The primary objective is to evaluate the efficacy of orally administered cebranopadol in comparison with morphine sulfate PR in subjects suffering from chronic moderate to severe pain related to cancer.The secondary objective is to compare the…
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Outcome measures
Primary outcome
The primary endpoint is the average amount of daily rescue medication intake
over the last 2 weeks of the Maintenance Phase.
Secondary outcome
The secondary efficacy endpoint is the proportion of subjects with clinically
relevant pain reduction over the last 2 weeks of the Maintenance Phase.
Definition of clinically relevant pain reduction:
* Average pain intensity of <4 points on the 11-point NRS
Or
* Reduction in average pain intensity by *30% (compared to the baseline
assessment)
Or
* Reduction in average pain intensity by *2 points (compared to the baseline
assessment)
(The average pain intensity is the average of the 24-hour pain intensities over
the last 2 weeks of the Maintenance Phase)
The secondary safety endpoint is the frequency of treatment emergent adverse
events (TEAEs).
Background summary
The most widely accepted algorithm for the treatment of chronic malignant
tumor-related pain was developed by the World Health Organization.
Step III of the WHO ladder is treatment with a *strong opioid* such as
morphine.
Morphine has been widely accepted as gold standard in the analgesic management
of severe pain and cancer pain
Despite the high analgesic efficacy, treatment with strong opioids in pain is
influenced by their side effect profile such as nausea, vomiting, sedation,
constipation, addiction, development of tolerance, and respiratory depression.
Cebranopadol is a highly potent mixed nociceptin/orphanin FQ peptide
(NOP)/opioid receptor agonist with central antinociceptive activity found to be
highly effective in animal models of acute pain, visceral and inflammatory pain
as well as chronic mono- and poly-neuropathic and bone cancer pain. In acute
pain, cebranopadol is approximately equi-potent to the strong opioid fentanyl.
In neuropathic pain, cebranopadol is about 10 times to 100 times more potent
than in acute pain whereas classical opioids generally have the same potency in
both pain conditions.
Cebranopadol is currently in pghase 2/ 3 clinical development for the treatment
of chronic pain indications in EU and US.
The proposed trial is part of a comprehensive clinical development plan
designed to meet the requirements of the Note for Guidance for Nociceptive Pain
(CPMP/EWP/612/00). This guideline requests that several pain models are
investigated including cancer pain as a model for severe chronic pain to
achieve the targeted indication.
The main goal of this trial is to explore the efficacy and safety of treatment
with cebranopadol compared to a standard treatment with morphine sulfate PR in
patients suffering from moderate to severe chronic cancer pain.
The trial is designed as a non-inferiority trial for efficacy. The trial does
not include a placebo arm for ethical and feasibility reasons.
Morphine sulfate PR (twice daily formulation) was chosen as active comparator,
as this medication shares the µ-agonistic mechanism of action with
cebranopadol, and is one of the most commonly used opioid analgesics in this
patient population.
Study objective
The primary objective is to evaluate the efficacy of orally administered
cebranopadol in comparison with morphine sulfate PR in subjects suffering from
chronic moderate to severe pain related to cancer.
The secondary objective is to compare the safety and tolerability of
cebranopadol and morphine sulfate PR.
Study design
This is a randomized, multi-site, double-blind, double-dummy, active control,
parallel group, multiple dose, oral administration, Phase III trial, in
approximately 524 subjects. Scheduled during the Treatment Period are a 16-day
Titration Phase and a 28-day Maintenance Phase.
The maximum duration of the trial, including the Enrollment Period, Treatment
Period, and the Follow-up Period, for an individual subject will be
approximately 10 weeks. The sponsor may decide to offer an extension trial to
subjects who complete this trial. If this trial will be offered, it
will be a separate trial protocol and the option to take part will also depend
on approvals by local authorities and IECs, however, these may not be the only
reasons.
Intervention
Subjects who comply with all inclusion criteria and do not meet any of the
exclusion criteria will be randomly assigned to one of the 2 treatment arms
(Cebranopadol versus Morphine sulfate PR) in the ratio 1:1
The IMP will be taken orally twice daily from the next day of Visit 2
throughout the Titration Phase and the Maintenance Phase, and on the day of
Visit 11 (including the evening dose). The IMP intake must be documented in
the e-diary during the treatment period on a daily basis.
The different daily doses during the Titration Phase and the Maintenance Phase
will be administered using the available dose strengths of cebranopadol (200
µg, 400 µg, 600 µg) and morphine (15 mg, 30 mg, and 45 mg) and the matching
placebo tablets or capsules.
Cebranopadol
The starting dose of cebranopadol will be 200 µg per day.
The maximum daily dose of cebranopadol is 1000 µg.
The minimum daily dose of cebranopadol is 200 µg.
The incremental/decremental dose of cebranopadol is 200 µg per day.
Morphine sulfate PR
The starting dose of morphine sulfate PR will be 30 mg per day (divided into 2
intakes).
The maximum daily dose of morphine sulfate PR is 150 mg (divided into 2
intakes).
The minimum daily dose of morphine sulfate PR is 30 mg (divided into 2 intakes).
The incremental/decremental dose of morphine sulfate PR is 30 mg per day
(divided into 2 intakes).
The aim of the titration is to reach the subject*s individual optimal dose
defined as a balance between self-reported analgesia and side effects. The
investigator will have access to each subject*s recordings of daily pain
ratings and usage of rescue medication, and should take these into account in
titration decisions.
If the tolerability is considered acceptable by both the subject and the
investigator, and there appears to be sub-optimal efficacy, i.e., high pain
intensity and/or the need to use rescue medication, the investigator should
titrate the subject to a higher dose. If the tolerability is considered
unacceptable by the subject or the investigator, the investigator should
down-titrate the dose.
The selected dose at the end of the Titration phase will be used by the
subjects during the Maintenance Phase. To ensure adequate efficacy assessments,
changes in dose during the Maintenance Phase will be prohibited.
Subjects will receive morphine sulfate IR (10 mg) as rescue medication in
addition to the IMP. Subjects will be instructed on the maximum allowable
dosage of rescue medication during the various stages of the trial, to be used
e.g. in case of breakthrough pain. The daily use of rescue medication will be
recorded in the electronic diary and will be discussed with the investigator.
Study burden and risks
Burden for the subject
Within the 10 weeks of study participation, the subject will visit the hospital
7 times and have 6 telephone appointments with the study doctor.
The duration of the hospital visits will approximately be 1.5 hours. During
these visits the following actions occur: physical examination, collection of
demographic data, discussion of medical history, checking eligibility criteria,
making 12-lead ECG, blood collection, urinalysis, urine drug test, pregnancy
test (if applicable), discussing adverse events, discussing concomitant
medication and explaning the use of the electronic diary. During three of those
visits the subject will complete various questionnaires.
The telephone appointments will take about 15 minutes during which side
effects, pain experience, use of rescue medication, use of concomitant
medication, usage of the electronic diary and dose titration will be discussed.
During the entire period subjects take their study medication twice daily.
These intakes will be recorded in an electronic diary together with the pain
scores as well as any rescue medication they have taken.
All female subjects of childbearing potential must use adequately acceptable
methods of birth control to prevent pregnancy. Male subjects have adequate
contraception use in research to prevent pregnancy of their partners
Medication-related risks
Known side effects of Cebranopadol are dizziness, drowsiness, headache, nausea
and constipation.
Most Common side effects of Moriphine Sulphate are drowsiness, nausea, vomiting
and constipation.
Blood sampling related risks
During six hospital visits blood samples will be taken. The insertion of the
needle can be painful or there may be blue spots developing at the injection
site. In addition, the subject may suffer from dizziness, light headedness or
fainting.
Zieglerstrasse 6
Aachen 52099
DE
Zieglerstrasse 6
Aachen 52099
DE
Listed location countries
Age
Inclusion criteria
1. Subjects must have signed an informed consent form (ICF) indicating that they understand the purpose of and procedures required for the trial and are willing to participate in the trial.
2. Subjects must be at least 18 years of age at the Enrollment Visit (Visit 1).
3. Women of childbearing potential must have a negative pregnancy test at Visit 1 and Visit 2 and must not be lactating at Visit 1. Subjects must be willing to use medically acceptable and highly
effective methods of birth control. For women of childbearing potential a medically acceptable and highly effective method of birth control is defined as any form of contraception with a low failure rate defined as <1% per year. For men: Men have to use barrier contraception (condom) during sexual intercourse from the first administration of IMP until 4 weeks after the End of Treatment Visit. The male subject has to take care that the female sexual partner uses at least 1 additional method of contraception with a low failure rate defined as <1% per year (e.g., oral
contraceptives) during this time frame. A double-barrier method should be supplemented by the use of spermicidal agents.
4. Subjects fulfilling the following 4 criteria:
* Requiring daily basic pain analgesia diagnosed with active cancer including hematological malignant diseases.
* Receiving daily opioid treatment at doses not higher than 90 mg oral morphine or its equivalent (including World Health Organization [WHO] Step II and Step III analgesics) for an appropriate length of time.
* Dissatisfied (due to lack of efficacy or poor tolerability) with their current pain treatment.
* Suffering from cancer-related but not cancer therapy-related chronic pain for a period of *4 weeks prior to Visit 1.
5. Performance Status: Eastern Cooperation Oncology Group (ECOG) *2.;Additional inclusion criteria at Visit 2
6. Subjects with a mean score of *5 points (11-point NRS) for the *average pain intensity over the last 24 hours* calculated from the pain assessments recorded during the last 3 days prior to Visit 2
7. Compliance with the use of the e-diary defined as at least 3 out of 4 of the 24 hour NRS entries available during the last 4 days prior to and including the day of Visit 2.
Exclusion criteria
1. Evidence of ongoing alcohol/drug abuse or history of alcohol/drug abuse within the last 2 years in the investigator*s judgment, based on patient history and physical examination.
2. The subject has a clinically significant disease other than cancer which in the investigator's opinion may affect efficacy or safety assessments e.g., significant unstable cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurological, infectious disease, psychiatric (resulting in
disorientation, memory impairment or inability to report accurately) or metabolic disorders.
3. Subjects with any gastrointestinal disorder that could, in the investigator*s opinion, affect the absorption and/or elimination of IMP.
4. Any pre-scheduled major surgery during the trial.
5. Known to or suspected of not being able to comply with the trial protocol and the use of IMP.
6. History of seizure disorder and/or epilepsy or any condition associated with a significant risk of seizure or epilepsy.
7. Known history and/or presence of cerebral tumor or cerebral metastases.
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | EUCTR2012-001316035-GB |
| EudraCT | EUCTR201200131635-NL |
| CCMO | NL44650.098.13 |