Trial Outcomes & Findings for A Four-Arm Study Comparing the Analgesic Efficacy and Safety of Tramadol Once a Day 100, 200 and 300 mg Versus Placebo for the Treatment of Pain Due to Osteoarthritis of the Knee (NCT NCT00832416)

Results Overview

Percentage of difference in WOMAC Pain Subscale score between baseline and week 12. The WOMAC scale is a 24-item questionnaire divided in 3 subscales, using a 100mm visual analog scale ranging from no pain (0mm) to extreme pain (100mm). The WOMAC Pain Subscale results from the sum of 5 questions.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

565 participants

Primary outcome timeframe

Baseline to week 12

Results posted on

2012-04-30

Participant Flow

Participant milestones

Participant milestones
Measure	1: Tramadol Once A Day 100mg	2: Tramadol Once A Day 200mg	3: Tramadol Once A Day 300mg	4: Placebo
Overall Study STARTED	110	113	115	227
Overall Study COMPLETED	64	60	54	144
Overall Study NOT COMPLETED	46	53	61	83

Reasons for withdrawal

Reasons for withdrawal
Measure	1: Tramadol Once A Day 100mg	2: Tramadol Once A Day 200mg	3: Tramadol Once A Day 300mg	4: Placebo
Overall Study Lack of Efficacy	17	15	13	52
Overall Study Withdrawal by Subject	5	7	2	10
Overall Study Physician Decision	2	12	5	10
Overall Study Administrative	0	0	0	1
Overall Study Adverse Event	21	19	41	10
Overall Study Death	1	0	0	0

Baseline Characteristics

A Four-Arm Study Comparing the Analgesic Efficacy and Safety of Tramadol Once a Day 100, 200 and 300 mg Versus Placebo for the Treatment of Pain Due to Osteoarthritis of the Knee

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	1: Tramadol Once A Day 100mg n=110 Participants	2: Tramadol Once A Day 200mg n=113 Participants	3: Tramadol Once A Day 300mg n=115 Participants	4: Placebo n=227 Participants	Total n=565 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0.0 Participants n=21 Participants
Age, Categorical Between 18 and 65 years	69 Participants n=5 Participants	77 Participants n=7 Participants	66 Participants n=5 Participants	139 Participants n=4 Participants	351.0 Participants n=21 Participants
Age, Categorical >=65 years	41 Participants n=5 Participants	36 Participants n=7 Participants	49 Participants n=5 Participants	88 Participants n=4 Participants	214.0 Participants n=21 Participants
Age Continuous	59.8 years STANDARD_DEVIATION 9.0 • n=5 Participants	59.8 years STANDARD_DEVIATION 8.4 • n=7 Participants	61.0 years STANDARD_DEVIATION 9.6 • n=5 Participants	60.6 years STANDARD_DEVIATION 9.6 • n=4 Participants	60.4 years STANDARD_DEVIATION 9.3 • n=21 Participants
Sex: Female, Male Female	65 Participants n=5 Participants	64 Participants n=7 Participants	72 Participants n=5 Participants	140 Participants n=4 Participants	341.0 Participants n=21 Participants
Sex: Female, Male Male	45 Participants n=5 Participants	49 Participants n=7 Participants	43 Participants n=5 Participants	87 Participants n=4 Participants	224.0 Participants n=21 Participants

PRIMARY outcome

Timeframe: 12 weeks

Population: The analysis was performed using the full analysis population (All randomized patients who received at least one dose of the assigned study medication and had at least one post Baseline assessment of any functional scale). Last Individual value.

3-item Likert-scale: "How do you rate overall pain relief with the drug?" with 3 possible answers: "very effective", "effective", or "ineffective". The average of ratings at visits 2-5 was calculated as median, rounded up to the closest integer.

Outcome measures

Outcome measures
Measure	1: Tramadol Once A Day 100mg n=108 Participants	2: Tramadol Once A Day 200mg n=109 Participants	3: Tramadol Once A Day 300mg n=113 Participants	4: Placebo n=223 Participants
Patient Global Rating of Pain for the Study Period (12 Weeks) Very effective	19 participants	16 participants	26 participants	29 participants
Patient Global Rating of Pain for the Study Period (12 Weeks) Effective	50 participants	56 participants	56 participants	94 participants
Patient Global Rating of Pain for the Study Period (12 Weeks) Ineffective	39 participants	37 participants	31 participants	100 participants

PRIMARY outcome

Timeframe: Baseline to week 12

Population: The analysis was performed using the full analysis population (All randomized patients who received at least one dose of the assigned study medication and had at least one post Baseline assessment of any functional scale). Missing Values at Last Visit Imputed by Individual Last Post Baseline Value.

Percentage of difference in WOMAC Pain Subscale score between baseline and week 12. The WOMAC scale is a 24-item questionnaire divided in 3 subscales, using a 100mm visual analog scale ranging from no pain (0mm) to extreme pain (100mm). The WOMAC Pain Subscale results from the sum of 5 questions.

Outcome measures

Outcome measures
Measure	1: Tramadol Once A Day 100mg n=109 Participants	2: Tramadol Once A Day 200mg n=110 Participants	3: Tramadol Once A Day 300mg n=113 Participants	4: Placebo n=226 Participants
Percentage Difference Between WOMAC Pain Subscale Score From Baseline to the End of the Study (Week 12)	36.3 Percentage difference Standard Deviation 45.3	36.6 Percentage difference Standard Deviation 40.9	41.0 Percentage difference Standard Deviation 44.5	38.0 Percentage difference Standard Deviation 41.7

PRIMARY outcome

Timeframe: Baseline to week 12

Population: The analysis was performed using the full analysis population (All randomized patients who received at least one dose of the assigned study medication and had at least one post Baseline assessment of any functional scale). Missing Values at Last Visit Imputed by Individual Last Post Baseline Value.

Percentage of difference in WOMAC Physical Function Subscale score between baseline and week 12. The WOMAC scale is a 24-item questionnaire divided in 3 subscales, using a 100mm visual analog scale ranging from no pain (0mm) to extreme pain (100mm). The WOMAC Physical Function subscale results from the sum of 17 questions.

Outcome measures

Outcome measures
Measure	1: Tramadol Once A Day 100mg n=109 Participants	2: Tramadol Once A Day 200mg n=110 Participants	3: Tramadol Once A Day 300mg n=113 Participants	4: Placebo n=226 Participants
Percentage Difference Between WOMAC Physical Function Subscale Score From Baseline to the End of the Study (Week 12)	31.9 Percentage difference Standard Deviation 46.0	37.0 Percentage difference Standard Deviation 39.3	37.3 Percentage difference Standard Deviation 41.7	33.7 Percentage difference Standard Deviation 44.3

SECONDARY outcome

Timeframe: Week 0, week 3, week 6

Population: The analysis was performed using the full analysis population (All randomized patients who received at least one dose of the assigned study medication and had at least one post Baseline assessment of any functional scale). Missing Values at Last Visit Imputed by Individual Last Post Baseline Value.

Percentage of difference in WOMAC Pain Subscale score between baseline and intervening visits 2-4. The WOMAC scale is a 24-item questionnaire divided in 3 subscales, using a 100mm visual analog scale ranging from no pain (0mm) to extreme pain (100mm). The WOMAC Pain Subscale results from the sum of 5 questions.

Outcome measures

Outcome measures
Measure	1: Tramadol Once A Day 100mg n=109 Participants	2: Tramadol Once A Day 200mg n=110 Participants	3: Tramadol Once A Day 300mg n=113 Participants	4: Placebo n=226 Participants
Percentage Difference in WOMAC Pain Subscale Score From Baseline to Intervening Visits (Visits 2-4) Week 0 (Visit 2)	26.7 Percentage difference Standard Deviation 36.9	29.0 Percentage difference Standard Deviation 33.4	33.1 Percentage difference Standard Deviation 41.4	20.4 Percentage difference Standard Deviation 35.8
Percentage Difference in WOMAC Pain Subscale Score From Baseline to Intervening Visits (Visits 2-4) Week 3 (Visit 3)	35.2 Percentage difference Standard Deviation 40.9	36.0 Percentage difference Standard Deviation 40.3	42.3 Percentage difference Standard Deviation 40.6	35.1 Percentage difference Standard Deviation 39.4
Percentage Difference in WOMAC Pain Subscale Score From Baseline to Intervening Visits (Visits 2-4) Week 6 (Visit 4)	36.3 Percentage difference Standard Deviation 40.9	36.4 Percentage difference Standard Deviation 39.5	47.7 Percentage difference Standard Deviation 42.2	41.3 Percentage difference Standard Deviation 39.9

SECONDARY outcome

Timeframe: Week 0, week 3, week 6

Population: The analysis was performed using the full analysis population (All randomized patients who received at least one dose of the assigned study medication and had at least one post Baseline assessment of any functional scale). Missing Values at Last Visit Imputed by Individual Last Post Baseline Value.

Percentage of difference in WOMAC Physical Function Subscale score between baseline and intervening visits 2-4. The WOMAC scale is a 24-item questionnaire divided in 3 subscales. The WOMAC Physical Function Subscale comprises 17 questions each rated on a 100mm visual analog scale (VAS) ranging from no pain (0mm) to extreme pain (100mm).

Outcome measures

Outcome measures
Measure	1: Tramadol Once A Day 100mg n=109 Participants	2: Tramadol Once A Day 200mg n=110 Participants	3: Tramadol Once A Day 300mg n=113 Participants	4: Placebo n=226 Participants
Percentage Difference in WOMAC Physical Function Subscale Score From Baseline to Intervening Visits (Visits 2-4) Week 0 (Visit 2)	23.4 Percentage difference Standard Deviation 37.1	26.4 Percentage difference Standard Deviation 30.9	29.3 Percentage difference Standard Deviation 37.9	18.5 Percentage difference Standard Deviation 37.7
Percentage Difference in WOMAC Physical Function Subscale Score From Baseline to Intervening Visits (Visits 2-4) Week 3 (Visit 3)	33.3 Percentage difference Standard Deviation 40.7	36.5 Percentage difference Standard Deviation 34.4	41.0 Percentage difference Standard Deviation 39.7	33.7 Percentage difference Standard Deviation 38.2
Percentage Difference in WOMAC Physical Function Subscale Score From Baseline to Intervening Visits (Visits 2-4) Week 6 (Visit 4)	33.5 Percentage difference Standard Deviation 39.8	37.0 Percentage difference Standard Deviation 36.8	47.7 Percentage difference Standard Deviation 43.8	38.3 Percentage difference Standard Deviation 37.8

SECONDARY outcome

Timeframe: 12 weeks

Population: The analysis was performed using the full analysis population (All randomized patients who received at least one dose of the assigned study medication and had at least one post Baseline assessment of any functional scale). Missing Values at Last Visit Imputed by Individual Last Post Baseline Value.

Patients rated their knee pain by marking a 100mm Visual Analogue Scale, ranging from no pain (0mm) to extreme pain (100mm).

Outcome measures

Outcome measures
Measure	1: Tramadol Once A Day 100mg n=109 Participants	2: Tramadol Once A Day 200mg n=110 Participants	3: Tramadol Once A Day 300mg n=113 Participants	4: Placebo n=226 Participants
Multiple Dose Effect Using 24-hour VAS Pain Questionnaire Pain at lunchtime (last individual visit)	40.5 mm Standard Deviation 29.9	38.2 mm Standard Deviation 29.6	36.6 mm Standard Deviation 29.4	38.5 mm Standard Deviation 29.5
Multiple Dose Effect Using 24-hour VAS Pain Questionnaire Pain at bed time (last individual visit)	41.2 mm Standard Deviation 30.7	41.1 mm Standard Deviation 29.9	37.3 mm Standard Deviation 30.2	39.7 mm Standard Deviation 29.4
Multiple Dose Effect Using 24-hour VAS Pain Questionnaire Pain Before next morning dose (last individ visit)	41.1 mm Standard Deviation 30.1	42.0 mm Standard Deviation 29.5	35.5 mm Standard Deviation 29.3	38.5 mm Standard Deviation 29.8

SECONDARY outcome

Timeframe: 12 weeks

Population: The analysis was performed using the full analysis population (All randomized patients who received at least one dose of the assigned study medication and had at least one post Baseline assessment of any functional scale). Last Individual value.

The Investigator Global Rating of Pain is a 3-item Likert-scale to answer the following question: "How do you rate this patient's overall pain relief with the drug?" with 3 possible answers: "very effective", "effective", or "ineffective".

Outcome measures

Outcome measures
Measure	1: Tramadol Once A Day 100mg n=108 Participants	2: Tramadol Once A Day 200mg n=109 Participants	3: Tramadol Once A Day 300mg n=111 Participants	4: Placebo n=223 Participants
Investigator Global Rating of Pain Relief Very effective	20 participants	14 participants	22 participants	29 participants
Investigator Global Rating of Pain Relief Effective	49 participants	58 participants	57 participants	98 participants
Investigator Global Rating of Pain Relief Ineffective	39 participants	37 participants	32 participants	96 participants

SECONDARY outcome

Timeframe: 12 weeks

Population: Safety population: all randomized patients who received at least one dose of the assigned study medication.

Reasons for withdrawal from the trial were collected and the percentage of participants who dropped out from trial were calculated by dropout reason

Outcome measures

Outcome measures
Measure	1: Tramadol Once A Day 100mg n=110 Participants	2: Tramadol Once A Day 200mg n=113 Participants	3: Tramadol Once A Day 300mg n=115 Participants	4: Placebo n=227 Participants
Percentage of Participants Who Dropped Out From Trial by Dropout Reason Administrative	0 percentage of participants	0 percentage of participants	0 percentage of participants	0.4 percentage of participants
Percentage of Participants Who Dropped Out From Trial by Dropout Reason Lack of efficacy	15.5 percentage of participants	13.3 percentage of participants	11.3 percentage of participants	22.9 percentage of participants
Percentage of Participants Who Dropped Out From Trial by Dropout Reason Patient request	4.5 percentage of participants	6.2 percentage of participants	1.7 percentage of participants	4.4 percentage of participants
Percentage of Participants Who Dropped Out From Trial by Dropout Reason Investigator initiated discontinuation	1.8 percentage of participants	10.6 percentage of participants	4.3 percentage of participants	4.4 percentage of participants
Percentage of Participants Who Dropped Out From Trial by Dropout Reason Adverse event	19.1 percentage of participants	16.8 percentage of participants	35.7 percentage of participants	4.4 percentage of participants
Percentage of Participants Who Dropped Out From Trial by Dropout Reason Death	0.9 percentage of participants	0 percentage of participants	0 percentage of participants	0 percentage of participants

Adverse Events

1: Tramadol Once A Day 100mg

Serious events: 2 serious events

Other events: 31 other events

Deaths: 0 deaths

2: Tramadol Once A Day 200mg

Serious events: 1 serious events

Other events: 49 other events

Deaths: 0 deaths

3: Tramadol Once A Day 300mg

Serious events: 4 serious events

Other events: 57 other events

Deaths: 0 deaths

4: Placebo

Serious events: 3 serious events

Other events: 38 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	1: Tramadol Once A Day 100mg n=110 participants at risk	2: Tramadol Once A Day 200mg n=113 participants at risk	3: Tramadol Once A Day 300mg n=115 participants at risk	4: Placebo n=227 participants at risk
Psychiatric disorders Bipolar disorder NEC	0.91% 1/110 • Number of events 1	0.00% 0/113	0.00% 0/115	0.00% 0/227
Vascular disorders Deep venous thrombosis NOS	0.91% 1/110 • Number of events 1	0.00% 0/113	0.00% 0/115	0.00% 0/227
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer invasive NOS	0.00% 0/110	0.88% 1/113 • Number of events 1	0.00% 0/115	0.00% 0/227
Vascular disorders Aortic aneurysm	0.00% 0/110	0.00% 0/113	0.87% 1/115 • Number of events 1	0.00% 0/227
Gastrointestinal disorders Pancreatitis aggravated	0.00% 0/110	0.00% 0/113	0.87% 1/115 • Number of events 1	0.00% 0/227
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Thyroid neoplasm NOS	0.00% 0/110	0.00% 0/113	0.87% 1/115 • Number of events 1	0.00% 0/227
Cardiac disorders Acute myocardial infarction	0.91% 1/110 • Number of events 1	0.00% 0/113	0.00% 0/115	0.00% 0/227
Gastrointestinal disorders Faecal impaction	0.00% 0/110	0.00% 0/113	0.87% 1/115 • Number of events 1	0.00% 0/227
Gastrointestinal disorders Gastroenteritis viral NOS	0.00% 0/110	0.00% 0/113	0.00% 0/115	0.44% 1/227 • Number of events 1
Gastrointestinal disorders Rectal prolapse	0.00% 0/110	0.00% 0/113	0.00% 0/115	0.44% 1/227 • Number of events 1
Vascular disorders Venous thrombosis NOS limb	0.00% 0/110	0.00% 0/113	0.00% 0/115	0.44% 1/227 • Number of events 1

Other adverse events

Other adverse events
Measure	1: Tramadol Once A Day 100mg n=110 participants at risk	2: Tramadol Once A Day 200mg n=113 participants at risk	3: Tramadol Once A Day 300mg n=115 participants at risk	4: Placebo n=227 participants at risk
Gastrointestinal disorders Constipation	9.1% 10/110 • Number of events 10	15.0% 17/113 • Number of events 20	15.7% 18/115 • Number of events 20	6.6% 15/227 • Number of events 17
Nervous system disorders Dizziness	6.4% 7/110 • Number of events 7	17.7% 20/113 • Number of events 20	21.7% 25/115 • Number of events 33	2.2% 5/227 • Number of events 6
Nervous system disorders Nausea	15.5% 17/110 • Number of events 18	22.1% 25/113 • Number of events 29	27.8% 32/115 • Number of events 39	6.2% 14/227 • Number of events 14
Gastrointestinal disorders Vomiting	3.6% 4/110 • Number of events 4	7.1% 8/113 • Number of events 9	12.2% 14/115 • Number of events 18	0.88% 2/227 • Number of events 2
Nervous system disorders Headache	6.4% 7/110 • Number of events 8	5.3% 6/113 • Number of events 12	8.7% 10/115 • Number of events 12	6.6% 15/227 • Number of events 17

Additional Information

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Phone: 1 450 686 1017

Results disclosure agreements

Principal investigator is a sponsor employee Prior to submitting results communications, the investigator shall allow Labopharm at least 30 days to review the proposed communication. If the proposed publication/disclosure risks Labopharm's ability to patent any invention related to the study, the publication or disclosure will be modified or delayed to allow Labopharm to seek patent protection. This statement does not give Labopharm any editorial rights other than to restrict the disclosure of Labopharm's confidential information.
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Restriction type: OTHER