6 • n=10 Participants • FPS-R data at baseline were available for 32 participants on tapentadol PR and for 19 participants on morphine PR (51 of 69 participants overall).	6.1 units on a scale STANDARD_DEVIATION 3.1 • n=16 Participants • FPS-R data at baseline were available for 32 participants on tapentadol PR and for 19 participants on morphine PR (51 of 69 participants overall).
Pain intensity (FPS-R) 12 years to less than 18 years	3.1 units on a scale STANDARD_DEVIATION 2.7 • n=13 Participants • FPS-R data at baseline were available for 32 participants on tapentadol PR and for 19 participants on morphine PR (51 of 69 participants overall).	4.0 units on a scale STANDARD_DEVIATION 3.1 • n=22 Participants • FPS-R data at baseline were available for 32 participants on tapentadol PR and for 19 participants on morphine PR (51 of 69 participants overall).	3.7 units on a scale STANDARD_DEVIATION 2.9 • n=35 Participants • FPS-R data at baseline were available for 32 participants on tapentadol PR and for 19 participants on morphine PR (51 of 69 participants overall).
Pain intensity (VAS) 6 years to less than 12 years	75.3 units on a scale STANDARD_DEVIATION 14.6 • n=6 Participants • VAS data at baseline were available for 32 participants on tapentadol PR and for 19 participants on morphine PR (51 of 69 participants overall).	59.1 units on a scale STANDARD_DEVIATION 32.8 • n=10 Participants • VAS data at baseline were available for 32 participants on tapentadol PR and for 19 participants on morphine PR (51 of 69 participants overall).	65.2 units on a scale STANDARD_DEVIATION 28.0 • n=16 Participants • VAS data at baseline were available for 32 participants on tapentadol PR and for 19 participants on morphine PR (51 of 69 participants overall).
Pain intensity (VAS) 12 years to less than 18 years	39.5 units on a scale STANDARD_DEVIATION 32.4 • n=13 Participants • VAS data at baseline were available for 32 participants on tapentadol PR and for 19 participants on morphine PR (51 of 69 participants overall).	42.7 units on a scale STANDARD_DEVIATION 31.6 • n=22 Participants • VAS data at baseline were available for 32 participants on tapentadol PR and for 19 participants on morphine PR (51 of 69 participants overall).	41.5 units on a scale STANDARD_DEVIATION 31.5 • n=35 Participants • VAS data at baseline were available for 32 participants on tapentadol PR and for 19 participants on morphine PR (51 of 69 participants overall).
Region of Enrollment Hungary	0 Participants n=24 Participants	1 Participants n=45 Participants	1 Participants n=69 Participants
Region of Enrollment Italy	0 Participants n=24 Participants	3 Participants n=45 Participants	3 Participants n=69 Participants
Region of Enrollment Portugal	4 Participants n=24 Participants	3 Participants n=45 Participants	7 Participants n=69 Participants
Region of Enrollment Spain	1 Participants n=24 Participants	1 Participants n=45 Participants	2 Participants n=69 Participants
Region of Enrollment United Kingdom	1 Participants n=24 Participants	7 Participants n=45 Participants	8 Participants n=69 Participants
Region of Enrollment Chile	3 Participants n=24 Participants	4 Participants n=45 Participants	7 Participants n=69 Participants
Region of Enrollment France	5 Participants n=24 Participants	9 Participants n=45 Participants	14 Participants n=69 Participants
Region of Enrollment Germany	4 Participants n=24 Participants	5 Participants n=45 Participants	9 Participants n=69 Participants
Region of Enrollment Belgium	0 Participants n=24 Participants	1 Participants n=45 Participants	1 Participants n=69 Participants
Region of Enrollment Bulgaria	6 Participants n=24 Participants	11 Participants n=45 Participants	17 Participants n=69 Participants

PRIMARY outcome

Timeframe: From Day 1 up to Day 14 (End of Part 1)

Population: Full Analysis Set; missing pain assessments (last 3 days) were imputed using multiple imputation.

Outcome measures

Outcome measures
Measure	Morphine Prolonged-release (Part 1) n=24 Participants The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.	Tapentadol Prolonged-release (Part 1) n=45 Participants The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.	Tapentadol Prolonged-release (Part 2) 36 Participants who completed Part 1 of the trial (26 on tapentadol PR and 10 participants on morphine PR) continued treatment or switched to treatment with tapentadol PR for up to 12 months in Part 2. Participants on tapentadol PR in Part 1 continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants on morphine PR in Part 1 were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily.	Observation Period After Tapentadol in Part 2 Participants who completed tapentadol PR or morphine PR treatment in Part 1 of the study could enter the Observation Period for up to 12 months (with standard-of-care treatment if needed) after they had discontinued from tapentadol PR treatment in Part 2.
Number of Participants Classified as Responder (Part 1)	19 Participants	32 Participants	—	—

SECONDARY outcome

Timeframe: From Day 1 to Day 14 (End of Part 1)

Population: Safety Set

Constipation was assessed using the modified constipation assessment scale (mCAS). This is an 8-item questionnaire where the observer has scored constipation on a nominal scale (no Problem \[score 0\], some problem \[score 1\] or severe Problem \[score 2\]). The response to an item could also be scored as "unable to assess". The Total Score can vary from 0-16; the higher the Total Score the higher the extent of constipation. A positive change from Day 1 to Day 14 indicates a worsening, a negative change an improvement.

Outcome measures

Outcome measures
Measure	Morphine Prolonged-release (Part 1) n=24 Participants The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.	Tapentadol Prolonged-release (Part 1) n=45 Participants The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.	Tapentadol Prolonged-release (Part 2) 36 Participants who completed Part 1 of the trial (26 on tapentadol PR and 10 participants on morphine PR) continued treatment or switched to treatment with tapentadol PR for up to 12 months in Part 2. Participants on tapentadol PR in Part 1 continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants on morphine PR in Part 1 were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily.	Observation Period After Tapentadol in Part 2 Participants who completed tapentadol PR or morphine PR treatment in Part 1 of the study could enter the Observation Period for up to 12 months (with standard-of-care treatment if needed) after they had discontinued from tapentadol PR treatment in Part 2.
Extent of Constipation (Part 1) Day 1	2.7 score on a scale Standard Deviation 3.0	1.5 score on a scale Standard Deviation 1.4	—	—
Extent of Constipation (Part 1) Day 14	2.7 score on a scale Standard Deviation 2.4	1.8 score on a scale Standard Deviation 2.0	—	—
Extent of Constipation (Part 1) Change from Day 1	-0.1 score on a scale Standard Deviation 1.6	0.4 score on a scale Standard Deviation 2.4	—	—

SECONDARY outcome

Timeframe: Part 1: Day 1 (Start of Part 1) to Day 14; Part 2: Day 15 to Day 379 (End of Part 2)

Population: Safety Set

Tolerability was assessed by the number of participants with exactly 1 to more than 5 treatment emergent adverse events (TEAE) by treatment group during the different trial periods, on a participant level. In addition, tolerability was assessed by the number of participants with TEAEs which were considered by the investigator to be at least possibly related to the treatment the participant received.

Outcome measures

Outcome measures
Measure	Morphine Prolonged-release (Part 1) n=24 Participants The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.	Tapentadol Prolonged-release (Part 1) n=45 Participants The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.	Tapentadol Prolonged-release (Part 2) n=36 Participants 36 Participants who completed Part 1 of the trial (26 on tapentadol PR and 10 participants on morphine PR) continued treatment or switched to treatment with tapentadol PR for up to 12 months in Part 2. Participants on tapentadol PR in Part 1 continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants on morphine PR in Part 1 were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily.	Observation Period After Tapentadol in Part 2 Participants who completed tapentadol PR or morphine PR treatment in Part 1 of the study could enter the Observation Period for up to 12 months (with standard-of-care treatment if needed) after they had discontinued from tapentadol PR treatment in Part 2.
Tolerability Over the Complete Trial Period Participants without any TEAE	12 participants	19 participants	6 participants	—
Tolerability Over the Complete Trial Period Participants with at least 1 TEAE	12 participants	26 participants	30 participants	—
Tolerability Over the Complete Trial Period Participants with exactly 1 TEAE	1 participants	7 participants	5 participants	—
Tolerability Over the Complete Trial Period Participants with exactly 2 TEAEs	2 participants	5 participants	2 participants	—
Tolerability Over the Complete Trial Period Participants with exactly 3 TEAEs	2 participants	4 participants	2 participants	—
Tolerability Over the Complete Trial Period Participants with exactly 4 TEAEs	2 participants	1 participants	4 participants	—
Tolerability Over the Complete Trial Period Participants with exactly 5 TEAEs	1 participants	3 participants	3 participants	—
Tolerability Over the Complete Trial Period Participants with more than 5 TEAEs	4 participants	6 participants	14 participants	—
Tolerability Over the Complete Trial Period Participants with related TEAEs	6 participants	12 participants	13 participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: From Baseline up to Day 14 (End of Part 1) or early discontinuation

Population: Full Analysis Set

Pain intensity was assessed by scoring "Pain right now" twice daily up to Day 14 by every participant using the Visual Analog Scale (VAS) as well as the Faces Pain Scale-Revised (FPS-R) in an electronic diary. Pain intensity was first documented using the VAS and directly thereafter the FPS-R. If required, pain intensity diary entry could be assisted by the legal guardian or a health care provider. The VAS is scored from 0, equivalent to "no pain", to 100, equivalent to "pain as bad as it could be". The FPS-R is a validated self-reported 6-point scale with 0 representing "no pain" and 10 representing "very much pain". Facial representations were used to indicate how much the pain hurts. The "pain right now" scores at baseline (last evaluation before starting IMP) and the mean of last 6 assessments collected up to the time point of last IMP intake in Part 1 (i.e., Day 14 or the day of early discontinuation) were used for the calculation of the change in pain intensity from baseline.

Outcome measures

Outcome measures
Measure	Morphine Prolonged-release (Part 1) n=24 Participants The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.	Tapentadol Prolonged-release (Part 1) n=45 Participants The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.	Tapentadol Prolonged-release (Part 2) 36 Participants who completed Part 1 of the trial (26 on tapentadol PR and 10 participants on morphine PR) continued treatment or switched to treatment with tapentadol PR for up to 12 months in Part 2. Participants on tapentadol PR in Part 1 continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants on morphine PR in Part 1 were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily.	Observation Period After Tapentadol in Part 2 Participants who completed tapentadol PR or morphine PR treatment in Part 1 of the study could enter the Observation Period for up to 12 months (with standard-of-care treatment if needed) after they had discontinued from tapentadol PR treatment in Part 2.
Change in Pain Intensity in the Open-label, Active-controlled Treatment Period (Part 1) Pain intensity change from Baseline (FPS-R)	-2.0 units on a scale Standard Deviation 3.5	-1.9 units on a scale Standard Deviation 3.4	—	—
Change in Pain Intensity in the Open-label, Active-controlled Treatment Period (Part 1) Pain intensity change from Baseline (VAS)	-23.4 units on a scale Standard Deviation 36.9	-18.8 units on a scale Standard Deviation 33.5	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: From Day 15 to Day 379 (End of Part 2)

Population: Full Analysis Set; data from 9 subjects who completed the visit 12 months after start of Part 2 were analyzed.

Pain intensity was assessed by scoring "Pain right now" using the Visual Analog Scale (VAS) as well as the Faces Pain Scale-Revised (FPS-R) at each visit. The pain intensity was first documented using the VAS and directly thereafter the FPS-R. If required, pain intensity assessments could be assisted by the legal guardian or a health care provider. The VAS is scored from 0, equivalent to "no pain", to 100, equivalent to "pain as bad as it could be". The FPS-R is a validated self-reported 6-point scale with 0 representing "no pain" and 10 representing "very much pain". Facial representations were used to indicate how much the pain hurts. The "pain right now" score at the tapentadol baseline (last evaluation before or at Day 15) and at the last assessment for those subjects who completed the 12 months treatment of Part 2 were used for the calculation of the change in pain intensity from the tapentadol baseline.

Outcome measures

Outcome measures
Measure	Morphine Prolonged-release (Part 1) n=9 Participants The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.	Tapentadol Prolonged-release (Part 1) The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.	Tapentadol Prolonged-release (Part 2) 36 Participants who completed Part 1 of the trial (26 on tapentadol PR and 10 participants on morphine PR) continued treatment or switched to treatment with tapentadol PR for up to 12 months in Part 2. Participants on tapentadol PR in Part 1 continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants on morphine PR in Part 1 were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily.	Observation Period After Tapentadol in Part 2 Participants who completed tapentadol PR or morphine PR treatment in Part 1 of the study could enter the Observation Period for up to 12 months (with standard-of-care treatment if needed) after they had discontinued from tapentadol PR treatment in Part 2.
Change in Pain Intensity in the Tapentadol Open-label Extension Period (Part 2) Pain intensity change (FPR-S) from Day 15	0 units on a scale Standard Deviation 2.8	—	—	—
Change in Pain Intensity in the Tapentadol Open-label Extension Period (Part 2) Pain intensity change (VAS) from Day 15	-11.7 units on a scale Standard Deviation 29.0	—	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: From Day 1 up to Day 14 (End of Part 1)

Population: Full Analysis Set

Due to an overall low intake of rescue medication, it was not appropriate to present the number of doses of oral morphine solution used at different dose levels of investigational medicinal product (IMP) but the average daily dose (milligrams per kilogram body weight) for the treatment period and a modified average daily dose. Average daily dose and modified average daily dose were both calculated based on drug accountability. For the modified average daily doses, implausible values were excluded from the analysis, i.e., the amount of rescue medication that was lost due to a broken bottle was excluded from the analysis and negative amounts of rescue medication intakes due to measurement inaccuracies for bottle weights were considered as no intake.

Outcome measures

Outcome measures
Measure	Morphine Prolonged-release (Part 1) n=24 Participants The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.	Tapentadol Prolonged-release (Part 1) n=45 Participants The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.	Tapentadol Prolonged-release (Part 2) 36 Participants who completed Part 1 of the trial (26 on tapentadol PR and 10 participants on morphine PR) continued treatment or switched to treatment with tapentadol PR for up to 12 months in Part 2. Participants on tapentadol PR in Part 1 continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants on morphine PR in Part 1 were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily.	Observation Period After Tapentadol in Part 2 Participants who completed tapentadol PR or morphine PR treatment in Part 1 of the study could enter the Observation Period for up to 12 months (with standard-of-care treatment if needed) after they had discontinued from tapentadol PR treatment in Part 2.
Use of Rescue Medication in the Open-Label, Active-controlled Treatment Period (Part 1) Average daily dose	0.07 milligrams per kilogram per day Standard Deviation 0.154	0.46 milligrams per kilogram per day Standard Deviation 2.426	—	—
Use of Rescue Medication in the Open-Label, Active-controlled Treatment Period (Part 1) Modified average daily dose	0.08 milligrams per kilogram per day Standard Deviation 0.160	0.11 milligrams per kilogram per day Standard Deviation 0.201	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: From Day 1 to Day 14 (End of Part 1)

Population: Pharmacokinetic Analysis Set

Tapentadol serum concentrations were measured in participants in the tapentadol treatment arm (Part 1). All participants who had quantifiable serum concentrations during the Treatment Period were included in the descriptive pharmacokinetic analysis. Data from participants who vomited within 6 hours of administration of IMP during the Treatment Period were carefully assessed to decide if the data should be included in the pharmacokinetic analysis.

Outcome measures

Outcome measures
Measure	Morphine Prolonged-release (Part 1) n=44 Participants The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.	Tapentadol Prolonged-release (Part 1) n=12 Participants The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.	Tapentadol Prolonged-release (Part 2) n=32 Participants 36 Participants who completed Part 1 of the trial (26 on tapentadol PR and 10 participants on morphine PR) continued treatment or switched to treatment with tapentadol PR for up to 12 months in Part 2. Participants on tapentadol PR in Part 1 continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants on morphine PR in Part 1 were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily.	Observation Period After Tapentadol in Part 2 Participants who completed tapentadol PR or morphine PR treatment in Part 1 of the study could enter the Observation Period for up to 12 months (with standard-of-care treatment if needed) after they had discontinued from tapentadol PR treatment in Part 2.
Serum Concentrations of Tapentadol (Part 1) Day 1	19.1 nanograms per milliliter Standard Deviation 19.57	17.2 nanograms per milliliter Standard Deviation 7.40	19.9 nanograms per milliliter Standard Deviation 22.99	—
Serum Concentrations of Tapentadol (Part 1) Day 14	44.7 nanograms per milliliter Standard Deviation 34.17	35.6 nanograms per milliliter Standard Deviation 18.14	48.5 nanograms per milliliter Standard Deviation 38.59	—

OTHER_PRE_SPECIFIED outcome

Timeframe: From Day 1 to Day 14 (End of Part1)

Population: Pharmacokinetic Analysis Set

Tapentadol-O-glucuronide is a metabolite of tapentadol. The body transforms tapentadol into its metabolites so that it can be more easily/quickly removed from the body. Tapentadol-O-glucuronide serum concentrations were measured in participants who received tapentadol PR in Part 1. All participants who had quantifiable serum concentrations were included in the descriptive pharmacokinetic analysis. Data from participants who vomited within 6 hours of administration of IMP during Part 1 were carefully assessed to decide if they should be included in the pharmacokinetic analysis.

Outcome measures

Outcome measures
Measure	Morphine Prolonged-release (Part 1) n=44 Participants The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.	Tapentadol Prolonged-release (Part 1) n=12 Participants The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.	Tapentadol Prolonged-release (Part 2) n=32 Participants 36 Participants who completed Part 1 of the trial (26 on tapentadol PR and 10 participants on morphine PR) continued treatment or switched to treatment with tapentadol PR for up to 12 months in Part 2. Participants on tapentadol PR in Part 1 continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants on morphine PR in Part 1 were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily.	Observation Period After Tapentadol in Part 2 Participants who completed tapentadol PR or morphine PR treatment in Part 1 of the study could enter the Observation Period for up to 12 months (with standard-of-care treatment if needed) after they had discontinued from tapentadol PR treatment in Part 2.
Serum Concentrations of Tapentadol-O-glucuronide (Part 1) Day 1	731.7 nanograms per milliliter Standard Deviation 840.02	603.2 nanograms per milliliter Standard Deviation 312.11	786.7 nanograms per milliliter Standard Deviation 984.42	—
Serum Concentrations of Tapentadol-O-glucuronide (Part 1) Day 14	1557.3 nanograms per milliliter Standard Deviation 1187.24	1223.8 nanograms per milliliter Standard Deviation 511.27	1700.3 nanograms per milliliter Standard Deviation 1363.41	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 8 (Part 1)

Population: Full Analysis Set

Palatability was determined in Part 1 by asking the participant "How does the medication taste". The participant was requested to give a score on a 5-point hedonic faces rating scale in combination with a verbal rating. The response can range from really bad to really good.

Outcome measures

Outcome measures
Measure	Morphine Prolonged-release (Part 1) n=24 Participants The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.	Tapentadol Prolonged-release (Part 1) n=45 Participants The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.	Tapentadol Prolonged-release (Part 2) 36 Participants who completed Part 1 of the trial (26 on tapentadol PR and 10 participants on morphine PR) continued treatment or switched to treatment with tapentadol PR for up to 12 months in Part 2. Participants on tapentadol PR in Part 1 continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants on morphine PR in Part 1 were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily.	Observation Period After Tapentadol in Part 2 Participants who completed tapentadol PR or morphine PR treatment in Part 1 of the study could enter the Observation Period for up to 12 months (with standard-of-care treatment if needed) after they had discontinued from tapentadol PR treatment in Part 2.
Palatability of Study Medication (Part 1, Day 8) Good	7 Participants	12 Participants	—	—
Palatability of Study Medication (Part 1, Day 8) Really good	3 Participants	6 Participants	—	—
Palatability of Study Medication (Part 1, Day 8) Missing	1 Participants	4 Participants	—	—
Palatability of Study Medication (Part 1, Day 8) Really bad	0 Participants	0 Participants	—	—
Palatability of Study Medication (Part 1, Day 8) Bad	0 Participants	2 Participants	—	—
Palatability of Study Medication (Part 1, Day 8) A bit bad/a bit good	13 Participants	21 Participants	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 14 (Part 1)

Population: Full Analysis Set

Outcome measures

Outcome measures
Measure	Morphine Prolonged-release (Part 1) n=24 Participants The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.	Tapentadol Prolonged-release (Part 1) n=45 Participants The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.	Tapentadol Prolonged-release (Part 2) 36 Participants who completed Part 1 of the trial (26 on tapentadol PR and 10 participants on morphine PR) continued treatment or switched to treatment with tapentadol PR for up to 12 months in Part 2. Participants on tapentadol PR in Part 1 continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants on morphine PR in Part 1 were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily.	Observation Period After Tapentadol in Part 2 Participants who completed tapentadol PR or morphine PR treatment in Part 1 of the study could enter the Observation Period for up to 12 months (with standard-of-care treatment if needed) after they had discontinued from tapentadol PR treatment in Part 2.
Palatability of Study Medication (Part 1, Day 14) Really bad	0 Participants	0 Participants	—	—
Palatability of Study Medication (Part 1, Day 14) Bad	0 Participants	1 Participants	—	—
Palatability of Study Medication (Part 1, Day 14) A bit bad/a bit good	9 Participants	23 Participants	—	—
Palatability of Study Medication (Part 1, Day 14) Good	9 Participants	11 Participants	—	—
Palatability of Study Medication (Part 1, Day 14) Really good	6 Participants	9 Participants	—	—
Palatability of Study Medication (Part 1, Day 14) Missing	0 Participants	1 Participants	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 8 (Part 1)

Population: Full Analysis Set

Acceptability of the study medication was determined in Part 1 by asking the participant "Swallowing the medication is...". The participant was requested to give a score on a 5-point hedonic faces rating scale in combination with a verbal rating. The response can range from really difficult to really easy.

Outcome measures

Outcome measures
Measure	Morphine Prolonged-release (Part 1) n=24 Participants The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.	Tapentadol Prolonged-release (Part 1) n=45 Participants The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.	Tapentadol Prolonged-release (Part 2) 36 Participants who completed Part 1 of the trial (26 on tapentadol PR and 10 participants on morphine PR) continued treatment or switched to treatment with tapentadol PR for up to 12 months in Part 2. Participants on tapentadol PR in Part 1 continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants on morphine PR in Part 1 were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily.	Observation Period After Tapentadol in Part 2 Participants who completed tapentadol PR or morphine PR treatment in Part 1 of the study could enter the Observation Period for up to 12 months (with standard-of-care treatment if needed) after they had discontinued from tapentadol PR treatment in Part 2.
Acceptability of Study Medication (Part 1, Day 8) Difficult	0 Participants	3 Participants	—	—
Acceptability of Study Medication (Part 1, Day 8) A bit difficult/a bit easy	3 Participants	5 Participants	—	—
Acceptability of Study Medication (Part 1, Day 8) Easy	8 Participants	9 Participants	—	—
Acceptability of Study Medication (Part 1, Day 8) Really easy	12 Participants	24 Participants	—	—
Acceptability of Study Medication (Part 1, Day 8) Missing	1 Participants	4 Participants	—	—
Acceptability of Study Medication (Part 1, Day 8) Really difficult	0 Participants	0 Participants	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 14 (End of Part 1)

Population: Full Analysis Set

Outcome measures

Outcome measures
Measure	Morphine Prolonged-release (Part 1) n=24 Participants The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.	Tapentadol Prolonged-release (Part 1) n=45 Participants The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.	Tapentadol Prolonged-release (Part 2) 36 Participants who completed Part 1 of the trial (26 on tapentadol PR and 10 participants on morphine PR) continued treatment or switched to treatment with tapentadol PR for up to 12 months in Part 2. Participants on tapentadol PR in Part 1 continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants on morphine PR in Part 1 were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily.	Observation Period After Tapentadol in Part 2 Participants who completed tapentadol PR or morphine PR treatment in Part 1 of the study could enter the Observation Period for up to 12 months (with standard-of-care treatment if needed) after they had discontinued from tapentadol PR treatment in Part 2.
Acceptability of Study Medication (Part 1, Day 14) Difficult	0 Participants	1 Participants	—	—
Acceptability of Study Medication (Part 1, Day 14) Really difficult	1 Participants	1 Participants	—	—
Acceptability of Study Medication (Part 1, Day 14) A bit difficult/a bit easy	2 Participants	7 Participants	—	—
Acceptability of Study Medication (Part 1, Day 14) Easy	8 Participants	16 Participants	—	—
Acceptability of Study Medication (Part 1, Day 14) Really easy	13 Participants	19 Participants	—	—
Acceptability of Study Medication (Part 1, Day 14) Missing	0 Participants	1 Participants	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: From baseline (Day 15 or switch) to last assessment (up to Day 379 of Part 2)

Population: Safety Set

Constipation was assessed using the modified constipation assessment scale (mCAS). This is an 8-item questionnaire where the observer has scored constipation on a nominal scale (no problem \[score 0\], some problem \[score 1\] or severe problem \[score 2\]). The response to an item could also be scored as "unable to assess". The Total Score can vary from 0-16; the higher the Total Score the higher the extent of constipation. A positive change from baseline to last assessment indicates a worsening, a negative change an improvement.

Outcome measures

Outcome measures
Measure	Morphine Prolonged-release (Part 1) n=36 Participants The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.	Tapentadol Prolonged-release (Part 1) n=18 Participants The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.	Tapentadol Prolonged-release (Part 2) n=14 Participants 36 Participants who completed Part 1 of the trial (26 on tapentadol PR and 10 participants on morphine PR) continued treatment or switched to treatment with tapentadol PR for up to 12 months in Part 2. Participants on tapentadol PR in Part 1 continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants on morphine PR in Part 1 were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily.	Observation Period After Tapentadol in Part 2 n=26 Participants Participants who completed tapentadol PR or morphine PR treatment in Part 1 of the study could enter the Observation Period for up to 12 months (with standard-of-care treatment if needed) after they had discontinued from tapentadol PR treatment in Part 2.
Extent of Constipation (Part 2) Baseline	2.3 units on a scale Standard Deviation 2.4	1.8 units on a scale Standard Deviation 2.3	2.5 units on a scale Standard Deviation 2.5	1.5 units on a scale Standard Deviation 2.5
Extent of Constipation (Part 2) Last assessment	1.8 units on a scale Standard Deviation 2.7	0.4 units on a scale Standard Deviation 0.8	0.4 units on a scale Standard Deviation 1.2	0.8 units on a scale Standard Deviation 1.7
Extent of Constipation (Part 2) Change from baseline	-0.7 units on a scale Standard Deviation 3.3	-1.4 units on a scale Standard Deviation 2.1	-1.6 units on a scale Standard Deviation 1.7	-1.4 units on a scale Standard Deviation 2.7

OTHER_PRE_SPECIFIED outcome

Timeframe: From Day 1 to Day 386 (End of Part 2 + 7 days)

Population: Safety Set

Opiate withdrawal symptoms were assessed using the Subjective Opiate Withdrawal Scale (SOWS) questionnaire. The SOWS is designed to reflect common motoric, autonomic, musculoskeletal, and psychic signs and symptoms of opiate withdrawal. Each participant was requested to rate the first 15 items of the 16-item questionnaire for 7 days after last IMP intake. Participants rated the intensity of specific signs and symptoms on a scale of 0 (not at all) to 4 (extremely). The minimum overall score is 0, the maximum score is 64. SOWS Total Score at baseline (i.e., for Part 1 = Day 14-17, for Part 2 = Day 352-380, or the day after an early termination visit (Part 1/2)), and changes from baseline 2-7 days after last intake of IMP in Part 1 (= up to Day 23) and in Part 2 (= up to Day 386) are presented.

Outcome measures

Outcome measures
Measure	Morphine Prolonged-release (Part 1) n=24 Participants The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.	Tapentadol Prolonged-release (Part 1) n=45 Participants The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.	Tapentadol Prolonged-release (Part 2) n=36 Participants 36 Participants who completed Part 1 of the trial (26 on tapentadol PR and 10 participants on morphine PR) continued treatment or switched to treatment with tapentadol PR for up to 12 months in Part 2. Participants on tapentadol PR in Part 1 continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants on morphine PR in Part 1 were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily.	Observation Period After Tapentadol in Part 2 Participants who completed tapentadol PR or morphine PR treatment in Part 1 of the study could enter the Observation Period for up to 12 months (with standard-of-care treatment if needed) after they had discontinued from tapentadol PR treatment in Part 2.
Change From Baseline in Subjective Opiate Withdrawal Scale (SOWS) Total score at baseline	4.0 units on a scale Standard Deviation 3.8	6.9 units on a scale Standard Deviation 7.6	6.1 units on a scale Standard Deviation 6.0	—
Change From Baseline in Subjective Opiate Withdrawal Scale (SOWS) Change Day 2 after last IMP intake	-0.4 units on a scale Standard Deviation 2.0	-1.7 units on a scale Standard Deviation 2.5	-0.7 units on a scale Standard Deviation 2.8	—
Change From Baseline in Subjective Opiate Withdrawal Scale (SOWS) Change Day 3 after last IMP intake	-1.6 units on a scale Standard Deviation 2.7	-2.3 units on a scale Standard Deviation 4.9	-0.3 units on a scale Standard Deviation 3.1	—
Change From Baseline in Subjective Opiate Withdrawal Scale (SOWS) Change Day 4 after last IMP intake	-1.7 units on a scale Standard Deviation 4.4	-3.9 units on a scale Standard Deviation 4.7	-0.1 units on a scale Standard Deviation 3.6	—
Change From Baseline in Subjective Opiate Withdrawal Scale (SOWS) Change Day 5 after last IMP intake	-1.6 units on a scale Standard Deviation 3.6	-3.8 units on a scale Standard Deviation 5.1	0 units on a scale Standard Deviation 5.0	—
Change From Baseline in Subjective Opiate Withdrawal Scale (SOWS) Change Day 6 after last IMP intake	-2.3 units on a scale Standard Deviation 3.6	-3.6 units on a scale Standard Deviation 4.6	-0.6 units on a scale Standard Deviation 3.1	—
Change From Baseline in Subjective Opiate Withdrawal Scale (SOWS) Change Day 7 after last IMP intake	-2.7 units on a scale Standard Deviation 3.9	-5.1 units on a scale Standard Deviation 6.3	-1.4 units on a scale Standard Deviation 2.8	—

OTHER_PRE_SPECIFIED outcome

Timeframe: From first day in Part 1 (Day 1) to last day in Part 1

The time to discontinuation from IMP due to lack of efficacy was planned to be analyzed for both treatment arms (tapentadol PR and morphine PR) in Part 1 of the trial. However, no participant was reported with early discontinuation from IMP due to lack of efficacy. Consequently, no time to discontinuation can be reported.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: From first day in Part 2 (Day 15) to last day in Part 2 (Day 379)

Population: Safety Set; 3 participants with early discontinuation from IMP due to lack of efficacy

The time to discontinuation from IMP due to lack of efficacy was analyzed for tapentadol PR treatment in Part 2 of the trial.

Outcome measures

Outcome measures
Measure	Morphine Prolonged-release (Part 1) n=3 Participants The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.	Tapentadol Prolonged-release (Part 1) The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.	Tapentadol Prolonged-release (Part 2) 36 Participants who completed Part 1 of the trial (26 on tapentadol PR and 10 participants on morphine PR) continued treatment or switched to treatment with tapentadol PR for up to 12 months in Part 2. Participants on tapentadol PR in Part 1 continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants on morphine PR in Part 1 were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily.	Observation Period After Tapentadol in Part 2 Participants who completed tapentadol PR or morphine PR treatment in Part 1 of the study could enter the Observation Period for up to 12 months (with standard-of-care treatment if needed) after they had discontinued from tapentadol PR treatment in Part 2.
Time to Discontinuation (Lack of Efficacy) in Part 2	30.9 weeks Interval 9.0 to 36.0	—	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: From first day in Part 1 (Day 1) to last day in Part 1 (Day 14)

The time to discontinuation from IMP due to treatment emergent adverse events (TEAEs) was analyzed for both treatment arms (tapentadol PR and morphine PR) in Part 1 of the study. Note that no participant discontinued due to a TEAE in the morphine PR arm, and 2 participants in the tapentadol PR arm.

Outcome measures

Outcome measures
Measure	Morphine Prolonged-release (Part 1) n=24 Participants The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.	Tapentadol Prolonged-release (Part 1) n=45 Participants The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.	Tapentadol Prolonged-release (Part 2) 36 Participants who completed Part 1 of the trial (26 on tapentadol PR and 10 participants on morphine PR) continued treatment or switched to treatment with tapentadol PR for up to 12 months in Part 2. Participants on tapentadol PR in Part 1 continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants on morphine PR in Part 1 were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily.	Observation Period After Tapentadol in Part 2 Participants who completed tapentadol PR or morphine PR treatment in Part 1 of the study could enter the Observation Period for up to 12 months (with standard-of-care treatment if needed) after they had discontinued from tapentadol PR treatment in Part 2.
Time to Discontinuation (Treatment Emergent Adverse Events) in Part 1	NA days No participant discontinued due to a TEAE in the morphine PR arm.	3.0 days Interval 2.0 to 4.0	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: From first day in Part 2 (Day 15) to last day in Part 2 (Day 379)

Population: Safety Set; 3 participants discontinued due to treatment emergent adverse events.

The time to discontinuation from IMP due to treatment emergent adverse events (TEAEs) was analyzed for tapentadol PR treatment in Part 2 of the study.

Outcome measures

Outcome measures
Measure	Morphine Prolonged-release (Part 1) n=36 Participants The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.	Tapentadol Prolonged-release (Part 1) The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.	Tapentadol Prolonged-release (Part 2) 36 Participants who completed Part 1 of the trial (26 on tapentadol PR and 10 participants on morphine PR) continued treatment or switched to treatment with tapentadol PR for up to 12 months in Part 2. Participants on tapentadol PR in Part 1 continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants on morphine PR in Part 1 were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily.	Observation Period After Tapentadol in Part 2 Participants who completed tapentadol PR or morphine PR treatment in Part 1 of the study could enter the Observation Period for up to 12 months (with standard-of-care treatment if needed) after they had discontinued from tapentadol PR treatment in Part 2.
Time to Discontinuation (Treatment Emergent Adverse Events) in Part 2	5.3 weeks Interval 3.0 to 24.0	—	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: From Day 1 up to Day 14 (End of Part 1)

Population: Full Analysis Set

Morphine oral solution could be given during Part 1 as rescue medication in both treatment groups. The dose per rescue medication intake was 1/6 of the total daily dose of the scheduled tapentadol or morphine PR intakes. Rescue medication administration times and doses were recorded. 18 Participants in the morphine PR group and 27 participants in the tapentadol PR group had no documented intake of rescue medication between Day 1 and Day 14. Summary statistics were calculated based on participants with any intake, i.e., those that took at least 1 dose of rescue medication. The mean (standard deviation) time (hours) to first dose of rescue medication following the first dose of the IMP (on Day 1) is presented.

Outcome measures

Outcome measures
Measure	Morphine Prolonged-release (Part 1) n=24 Participants The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.	Tapentadol Prolonged-release (Part 1) n=45 Participants The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.	Tapentadol Prolonged-release (Part 2) 36 Participants who completed Part 1 of the trial (26 on tapentadol PR and 10 participants on morphine PR) continued treatment or switched to treatment with tapentadol PR for up to 12 months in Part 2. Participants on tapentadol PR in Part 1 continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants on morphine PR in Part 1 were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily.	Observation Period After Tapentadol in Part 2 Participants who completed tapentadol PR or morphine PR treatment in Part 1 of the study could enter the Observation Period for up to 12 months (with standard-of-care treatment if needed) after they had discontinued from tapentadol PR treatment in Part 2.
Time to First Intake of Rescue Medication in the Open-label, Active-controlled Treatment Period (Part 1) Participants with rescue medication intake	39.7 hours Standard Deviation 63.75	74.6 hours Standard Deviation 94.45	—	—
Time to First Intake of Rescue Medication in the Open-label, Active-controlled Treatment Period (Part 1) Participants with no rescue medication intake	NA hours Standard Deviation NA No documented intake of rescue medication between Day 1 and Day 14.	NA hours Standard Deviation NA No documented intake of rescue medication between Day 1 and Day 14.	—	—

Adverse Events

Morphine Prolonged-release (Part 1)

Serious events: 1 serious events

Other events: 11 other events

Deaths: 0 deaths

Tapentadol Prolonged-release (Part 1)

Serious events: 3 serious events

Other events: 26 other events

Deaths: 0 deaths

Overall (Part 1)

Serious events: 4 serious events

Other events: 37 other events

Deaths: 0 deaths

Tapentadol Prolonged-release in Part 2

Serious events: 13 serious events

Other events: 30 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

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Results disclosure agreements

Principal investigator is a sponsor employee The sponsor reserves the right to review any proposed presentation of the results of this trial before they are submitted for publication or public disclosure. Neither party (e.g., the sponsor, the coordinating investigator) has the right to prohibit publication or public disclosure unless it can be shown to affect possible patent rights.
Publication restrictions are in place

Restriction type: OTHER