Osteoarthritis
Conditions
Keywords
Osteoarthritis, lacosamide, VIMPAT
Brief summary
The purpose of this trial is to evaluate the effectiveness, safety and tolerability of lacosamide (LCM) 400mg/day in treating the signs and symptoms of osteoarthritis of the knee.
Detailed description
LCM is an investigational drug that is being studied as a treatment in male and female patients who are diagnosed with osteoarthritis of the knee and require therapeutic doses of NSAIDs, COX-2 NSAIDs and/or paracetamol. This trial will be conducted exclusively in Europe. The study has an adaptive 3-stage group sequential design. The trial will last a total of 17 weeks. There will be a 2 week period to wean off current medication, followed by a 4 week period where the patient will receive placebo (inactive drug) or gradually increasing doses of LCM up to the target dose of 400mg/day. The target dose or placebo will be maintained for 8 weeks followed by a 1 week reduction period then a 2 week safety follow up period. The last subject is expected to be enrolled in December 2007. The study was terminated based on the outcome of the planned first interim analysis, which was performed as defined in the protocol in a subset of patients. It was decided not to continue the trial. No safety concerns were identified.
Interventions
DRUGlacosamide
50 or 100mg tablet, 400mg daily, for 12 weeks
OTHERPlacebo
50 or 100mg tablet, 400mg daily, for 12 weeks, matched to Lacosamide
Sponsors
UCB Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Subject has symptomatic osteoarthritis of the knee diagnosed using clinical and radiographic evidence as well as ACR criteria with symptom duration of at least 6 months. * Subject requires therapeutic dose of an NSAID, COX-2 NSAID, and/or paracetamol/acetaminophen for osteoarthritis pain of the index knee and has taken that medication at least 5 days per week for the last 4 weeks prior to the screening visit (Visit 1).
Exclusion criteria
* Subject is not able to withdraw NSAIDs, COX-2 NSAIDs and/or paracetamol * Subject is taking analgesic other than NSAIDs COX-2 NSAIDs and/or paracetamol * Subject is planning to begin or stop treatment with glucosamine and/or chondroitin during the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change of the Western Ontario and McMaster Universities (WOMAC) Pain Subscale Score (Visual Analogue Scale Version) From Baseline to the End of the 8 Week Maintenance Period | Baseline, end of 8 week Maintenance Period | The Visual Analogue Scale (VAS) version of the WOMAC pain subscale ranges from 0 to 100, high values describe high grade of pain. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to End of 8 Week Maintenance Period in WOMAC Stiffness Subscale Score. | Baseline, end of 8 week Maintenance Period | The WOMAC stiffness subscale score (Visual Analogue Scale version) ranges from 0 to 100, high values describe high grade of stiffness. |
| Change From Baseline to End of 8 Week Maintenance Period in Total WOMAC Score. | Baseline, end of 8 week Maintenance Period | The WOMAC total score is the sum of the normalized subscale scores for pain, stiffness, and physical function and ranges from 0 to 300, high values describe high grade of impact. |
| Patient's Global Impression of Change From Baseline at the End of 8 Week Maintenance Period. | at the end of 8 week Maintenance Period | Patient's global impression of change from baseline is a score that ranges from 'very much worse' to 'very much improved'. |
| Change From Baseline to End of 8 Week Maintenance Period in WOMAC Physical Function Subscale Score. | Baseline, end of 8 week Maintenance Period | The WOMAC physical function subscale score (Visual Analogue Scale version) ranges from 0 to 100, high values describe high grade of difficulty in performing daily activities. |
| Amount of Rescue Medication Use During 8 Week Maintenance Period. | during 8 week Maintenance Period | Use of rescue medication is expressed in number of tablets equivalent to 500 mg Paracetamol per day. |
| Change From Baseline to End of 8 Week Maintenance Period in Perception of Pain Interference With Subject's Sleep. | Baseline, end of 8 week Maintenance Period | Pain interference with sleep refers to patient's last evening prior to the visit and was assessed using a 100mm visual analog scale (VAS). The VAS ranges from 0 (did not interfere) to 100 (completely interfered). |
| Change From Baseline to End of 8 Week Maintenance Period in Profile of Mood States (Total Mood Disturbance Score). | Baseline, end of 8 week Maintenance Period | Total Mood Disturbance score sums up over the domain scores regarding Tension-anxiety, Depression-ejection, Anger-hostility, Vigor-activity (was subtracted), Fatigue-inertia, Confusion-bewilderment. Domain scores were derived as sum of the respective items and range from 0 to 20. With exception of Vigor-activity high values describe bad mood. |
| Response at the End of 8 Week Maintenance Period Versus Baseline Based on the (Slightly Modified)Criteria of the Osteoarthritis Research Society International (OARSI) and the Outcome Measures in Rheumatology Initiative (OMERACT). | Baseline, end of 8 week Maintenance Period | Improvement = reduction of \>= 20% and \>= 10 mm in both WOMAC pain and physical function subscale. Those who met the criteria in either of the subscales had improved if response to Patient's Global Impression of change from baseline was at least 'mildly improved'. High improvement = reduction of \>= 50% and \>= 20 mm in either of the subscales. Response = either high improvement or improvement. |
Countries
Czechia, Germany, Hungary, Poland, Romania, Sweden, United Kingdom
Participant flow
Recruitment details
Trial utilized an adaptive 3-stage group sequential design. The Data Monitoring Committee had recommended to stop the trial after the first stage due to lack of efficacy. Results refer to the entire population randomized until discontinuation of study (including overrun).
Pre-assignment details
Of the 194 enrolled subjects, 149 subjects have been randomized until trial termination. The Participants flow refers to the randomized population. Of the 149 randomized subjects, 148 subjects have been treated and are included in the safety population, 145 have been included in the ITT population (Full Analysis Set).
Participants by arm
| Arm | Count |
|---|---|
| Lacosamide Lacosamide (LCM) 400 mg/day | 73 |
| Placebo Placebo | 76 |
| Total | 149 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 5 |
| Overall Study | Lack of Efficacy | 5 | 4 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Other | 2 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Lacosamide | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 33 Participants | 30 Participants | 63 Participants |
| Age, Categorical Between 18 and 65 years | 40 Participants | 46 Participants | 86 Participants |
| Age, Continuous | 61.0 years STANDARD_DEVIATION 8.03 | 62.3 years STANDARD_DEVIATION 6.74 | 61.7 years STANDARD_DEVIATION 7.4 |
| Region of Enrollment Czech Republic | 8 participants | 10 participants | 18 participants |
| Region of Enrollment Germany | 27 participants | 27 participants | 54 participants |
| Region of Enrollment Hungary | 20 participants | 22 participants | 42 participants |
| Region of Enrollment Poland | 9 participants | 9 participants | 18 participants |
| Region of Enrollment Romania | 9 participants | 8 participants | 17 participants |
| Sex: Female, Male Female | 52 Participants | 59 Participants | 111 Participants |
| Sex: Female, Male Male | 21 Participants | 17 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 72 | 13 / 76 |
| serious Total, serious adverse events | 4 / 72 | 2 / 76 |
Outcome results
Primary
Change of the Western Ontario and McMaster Universities (WOMAC) Pain Subscale Score (Visual Analogue Scale Version) From Baseline to the End of the 8 Week Maintenance Period
The Visual Analogue Scale (VAS) version of the WOMAC pain subscale ranges from 0 to 100, high values describe high grade of pain.
Time frame: Baseline, end of 8 week Maintenance Period
Population: Full Analysis Set (FAS), defined as all randomized subjects that have received at least one dose of trial medication and had at least one post-baseline WOMAC assessment. Last observation carried forward (LOCF) imputation method was applied in case of missing WOMAC assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lacosamide | Change of the Western Ontario and McMaster Universities (WOMAC) Pain Subscale Score (Visual Analogue Scale Version) From Baseline to the End of the 8 Week Maintenance Period | -24.85 Unit on a scale | Standard Deviation 23.75 |
| Placebo | Change of the Western Ontario and McMaster Universities (WOMAC) Pain Subscale Score (Visual Analogue Scale Version) From Baseline to the End of the 8 Week Maintenance Period | -28.49 Unit on a scale | Standard Deviation 22.27 |
Comparison: The ANCOVA analysis includes treatment and pooled site as factors and baseline score as covariate.p-value: 0.543895% CI: [-5.3, 10.02]ANCOVA
Secondary
Amount of Rescue Medication Use During 8 Week Maintenance Period.
Use of rescue medication is expressed in number of tablets equivalent to 500 mg Paracetamol per day.
Time frame: during 8 week Maintenance Period
Population: Full Analysis Set (FAS), defined as all randomized subjects that have received at least one dose of trial medication and had at least one post-baseline WOMAC assessment. Only subjects who entered the Maintenance Phase were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lacosamide | Amount of Rescue Medication Use During 8 Week Maintenance Period. | 0.48 tablets/day | Standard Deviation 0.62 |
| Placebo | Amount of Rescue Medication Use During 8 Week Maintenance Period. | 0.70 tablets/day | Standard Deviation 0.79 |
Secondary
Change From Baseline to End of 8 Week Maintenance Period in Perception of Pain Interference With Subject's Sleep.
Pain interference with sleep refers to patient's last evening prior to the visit and was assessed using a 100mm visual analog scale (VAS). The VAS ranges from 0 (did not interfere) to 100 (completely interfered).
Time frame: Baseline, end of 8 week Maintenance Period
Population: Full Analysis Set (FAS), defined as all randomized subjects that have received at least one dose of trial medication and had at least one post-baseline WOMAC assessment. Only subjects with non-missing values were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lacosamide | Change From Baseline to End of 8 Week Maintenance Period in Perception of Pain Interference With Subject's Sleep. | -19.8 Unit on a scale | Standard Deviation 26.55 |
| Placebo | Change From Baseline to End of 8 Week Maintenance Period in Perception of Pain Interference With Subject's Sleep. | -21.6 Unit on a scale | Standard Deviation 26.76 |
Secondary
Change From Baseline to End of 8 Week Maintenance Period in Profile of Mood States (Total Mood Disturbance Score).
Total Mood Disturbance score sums up over the domain scores regarding Tension-anxiety, Depression-ejection, Anger-hostility, Vigor-activity (was subtracted), Fatigue-inertia, Confusion-bewilderment. Domain scores were derived as sum of the respective items and range from 0 to 20. With exception of Vigor-activity high values describe bad mood.
Time frame: Baseline, end of 8 week Maintenance Period
Population: Full Analysis Set (FAS), defined as all randomized subjects that have received at least one dose of trial medication and had at least one post-baseline WOMAC assessment. Only subjects with non-missing values were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lacosamide | Change From Baseline to End of 8 Week Maintenance Period in Profile of Mood States (Total Mood Disturbance Score). | 0.9 Unit on a scale | Standard Deviation 17.99 |
| Placebo | Change From Baseline to End of 8 Week Maintenance Period in Profile of Mood States (Total Mood Disturbance Score). | -4.5 Unit on a scale | Standard Deviation 14.25 |
Secondary
Change From Baseline to End of 8 Week Maintenance Period in Total WOMAC Score.
The WOMAC total score is the sum of the normalized subscale scores for pain, stiffness, and physical function and ranges from 0 to 300, high values describe high grade of impact.
Time frame: Baseline, end of 8 week Maintenance Period
Population: Full Analysis Set (FAS), defined as all randomized subjects that have received at least one dose of trial medication and had at least one post-baseline WOMAC assessment. LOCF imputation method was applied in case of missing WOMAC assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lacosamide | Change From Baseline to End of 8 Week Maintenance Period in Total WOMAC Score. | -60.85 Unit on a scale | Standard Deviation 66.85 |
| Placebo | Change From Baseline to End of 8 Week Maintenance Period in Total WOMAC Score. | -75.24 Unit on a scale | Standard Deviation 65.61 |
Comparison: The ANCOVA analysis includes treatment and pooled site as factors and baseline score as covariate.p-value: 0.344595% CI: [-11.65, 33.13]ANCOVA
Secondary
Change From Baseline to End of 8 Week Maintenance Period in WOMAC Physical Function Subscale Score.
The WOMAC physical function subscale score (Visual Analogue Scale version) ranges from 0 to 100, high values describe high grade of difficulty in performing daily activities.
Time frame: Baseline, end of 8 week Maintenance Period
Population: Full Analysis Set (FAS), defined as all randomized subjects that have received at least one dose of trial medication and had at least one post-baseline WOMAC assessment. LOCF imputation method was applied in case of missing WOMAC assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lacosamide | Change From Baseline to End of 8 Week Maintenance Period in WOMAC Physical Function Subscale Score. | -17.09 Unit on a scale | Standard Deviation 21.74 |
| Placebo | Change From Baseline to End of 8 Week Maintenance Period in WOMAC Physical Function Subscale Score. | -23.31 Unit on a scale | Standard Deviation 22.45 |
Comparison: The ANCOVA analysis includes treatment and pooled site as factors and baseline score as covariate.p-value: 0.202295% CI: [-2.62, 12.28]ANCOVA
Secondary
Change From Baseline to End of 8 Week Maintenance Period in WOMAC Stiffness Subscale Score.
The WOMAC stiffness subscale score (Visual Analogue Scale version) ranges from 0 to 100, high values describe high grade of stiffness.
Time frame: Baseline, end of 8 week Maintenance Period
Population: Full Analysis Set (FAS), defined as all randomized subjects that have received at least one dose of trial medication and had at least one post-baseline WOMAC assessment. LOCF imputation method was applied in case of missing WOMAC assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lacosamide | Change From Baseline to End of 8 Week Maintenance Period in WOMAC Stiffness Subscale Score. | -18.92 Unit on a scale | Standard Deviation 26.11 |
| Placebo | Change From Baseline to End of 8 Week Maintenance Period in WOMAC Stiffness Subscale Score. | -23.43 Unit on a scale | Standard Deviation 24 |
Comparison: The ANCOVA analysis includes treatment and pooled site as factors and baseline score as covariate.p-value: 0.66595% CI: [-6.36, 9.93]ANCOVA
Secondary
Patient's Global Impression of Change From Baseline at the End of 8 Week Maintenance Period.
Patient's global impression of change from baseline is a score that ranges from 'very much worse' to 'very much improved'.
Time frame: at the end of 8 week Maintenance Period
Population: Full Analysis Set (FAS), defined as all randomized subjects that have received at least one dose of trial medication and had at least one post-baseline WOMAC assessment. Only subjects with non-missing measurements of Patient's global impression of change from baseline were included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lacosamide | Patient's Global Impression of Change From Baseline at the End of 8 Week Maintenance Period. | Much worse | 1 Participants |
| Lacosamide | Patient's Global Impression of Change From Baseline at the End of 8 Week Maintenance Period. | Much improved | 15 Participants |
| Lacosamide | Patient's Global Impression of Change From Baseline at the End of 8 Week Maintenance Period. | No change | 18 Participants |
| Lacosamide | Patient's Global Impression of Change From Baseline at the End of 8 Week Maintenance Period. | Very much improved | 8 Participants |
| Lacosamide | Patient's Global Impression of Change From Baseline at the End of 8 Week Maintenance Period. | Worse | 10 Participants |
| Lacosamide | Patient's Global Impression of Change From Baseline at the End of 8 Week Maintenance Period. | Much + very much improved | 23 Participants |
| Lacosamide | Patient's Global Impression of Change From Baseline at the End of 8 Week Maintenance Period. | Mildly improved | 12 Participants |
| Lacosamide | Patient's Global Impression of Change From Baseline at the End of 8 Week Maintenance Period. | Much + very much + mildly improved | 35 Participants |
| Lacosamide | Patient's Global Impression of Change From Baseline at the End of 8 Week Maintenance Period. | Very much worse | 4 Participants |
| Placebo | Patient's Global Impression of Change From Baseline at the End of 8 Week Maintenance Period. | Much + very much + mildly improved | 46 Participants |
| Placebo | Patient's Global Impression of Change From Baseline at the End of 8 Week Maintenance Period. | Very much worse | 1 Participants |
| Placebo | Patient's Global Impression of Change From Baseline at the End of 8 Week Maintenance Period. | Much worse | 5 Participants |
| Placebo | Patient's Global Impression of Change From Baseline at the End of 8 Week Maintenance Period. | Worse | 10 Participants |
| Placebo | Patient's Global Impression of Change From Baseline at the End of 8 Week Maintenance Period. | No change | 10 Participants |
| Placebo | Patient's Global Impression of Change From Baseline at the End of 8 Week Maintenance Period. | Mildly improved | 30 Participants |
| Placebo | Patient's Global Impression of Change From Baseline at the End of 8 Week Maintenance Period. | Much improved | 13 Participants |
| Placebo | Patient's Global Impression of Change From Baseline at the End of 8 Week Maintenance Period. | Very much improved | 3 Participants |
| Placebo | Patient's Global Impression of Change From Baseline at the End of 8 Week Maintenance Period. | Much + very much improved | 16 Participants |
Secondary
Response at the End of 8 Week Maintenance Period Versus Baseline Based on the (Slightly Modified)Criteria of the Osteoarthritis Research Society International (OARSI) and the Outcome Measures in Rheumatology Initiative (OMERACT).
Improvement = reduction of \>= 20% and \>= 10 mm in both WOMAC pain and physical function subscale. Those who met the criteria in either of the subscales had improved if response to Patient's Global Impression of change from baseline was at least 'mildly improved'. High improvement = reduction of \>= 50% and \>= 20 mm in either of the subscales. Response = either high improvement or improvement.
Time frame: Baseline, end of 8 week Maintenance Period
Population: Full Analysis Set (FAS), defined as all randomized subjects that have received at least one dose of trial medication and had at least one post-baseline WOMAC assessment. Dropouts due to lack of efficay were defined as non-responders. For dropouts due to any other reason LOCF was applied to the underlying WOMAC subscale scores.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lacosamide | Response at the End of 8 Week Maintenance Period Versus Baseline Based on the (Slightly Modified)Criteria of the Osteoarthritis Research Society International (OARSI) and the Outcome Measures in Rheumatology Initiative (OMERACT). | Response | 38 participants |
| Lacosamide | Response at the End of 8 Week Maintenance Period Versus Baseline Based on the (Slightly Modified)Criteria of the Osteoarthritis Research Society International (OARSI) and the Outcome Measures in Rheumatology Initiative (OMERACT). | High improvement | 33 participants |
| Lacosamide | Response at the End of 8 Week Maintenance Period Versus Baseline Based on the (Slightly Modified)Criteria of the Osteoarthritis Research Society International (OARSI) and the Outcome Measures in Rheumatology Initiative (OMERACT). | Improvement | 38 participants |
| Placebo | Response at the End of 8 Week Maintenance Period Versus Baseline Based on the (Slightly Modified)Criteria of the Osteoarthritis Research Society International (OARSI) and the Outcome Measures in Rheumatology Initiative (OMERACT). | High improvement | 32 participants |
| Placebo | Response at the End of 8 Week Maintenance Period Versus Baseline Based on the (Slightly Modified)Criteria of the Osteoarthritis Research Society International (OARSI) and the Outcome Measures in Rheumatology Initiative (OMERACT). | Improvement | 52 participants |
| Placebo | Response at the End of 8 Week Maintenance Period Versus Baseline Based on the (Slightly Modified)Criteria of the Osteoarthritis Research Society International (OARSI) and the Outcome Measures in Rheumatology Initiative (OMERACT). | Response | 52 participants |
Comparison: Analysis of 'response' based on a likelihood ratio test with treatment and pooled site as factors.p-value: 0.041895% CI: [0.245, 0.974]Likelihood ratio test