| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Osteoarthritic Knee Pain. |
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| E.1.1.1 | Medical condition in easily understood language |
| Pain in the knee caused by osteoarthrosis. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10029877 |
| E.1.2 | Term | OA knee |
| E.1.2 | System Organ Class | 100000004859 |
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| 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 |
| To assess which pain mechanisms (with specific focus on the descending inhibition) are modulated by daily administration of 2 x 100-250 mg tapentadol PR compared to 2 x 20-50 mg oxycodone CR in subjects with osteoarthritic (OA) knee pain during a treatment period of 4-weeks (preceded to a titration period of up to 15 days). |
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| E.2.2 | Secondary objectives of the trial |
To evaluate if changes in any of the mechanism based experimental pain assessment parameters can explain changes in clinical outcome parameters (reduction in clinical pain intensity).
To profile drug responders- versus non-responders based on pain mechanisms involved.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent (IRB/IEC specific) has been obtained prior to initiation of any protocol required procedures.
2. Male or female between 40 and 80 years of age. Females of childbearing potential must have a negative urine pregnancy test at screening.
3. Body weight >40 kg and <150 kg with a body mass index (BMI) between 19-40 kg/m2 inclusive.
4. Idiopathic osteoarthritic knee pain (index knee) diagnosed in accordance with the American College of Rheumatology (ACR) modified clinical classification criteria (Altman et al, 1986) and verified radiologically as Kellgren-Lawrence grade I, II or III (Kellgren and Lawrence, 1957) at the index knee. The clinical diagnosis of OA will be confirmed by the ACR clinical and radiographic criteria for classification of idiopathic OA based upon the following criteria (index knee):
a. Knee pain for at least 14 days per month for the 3 months before study entry.
b. Osteophytes (with radiographic evidence).
c. And at least 1 of the following 3 conditions: Age >50, or morning stiffness <30 minutes, or crepitus.
d. X-ray images of the knee joints are available confirming OA. X-ray images older than12 months cannot be used. New photos are needed to confirm the diagnostic criteria for OA.
5. For the index knee, the average of the worst daily pain score over the last 14 days prior to day 0 (i.e. days -14 to day -1) must be 5.0 to 9.0. The 14-day average score will be derived from worst daily pain scores recorded in a diary for the index knee.
6. Discontinued use of all analgesic medications (including over-the-counter [OTC] analgesics/ Non-Steroidal Anti-Inflammatory Drug (NSAID) at least 3 days prior to visit 2 (subjects are allowed limited use of analgesic medications, refer to section on Permissible Medications/Treatments).
7. Have agreed to maintain the same activity level throughout the course of the study.
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| E.4 | Principal exclusion criteria |
1. A history of recurrent seizures other than febrile seizures.
2. A history of frequent and/or severe allergic reaction with multiple medication.
3. A current or recent history, as determined by the investigator or his delegates, of severe, progressive, and/or uncontrolled renal, including severe renal impairment, hepatic, including severe impaired liver function, hematological, gastrointestinal, endocrine, pulmonary, including respiratory depression, COPD or acute severe asthma, cardiac, including cor pulmonale, neurological, psychiatric or cerebral disease which could interfere with the subject's participation in the study.
4. At screening, have an abnormality in the 12-lead ECG that, in the opinion of the investigator, increases the risks associated with participation in the study. In addition, subjects with following findings will be excluded:
a. Confirmed Bazett’s corrected QT (QTcB) interval > 450 msec for men and > 470 msec for women at screening.
b. Bundle branch blocks and other conduction abnormalities other than: i) mild first degree atrio-ventricular block, ii) left anterior hemi block due to left axis deviation, iii) right bundle branch block of benign origin i.e. not caused by other cardiac disease.
c. Irregular rhythms other than sinus arrhythmia or occasional supraventricular or ventricular ectopic beats,
d. History of unexplained syncope,
e. Family history of unexplained sudden death or sudden death due to long QT syndrome,
f. T-wave configurations are not of sufficient quality for assessing QT interval determination, as assessed by the investigator.
5. An alanine aminotransaminase. Moderate or greater hepatic impairment.
6. Prior renal transplant, current renal dialysis or severe renal insufficiency or serum creatinine.
7. Pregnant female, breast feeding or planning a pregnancy during the study period. Females of child-bearing potential, not using a reliable means of contraception (refer to section 8.5.3 – reliable contraception).
8. Active malignancy of any type or a history of malignancy within the last 5 years (except basal cell carcinoma of the skin that has been excised prior to study start).
9. Any excluded medications (analgesic medications) that cannot be discontinued during the screening period (3 days prior to visit 2).
10. Treatment within the last 30 days with a drug that has not received regulatory approval.
11. Substance abuse or dependence, not nicotine/caffeine.
12. A high risk of infection.
13. A history of, or suspected, demyelinating disease of the central nervous system.
14. An autoimmune disorder.
15. Not fully understand the EPM procedures.
16. Investigator site personnel directly affiliated with this study and/or their immediate family.
17. Diagnosed with any condition suggestive of a secondary cause of knee OA.
18. History of surgery in the index knee within 3 months or planned surgery.
19. Complicated prior injury to the index knee within 12 months.
20. Diagnosed with Kellgren and Lawrence grade 0 or IV.
21. Use of lower extremity assistive devices.
22. Prior synovial fluid analysis showing a WBC≥2000mm.
23. A confounding painful condition that may interfere with assessment.
24. Any other musculoskeletal or arthritic condition that may affect the interpretation of clinical efficacy and/or safety data or otherwise contraindicates participation in this clinical study.
25. Have used corticosteroids prior to baseline: a. Intra-articular injection of steroids into the index knee or into any other site than the index knee within the previous 3 months; b. Intra-muscular corticosteroid injections within the previous 3 months; c. Oral corticosteroids within the previous 1 month.
26. Initiated or changed their established physiotherapy program within the last 14 day prior to visit 3.
27. Not recorded a minimum of 10 days of diary data of the last 14 days immediately preceding visit 3.
28. Currently on strong opioids or have been within the past 3 months. .
29. Increased intracranial pressure, hypovolemia, symptomatic hypotension, prostatism, Untreated hypothyroidism, paralytic ileus or pancreatitis.
30. Treatment with MAO-inhibitors, rifampicin and CNS depressants (e.g. benzodiazepines, barbiturates, phenytoin, anti-depressants, anti-psychotics, and sedating antihistamines),
31. Allergic to the active ingredient of tapentadol or oxycodone or one or more of the excipients.
32. Uncontrolled arterial hypertension.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
As the primary objective of this study is assessment of which pain mechanisms are modulated by study drug administration, the primary endpoints will include Experimental mechanism based Pain Measures (EPMs) as listed below:
• Quantitative Sensory Testing (QST) of joint pain (pressure pain thresholds from 3 knee joint locations of most painful side)
• Spreading sensitization (pressure pain threshold from tibialis anterior of the most painful knee and from the extensor carpi radialis longus muscle on the ipsilateral site)
• Pain areas (area of pain drawings)
• Wind-up like pain (repeated mechanical pressure stimulation to the most painful knee site and tibialis anterior muscle)
• Descending noxious inhibitory control (combining pressure pain at the knee, leg and arm and pressure pain to cuff inflation)
• Cuff evoked pain (cuff algometry)
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Subjects will be randomized to one of two treatment arms:
Arm 1 (titrated from 50 mg up to max. 250 mg x 2/day tapentadol PR).
or
Arm 2 (titrated from 10 mg up to max. 50 mg x 2/day oxycodone CR).
The treatment period is 4 weeks preceded by an up to 15 day's titration.
Experimental mechanism based Pain Measures (EPMs) to be performed at visit: 3 and 6. A demonstration of the tests at visit 2. |
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| E.5.2 | Secondary end point(s) |
| Change of pain severity from baseline to end of the study, as measured by the weekly mean of the daily 24-hour average pain score (APS), night pain and worst daily pain, Pain Quality Assessment Scale (PQAS), Brief Pain Inventory (BPI), Investigator and Patient Global Assessment of Changes (IGIC and PGAC), Western Ontario and McMaster (WOMAC) OA physical function, time and pain intensity from the 40 m self-paced walk test, time and pain intensity from the 11 step stair climb test, DoloTest® and PainDetect. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints for questionaires:
PQAS, IGIC and PGAC; visit 3 and 6.
BPI, WOMAC, self-paced walk test, stair climb test, DoloTest and PD-Q; visit 1, 3, 5 and 6. |
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| 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 | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 12 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 12 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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