Evaluation of Effectiveness and Tolerability of Tapentadol Hydrochloride in Subjects With Severe Pain Due to Osteoarthritis Taking Either WHO Step I or Step II Analgesics or no Regular Analgesic

• Sponsor: Grünenthal GmbH (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00983073
• Collaborator: (none)
• Enrollment: 224
• Locations: 24
• Arm: 1
• Duration (Months): 12
• Patients Per Site: 9.3
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

The main objective of the study is to evaluate the effectiveness, tolerability, and safety of tapentadol hydrochloride prolonged release in participants suffering from severe chronic pain due to osteoarthritis of the knee who are taking either WHO Step I or Step II analgesics or no regular analgesics. This is a clinical effectiveness trial designed to establish a link between anticipated clinical outcomes and the clinical practice by means of selected measures of clinical and subject-reported outcome.

The trial will compare the effectiveness of previous analgesic treatment (either WHO Step I or Step II analgesics or no regular analgesics) with that of tapentadol hydrochloride prolonged release (PR) treatment during defined periods of evaluation.

Condition or Disease	Intervention/Treatment	Phase
Chronic Pain; Osteoarthritis	Drug: Tapentadol	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 224 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Evaluation of the Effectiveness and Tolerability of Tapentadol Hydrochloride Prolonged Release, and Tapentadol Hydrochloride Immediate Release on Demand, in Subjects With Uncontrolled Severe Chronic Pain Due to Osteoarthritis of the Knee Taking Either WHO Step I or Step II Analgesics or no Regular Analgesics.
• Study Start Date: Sep 1, 2009
• Actual Primary Completion Date: Jun 1, 2010
• Actual Study Completion Date: Sep 1, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Tapentadol Tapentadol PR was given orally twice a day. A maximum of 2 oral Tapentadol IR tablets per day, with a minimum of a 4 hour interval between doses, were taken if there were acute pain episodes. The total daily dose of Tapentadol PR and IR were not permitted to exceed 500 mg per day.

Drug: Tapentadol; Tapentadol Prolonged Release (PR) Titration and Optimal Dose Period: Starting at 50 mg Tapentadol PR twice daily, adjusting at 50 mg PR steps (upwards or downwards) as necessary to achieve a balance between pain relief and a satisfactory level of tolerability. Participants were not permitted to exceed 500 mg of Tapentadol per day. Maintenance Period: Participants continuing on the dose established in the previous period.; Other Names: Nucynta Palexia

Outcome Measures

Primary Outcome Measures

1. The Primary Endpoint is Defined as the Change From Week -1 of the Average Pain Intensity Score on an 11-point NRS-3 at Week 6. [Baseline to end of week 6]

   For this pain assessment, the participant was to indicate the level of average pain experienced over the previous 3 days 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". The value indicates the change from the baseline value on the 0 to 10 scale. A Negative value indicates a reduction in pain intensity from the baseline average pain intensity.

Secondary Outcome Measures

1. Average Pain Intensity Before the Start of Tapentadol Treatment [Baseline]

   For this pain assessment, the participant was to indicate the level of average pain experienced over the previous 3 days 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".

2. Change in Average Pain Intensity After 6 Weeks of Tapentadol PR Treatment [Baseline; End of Week 6 (6 Weeks)]

   For this pain assessment, the participant was to indicate the level of average pain experienced over the previous 3 days 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". The value indicates the change from the baseline value on the 0 to 10 scale. A Negative value indicates a reduction in pain intensity from the baseline average pain intensity.

3. Change in Average Pain Intensity After 12 Weeks of Tapentadol PR Treatment [Baseline; End of Week 12 (12 Weeks)]

   For this pain assessment, the participant was to indicate the level of average pain experienced over the previous 3 days 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". The value indicates the change from the baseline value on the 0 to 10 scale. A Negative value indicates a reduction in pain intensity from the baseline average pain intensity.

4. EuroQol-5 (EQ-5D) Health Status Index Outcome Over Time [Baseline; End of Week 6 (6 Weeks)]

   The participant scored the EuroQol-5. This is a five dimensional health state classification. Each dimension is assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, with 1.00 indicating "full health" and 0 representing dead. The positive values indicate that during the study the health status improved.

5. EuroQol-5 (EQ-5D) Health Status Index Outcome Over Time [Baseline; End of Week 12 (12 Weeks)]

   The participant scored the EuroQol-5. This is a five dimensional health state classification. Each dimension is assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, with 1.00 indicating "full health" and 0 representing dead. The positive values indicate that during the study the health status improved.

6. Change in Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS) [Baseline; End of Week 6 (6 Weeks)]

   EuroQoL-5D Health State Visual Analog Scale (VAS) is a participant rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state. The values indicated represent the change from the baseline, a positive value indicates an improvement.

7. Change in Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS) [Baseline, End of Week 12 (12 Weeks)]

   EuroQoL-5D Health State Visual Analog Scale (VAS) is a participant rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state. The values indicated represent the change from the baseline, a positive value indicates an improvement.

8. Patient Global Impression of Change [Baseline; End of Week 6 (6 Weeks)]

   In the Patient Global Impression of Change (PGIC) the participant indicates the perceived change over the treatment period. The participant is requested to choose one of seven categories. Scores range from very much improved to very much worse.

9. Patient Global Impression of Change [Baseline; End of Week 12 (12 Weeks)]

   In the Patient Global Impression of Change (PGIC) the participant indicates the perceived change over the treatment period. The participant is requested to choose one of seven categories. Scores range from very much improved to very much worse.

10. Clinical Global Impression of Change [Baseline; End of Week 6 (6 Weeks)]

    In the Clinical Global Impression of Change (CGIC) the clinician indicates the perceived change over the treatment period. The clinician is requested to choose one of seven categories. Scores range from very much improved to very much worse.

11. Clinical Global Impression of Change [Baseline; End of Week 12 (12 Weeks)]

    In the Clinical Global Impression of Change (CGIC) the clinician indicates the perceived change over the treatment period. The clinician is requested to choose one of seven categories. Scores range from very much improved to very much worse.

12. Participant's Satisfaction With Previous Analgesic Treatment [Baseline]

    Participants were requested to rate their previous analgesic medication on a 5-point scale. Previous medication was rated as excellent, very good, good, fair and poor.

13. Participant's Satisfaction With New Analgesic Treatment, i.e Tapentadol. [Baseline; End of Week 6 (6 Weeks)]

    Participants were requested to rate their tapentadol (new) analgesic medication on a 5-point scale. The medication was rated as excellent, very good, good, fair and poor.

14. Participant's Satisfaction With New Analgesic Treatment, i.e Tapentadol. [Baseline; End of Week 12 (12 Weeks)]

    Participants were requested to rate their tapentadol (new) analgesic medication on a 5-point scale. The medication was rated as excellent, very good, good, fair and poor.

15. Baseline Western Ontario McMaster Questionnaire (WOMAC) Global Score Assessing Pain, Disability and Joint Stiffness of the Knee [Baseline]

    Western Ontario McMaster Questionnaire (WOMAC) Global Score: WOMAC is measured with a Likert ordinal scale (the participant gives one of 5 possible answers) A higher score indicate that a symptom is bothersome or disabling. The WOMAC is a self-administered questionnaire and has 24 questions: Pain, Stiffness and Physical Function. The possible scores range from 0-20 for pain, 0-8 for stiffness, 0-68 for physical function and these are then summed 0-96 for the global score. A lower score indicates a lower level of symptoms and or disability.

16. Change From Baseline in the Western Ontario McMaster Questionnaire (WOMAC) Global Score Assessing Pain, Disability and Joint Stiffness of the Knee Over the Last Week at Week 6 [Baseline; End of Week 6 (6 Weeks)]

    The WOMAC is a self-administered questionnaire and has 24 questions: Pain, Stiffness and Physical Function. The possible scores range from 0-20 for pain, 0-8 for stiffness, 0-68 for physical function and these are then summed 0-96 for the global score. The negative value indicates that there has been an improvement since baseline, the higher the value the greater the change since baseline.

17. Change From Baseline in the Western Ontario McMaster Questionnaire (WOMAC) Global Score Assessing Pain, Disability and Joint Stiffness of the Knee Over the Last Week at Week 12 [Baseline; End of Week 12 (12 Weeks)]

    The WOMAC is a self-administered questionnaire and has 24 questions: Pain, Stiffness and Physical Function. The possible scores range from 0-20 for pain, 0-8 for stiffness, 0-68 for physical function and these are then summed 0-96 for the global score. The negative value indicates that there has been an improvement since baseline, the higher the value the greater the change since baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Participants have signed an Informed Consent Form indicating that they understand the purpose of and the procedures required for the trial and are willing to participate in it.

2. Participants are men or non-pregnant, non-lactating women. Sexually active women must be postmenopausal, surgically sterile, or practicing an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double barrier method, contraceptive patch, male partner sterilization) before entry and throughout the trial. Women of childbearing potential must have a negative pregnancy test at screening.

3. Participants must be appropriately communicative to verbalize and to differentiate with regard to location and intensity of the pain.

4. Participants must be at least 40 years of age.

5. Participants must have a diagnosis of osteoarthritis of the knee based on the American

College of Rheumatology (ACR) classification criteria:

• Knee pain and

• Radiographic osteophytes or

• Knee pain and

• Aged 40 years or above, and

• Morning stiffness of less than 30 minutes of duration and

• Crepitus on motion.

1. Participants must have pain at the reference joint which has been present for at least 3 months.

2. Participant's pain must require a strong analgesic (defined as WHO Step III) as judged by the Investigator.

3. Participants must report a rate of satisfaction with their previous analgesic regimen not exceeding "fair" on a participant satisfaction with treatment scale (5-point VRS).

4. If under regular, daily pretreatment:

• Participants must be taking a WHO Step I or Step II analgesic medication for osteoarthritis of the knee on a daily basis for at least 2 weeks prior to the Screening Visit.

• The Investigator considers dose increase of WHO Step I analgesics (as mono- or combination therapy) and/or continuation with or dose increase of WHO Step II analgesics inadequate for the individual participant, whatever applicable.

• Participants must have an average pain intensity score (NRS 3) greater than 5 points during the last 3 days prior to the Screening Visit.

OR if no regular analgesic pretreatment is reported:

• Participants must have an average pain intensity score (NRS-3)greater than 6 points in the last 3 days prior to the Screening Visit and related to osteoarthritis.

Exclusion Criteria:

1. Presence of a clinically significant disease or laboratory findings that in the Investigator's opinion may affect efficacy or safety assessments.

2. Presence of active systemic or local infection, that may, in the opinion of the Investigator, affect the efficacy, quality of life/function or safety assessments.

3. History of alcohol or drug abuse, or suspicion thereof in the Investigator's judgment.

4. Presence of concomitant autoimmune inflammatory conditions.

5. Known history of or laboratory values reflecting severe renal impairment.

6. Known history of moderately or severely impaired hepatic function.

7. History of or active hepatitis B or C within the past 3 months or history of HIV infection.

8. History of seizure disorder or epilepsy.

9. Any of the following within 1 year: mild/moderate traumatic brain injury, stroke, transient ischemic attack, or brain neoplasm. 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 h) or residual sequelae suggesting transient changes in consciousness.

10. Pregnant or breast-feeding.

11. History of allergy to, or hypersensitivity to tapentadol hydrochloride or its excipients, or contraindications related to tapentadol hydrochloride including:

• Participants with acute or severe bronchial asthma or hypercapnia.

• Participants who have or are suspected of having paralytic ileus.

1. 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.

2. Participation in another trial concurrently or within 4 weeks prior to the Screening Visit.

3. Known to or suspected of not being able to comply with the protocol and the use of the investigational medicinal product.

4. Use of monoamine oxidase inhibitors within 14 days before the Screening Visit.

5. Non-stable dosing of selective serotonin reuptake inhibitors within 30 days before the Screening Visit (Doses must remain stable during the trial).

6. Osteoarthritis in a flare state.

7. Use of intra-articular injections of hyaluronic acid in the reference joint within 3 months before the Screening Visit.

8. Presence of conditions other than osteoarthritis of the reference joint that could confound the assessment or self-evaluation of pain, e.g., anatomical deformities, significant skin conditions such as abscess or syndromes with widespread pain such as fibromyalgia. Participants with osteoarthritis at joints other than the reference joint will not be excluded as long as the reference joint is the source of main pain and disability.

9. History and clinical signs at the reference joint of crystal-induced (e.g., gout, pseudo-gout), metabolic, infectious and autoimmune disease.

10. Any concomitant painful condition that could interfere with the participants' trial assessments or with their ability to differentiate the current joint pain from other painful conditions.

11. Any painful procedures during the trial (e.g., major surgery, including the reference joint) that may, in the opinion of the Investigator, affect the efficacy or safety assessments.

12. Pending litigation due to chronic pain or disability.

13. Intake of Step III analgesics within the 30 days prior to the Screening Visit.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Site 1	Belfort		France
2	Site 4	Marseille		France
3	Site 2	Murs Erigné		France
4	Site 3	Nantes		France
5	Site 5	Berlin		Germany
6	Site 2	Köln Dünnwald		Germany
7	Site 4	Leipzig		Germany
8	Site 6	Leipzig		Germany
9	Site 1	Marl		Germany
10	Site 3	Meine		Germany
11	Site 8	Rudolstadt		Germany
12	Site 4	Lodz		Poland
13	Site 2	Warsawa		Poland
14	Site 2	A Coruna		Spain
15	Site 7	A Coruna		Spain
16	Site 6	Lugo		Spain
17	Site 3	Madrid		Spain
18	Site 1	Torrelavega		Spain
19	Site 3	London		United Kingdom
20	Site 9	London		United Kingdom
21	Site 06	Manchester		United Kingdom
22	Site 08	Portsmouth		United Kingdom
23	Site 1	Solihull		United Kingdom
24	Site 4	Swansea		United Kingdom

Sponsors and Collaborators

• Grünenthal GmbH

Investigators

• Principal Investigator: Jaime Calvo, Dr. MD, Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria Santander, Spain

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Grünenthal GmbH
• ClinicalTrials.gov Identifier: NCT00983073
• Other Study ID Numbers: 441172; 2009-010423-58
• First Posted: Sep 23, 2009
• Last Update Posted: Oct 21, 2019
• Last Verified: Oct 1, 2019

• Keywords provided by Grünenthal GmbH: Osteoarthritis; Pain; Assessment; Tapentadol; Centrally acting analgesic; Chronic pain due to osteoarthritis
• Additional relevant MeSH terms: Osteoarthritis; Chronic Pain; Tapentadol

Study Results

Participant Flow

Recruitment Details	The enrollment of the first participant was on the 21 September 2009 and was completed on 02 September 2010 (when the last subject completed the last follow-up examination).
Pre-assignment Detail	The Trial had a duration of 13 weeks. The one week Observation Period did not involve dosing with Tapentadol. For Tapentadol analyses purposes the first 6 weeks of dosing with Tapentadol are reported as one period, Titration and Optimal Dose Period. The last 6 weeks on Tapentadol are reported as the Maintenance Period.

Arm/Group Title	Tapentadol PR
Arm/Group Description	All participants started with 50 mg tapentadol hydrochloride PR (twice daily). The dose of tapentadol hydrochloride PR was adjusted to a level that provided adequate analgesia (upwards or downwards on a weekly basis as needed). After 5 weeks the dose of tapentadol hydrochloride PR was kept stable. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). Tapentadol hydrochloride IR 50 mg (no more than twice daily; at least 4 hours apart) was considered as medication for acute pain episodes however, participants were not permitted to dose tapentadol hydrochloride IR once 500 mg tapentadol hydrochloride PR dose was reached.
Period Title: Observation Period
STARTED	224
COMPLETED	200
NOT COMPLETED	24
Period Title: Observation Period
STARTED	200
COMPLETED	160
NOT COMPLETED	40
Period Title: Observation Period
STARTED	160
COMPLETED	144
NOT COMPLETED	16

Baseline Characteristics

Arm/Group Title	Tapentadol PR
Arm/Group Description	All participants started with 50 mg tapentadol hydrochloride PR (twice daily). The dose of tapentadol hydrochloride PR was adjusted to a level that provided adequate analgesia (upwards or downwards on a weekly basis as needed). After 5 weeks the dose of tapentadol hydrochloride PR was kept stable. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). Tapentadol hydrochloride IR 50 mg (no more than twice daily; at least 4 hours apart) was considered as medication for acute pain episodes however, participants were not permitted to dose tapentadol hydrochloride IR once 500 mg tapentadol hydrochloride PR dose was reached.
Overall Participants	200
Age, Customized (years) [Mean (Standard Deviation) ]
40 years and older	67.4 (10.8)
Sex: Female, Male (Count of Participants)
Female	135 67.5%
Male	65 32.5%
Region of Enrollment (participants) [Number]
France	24 12%
Poland	6 3%
Spain	57 28.5%
Germany	91 45.5%
United Kingdom	22 11%
Baseline Average Pain Intensity (Units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Units on a scale]	7.5 (1.08)

Outcome Measures

1. Primary Outcome

Title	The Primary Endpoint is Defined as the Change From Week -1 of the Average Pain Intensity Score on an 11-point NRS-3 at Week 6.
Description	For this pain assessment, the participant was to indicate the level of average pain experienced over the previous 3 days 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". The value indicates the change from the baseline value on the 0 to 10 scale. A Negative value indicates a reduction in pain intensity from the baseline average pain intensity.
Time Frame	Baseline to end of week 6

Outcome Measure Data

Analysis Population Description

All participants who had at least one dose of study medication and one post-baseline pain intensity assessment. Last Observation Carried Forward (LOCF).

Arm/Group Title	Tapentadol PR
Arm/Group Description	All participants started with 50 mg tapentadol hydrochloride PR (twice daily). The dose of tapentadol hydrochloride PR was adjusted to a level that provided adequate analgesia (upwards or downwards on a weekly basis as needed). After 5 weeks the dose of tapentadol hydrochloride PR was kept stable. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). Tapentadol hydrochloride IR 50 mg (no more than twice daily; at least 4 hours apart) was considered as medication for acute pain episodes however, participants were not permitted to dose tapentadol hydrochloride IR once 500 mg tapentadol hydrochloride PR dose was reached.
Measure Participants	193
Mean (Standard Deviation) [Units on a scale]	-3.4 (2.10)

2. Secondary Outcome

Title	Average Pain Intensity Before the Start of Tapentadol Treatment
Description	For this pain assessment, the participant was to indicate the level of average pain experienced over the previous 3 days 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".
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tapentadol PR
Arm/Group Description	All participants started with 50 mg tapentadol hydrochloride PR (twice daily). The dose of tapentadol hydrochloride PR was adjusted to a level that provided adequate analgesia (upwards or downwards on a weekly basis as needed). After 5 weeks the dose of tapentadol hydrochloride PR was kept stable. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). Tapentadol hydrochloride IR 50 mg (no more than twice daily; at least 4 hours apart) was considered as medication for acute pain episodes however, participants were not permitted to dose tapentadol hydrochloride IR once 500 mg tapentadol hydrochloride PR dose was reached.
Measure Participants	195
Mean (Standard Deviation) [units on a scale]	7.5 (1.08)

3. Secondary Outcome

Title	Change in Average Pain Intensity After 6 Weeks of Tapentadol PR Treatment
Description	For this pain assessment, the participant was to indicate the level of average pain experienced over the previous 3 days 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". The value indicates the change from the baseline value on the 0 to 10 scale. A Negative value indicates a reduction in pain intensity from the baseline average pain intensity.
Time Frame	Baseline; End of Week 6 (6 Weeks)

Outcome Measure Data

Analysis Population Description

Number of participants with data available.

Arm/Group Title	Tapentadol PR
Arm/Group Description	All participants started with 50 mg tapentadol hydrochloride PR (twice daily). The dose of tapentadol hydrochloride PR was adjusted to a level that provided adequate analgesia (upwards or downwards on a weekly basis as needed). After 5 weeks the dose of tapentadol hydrochloride PR was kept stable. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). Tapentadol hydrochloride IR 50 mg (no more than twice daily; at least 4 hours apart) was considered as medication for acute pain episodes however, participants were not permitted to dose tapentadol hydrochloride IR once 500 mg tapentadol hydrochloride PR dose was reached.
Measure Participants	160
Mean (Standard Deviation) [units on a scale]	-3.8 (1.94)

4. Secondary Outcome

Title	Change in Average Pain Intensity After 12 Weeks of Tapentadol PR Treatment
Description	For this pain assessment, the participant was to indicate the level of average pain experienced over the previous 3 days 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". The value indicates the change from the baseline value on the 0 to 10 scale. A Negative value indicates a reduction in pain intensity from the baseline average pain intensity.
Time Frame	Baseline; End of Week 12 (12 Weeks)

Outcome Measure Data

Analysis Population Description

Number of participants with data available.

Arm/Group Title	Tapentadol PR
Arm/Group Description	All participants started with 50 mg tapentadol hydrochloride PR (twice daily). The dose of tapentadol hydrochloride PR was adjusted to a level that provided adequate analgesia (upwards or downwards on a weekly basis as needed). After 5 weeks the dose of tapentadol hydrochloride PR was kept stable. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). Tapentadol hydrochloride IR 50 mg (no more than twice daily; at least 4 hours apart) was considered as medication for acute pain episodes however, participants were not permitted to dose tapentadol hydrochloride IR once 500 mg tapentadol hydrochloride PR dose was reached.
Measure Participants	125
Mean (Standard Deviation) [units on a scale]	-4.4 (1.91)

5. Secondary Outcome

Title	EuroQol-5 (EQ-5D) Health Status Index Outcome Over Time
Description	The participant scored the EuroQol-5. This is a five dimensional health state classification. Each dimension is assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, with 1.00 indicating "full health" and 0 representing dead. The positive values indicate that during the study the health status improved.
Time Frame	Baseline; End of Week 6 (6 Weeks)

Outcome Measure Data

Analysis Population Description

Number of participants with data available.

Arm/Group Title	Tapentadol PR
Arm/Group Description	All participants started with 50 mg tapentadol hydrochloride PR (twice daily). The dose of tapentadol hydrochloride PR was adjusted to a level that provided adequate analgesia (upwards or downwards on a weekly basis as needed). After 5 weeks the dose of tapentadol hydrochloride PR was kept stable. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). Tapentadol hydrochloride IR 50 mg (no more than twice daily; at least 4 hours apart) was considered as medication for acute pain episodes however, participants were not permitted to dose tapentadol hydrochloride IR once 500 mg tapentadol hydrochloride PR dose was reached.
Measure Participants	159
Mean (Standard Deviation) [Units on a scale]	0.23 (0.30)

6. Secondary Outcome

Title	EuroQol-5 (EQ-5D) Health Status Index Outcome Over Time
Description	The participant scored the EuroQol-5. This is a five dimensional health state classification. Each dimension is assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, with 1.00 indicating "full health" and 0 representing dead. The positive values indicate that during the study the health status improved.
Time Frame	Baseline; End of Week 12 (12 Weeks)

Outcome Measure Data

Analysis Population Description

Number of participants with data available

Arm/Group Title	Tapentadol PR
Arm/Group Description	All participants started with 50 mg tapentadol hydrochloride PR (twice daily). The dose of tapentadol hydrochloride PR was adjusted to a level that provided adequate analgesia (upwards or downwards on a weekly basis as needed). After 5 weeks the dose of tapentadol hydrochloride PR was kept stable. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). Tapentadol hydrochloride IR 50 mg (no more than twice daily; at least 4 hours apart) was considered as medication for acute pain episodes however, participants were not permitted to dose tapentadol hydrochloride IR once 500 mg tapentadol hydrochloride PR dose was reached.
Measure Participants	125
Mean (Standard Deviation) [Units on a scale]	0.27 (0.34)

7. Secondary Outcome

Title	Change in Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS)
Description	EuroQoL-5D Health State Visual Analog Scale (VAS) is a participant rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state. The values indicated represent the change from the baseline, a positive value indicates an improvement.
Time Frame	Baseline; End of Week 6 (6 Weeks)

Outcome Measure Data

Analysis Population Description

Number of participants with data available.

Arm/Group Title	Tapentadol PR
Arm/Group Description	All participants started with 50 mg tapentadol hydrochloride PR (twice daily). The dose of tapentadol hydrochloride PR was adjusted to a level that provided adequate analgesia (upwards or downwards on a weekly basis as needed). After 5 weeks the dose of tapentadol hydrochloride PR was kept stable. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). Tapentadol hydrochloride IR 50 mg (no more than twice daily; at least 4 hours apart) was considered as medication for acute pain episodes however, participants were not permitted to dose tapentadol hydrochloride IR once 500 mg tapentadol hydrochloride PR dose was reached.
Measure Participants	158
Mean (Standard Deviation) [Units on a scale]	15.8 (22.8)

8. Secondary Outcome

Title	Change in Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS)
Description	EuroQoL-5D Health State Visual Analog Scale (VAS) is a participant rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state. The values indicated represent the change from the baseline, a positive value indicates an improvement.
Time Frame	Baseline, End of Week 12 (12 Weeks)

Outcome Measure Data

Analysis Population Description

Number of participants with data available

Arm/Group Title	Tapentadol PR
Arm/Group Description	All participants started with 50 mg tapentadol hydrochloride PR (twice daily). The dose of tapentadol hydrochloride PR was adjusted to a level that provided adequate analgesia (upwards or downwards on a weekly basis as needed). After 5 weeks the dose of tapentadol hydrochloride PR was kept stable. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). Tapentadol hydrochloride IR 50 mg (no more than twice daily; at least 4 hours apart) was considered as medication for acute pain episodes however, participants were not permitted to dose tapentadol hydrochloride IR once 500 mg tapentadol hydrochloride PR dose was reached.
Measure Participants	125
Mean (Standard Deviation) [Units on a scale]	19.5 (26.6)

9. Secondary Outcome

Title	Patient Global Impression of Change
Description	In the Patient Global Impression of Change (PGIC) the participant indicates the perceived change over the treatment period. The participant is requested to choose one of seven categories. Scores range from very much improved to very much worse.
Time Frame	Baseline; End of Week 6 (6 Weeks)

Outcome Measure Data

Analysis Population Description

Number of participants with data available

Arm/Group Title	Tapentadol PR
Arm/Group Description	All participants started with 50 mg tapentadol hydrochloride PR (twice daily). The dose of tapentadol hydrochloride PR was adjusted to a level that provided adequate analgesia (upwards or downwards on a weekly basis as needed). After 5 weeks the dose of tapentadol hydrochloride PR was kept stable. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). Tapentadol hydrochloride IR 50 mg (no more than twice daily; at least 4 hours apart) was considered as medication for acute pain episodes however, participants were not permitted to dose tapentadol hydrochloride IR once 500 mg tapentadol hydrochloride PR dose was reached.
Measure Participants	159
Very Much Improved	14 7%
Much Improved	75 37.5%
Minimally Improved	58 29%
No Change	8 4%
Minimally Worse	2 1%
Much Worse	2 1%
Very Much Worse	0 0%

10. Secondary Outcome

Title	Patient Global Impression of Change
Description	In the Patient Global Impression of Change (PGIC) the participant indicates the perceived change over the treatment period. The participant is requested to choose one of seven categories. Scores range from very much improved to very much worse.
Time Frame	Baseline; End of Week 12 (12 Weeks)

Outcome Measure Data

Analysis Population Description

Number of participants with data available

Arm/Group Title	Tapentadol PR
Arm/Group Description	All participants started with 50 mg tapentadol hydrochloride PR (twice daily). The dose of tapentadol hydrochloride PR was adjusted to a level that provided adequate analgesia (upwards or downwards on a weekly basis as needed). After 5 weeks the dose of tapentadol hydrochloride PR was kept stable. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). Tapentadol hydrochloride IR 50 mg (no more than twice daily; at least 4 hours apart) was considered as medication for acute pain episodes however, participants were not permitted to dose tapentadol hydrochloride IR once 500 mg tapentadol hydrochloride PR dose was reached.
Measure Participants	125
Very Much Improved	23 11.5%
Much Improved	64 32%
Minimally Improved	33 16.5%
No Change	5 2.5%
Minimally Worse	0 0%
Much Worse	0 0%
Very Much Worse	0 0%

11. Secondary Outcome

Title	Clinical Global Impression of Change
Description	In the Clinical Global Impression of Change (CGIC) the clinician indicates the perceived change over the treatment period. The clinician is requested to choose one of seven categories. Scores range from very much improved to very much worse.
Time Frame	Baseline; End of Week 6 (6 Weeks)

Outcome Measure Data

Analysis Population Description

Number of participants with data available

Arm/Group Title	Tapentadol PR
Arm/Group Description	All participants started with 50 mg tapentadol hydrochloride PR (twice daily). The dose of tapentadol hydrochloride PR was adjusted to a level that provided adequate analgesia (upwards or downwards on a weekly basis as needed). After 5 weeks the dose of tapentadol hydrochloride PR was kept stable. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). Tapentadol hydrochloride IR 50 mg (no more than twice daily; at least 4 hours apart) was considered as medication for acute pain episodes however, participants were not permitted to dose tapentadol hydrochloride IR once 500 mg tapentadol hydrochloride PR dose was reached.
Measure Participants	160
Very Much Improved	14 7%
Much Improved	88 44%
Minimally Improved	47 23.5%
No Change	7 3.5%
Minimally Worse	2 1%
Much Worse	1 0.5%
Very Much Worse	1 0.5%

12. Secondary Outcome

Title	Clinical Global Impression of Change
Description	In the Clinical Global Impression of Change (CGIC) the clinician indicates the perceived change over the treatment period. The clinician is requested to choose one of seven categories. Scores range from very much improved to very much worse.
Time Frame	Baseline; End of Week 12 (12 Weeks)

Outcome Measure Data

Analysis Population Description

Number of participants with data available

Arm/Group Title	Tapentadol PR
Arm/Group Description	All participants started with 50 mg tapentadol hydrochloride PR (twice daily). The dose of tapentadol hydrochloride PR was adjusted to a level that provided adequate analgesia (upwards or downwards on a weekly basis as needed). After 5 weeks the dose of tapentadol hydrochloride PR was kept stable. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). Tapentadol hydrochloride IR 50 mg (no more than twice daily; at least 4 hours apart) was considered as medication for acute pain episodes however, participants were not permitted to dose tapentadol hydrochloride IR once 500 mg tapentadol hydrochloride PR dose was reached.
Measure Participants	125
Very Much Improved	28 14%
Much Improved	68 34%
Minimally Improved	27 13.5%
No Change	2 1%
Minimally Worse	0 0%
Much Worse	0 0%
Very Much Worse	0 0%

13. Secondary Outcome

Title	Participant's Satisfaction With Previous Analgesic Treatment
Description	Participants were requested to rate their previous analgesic medication on a 5-point scale. Previous medication was rated as excellent, very good, good, fair and poor.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Number of participants with data available.

Arm/Group Title	Tapentadol PR
Arm/Group Description	All participants started with 50 mg tapentadol hydrochloride PR (twice daily). The dose of tapentadol hydrochloride PR was adjusted to a level that provided adequate analgesia (upwards or downwards on a weekly basis as needed). After 5 weeks the dose of tapentadol hydrochloride PR was kept stable. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). Tapentadol hydrochloride IR 50 mg (no more than twice daily; at least 4 hours apart) was considered as medication for acute pain episodes however, participants were not permitted to dose tapentadol hydrochloride IR once 500 mg tapentadol hydrochloride PR dose was reached.
Measure Participants	194
Excellent	0 0%
Very Good	0 0%
Good	4 2%
Fair	132 66%
Poor	62 31%

14. Secondary Outcome

Title	Participant's Satisfaction With New Analgesic Treatment, i.e Tapentadol.
Description	Participants were requested to rate their tapentadol (new) analgesic medication on a 5-point scale. The medication was rated as excellent, very good, good, fair and poor.
Time Frame	Baseline; End of Week 6 (6 Weeks)

Outcome Measure Data

Analysis Population Description

Number of participants with data available

Arm/Group Title	Tapentadol PR
Arm/Group Description	All participants started with either 50 mg tapentadol hydrochloride PR (twice daily). The dose of tapentadol hydrochloride PR was adjusted to a level that provided adequate analgesia (upwards or downwards on a weekly basis as needed). After 5 weeks the dose of tapentadol hydrochloride PR was kept stable. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). Tapentadol hydrochloride IR 50 mg (no more than twice daily; at least 4 hours apart) was considered as medication for acute pain episodes however, participants were not permitted to dose tapentadol hydrochloride IR once 500 mg tapentadol hydrochloride PR dose was reached.
Measure Participants	160
Excellent	16 8%
Very Good	39 19.5%
Good	88 44%
Fair	17 8.5%
Poor	0 0%

15. Secondary Outcome

Title	Participant's Satisfaction With New Analgesic Treatment, i.e Tapentadol.
Description	Participants were requested to rate their tapentadol (new) analgesic medication on a 5-point scale. The medication was rated as excellent, very good, good, fair and poor.
Time Frame	Baseline; End of Week 12 (12 Weeks)

Outcome Measure Data

Analysis Population Description

Number of participants with data available

Arm/Group Title	Tapentadol PR
Arm/Group Description	All participants started with 50 mg tapentadol hydrochloride PR (twice daily). The dose of tapentadol hydrochloride PR was adjusted to a level that provided adequate analgesia (upwards or downwards on a weekly basis as needed). After 5 weeks the dose of tapentadol hydrochloride PR was kept stable. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). Tapentadol hydrochloride IR 50 mg (no more than twice daily; at least 4 hours apart) was considered as medication for acute pain episodes however, participants were not permitted to dose tapentadol hydrochloride IR once 500 mg tapentadol hydrochloride PR dose was reached.
Measure Participants	125
Excellent	16 8%
Very Good	45 22.5%
Good	54 27%
Fair	9 4.5%
Poor	1 0.5%

16. Secondary Outcome

Title	Baseline Western Ontario McMaster Questionnaire (WOMAC) Global Score Assessing Pain, Disability and Joint Stiffness of the Knee
Description	Western Ontario McMaster Questionnaire (WOMAC) Global Score: WOMAC is measured with a Likert ordinal scale (the participant gives one of 5 possible answers) A higher score indicate that a symptom is bothersome or disabling. The WOMAC is a self-administered questionnaire and has 24 questions: Pain, Stiffness and Physical Function. The possible scores range from 0-20 for pain, 0-8 for stiffness, 0-68 for physical function and these are then summed 0-96 for the global score. A lower score indicates a lower level of symptoms and or disability.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Number of participants with data available

Arm/Group Title	Tapentadol PR
Arm/Group Description	All participants started with 50 mg tapentadol hydrochloride PR (twice daily). The dose of tapentadol hydrochloride PR was adjusted to a level that provided adequate analgesia (upwards or downwards on a weekly basis as needed). After 5 weeks the dose of tapentadol hydrochloride PR was kept stable. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). Tapentadol hydrochloride IR 50 mg (no more than twice daily; at least 4 hours apart) was considered as medication for acute pain episodes however, participants were not permitted to dose tapentadol hydrochloride IR once 500 mg tapentadol hydrochloride PR dose was reached.
Measure Participants	195
Mean (Standard Deviation) [units on a scale]	53.6 (14.58)

17. Secondary Outcome

Title	Change From Baseline in the Western Ontario McMaster Questionnaire (WOMAC) Global Score Assessing Pain, Disability and Joint Stiffness of the Knee Over the Last Week at Week 6
Description	The WOMAC is a self-administered questionnaire and has 24 questions: Pain, Stiffness and Physical Function. The possible scores range from 0-20 for pain, 0-8 for stiffness, 0-68 for physical function and these are then summed 0-96 for the global score. The negative value indicates that there has been an improvement since baseline, the higher the value the greater the change since baseline.
Time Frame	Baseline; End of Week 6 (6 Weeks)

Outcome Measure Data

Analysis Population Description

Number of participants with data available

Arm/Group Title	Tapentadol PR
Arm/Group Description	All participants started with 50 mg tapentadol hydrochloride PR (twice daily). The dose of tapentadol hydrochloride PR was adjusted to a level that provided adequate analgesia (upwards or downwards on a weekly basis as needed). After 5 weeks the dose of tapentadol hydrochloride PR was kept stable. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). Tapentadol hydrochloride IR 50 mg (no more than twice daily; at least 4 hours apart) was considered as medication for acute pain episodes however, participants were not permitted to dose tapentadol hydrochloride IR once 500 mg tapentadol hydrochloride PR dose was reached.
Measure Participants	159
Mean (Standard Deviation) [units on a scale]	-21.0 (18.82)

18. Secondary Outcome

Title	Change From Baseline in the Western Ontario McMaster Questionnaire (WOMAC) Global Score Assessing Pain, Disability and Joint Stiffness of the Knee Over the Last Week at Week 12
Description	The WOMAC is a self-administered questionnaire and has 24 questions: Pain, Stiffness and Physical Function. The possible scores range from 0-20 for pain, 0-8 for stiffness, 0-68 for physical function and these are then summed 0-96 for the global score. The negative value indicates that there has been an improvement since baseline, the higher the value the greater the change since baseline.
Time Frame	Baseline; End of Week 12 (12 Weeks)

Outcome Measure Data

Analysis Population Description

Number of participants with data available

Arm/Group Title	Tapentadol PR
Arm/Group Description	All participants started with 50 mg tapentadol hydrochloride PR (twice daily). The dose of tapentadol hydrochloride PR was adjusted to a level that provided adequate analgesia (upwards or downwards on a weekly basis as needed). After 5 weeks the dose of tapentadol hydrochloride PR was kept stable. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). Tapentadol hydrochloride IR 50 mg (no more than twice daily; at least 4 hours apart) was considered as medication for acute pain episodes however, participants were not permitted to dose tapentadol hydrochloride IR once 500 mg tapentadol hydrochloride PR dose was reached.
Measure Participants	125
Mean (Standard Deviation) [units on a scale]	-27.6 (19.52)

Adverse Events

Time Frame	From first tapentadol dose to the end of week 12 of tapentadol treatment.
Arm/Group Title	Tapentadol PR
Arm/Group Description	All participants started with 50 mg tapentadol hydrochloride PR (twice daily). The dose of tapentadol hydrochloride PR was adjusted to a level that provided adequate analgesia (upwards or downwards on a weekly basis as needed). After 5 weeks the dose of tapentadol hydrochloride PR was kept stable. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). Tapentadol hydrochloride IR 50 mg (no more than twice daily; at least 4 hours apart) was considered as medication for acute pain episodes however, participants were not permitted to dose tapentadol hydrochloride IR once 500 mg tapentadol hydrochloride PR dose was reached.
All Cause Mortality
	Tapentadol PR
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Tapentadol PR
	Affected / at Risk (%)	# Events
Total	8/200 (4%)
Cardiac disorders
Angina unstable	1/200 (0.5%)
Myocardial infarction	1/200 (0.5%)
Infections and infestations
Cellulitis	1/200 (0.5%)
Respiratory Tract Infection	1/200 (0.5%)
Urinary tract infection	1/200 (0.5%)
Injury, poisoning and procedural complications
Radius fracture	1/200 (0.5%)
Musculoskeletal and connective tissue disorders
Back pain	1/200 (0.5%)
Nervous system disorders
Facial palsy	1/200 (0.5%)
Psychiatric disorders
Panic attack	1/200 (0.5%)
Vascular disorders
Deep vein thrombosis	1/200 (0.5%)
Other (Not Including Serious) Adverse Events
	Tapentadol PR
	Affected / at Risk (%)	# Events
Total	142/200 (71%)
Gastrointestinal disorders
Constipation	21/200 (10.5%)
Diarrhoea	11/200 (5.5%)
Dry Mouth	20/200 (10%)
Nausea	26/200 (13%)
Vomiting	10/200 (5%)
General disorders
Fatigue	21/200 (10.5%)
Infections and infestations
Nasopharyngitis	16/200 (8%)
Nervous system disorders
Dizziness	24/200 (12%)
Headache	13/200 (6.5%)
Somnolence	14/200 (7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Grünenthal reserves the right to review any publication pertaining to the trial before it is submitted for publication. Neither party has the right to prohibit publication unless publication can be shown to affect possible patent rights.