Clinical Trial Results:
An open-label, multi-site trial to describe the safety and tolerability of oral cebranopadol administered for 26 weeks in subjects with cancer-related pain who have completed treatment in the KF6005/07 trial
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Summary
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EudraCT number |
2013-001877-26 |
Trial protocol |
SE GB BE HU SK AT DE DK PL ES BG NL HR |
Global end of trial date |
03 May 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
29 Jan 2017
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First version publication date |
29 Jan 2017
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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 |
KF6005/09
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Additional study identifiers
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ISRCTN number |
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US NCT number |
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WHO universal trial number (UTN) |
U1111-1144-0778 | ||
Other trial identifiers |
Grünenthal GmbH: 168935 | ||
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Sponsors
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Sponsor organisation name |
Grünenthal GmbH
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Sponsor organisation address |
Zieglerstr. 6, Aachen, Germany, 52099
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Public contact |
GRT Trial Information Desk, Grünenthal GmbH, 0049 2415693223, clinical-trials@grunenthal.com
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Scientific contact |
GRT Trial Information Desk, Grünenthal GmbH, 0049 2415693223, clinical-trials@grunenthal.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
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 |
12 Oct 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
03 May 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
03 May 2016
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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 |
The primary objective of this trial is to describe the safety and tolerability of prolonged exposure to cebranopadol in subjects suffering from cancer related pain
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Protection of trial subjects |
The trial was conducted according to ICH-GCP guidelines, the applicable local laws, and in accordance with the ethical principles that have their origins in the Declaration of Helsinki. Regulatory and competent authorities were notified of the trial as required by national regulations, and, where necessary, relevant authorization was obtained. Subjects were informed and monitored by the investigator not to take prohibited medications. Subjects were followed-up at a regular basis with a total of 15 planned visits over 28 weeks. A final follow-up visit was planned 2 weeks after the last intake of cebranopadol Investigational Medicinal Product (IMP).
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Background therapy |
Allowed concomitant treatments with certain limitations were: - Hypnotics. - Anti-emetics for treatment of adverse events or as part of a chemotherapy and/or radiotherapy regimen. - Non-steroidal anti-inflammatory & antirheumatic drugs & non-opioid analgesics. - Chemotherapy & hormonal anti-cancer therapy. - Radiotherapy (pain-relieving radiotherapy was not allowed). - Laxatives. - Serotonin & noradrenaline reuptake inhibitors, anticonvulsants, neuroleptics and antiparkinsonian drugs - Physiotherapy and other non-pharmacological pain therapy. - Corticosteroids and bisphosphonates. - Strong inducers or inhibitors of cytochrome P450 3A4, if stable during treatment and until the follow-up visit (starting from the 2 weeks before enrollment into the KF6005/07 trial). - Investigators were free to prescribe on demand medication (within limits - if not listed as forbidden medication). This medication could be used in case of unbearable or breakthrough pain according to the respective summary of product characteristics. | ||
Evidence for comparator |
There was no comparator in this trial. | ||
Actual start date of recruitment |
18 Dec 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 |
Poland: 17
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Country: Number of subjects enrolled |
Romania: 2
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Country: Number of subjects enrolled |
Bulgaria: 4
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Country: Number of subjects enrolled |
Hungary: 2
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Country: Number of subjects enrolled |
Serbia: 4
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Country: Number of subjects enrolled |
Austria: 3
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Country: Number of subjects enrolled |
Belgium: 1
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Country: Number of subjects enrolled |
Denmark: 2
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Country: Number of subjects enrolled |
Germany: 20
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Country: Number of subjects enrolled |
Slovakia: 21
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Worldwide total number of subjects |
76
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EEA total number of subjects |
72
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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) |
43
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From 65 to 84 years |
33
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85 years and over |
0
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Recruitment
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Recruitment details |
First subject was enrolled on the 18 Dec 2013 (first dose taken on the 19 Dec 2013) and the last subject completed the trial on the 03 May 2016. All subjects in this trial completed the maintenance period in the KF6005/07 trial. | ||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Subjects who completed treatment in KF6005/07 and who were still in need of around-the-clock pain analgesia with strong opioids directly entered the KF6005/09 trial from the KF6005/07 trial. Seventy-six subjects (37 previously on cebranopadol and 39 subjects previously morphine treatment) were enrolled in this trial. | ||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||
Blinding implementation details |
Subjects who completed the treatment in KF6005/07 were to start on a daily dose of 200 or 400 µg cebranopadol in the KF6005/09 trial. The treatment code from the KF6005/07 was not unblinded at the time when the subject started the cebranopadol treatment. All subjects were titrated to their optimal dose.
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Arms
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Arm title
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Cebranopadol | ||||||||||||||||||||||||||||||
Arm description |
Subjects who completed the treatment in KF6005/07 and were suitable and willing to participate in this trial went into a Titration Phase (approximately 2 weeks). During the Titration Phase, the subjects were titrated to their individual optimal daily dose of cebranopadol, defined as a balance between self-reported analgesia and side effects. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Cebranopadol film-coated tablets
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Investigational medicinal product code |
GRT6005
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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 |
Subjects started on a cebranopadol treatment based on a predefined set of criteria. The decision on up-titration took place after 4 days of IMP use on certain dose level (exception: first dose level). Subjects were allowed to titrate up to a maximum daily dose of 1000 µg/day. Subjects were instructed to take cebranopadol orally once daily in the morning. The recommendation was to take cebranopadol between 06:00 h and 10:00 h, with a glass of water. The dose selected at the end of the Titration Phase was used during the Maintenance Phase. However, the dose could have been adjusted during the Maintenance Phase. Additionally, at any time during the trial, the dose may be discontinued for a certain period of time (e.g., because of adverse events). During the Titration Phase and the Maintenance Phase, all subjects were permitted to receive treatment for unbearable (breakthrough) pain.
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
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End points reporting groups
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Reporting group title |
Cebranopadol
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Reporting group description |
Subjects who completed the treatment in KF6005/07 and were suitable and willing to participate in this trial went into a Titration Phase (approximately 2 weeks). During the Titration Phase, the subjects were titrated to their individual optimal daily dose of cebranopadol, defined as a balance between self-reported analgesia and side effects. | ||
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End point title |
Incidence of treatment emergent adverse events [1] | ||||||
End point description |
The safety of cebranopadol was assessed by the number of subjects with treatment emergent adverse events (TEAEs). A TEAE was any adverse event that occurred after the first administration of IMP, i.e. cebranopadol in this trial. In addition, pretreatment adverse events which worsened during the treatment period were also considered TEAEs.
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End point type |
Primary
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End point timeframe |
up to 28 weeks (26 weeks of cebranopadol treatment and 2 weeks follow-up after the last dose was planned per subject).
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The primary end point for this open-label, single-arm trial was the incidence of Treatment Emergent Adverse Events during the 26 week open-label treatment period and the 2 week follow-up period. This was collected to assess long term safety on cebranopadol. No statistical testing or inference was planned on this primary objective. |
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End point title |
Intensity of Treatment Emergent Adverse Events | ||||||||||||
End point description |
A treatment emergent adverse event (TEAE) was any adverse event that occurred after the first administration of IMP, i.e. cebranopadol in this trial. In addition, pretreatment adverse events which worsened during the treatment period were also considered TEAEs. The “intensity” of adverse event were classified as: Mild: signs and symptoms which can be easily tolerated. Symptoms could be ignored and disappeared when the participant is distracted. Moderate: symptoms caused discomfort but were tolerable, they could not be ignored and affect concentration. Severe: symptoms affected the usual daily activity.
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End point type |
Secondary
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End point timeframe |
up to 28 weeks (26 weeks of cebranopadol treatment)
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| Notes [2] - There were a total of 661 reported Treatment Emergent Adverse Events reported in 76 subjects. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Changes from baseline in the average pain intensity | ||||||||
End point description |
The subject scored their average pain intensity during the last week on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine". Absolute change from baseline for average pain intensity during the last week were summarized descriptively for all subjects that scored their pain intensities.
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End point type |
Secondary
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End point timeframe |
Baseline Visit to Visit 14 (End of Treatment Visit) , i.e. up to 26 weeks.
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| Notes [3] - Subjects with data available. |
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
A treatment emergent adverse event was any adverse event that occurred after the first administration of IMP, i.e. cebranopadol in this trial. In addition, pretreatment adverse events which worsened during the treatment period were also considered TEAEs.
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Adverse event reporting additional description |
One subject experienced a serious non-treatment emergent adverse event preferred term "malignant neoplasm progression" before starting cebranopadol in this trial.
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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 |
18.1
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Reporting groups
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Reporting group title |
Cebranopadol
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Reporting group description |
Subjects who completed the treatment in KF6005/07 and were willing to participate in this trial went into a Titration Phase (approximately 2 weeks). During the Titration Phase, the subjects were titrated to their individual optimal daily dose of cebranopadol, defined as a balance between self-reported analgesia and side effects. The dose selected at the end of the Titration Phase was used during the Maintenance Phase. However, the dose could have been adjusted during the Maintenance Phase. During the Titration Phase and the Maintenance Phase, all subjects were permitted to receive treatment for unbearable (breakthrough) pain. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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05 Mar 2015 |
Protocol Amendment dated 06 Jan 2015.
Protocol exclusion and discontinuation criteria on creatinine clearance were adapted based on new scientific data.
Clarifications were made for allowed concomitant medication and therapies medications affecting the QT interval.
Clarifications were made for when the Child-Pugh score has to be assessed.
The time window for the Follow-up Visit was specified.
Reference to Forest Research Institute was removed as they are no longer involved in the development of cebranopadol. |
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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 | |||
