Clinical Trials Register

Summary
EudraCT Number:	2012-001772-11
Sponsor's Protocol Code Number:	OXN2505
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-10-07
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Czechia - SUKL

A.2

EudraCT number

2012-001772-11

A.3

Full title of the trial

An exploratory, double-blind, double-dummy, randomised, 2-period, crossover, Phase IIa study to assess the influence of oxycodone/naloxone prolonged-release tablets (OXN PR) and oxycodone prolonged-release tablets (OxyPR) on intestinal microbiota and other gastrointestinal parameters in subjects suffering from non-malignant pain requiring an equivalent of 20 – 50 mg oxycodone prolonged-release per day

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study which assesses the effects of two pain medications: oxycodone/naloxone prolonged-release tablets (OXN PR) and oxycodone prolonged-release tablets (OxyPR) on the gastrointestinal system of subjects suffering from non-cancer pain

A.4.1

Sponsor's protocol code number

OXN2505

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Mundipharma Research GmbH & Co. KG
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Mundipharma Research GmbH & Co. KG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Mundipharma Research GmbH & Co.KG
B.5.2	Functional name of contact point	Clinical Trial Contact
B.5.3	Address:
B.5.3.1	Street Address	Hoehenstrasse 10
B.5.3.2	Town/ city	Limburg
B.5.3.3	Post code	65549
B.5.3.4	Country	Germany
B.5.4	Telephone number	00496431701453
B.5.5	Fax number	004964317018453
B.5.6	E-mail	info@contact-clinical-trial.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Targinact 5 mg/2.5 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Napp Pharmaceuticals Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	oxycodone/naloxone 5 mg/ 2.5 mg prolonged release tablet
D.3.2	Product code	OXN5/2.5 mg PR
D.3.4	Pharmaceutical form	Prolonged-release tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	OXYCODONE HYDROCHLORIDE
D.3.9.1	CAS number	124-90-3
D.3.9.2	Current sponsor code	Not applicable
D.3.9.3	Other descriptive name	Oxycodone hydrochloride
D.3.9.4	EV Substance Code	SUB03583MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NALOXONE HYDROCHLORIDE DIHYDRATE
D.3.9.1	CAS number	51481-60-8
D.3.9.2	Current sponsor code	Not applicable
D.3.9.3	Other descriptive name	Naloxone hydrochloride dihydrate
D.3.9.4	EV Substance Code	SUB03382MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Targinact 10mg/5mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Napp Pharmaceuticals Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Oxycodone/naloxone 10 mg/5 mg prolonged release tablet
D.3.2	Product code	OXN10/5 mg PR
D.3.4	Pharmaceutical form	Prolonged-release tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	OXYCODONE HYDROCHLORIDE
D.3.9.1	CAS number	124-90-3
D.3.9.2	Current sponsor code	Not applicable
D.3.9.3	Other descriptive name	Oxycodone hydrochloride
D.3.9.4	EV Substance Code	SUB03583MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NALOXONE HYDROCHLORIDE DIHYDRATE
D.3.9.1	CAS number	51481-60-8
D.3.9.2	Current sponsor code	Not applicable
D.3.9.3	Other descriptive name	Naloxone hydrochloride dihydrate
D.3.9.4	EV Substance Code	SUB03382MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Targinact 20 mg/10 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Napp Pharmaceuticals Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	oxycodone/naloxone 20 mg/ 10 mg prolonged release tablet
D.3.2	Product code	OXN 20/10 mg PR
D.3.4	Pharmaceutical form	Prolonged-release tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	OXYCODONE HYDROCHLORIDE
D.3.9.1	CAS number	124-90-3
D.3.9.2	Current sponsor code	Not applicable
D.3.9.3	Other descriptive name	Oxycodone hydrochloride
D.3.9.4	EV Substance Code	SUB03583MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NALOXONE HYDROCHLORIDE DIHYDRATE
D.3.9.1	CAS number	51481-60-8
D.3.9.2	Current sponsor code	Not applicable
D.3.9.3	Other descriptive name	Naloxone hydrochloride dihydrate
D.3.9.4	EV Substance Code	SUB03382MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 4
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	OxyContin 5 mg prolonged release tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Napp Pharmaceuticals Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Oxycodone prolonged release tablet 5mg
D.3.4	Pharmaceutical form	Prolonged-release tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	OXYCODONE HYDROCHLORIDE
D.3.9.1	CAS number	124-90-3
D.3.9.2	Current sponsor code	Not applicable
D.3.9.3	Other descriptive name	Oxycodone Hydrochloride
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 5
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	OxyContin 10mg prolonged release tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Napp Pharmaceuticals Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Oxycodone prolonged release tablet 10mg
D.3.2	Product code	OxyPR 10mg
D.3.4	Pharmaceutical form	Prolonged-release tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	OXYCODONE HYDROCHLORIDE
D.3.9.1	CAS number	124-90-3
D.3.9.2	Current sponsor code	Not applicable
D.3.9.3	Other descriptive name	Oxycodone hydrochloride
D.3.9.4	EV Substance Code	SUB03583MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 6
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	OxyContin 20mg prolonged release tablet
D.2.1.1.2	Name of the Marketing Authorisation holder	Napp Pharmaceuticals Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Oxycodone prolonged release tablet 20mg
D.3.2	Product code	OxyPR 20mg
D.3.4	Pharmaceutical form	Prolonged-release tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	OXYCODONE HYDROCHLORIDE
D.3.9.1	CAS number	124-90-3
D.3.9.2	Current sponsor code	Not applicable
D.3.9.3	Other descriptive name	Oxycodone hydrochloride
D.3.9.4	EV Substance Code	SUB03583MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Prolonged-release tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Prolonged-release tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 3
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Prolonged-release tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 4
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Prolonged-release tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 5
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Prolonged-release tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 6
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Prolonged-release tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

The intended indication is:
Chronic severe non malignant pain, requiring opioids.

E.1.1.1

Medical condition in easily understood language

Chronic severe non malignant pain, requiring opioids.

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.0
E.1.2	Level	PT
E.1.2	Classification code	10033371
E.1.2	Term	Pain
E.1.2	System Organ Class	10018065 - General disorders and administration site conditions

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

• Quantitative analysis of intestinal microbiota as determined in stool samples of subjects treated with OXN PR compared to those treated with OxyPR.
• To assess orocaecal transit time on the basis of intestinal absorption and intermediary bacterial metabolism as determined by breath tests (H2 breath test, CH4 breath test) in subjects treated with OXN PR compared to those treated with OxyPR.

E.2.2

Secondary objectives of the trial

This study has ten further, exploratory objectives. Only the first four objectives can be listed here. Please refer to the protocol for the full list.

• To explore the impact of OXN PR and OxyPR on the intestinal and serum metabolome by assessing the metabolites and mapping of respective compounds to corresponding metabolic pathways using the metabolomics technology.
• To determine the change in abdominal girth in subjects treated with OXN PR compared to those treated with OxyPR.
• To assess the stool consistency based on the Bristol Stool Form Scale (BSFS) in subjects treated with OXN PR compared to those treated with OxyPR.
• To assess symptoms of constipation in subjects taking OXN PR compared to subjects taking OxyPR as measured by the Bowel Function Index (BFI).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female subjects at least 18 years (females less than one year post-menopausal must have a negative serum or urine pregnancy test prior to the first dose of study medication, be non-lactating, and willing to use adequate and highly effective methods of contraception throughout the study. A highly effective method of birth control is defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as sterilisation, implants, injectables, combined oral contraceptives, some IUDs (Intrauterine Device, hormonal), sexual abstinence or vasoectomised partner).
2. Subjects who are receiving WHO step II/III opioid analgesic medication for the treatment of non-malignant pain and who require daily opioid treatment for pain with WHO step III opioid therapy for the duration of the study, based on Investigator’s judgement.
3. Documented history of non-malignant pain that requires around-the-clock opioid therapy (20 - 50 mg oxycodone PR equivalent per day for a minimum of study duration).
4. Subjects with constipation caused or aggravated by opioids:
• Subject’s medical need of regular intake of laxatives to have at least 3 bowel evacuations per week, or having less than 3 bowel evacuations when not taking a laxative.
• In the opinion of the subject and investigator confirm that the subjects constipation is induced, or worsened by the subjects prestudy opioid medication (present at Screening).
5. Subjects must be willing to discontinue their current opioid analgesic routine.
6. Subjects must be willing to discontinue their current laxative regimen and willing to comply with the use of bisacodyl suppository as laxative rescue medication.
7. Subjects taking daily natural dietary fiber supplementation are eligible if they can maintain their diet throughout the study, and in the investigator’s opinion are willing and able to maintain adequate hydration.
8. Subjects willing to remain stable on their routine dietary habit.
9. Subjects must be willing and able (e.g. mental and physical condition) to participate in all aspects of the study, including use of medication, completion of subjective evaluations, attending scheduled visits at pain management and gastroenterologist clinics, completing telephone contacts, and compliance with protocol requirements as evidenced by providing written, informed consent.
10. In the investigator’s opinion the subject’s non-analgesic concomitant medications, including those medications for the treatment of depression are thought to be stable, and will remain stable throughout the Double-blind Phase of the study.
11. In the investigator’s opinion the non opioid analgesic medication dose will remain stable during the Double-blind Phase.
12. Subjects, who are dissatisfied (lack of efficacy or unacceptable tolerability) with their current WHO step II/III opioid analgesic medication.

E.4

Principal exclusion criteria

1) Any history of hypersensitivity to oxycodone, naloxone, related products or other ingredients of the study treatments.
2) Any contraindication to oxycodone, naloxone, or any non-investigational medicinal products (NIMPs) that will be used by subjects during the study.
3) Active alcohol or drug abuse and/or history of opioid abuse.
4) Subjects receiving hypnotics or other central nervous system (CNS) depressants that, in the investigator’s opinion, may pose a risk of additional CNS depression with opioid study treatments.
5) Subjects presently taking, or who have taken naloxone and naltrexone <= 30 days prior to the start of the Screening Period.
6) Subjects receiving enemas on regular basis within the last 4 weeks prior to the start of the Screening Period.
7) Continuous systemic use of antibiotics and/or steroids within the last 4 weeks prior to the start of the Screening Period and during the study period.
8) Evidence of clinically significant cardiovascular, renal, hepatic, gastrointestinal (e.g. paralytic ileus), or psychiatric disease, as determined by medical history, clinical laboratory tests, ECG results, and physical examination, that would place the subject at risk upon exposure to the study treatments or that may confound the analysis and/or interpretation of the study results.
9) Chronic or intermittent pain that results from Fibromyalgia or Rheumatoid Arthritis.
10) Subjects with uncontrolled seizures or convulsive disorder.
11) Surgery within 2 months prior to the start of the Screening Period, or planned surgery during the 7-week Double-Blind Phase that may affect GI motility or pain.
12) Subjects suffering from chronic diarrhoea.
13) Subjects suffering from ulcerative colitis or Crohn’s disease.
14) Subjects with a diagnosis of clinically relevant hereditary or acquired autonomic neuropathies which could have an impact on and compromise study outcomes (see Section 18).
15) Subjects with a diagnosis of food intolerance (e.g. lactose, gluten), inflammatory and/or autoimmune diseases (see Section 18).
16) Subjects with untreated hypothyroidism, Addison’s disease, increase of intracranial pressure.
17) Subjects with known or suspected hereditary fructose intolerance.
18) Subjects who are unable to perform breath test.
19) Subjects having abnormal aspartate aminotransferase (AST; SGOT), alanine aminotransferase (ALT; SGPT), or alkaline phosphatase levels (> 3 times the upper limit of normal) or an abnormal total bilirubin and/or creatinine level(s) (> 1.5 times the upper limit of normal), gamma glutamyl transpeptidase (GGT or GGTP) ≥ 3 times the upper limit of normal.
20) Subjects who participated in a clinical research study involving a new chemical entity or an experimental drug within 30 days of study entry (defined as the start of the Screening Period).
21) Subjects institutionalized by court or administrative order.
22) Subjects with a history of GI tract surgery, e.g. gastrectomy (Billroth I, Billroth II, Roux-en-Y), bariartric surgery, gastrostomy, colostomy, colectomy, ileostomy etc.).
23) Subjects receiving oral hypoglycemic drugs, with a Hb1Ac concentration > 8% at the Screening Visit (Visit 1).
24) Subjects who require insulin for the treatment of diabetes mellitus.

E.5 End points

E.5.1

Primary end point(s)

Only exploratory endpoints in this study

E.5.1.1

Timepoint(s) of evaluation of this end point

Not applicable

E.5.2

Secondary end point(s)

Not applicable

E.5.2.1

Timepoint(s) of evaluation of this end point

Not applicable

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

It is an exploratory study which evaluates the effect of the IMPs on the gastrointestinal system (intestinal microbiota and gastrointestinal parameters).

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

double dummy

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

130

F.4.2.2

In the whole clinical trial

130

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After termination of the study subjects should be prescribed registered prolonged-release opioids and immediate-release opioids for the treatment of breakthrough pain according to the Subject’s or Investigator’s general practitioner judgment to establish the daily opioid dose needed for continuation of chronic pain treatment. When the Subject no longer needs the prescribed opioid therapy for their chronic pain condition it is advisable to taper the dose gradually.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-01-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-12-11

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-02-17

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