| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| The trial population, comprising patients with cancer pain requiring WHO Step III analgesics, will represent the typical population suffering from cancer-related pain. Patient having various types of cancer will be included. The pain condition affecting cancer patients represents a mixed type of pain as it is composed of various pain components (i.e., visceral, neuropathic, and somatic) of different dominance depending on the type of cancer, its stage, localization, and previous treatments. |
|
| E.1.1.1 | Medical condition in easily understood language |
| In this clinical trial patients with chronic, cancer related pain will be recruited. Chronic pain is among the most important of symptoms associated with the course of cancer disease. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Symptoms and general pathology [C23] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10058019 |
| E.1.2 | Term | Cancer pain |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objective is to compare the safety and tolerability of cebranopadol and morphine sulfate PR. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 less than 1% per year. For example:
• Hormonal contraceptives for at least 2 months prior to the Enrollment Visit (Visit 1) and until at least 4 weeks after the End of Treatment Visit (Visit 11).
• An intra-uterine device.
Additional barrier contraception must be used by the partner for the duration of the trial, defined as from the time of the Enrollment Visit until 4 weeks after the End of Treatment Visit. Women of non-childbearing potential may be included if post-menopausal for at least 2 years and 55 years or more old.
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 less than 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 greater or equal to 4 weeks prior to Visit 1.
5. Performance Status: Eastern Cooperation Oncology Group (ECOG) less than or equal to 2.
Additional inclusion criteria at Visit 2
6. Subjects with a mean score of 5 points or more (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. |
|
| E.4 | Principal 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.
8. Subjects with moderate to severe hepatic impairment corresponding to Child-Pugh classification B and C. Subjects with impaired hepatic cellular integrity indicated by aspartate transaminase (AST) or alanine transaminase (ALT) greater than 3 times the upper limit of normal (ULN) at the Enrollment Visit (Visit 1).
9. Inadequate baseline bone marrow reserve with a white blood cell count less than 2000/μL, a platelet count less than or equal to 100 000/μL, and a hemoglobin level less than 8 g/dL at the Enrollment Visit (Visit 1).
10. Subjects with impaired renal function. Creatinine clearance less than 45 mL per minute at the Enrollment Visit (Visit 1) (calculated from the Cockcroft-Gault formula).
11. Subjects taking any forbidden concomitant medications or not being able to follow the rules of use of prior and concomitant treatment.
12. Uncontrolled hypertension (repeated measurements of systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 95 mmHg).
13. Clinically relevant history of hypersensitivity, allergy or contraindications to opioid medication or any of the excipients of morphine sulfate (PR or IR), or cebranopadol film-coated tablets.
14. Chronic hepatitis B or C, or human immunodeficiency virus (HIV) known by history, or presence of active hepatitis B or C within the 3 months before the Enrollment Visit.
15. History of torsade de pointes and/or presence of risk factors for torsade de pointes (e.g., heart failure, hypokalemia, or bradycardia).
16. Marked prolongation of QTcF (greater than 450 ms) at the Enrollment Visit (Visit 1) confirmed by repeated measurement.
17. Employees of the sponsor, investigator, or trial site or family members of the employees, sponsor, or investigator.
18. Concurrent participation in another trial or planning to be enrolled in another clinical trial (i.e., administration of experimental treatment in another clinical trial) during the course of this trial(does not include observational studies).
19. Previous participation in this or other trials with cebranopadol with the following exceptions:
• Subjects who failed enrollment in this trial only because of exclusion criterion 10, which was changed in Amendment 04, and
who may now be eligible can be re-enrolled.
• Subjects who failed enrollment due to technical failure of equipment (e.g., ECG machine and e-diary device).
20. Have received an experimental drug or used an experimental medical device within 30 days before the planned start of treatment.
21. Currently not receiving opioid treatment for cancer-related pain (i.e.,opioid naïve). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the average amount of daily rescue medication intake over the last 2 weeks of the Maintenance Phase. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Last 2 weeks of the Maintenance Phase |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoint is the proportion of subjects with clinically relevant pain reduction over the last 2 weeks of the Maintenance Phase.
The secondary safety endpoint is the frequency of treatment emergent adverse events (TEAEs). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary efficacy endpoint - Last 2 weeks of the Maintenance Phase.
Secondary safety endpoint - up to 44 days of planned treatment. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| morphine prolonged release |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 | 90 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 90 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Austria |
| Belgium |
| Brazil |
| Bulgaria |
| Chile |
| Croatia |
| Denmark |
| France |
| Germany |
| Hungary |
| Mexico |
| Netherlands |
| Peru |
| Poland |
| Romania |
| Serbia |
| Slovakia |
| Spain |
| Sweden |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 10 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
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