| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Severe chronic low back pain with a neuropathic pain component |
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| E.1.1.1 | Medical condition in easily understood language |
| Severe chronic low back pain |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054095 |
| E.1.2 | Term | Neuropathic pain |
| E.1.2 | System Organ Class | 100000004852 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10024891 |
| E.1.2 | Term | Low back pain |
| E.1.2 | System Organ Class | 100000004859 |
|
| 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 effectiveness, safety, and tolerability of tapentadol PR versus oxycodone/naloxone PR in non-opioid pre-treated subjects with uncontrolled severe chronic low back pain with a neuropathic pain component. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate and compare tolerability profiles of tapentadol PR versus oxycodone/naloxone PR during the titration period and throughout the trial with a focus on gastrointestinal and central nervous system-related tolerability.
• To evaluate the impact of tapentadol PR and oxycodone/naloxone PR on neuropathic pain-related symptoms.
• To compare the impact on function and quality of life parameters between tapentadol PR and oxycodone/naloxone PR in subjects with severe chronic low back pain.
• To compare effectiveness in terms of reduction of pain intensity between tapentadol PR and oxycodone/naloxone PR during titration as well as throughout the entire treatment period in the trial.
• To investigate the impact of tapentadol PR versus oxycodone/naloxone PR on serum levels of sexual hormones
|
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Informed consent signed.
2. Male or female subject ≥18 years of age.
3. Women of childbearing potential must have a negative pregnancy test at the Enrollment Visit.
4. Women of childbearing potential must practice medically acceptable
methods of birth control during the trial.
5. Subjects must be appropriately communicative and able to differentiate with regard to location and intensity of the pain, and to complete the questionnaires used in this trial.
6. Subjects must have a diagnosis of chronic low back pain; chronic pain defined as pain lasting for at least 3 months prior to enrollment.
7. Subject’s pain must require a strong analgesic (defined as WHO Step III) as judged by the investigator.
8. Subjects who require a washout of co-analgesics at enrollment must have an average pain score (NRS-3) of 5 points or higher.
Subjects who do not require a washout of co-analgesics at enrollment must have an average pain intensity score (NRS-3) of 6 points or higher.
9. The painDETECT diagnostic screening questionnaire must be either “positive” (= score of 19 to 38 inclusive) or “unclear” (= score of 13 to 18 inclusive) or If the subject is being treated with a stable regimen of centrally acting co-analgesics, a “negative” painDETECT scorescore (but 9 points or higher) at the Enrollment Visit will be acceptable
Inclusion criteria at the Randomization Visit
10. Subjects must have an average pain intensity score (NRS-3) of 6 points or higher.
11. Subjects must score either “positive” (= score of 19 to 38 inclusive) or “unclear” (= score of 13 to 18 inclusive) on the painDETECT diagnostic screening questionnaire. |
|
| E.4 | Principal exclusion criteria |
1. Presence of a clinically significant disease or clinical laboratory values that in the investigator’s opinion may affect effectiveness, quality of life, or safety/tolerability assessments
2. Presences of active systemic or local infections that may, in the opinion of the investigator, affect the effectiveness, quality of life, or safety/tolerability assessments.
3. Employees of the investigator or trial site, with direct involvement in this trial or other trials under the direction of the investigator or trial site, as well as family members of employees of the investigator.
4. Participation in another trial concurrently, or within 4 weeks prior to the Enrollment Visit.
5. Known to or suspected of not being able to comply with the protocol and/or appropriate use of the IMPs.
6. Any painful procedures (e.g., major surgery) scheduled during the trial duration (Enrollment Visit until Final Evaluation Visit) that may, in the opinion of the investigator, affect the effectiveness, quality of life, or safety assessments.
7. Pending litigation or application for insurance/governmental benefits due to chronic pain or disability and/or if the granted benefits might be influenced by a successful participation in the trial.
8. Low back pain caused by cancer and/or metastatic diseases.
9. History of alcohol or drug abuse, or suspicion thereof in the investigator’s judgment.
10. Presence of concomitant autoimmune inflammatory conditions.
11. Subjects with acute intoxication with alcohol, hypnotics, centrally acting analgesics, or psychotropic active substances.
12. Subjects with severe renal impairment, i.e., estimated glomerular filtration rate less than 30 mL/min (according to the National Kidney Foundation 2002).
13. Known history of clinical laboratory values or current clinical laboratory values reflecting moderately or severely impaired hepatic function.
14. History of seizure disorder or epilepsy.
15. Any of the following within 1 year: mild/moderate traumatic brain injury, stroke, transient ischemic attack, or brain neoplasm (including brain metastases if present at the Enrollment Visit). Severe traumatic brain injury within 15 years (consisting of 1 or more of the following: brain contusion, intracranial hematoma, either unconsciousness or post traumatic amnesia lasting more than 24 hours) or residual sequelae.
16. Pregnant or breast-feeding women.
17. Severe respiratory depression with hypoxia and/or hypercapnia, acute or severe bronchial asthma or severe chronic obstructive pulmonary disease.
18. Presence or suspicion of paralytic ileus.
19. Subjects with severe cardiac impairment, e.g., New York Heart Association class >3, myocardial infarction less than 6 months prior to the Enrollment Visit, and/or unstable angina pectoris and/or cor pulmonale.
20. Subjects with known history of rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption.
21. History of allergy or hypersensitivity to tapentadol, oxycodone, naloxone, and their formulations.
22. Subjects with acute biliary obstruction or acute pancreatitis.
23. Subjects with hypothyroidism (including myxedema) or Addison’s disease.
24. Subjects taking any prohibited concomitant medication. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The first primary endpoint of this trial is defined as the change in the average pain intensity core during the last 3 days (numerical rating scale [NRS]-3 pain intensity scores) from the Randomization Visit to the end of continuation (Final Evaluation Visit, 12 weeks after the Randomization Visit).
The second primary endpoint will be the change in the patient assessment of constipation symptoms (PAC-SYM) total score from the Randomization Visit to the end of continuation (Final Evaluation Visit, 12 weeks after the Randomization Visit). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1.Comparison of relevant parameters related to the evaluation of early gastrointestinal treatment emergent adverse events (TEAEs) under tapentadol PR and oxycodone/naloxone PR.
2.
• Pain intensity scores on an 11-point NRS-3.
• PainDETECT scores.
• EuroQol-5 Dimension (EQ-5D) scores.
• NRS-3 pain intensity scores for pain radiating towards or into the leg.
• Worst pain (11-point NRS) during the last 24 hours prior to the assessment visit.
• Patient global impression of change (PGIC).
• Clinician’s global impression of change (CGIC).
• Neuropathic pain symptom inventory (NPSI).
• Short Form-12® health survey (SF-12) scores.
• Hospital anxiety and depression scale (HADS).
• Sleep evaluation score.
• Work productivity and activity impairment questionnaire (WPAI).
• Adverse events
• Overall discontinuation rates related to treatment arms
• Time to discontinuation from treatment (due to any reason).
• Time to discontinuation from treatment (due to adverse events).
• PAC-SYM.
• Vital signs.
• Clinical laboratory values.
• Medication used to treat the adverse events related to the IMPs.
• Hormone serum levels under treatment with IMPs:
• Aging males’ symptoms questionnaire |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. At respective site visits during the early treatment phase
2. At respective site visits as specified in the protocol |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| effectiveness and tolerability |
|
| 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) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| 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 | No |
| 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 | 35 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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