Clinical Trial Results:
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
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Summary
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EudraCT number |
2012-001772-11 |
Trial protocol |
CZ |
Global end of trial date |
09 Feb 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
24 Jul 2016
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First version publication date |
24 Jul 2016
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
OXN2505
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Mundipharma Research GmbH
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Sponsor organisation address |
Höhenstraße 10, Limburg, United Kingdom, D-65549
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Public contact |
Clinical Trial Contact , Mundipharma Research GmbH & Co. KG, +44 1223424900, info@contact-clinical-trial.com
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Scientific contact |
Clinical Trial Contact , Mundipharma Research GmbH & Co. KG, +44 1223424900, info@contact-clinical-trial.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
09 Feb 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
09 Feb 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
09 Feb 2015
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
• 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.
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Protection of trial subjects |
1) Inclusion criteria:
- Females less than one year post-menopausal had to have a negative pregnancy test prior to the first
dose of study treatment, 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 e.g.
sterilisation, implants, injectables, combined oral contraceptives, some intrauterine devices ((IUDs),
hormonal), sexual abstinence or vasectomised partner).
- Subjects had to 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 and GE centres, completing telephone contacts, and compliance with protocol requirements as evidenced by providing written, informed consent.
2) Exclusion criteria:
- Several exclusion criteria excluded subjects who were at risk from the use of IMP (e.g. those with hypersensitivity) or the study methods (please refer to protocol)
3) Dose discontinuation:
The Investigator(s) or subjects themselves may have stopped study treatment at any time for safety or personal reasons.
Subjects with serious diarrhoea, withdrawal syndrome, vital sign or laboratory abnormalities were also to be discontinued.
4) Safety assessments consisted of monitoring and recording all AEs and SAEs, observed or
volunteered, regardless of suspected causal relationship to the IMP. This included
reactions, interactions, accidents, illnesses, misuse and abuse. In addition, safety was assessed by
monitoring haematology, biochemistry, and urine values, periodic measurement of vital signs and ECGs
and the performance of physical examinations.
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Background therapy |
Non-Investigational Medicinal Products (NIMPs) included rescue mediation as well as substances used in the breath tests. - OxyIR use (Run-in Period and Double-Blind Phase, Opioid-treated subjects (OTS) only): OxyIR was the only allowed rescue pain medication. It was to be dosed no sooner than every 4 hours as needed. For subjects receiving 20, 30 or 40 mg/day of oxycodone PR, the single rescue dose of OxyIR was 5 mg. For subjects receiving 50 mg/day of oxycodone PR, the single rescue dose of OxyIR was 10 mg. - Bisacodyl (Run-in Period and Double-Blind Phase, OTS only): As rescue medication for constipation, only bisacodyl suppository were to be used no sooner than 72 hours after a subject’s most recent bowel movement. - Mouthwash (Vademecum med® concentrate or equivalent product) (breath tests at Gastroenterological (GE) centres): Five splatters in a half glass of tap water (appr. 0.1 Liter) were given to subjects prior to the first breath test assessment. - Lactulose (breath tests at GE centres): A test solution was prepared ahead of each breath test assessment, containing 10 g lactulose (15 mL solution of Bifiteral®) plus 200 mL tap water. - Glucose and Insulin: Both NIMPs were administered at GE centres on an “as required” basis and at the discretion of the Investigator in subjects diagnosed with diabetes mellitus. | ||
Evidence for comparator |
Oxycodone/naloxone prolonged release (OXN), the investigational drug in this study, has comparable analgesic effficacy as oxycodone prolonged release (OxyPR), but causes less opioid-induced bowel dysfunction. This study is aimed to generate data about different gastrointestinal parameters in response to treatment of constipated subjects with OXN PR and OxyPR. | ||
Actual start date of recruitment |
22 Jul 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Czech Republic: 30
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Country: Number of subjects enrolled |
Germany: 122
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Worldwide total number of subjects |
152
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EEA total number of subjects |
152
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
121
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From 65 to 84 years |
29
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85 years and over |
2
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Recruitment
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Recruitment details |
This study was conducted in 2 countries at 27 pain centres (23 sites in Germany, 4 sites in the Czech Republic) and 6 Gastrointestinal (GE) centres (5 sites in Germany, 1 site in the Czech Republic). In addition, 10 pain centres in Germany were initiated but did not recruit any subjects. | |||||||||||||||||||||
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Pre-assignment
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Screening details |
OTS were screened for up to 14 days, followed by a Run-in period of 7-28 days. During the Run-In Period subjects had their opioid therapy converted to open-label OxyPR, which was titrated to an effective analgesic dose between 20-50 mg of Oxy PR per day (20, 30, 40 or 50 mg per day). | |||||||||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
152 | |||||||||||||||||||||
Number of subjects completed |
108 [1] | |||||||||||||||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Adverse event, non-fatal: 6 | |||||||||||||||||||||
Reason: Number of subjects |
Consent withdrawn by subject: 2 | |||||||||||||||||||||
Reason: Number of subjects |
Run-in failure: 11 | |||||||||||||||||||||
Reason: Number of subjects |
Screening failure: 25 | |||||||||||||||||||||
| Notes [1] - The number of subjects reported to be in the pre-assignment period is not consistent with the number starting period 1. It is expected that the number completing the pre-assignment period are also present in the arms in period 1. Justification: As this is a cross-over study, 54 subjects started in each Treatment Group at the beginning of the double-blind Phase. Subjects who discontinued in cross-over period 1 were not included in subject numbers for cross-over period 2. |
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Period 1
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Period 1 title |
Double-blind period (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Investigator, Monitor, Data analyst, Carer, Assessor, Subject | |||||||||||||||||||||
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. Medication codes were not available until the completion of the study
and until clinical data base lock, except in the case of emergency. Unblinding of treatment in single
subject for regulatory reporting of SUSARs was done by designated drug safety personnel only
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Arms
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Are arms mutually exclusive |
No
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Arm title
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OXN PR | |||||||||||||||||||||
Arm description |
All subjects taking OXN PR in cross-over period 1 or cross-over period 2 | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Oxycodone/naloxone
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Investigational medicinal product code |
OXN PR
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
OXN PR and matching placebos in the DB-Phase were blinded and administered orally, prescribed q12h. Dosing was fixed and symmetrical (20, 30, 40 or 50 mg/day of oxycodone PR).
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Arm title
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OxyPR | |||||||||||||||||||||
Arm description |
All subjects taking OxyPR in cross-over period 1 or cross-over period 2 | |||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||
Investigational medicinal product name |
Oxycodone
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Investigational medicinal product code |
OxyPR
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
OxyPR and matching placebos in the DB-Phase were blinded and administered orally, prescribed q12h. Dosing was fixed and symmetrical (20, 30, 40 or 50 mg/day of oxycodone PR).
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Baseline characteristics reporting groups [1]
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Reporting group title |
Double-blind period
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same. Justification: As this is a cross-over study, 54 subjects started in each Treatment Group at the beginning of the double-blind Phase. Subjects who discontinued in cross-over period 1 were not included in subject numbers for cross-over period 2. |
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Subject analysis sets
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Subject analysis set title |
Full Analysis Population
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The full analysis population is defined as all randomised subjects who receive at least one dose of IMPs and have at least one post-baseline assessments of the primary efficacy variables in each of the two treatment periods.
All subjects which are part of the FAP are regarded as evaluable. In case that many subjects have only data from one treatment period a sensitivity analysis based on the reduced population will be considered
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Subject analysis set title |
Double Blind Safety Population
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The Double-blind safety population is defined as all enrolled subjects who were randomised and received at least one dose of IMP and have at least one safety assessment in the Double-Blind Phase.
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End points reporting groups
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Reporting group title |
OXN PR
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Reporting group description |
All subjects taking OXN PR in cross-over period 1 or cross-over period 2 | ||
Reporting group title |
OxyPR
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Reporting group description |
All subjects taking OxyPR in cross-over period 1 or cross-over period 2 | ||
Subject analysis set title |
Full Analysis Population
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The full analysis population is defined as all randomised subjects who receive at least one dose of IMPs and have at least one post-baseline assessments of the primary efficacy variables in each of the two treatment periods.
All subjects which are part of the FAP are regarded as evaluable. In case that many subjects have only data from one treatment period a sensitivity analysis based on the reduced population will be considered
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Subject analysis set title |
Double Blind Safety Population
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The Double-blind safety population is defined as all enrolled subjects who were randomised and received at least one dose of IMP and have at least one safety assessment in the Double-Blind Phase.
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End point title |
Orocaecal transit time | ||||||||||||
End point description |
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. Orocaecal time was measured by H2/CH4/ analysis of expired air of subjects (breath tests).
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End point type |
Primary
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End point timeframe |
Breath test assessments at 5 minute intervals for H2/CH4: 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180 + Extension by 1 hour if needed.
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Statistical analysis title |
Difference in LS Means | ||||||||||||
Statistical analysis description |
ANOVA with fixed terms for treatment, period and sequence and a random subject effect
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Comparison groups |
OXN PR v OxyPR
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Number of subjects included in analysis |
127
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Analysis specification |
Pre-specified
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Analysis type |
other [1] | ||||||||||||
P-value |
= 0.446 | ||||||||||||
Method |
ANOVA | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-6.42
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
-23.21 | ||||||||||||
upper limit |
10.37 | ||||||||||||
| Notes [1] - The H2-CH4-breath test provides the exhalation results of H2 and CH4 in the ppm unit, while the 1-13C-sodium acetate breath test measures the ratio between 12C and 13C in breath samples (given as delta‰) and calculates the DOB value (delta over basal, given as delta‰) and the percentage of the 13C-dose exhaled per hour as %13C dose/h. Gastric emptying time is defined as the time of maximum 13C-CO2 [%13C dose/h] exhalation. Orocaecal transit time is defined as the first timepoint where H2 [ppm] |
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Adverse events information
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Timeframe for reporting adverse events |
Events were recorded from the point at which the Informed Consent is signed until 7 days after the subject left the study. This included new AEs that were reported in the 7 days following the subject’s completion/discontinuation visit.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.0
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Reporting groups
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Reporting group title |
OXN PR
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Reporting group description |
All subjects taking OXN PR in cross-over period 1 or cross-over period 2 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
OxyPR
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Reporting group description |
All subjects taking OxyPR in cross-over period 1 or cross-over period 2 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 4.8% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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07 Mar 2013 |
Protocol Amendment No. 1 was a result of the German central Ethic Committee’s (cEC) response to the submission of the protocol 15-NOV-2012. The cEC responded on the 30 January 2013. The amendment is considered a “substantial amendment” as sections of it affect in- and exclusion criteria. In addition, minor text corrections and inconsistencies have been corrected. |
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16 May 2013 |
Protocol Amendment No. 2 was a result of the response letter by the German competent authority (BfArM) dated 02 April 2013. The Sponsor had obtained a conditional approval for the study. The condition was to submit a manufacturing license for the weighing and filling of 13C-Sodium Acetate. Since the process to get the manufacturing license for this product would have been very complex, involving release by a qualified person and additional documentation, the Sponsor decided to remove the 13C-Sodium Acetate breath test from the study. The amendment was considered a “substantial amendment” because of changes to study procedures. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
