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Clinical Trial Results:
A randomised, double-blind, double-dummy, parallel-group multicenter study to demonstrate improvement in symptoms of constipation and non-inferiority in analgesic efficacy in subjects with non-malignant or malignant pain that requires around-the-clock opioid therapy taking 50/25-80/40 mg twice daily as oxycodone/naloxone prolonged release (OXN PR) tablets compared to subjects taking 50-80 mg twice daily oxycodone prolonged release (OxyPR) tablets alone. During the open-label Extension Phase the efficacy and safety of OXN PR were assessed in doses up to OXN90/45 mg PR twice daily.

Summary
EudraCT number	2010-021995-27
Trial protocol	GB CZ DE FI DK RO
Global end of trial date	18 Aug 2014

Results information
Results version number	v3(current)
This version publication date	08 Jul 2016
First version publication date	12 Aug 2015
Other versions	v1 , v2
Version creation reason	Changes to summary attachments Remove user due to them leaving the company.

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

OXN3506

ISRCTN number

US NCT number

NCT01438567

WHO universal trial number (UTN)

Sponsor organisation name

Mundipharma Research GmbH & Co. KG

Sponsor organisation address

Höhenstrasse 10, Limburg, Germany, D-65549

Public contact

Clinical Trial Contact, Mundipharma Research GmbH & Co. KG, 0044 1223424900, info@contact-clinical-trial.com

Scientific contact

Clinical Trial Contact, Mundipharma Research GmbH & Co. KG, 0044 1223424900, info@contact-clinical-trial.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

18 Aug 2014

Is this the analysis of the primary completion data?

Yes

Primary completion date

18 Aug 2014

Global end of trial reached?

Yes

Global end of trial date

18 Aug 2014

Was the trial ended prematurely?

Main objective of the trial

Core study phase: 1. To demonstrate that subjects taking OXN PR have improvement in symptoms of constipation as measured by the Bowel Function Index (BFI) compared to subjects taking OxyPR. 2. To demonstrate non-inferiority of OXN PR compared to OxyPR with respect to the analgesic efficacy based on the subjects' "Average Pain over last 24 Hours" assessed at each Double-blind Phase visit as measured by the Pain Intensity Scale. Extension Phase: 3. To assess bowel function, pain and safety parameters.

Protection of trial subjects

The approved dose range of OXN PR is up to OXN80/40 mg PR per day, which is sufficient to manage a significant segment of the population of patients with severe pain. However, it is evident that there is a need of OXN PR daily doses higher than 80/40 mg. Currently, in the OXN PR SmPC allowance for this situation is made by the compromise that “for patients requiring higher doses of OXN PR, administration of supplemental oxycodone at the same time interval should be considered taking into account the maximum daily dose of 400 mg oxycodone PR”. However it is to be considered that in the case of supplemental oxycodone dosing the beneficial effect of naloxone on the bowel function may be impaired as also outlined in the current SmPC. Consequently, patients in need of higher doses would clearly benefit from the maintenance of the 2:1 ratio in doses beyond OXN80/40 mg PR per day. Based on the results from the Double-blind Phase of this study, it can be assumed that OXN PR can be used safely in patients requiring daily doses up to OXN160/80 mg PR per day. It is not expected that long-term use will cause any additional safety issues. Based on the available data, there is accumulating evidence that OXN PR is efficacious and generally well tolerated in doses up to OXN160/80 mg PR per day. Therefore it can be assumed that OXN PR can be used safely in patients requiring daily doses above OXN 80/40 mg PR per day and the administration of daily dose up to OXN180/90 mg PR in study OXN3506 does not add any risk to the subjects. OxyIR was the only allowed analgesic rescue medication. It was to be dosed no sooner than every 4 hours as needed. Six rescue doses of OxyIR was the total maximum amount of analgesic rescue medication per day. For a subject stabilised on 50 mg of OXN PR or OxyPR twice daily, the rescue dose of OxyIR would have been 15 mg; for a subject stabilised on 60 mg of OXN PR or OxyPR twice daily, the rescue dose of OxyIR would have been 20 mg; for a subject stab

Background therapy

Oxycodone immediate-release (IR) capsules (5, 10, 20 mg) was the only allowed analgesic rescue medication. It was to be dosed no sooner than every 4 hours as needed. Six rescue doses of OxyIR was the total maximum amount of analgesic rescue medication per day. For a subject stabilised on 50 mg of OXN PR or OxyPR twice daily, the rescue dose of OxyIR would have been 15 mg; for a subject stabilised on 60 mg of OXN PR or OxyPR twice daily, the rescue dose of OxyIR would have been 20 mg; for a subject stabilised on 70 or 80 mg of OXN PR or OxyPR twice daily, the rescue dose of OxyIR would have been 25 mg. Oral bisacodyl could be used as laxative rescue medication for constipation, no sooner than 72 hours after the subject’s most recent bowel movement. However, Investigators instructed their subjects that if they exhibited discomfort during the 72 hours period they could take oral bisacodyl as a laxative rescue medication for the treatment of constipation earlier than 72 hours after their most recent bowel movement. Overall the maximum allowed amount of bisacodyl was not to exceed 5 dosages bisacodyl 10 mg/day within 7 consecutive days. At the discretion of the Investigator, the bisacodyl dose may have been lowered (5 mg) if the Investigator/subject felt that the dose was higher than required to provide an adequate bowel movement.

Evidence for comparator

Actual start date of recruitment

15 Aug 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 4

Country: Number of subjects enrolled

Israel: 1

Country: Number of subjects enrolled

Poland: 55

Country: Number of subjects enrolled

Romania: 8

Country: Number of subjects enrolled

United Kingdom: 27

Country: Number of subjects enrolled

Czech Republic: 62

Country: Number of subjects enrolled

Denmark: 12

Country: Number of subjects enrolled

Finland: 3

Country: Number of subjects enrolled

France: 2

Country: Number of subjects enrolled

Germany: 69

Worldwide total number of subjects

243

EEA total number of subjects

238

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

181

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

All 243 subjects were enrolled at 66 sites in 11 countries between 26 Sep 2011 and 21 Nov 2013.

Screening details

363 subjects were enrolled, of whom 44 (12.1%) subjects were screening failures. The most frequently named reason for screening failure was failing of screening procedures in 25 subjects (6.9%). Adverse events led to the screening failure of 8 subjects (2.2%) and serious adverse events caused 3 screening failures (0.8%).

Period 1 title

Core study

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

During the double-blind Phase, the subject and all personnel involved with the conduct and the interpretation of the study, including the investigators, site personnel, and the Sponsor’s staff, were blinded to the medication codes. The randomisation schedule was filed securely by the Sponsor/IRT provider, in a manner such that blinding was properly maintained throughout the study.

Are arms mutually exclusive

Yes

OXN PR

Arm description

Arm type

Experimental

Investigational medicinal product name

Oxycodone/naloxone prolonged release

Investigational medicinal product code

OXN PR

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10/5, 20/10, and 40/20 mg OXN PR tablets administered 12 -hourly to give the following dose levels: OXN 50/25 mg PR, OXN 60/30 mg PR, OXN 70/35 mg PR and OXN 80/40 mg PR twice daily

OxyPR

Arm description

Arm type

Active comparator

Investigational medicinal product name

Oxycodone prolonged release

Investigational medicinal product code

OxyPR

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10, 20, and 40 mg OxyPR tablets plus matching placebos for 10/5, 20/10 and 40/20 mg OXN PR tablets to give dose levels of: OxyPR 50 mg, OxyPR 60 mg, OxyPR 70 mg and OxyPR 80 mg twice daily.

Number of subjects in period 1	OXN PR	OxyPR
Started	123	120
Completed	105	104
Not completed	18	16
Adverse event, serious fatal	1	3
Consent withdrawn by subject	6	8
Administrative	-	2
Adverse event, non-fatal	8	2
Not specified	1	-
Lack of efficacy	2	1

Period 2 title

Extension

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

OXN PR (Extension)

Arm description

Subjects who completed the 5 weeks Double-blind Phase, or subjects who discontinued the Double-blind Phase prematurely due to constipation, were eligible to enter the Extension Phase, which consisted of additional 24 weeks treatment with open-label OXN PR up to a maximum dose of OXN90/45 mg PR twice daily.

Arm type

Experimental

Investigational medicinal product name

Oxycodone/naloxone prolonged release

Investigational medicinal product code

OXN PR

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

All subjects who entered the Extension Phase started with the OxyPR dose which the subjects received at the end of the double-blind phase/early discontinuation. The switch to open-label OXN PR was done in a stepwise, double-blind, double-dummy manner during the first week of the Extension Phase. OxyIR was provided for the first 7 days of the Extension Phase only. The different dose levels were OXN50/25 mg PR, OXN60/30 mg PR, OXN70/35 mg PR and OXN80/40 mg PR twice daily. Titration up to the maximum daily dose of OXN90/45 mg PR twice daily was permitted from Visit 12 onwards. The different dose levels were OXN50/25 mg PR, OXN60/30 mg PR, OXN70/35 mg PR, OXN80/40 mg PR and OXN90/45 mg PR twice daily.

Number of subjects in period 2 ^[1]	OXN PR (Extension)
Started	195
Completed	167
Not completed	28
Consent withdrawn by subject	9
Administrative	1
Adverse event, non-fatal	16
Lack of efficacy	2

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Only those subjects who completed the 5 week Double-blind Phase or who discontinued the Double-blind Phase prematurely due to constipation were eligible to enter the Extension Phase. Altogether almost all subjects who had completed the Double-blind Phase (195 of the 209 subjects) continued to the Extension Phase.

Baseline characteristics

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Reporting group title

Core study

Reporting group description

This study was composed of three phases: a Pre-randomisation Phase, a Double-blind Phase and an Extension Phase. The Pre-randomisation Phase contained two periods: the Screening Period and the Run-in Period. The Screening Period involved prospective assessments and was designed to qualify subjects for participation in the Run-in Period. The Run-in Period was designed to titrate OxyPR to analgesic effect, qualify subjects for participation in the Double-blind Phase, e.g. confirm their constipation, and enable identification of a starting dose equivalent for the study medication to be used after randomisation. The Double-blind Phase was designed to demonstrate improvement in symptoms of constipation and non-inferiority in analgesic efficacy from OXN PR compared to subjects taking OxyPR tablets alone. This is the analysis of the core study, which summarises the results of the Pre-randomisation Phase and the Double-blind Phase.

Reporting group values	Core study	Total
Number of subjects	243	243
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	181	181
From 65-84 years	60	60
85 years and over	2	2
Gender categorical
Units: Subjects
Female	143	143
Male	100	100

Subject analysis set title

Full analysis population

Subject analysis set type

Full analysis

Subject analysis set description

Subjects who were randomised and received at least one dose of study medication during the Double-blind Phase and who had at least a one week Double-blind assessment of the primary efficacy variable, the BFI.

Subject analysis set title

Double-blind safety population

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects who received at least one dose of Double-blind study medication and had at least one safety assessment after that dose.

Subject analysis set title

Total exposure safety population (Extension phase)

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects who received at least one dose of OXN PR in the Extension Phase and had at least one safety assessment after the first dose of extension phase study medication.

Subject analysis set title

Received OXN PR during Double-blind phase (Extension Phase)

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects who had received OXN PR in the Double-blind Phase, and who started the Extension Phase.

Subject analysis set title

Received OxyPR during Double-blind phase (Extension phase)

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects who had received OxyPR in the Double-blind Phase, and who started the Extension Phase.

Subject analysis sets values	Full analysis population	Double-blind safety population	Total exposure safety population (Extension phase)	Received OXN PR during Double-blind phase (Extension Phase)	Received OxyPR during Double-blind phase (Extension phase)
Number of subjects	237	243	195	100	95
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	178	181	150
From 65-84 years	58	61	44
85 years and over	1	1	1
Age continuous
Units:
	( )	( )	( )	( )	( )
Gender categorical
Units: Subjects
Female	112	143	115
Male	77	100	80

End points

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Reporting group title

OXN PR

Reporting group description

Reporting group title

OxyPR

Reporting group description

Reporting group title

OXN PR (Extension)

Reporting group description

Subject analysis set title

Full analysis population

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Double-blind safety population

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects who received at least one dose of Double-blind study medication and had at least one safety assessment after that dose.

Subject analysis set title

Total exposure safety population (Extension phase)

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects who received at least one dose of OXN PR in the Extension Phase and had at least one safety assessment after the first dose of extension phase study medication.

Subject analysis set title

Received OXN PR during Double-blind phase (Extension Phase)

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects who had received OXN PR in the Double-blind Phase, and who started the Extension Phase.

Subject analysis set title

Received OxyPR during Double-blind phase (Extension phase)

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects who had received OxyPR in the Double-blind Phase, and who started the Extension Phase.

Primary: Improvement in Bowel Function Index

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End point title

Improvement in Bowel Function Index

End point description

The BFI is a 3-term questionnaire to measure constipation from the patient’s perspective. Study personnel asked the subject to rate ease of defecation, feeling of incomplete bowel evacuation and personal judgment of constipation in the last 7 days on a scale of 0 to 100, with lower numbers representing good and higher numbers representing poor bowel function. The BFI was assessed on Visit 1, 2 and 3 in the pre-randomisation Phase and on Visit 7,-10 in the Double-blind Phase.

End point type

Primary

End point timeframe

Change in BFI from baseline at start of double-blind phase (Visit 3) to 5 weeks.

End point values	OXN PR	OxyPR	Full analysis population
Number of subjects analysed	104	101	205
Units: Units
arithmetic mean (standard deviation)	-32.5 ( 26.96 )	-14.2 ( 22.65 )	-23.5 ( 26.52 )

Superiority of OXN vs oxycodone (BFI improvement)

Statistical analysis description

The objective of the analysis of BFI was to show that OXN PR is superior to OxyPR, using a one-tailed test at a 2.5% significance level. The null hypothesis was that there is no difference between the treatment groups. The alternative hypothesis was that there is a difference between the treatment groups. A mixed model repeated measures analysis of covariance of the BFI was carried out for Weeks 1, 2, 4 and 5 as repeated measures.

Comparison groups

OxyPR v OXN PR

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

< 0.001

Method

Repeated measures analysis

Parameter type

Mean difference (final values)

Point estimate

-16.05

Confidence interval

level

95%

sides

2-sided

lower limit

-22.23

upper limit

-9.86

Variability estimate

Standard error of the mean

Dispersion value

3.14

Notes
[1] - Full analysis population was used for this analysis.

Primary: Average pain over last 24 hours

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End point title

Average pain over last 24 hours

End point description

The subjects’ average pain over the last 24 hours as measured by the Pain Intensity Scale (NRS 0-10), with 0 meaning no pain and 10 meaning worst imaginable pain.

End point type

Primary

End point timeframe

Average pain over the last 24 hours at Week 5.

End point values	OXN PR	OxyPR
Number of subjects analysed	93	94
Units: Units
arithmetic mean (standard deviation)	3.6 ( 1.17 )	3.4 ( 1.32 )

Non-inferiority of OXN vs oxycodone (Average pain)

Statistical analysis description

The objective of the analysis of average pain over 24 hours was to show that OXN PR is non-inferior to OxyPR, using a one-tailed test at a 2.5% significance level. The null hypothesis was that the ratio between OXN PR and OxyPR in the ‘Average Pain over the last 24 hours’ is greater than or equal to 120%. The alternative hypothesis was that the ratio between OXN PR and OxyPR is lower than 120%. The change from baseline was analysed using a mixed model repeated measures analysis.

Comparison groups

OXN PR v OxyPR

Number of subjects included in analysis

187

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.001

Method

Repeated measures analysis

Parameter type

Mean difference (final values)

Point estimate

-0.65

Confidence interval

level

95%

sides

2-sided

lower limit

-0.99

upper limit

-0.3

Variability estimate

Standard error of the mean

Dispersion value

0.17

Other pre-specified: Improvement in Bowel Function Index (BFI) during Extension Phase

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End point title

Improvement in Bowel Function Index (BFI) during Extension Phase

End point description

End point type

Other pre-specified

End point timeframe

The change in BFI from baseline (visit 11) to week 24 (visit 19) was assessed in the Extension Phase.

End point values	OXN PR (Extension)	Total exposure safety population (Extension phase)	Received OXN PR during Double-blind phase (Extension Phase)	Received OxyPR during Double-blind phase (Extension phase)
Number of subjects analysed	164	164	85	79
Units: Units
arithmetic mean (standard deviation)	-18.9 ( 27.68 )	-18.9 ( 27.68 )	-8.3 ( 24.77 )	-30.4 ( 26.15 )

No statistical analyses for this end point

Other pre-specified: Average pain over last 24 hours during Extension phase

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End point title

Average pain over last 24 hours during Extension phase

End point description

The subjects’ average pain over the last 24 hours as measured by the Pain Intensity Scale (NRS 0-10), with 0 meaning no pain and 10 meaning worst imaginable pain.

End point type

Other pre-specified

End point timeframe

Change in 'Average pain over the last 24 hours' from baseline (visit 11) to week 24 (visit 19).

End point values	OXN PR (Extension)	Total exposure safety population (Extension phase)	Received OXN PR during Double-blind phase (Extension Phase)	Received OxyPR during Double-blind phase (Extension phase)
Number of subjects analysed	162	162	85	77
Units: Units
arithmetic mean (standard deviation)	0.1 ( 1.35 )	0.1 ( 1.35 )	0.2 ( 1.3 )	0.1 ( 1.41 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Treatment-emergent AEs that occurred during the Double-blind Phase were those with an onset date on or after the first dose of Double-blind study medication up to and including 7 days after the last dose of study medication.

Adverse event reporting additional description

Only treatment emergent AEs were included in the summary tables. A treatment emergent AE was defined as any AE (or worsening of an AE) with an onset date on or after the first dose of study medication . This also included AEs with an onset date up to and including 7 days after the last dose of study medication.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

14.0

Reporting group title

OXN PR

Reporting group description

Reporting group title

Total exposure safety population (Extension phase)

Reporting group description

Reporting group title

OxyPR

Reporting group description

Oxycodone prolonged-release

Serious adverse events	OXN PR	Total exposure safety population (Extension phase)	OxyPR
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 123 (2.44%)	21 / 195 (10.77%)	4 / 120 (3.33%)
number of deaths (all causes)	1	4	3
number of deaths resulting from adverse events	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm malignant
subjects affected / exposed	2 / 123 (1.63%)	2 / 195 (1.03%)	3 / 120 (2.50%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 2	0 / 2	0 / 3
Adenocarcinoma
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Lymphatic system neoplasm
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to central nervous system
subjects affected / exposed	0 / 123 (0.00%)	2 / 195 (1.03%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0
Prostate cancer
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Hot flush
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chills
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Drug ineffective
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Feeling cold
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	1 / 123 (0.81%)	0 / 195 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pleurisy
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Restlessness
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina unstable
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary ostial stenosis
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Extrasystoles
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sinus bradycardia
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Dental caries
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tooth disorder
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tooth loss
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Hyperhidrosis
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
Back pain
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myofascial pain syndrome
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Bone abscess
subjects affected / exposed	0 / 123 (0.00%)	0 / 195 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchistis
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 123 (0.00%)	0 / 195 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 123 (0.00%)	1 / 195 (0.51%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	OXN PR	Total exposure safety population (Extension phase)	OxyPR
Total subjects affected by non serious adverse events
subjects affected / exposed	67 / 123 (54.47%)	128 / 195 (65.64%)	57 / 120 (47.50%)
Nervous system disorders
Headache
subjects affected / exposed	2 / 123 (1.63%)	13 / 195 (6.67%)	2 / 120 (1.67%)
occurrences all number	2	15	2
General disorders and administration site conditions
Pain
subjects affected / exposed	5 / 123 (4.07%)	16 / 195 (8.21%)	4 / 120 (3.33%)
occurrences all number	8	25	12
Gastrointestinal disorders
Nausea
subjects affected / exposed	12 / 123 (9.76%)	12 / 195 (6.15%)	6 / 120 (5.00%)
occurrences all number	12	13	6
Diarrhoea
subjects affected / exposed	6 / 123 (4.88%)	15 / 195 (7.69%)	5 / 120 (4.17%)
occurrences all number	9	16	5
Constipation
subjects affected / exposed	2 / 123 (1.63%)	12 / 195 (6.15%)	2 / 120 (1.67%)
occurrences all number	2	13	2
Skin and subcutaneous tissue disorders
Hyperhidrosis
subjects affected / exposed	8 / 123 (6.50%)	11 / 195 (5.64%)	3 / 120 (2.50%)
occurrences all number	8	12	3

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Primary: Improvement in Bowel Function Index

Primary: Improvement in Bowel Function Index

Primary: Average pain over last 24 hours

Primary: Average pain over last 24 hours

Other pre-specified: Improvement in Bowel Function Index (BFI) during Extension Phase

Other pre-specified: Improvement in Bowel Function Index (BFI) during Extension Phase

Other pre-specified: Average pain over last 24 hours during Extension phase

Other pre-specified: Average pain over last 24 hours during Extension phase

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