A Two-Arm Study Comparing the Analgesic Efficacy and Safety of Tramadol HCl Once-a-Day Versus Placebo for the Treatment of Pain Due to Osteoarthritis

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00833794

Enrollment

1028

Registered

2009-02-02

Start date

2004-10-31

Completion date

2006-01-31

Last updated

2012-04-30

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Osteoarthritis, Pain

Brief summary

The purpose of this study is to compare the analgesic efficacy, safety and clinical benefit of Tramadol OAD tablets versus Placebo.

Interventions

DRUGTramadol Once a day

DRUGPlacebo

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

40 Years to 80 Years

Healthy volunteers

Inclusion criteria

for Open-Label phase: 1. Males or females 2. Must be between the ages of 40-80 3. Must meet the American College of Rheumatology (ACR) Clinical Classification Criteria for Osteoarthritis of the Knee: * Current knee pain * Less than 30 minutes of morning stiffness with or without crepitus on active motion * Confirmation either by arthroscopy or radiologist's report (X-rays showing osteophytes, joint space narrowing or subchondral bone sclerosis {eburnation}) within five years prior to entry into the study 4. Must have a history of exposure to treatment (for pain due to osteoarthritis (OA) of the knee) with Non-steroidal anti-inflammatory drugs (NSAIDs), COX II inhibitors or tramadol. 5. Must be taking one of the above medications on a regular basis in the 30 days prior to Visit 2 (S0). 6. Must meet the following criteria for severity of pain at Visit 2 (Day S0): * Have a score of ≥ 4 on the 11-point Numerical Rating Scale (PI-NRS; range: 0-10) * Have a total increase of ≥ 2 points on the 11-point Numerical Rating Scale (range: 0-10) compared to the rating at Visit 1 (Day SX) 7. Must have a erythrocyte sedimentation rate (ESR) \< 40 mm/hr 8. Must have oral and written language comprehension at a level sufficient to comply with the protocol and complete study-related materials 9. Must have signed and dated an approved written Informed Consent form in French, Spanish, English or Romanian, which has also been signed and dated by the Investigator (unless otherwise required by the ethics committee), prior to study participation

Exclusion criteria

for Open-Label phase: 1. Has known rheumatoid arthritis or any other rheumatic disease 2. Has secondary arthritis i.e. any of the following: septic arthritis; inflammatory joint disease; gout; pseudogout; Paget's disease; target joint fracture; acromegaly; fibromyalgia; Wilson's disease; Ochronosis; Haemochromatosis; Osteochondromatosis; heritable arthritic disorders; or collagen gene mutations 3. Has a history of bursitis of the knee (target knee) 4. Has a history of pain in the ipsilateral hip (target knee) 5. Has had a meniscal tear in the target knee within the last 12 months 6. Has had cartilage reconstruction procedure in the target knee 7. Has had a therapeutic arthroscopy procedure in the target knee within the last 12 months 8. Has a Body Mass Index (BMI) greater than 37 9. Has had a major illness, requiring hospitalisation during the 3 months before commencement of the screening period 10. Is unwilling to stop taking pain medication other than the study medication (for arthritis or other types of pain) or is unwilling to stop taking other medications for the treatment of OA 11. Has previously failed treatment with tramadol or discontinued treatment with tramadol due to adverse events 12. Has been taking other opioids (e.g. codeine, oxycodone, hydromorphone, etc.) for treatment of OA or other chronic conditions 13. Has received Corticosteroid Injections in the target knee within the last 3 months or Viscous injections in the target knee within the last 6 months 14. Has had treatment within the last 3 weeks with any of the following medications: monoamine oxidase inhibitors; tricyclic antidepressants and other tricyclic compounds (e.g. cyclobenzaprine, promethazine); neuroleptics; selective serotonin reuptake inhibitors; serotonin-norepinephrine reuptake inhibitors or any other drug that reduces seizure threshold 15. Has had treatment with another investigational agent within the last 30 days 16. Has a history of seizure disorder other than Infantile Febrile Seizures 17. Has a previous or current opioid dependency 18. Has a bowel disease causing malabsorption 19. Is pregnant, lactating or of childbearing potential and is unwilling to utilise a medically approved method of contraception during participation in this clinical trial 20. Has significant liver disease, defined as active hepatitis or elevated liver enzymes \>3 times the upper boundary of the normal range 21. Has significant renal disease (defined as creatinine clearance \<30 mL/min 22. Has a history of current or past substance abuse or dependence, other than nicotine 23. Has a known and documented allergy to tramadol or any structurally similar drugs (e.g. opiates) 24. Has a known and documented allergy to acetaminophen or any structurally similar drugs 25. Has any other condition that, in the opinion of the Investigators, would adversely affect the patient's ability to complete the study or its measures. Inclusion criteria for the double-blinded phase: * Patients must continue to meet the open-label eligibility criteria and * Must have a score of ≥ 4 on the Numerical Rating Scale (NRS) with a total increase of ≥ 2 points on the NRS compared to Visit 3(Day R14) and * Must not have taken any of the prohibited medications during the Open-label Phase.

Design outcomes

Primary

Measure	Time frame	Description
Pain Intensity Score as Measured by the 11-point Pain Intensity-Numerical Rating Scale Score at the End of the Study (Week 12 or Time of Discontinuation)	12 weeks	The Pain Intensity Score is an 11-point pain intensity numerical rating scale ranging from 0: no pain to 10: worst possible pain. The mean score at the end of the study (week 12 or time of discontinuation) was calculated.

Secondary

Measure	Time frame	Description
Pain Intensity Score Stratified by Dose, at the End of the Study (Week 12 or Time of Discontinuation)	12 weeks	Pain Intensity Score (an 11-point pain intensity numerical rating scale ranging from 0: no pain to 10: worst possible pain) was stratified by final dose level, at week 12 or time of discontinuation. The final optimum dose level based upon efficacy and tolerability was kept for the entire study. The mean score was calculated.
WOMAC Pain Subscale Score at the End of the Study (Week 12 or Time of Discontinuation)	12 weeks	Mean WOMAC Pain Subscale score at week 12. The WOMAC scale is a 24-item questionnaire divided in 3 subscales, using a 5-point Likert-scale ranging from no difficulty to extreme difficulty (0-none; 1-slight; 2-moderate; 3-severe; 4-extreme). The WOMAC pain subscale results from the sum of 5 pain questions. The maximum total score is 20.
WOMAC Physical Function Subscale Score at the End of the Study (Week 12 or Time of Discontinuation)	12 weeks	Mean WOMAC Physical Function Subscale score at week 12. The WOMAC scale is a 24-item questionnaire divided in 3 subscales, using a 5-point Likert-scale ranging from no difficulty to extreme difficulty (0-none; 1-slight; 2-moderate; 3-severe; 4-extreme). The WOMAC Physical Function subscale results from the sum of 17 physical function questions and the maximum possible score is 68.
Patient Global Impression of Change at the End of the Study (Week 12 or Time of Discontinuation)	12 weeks	This assessment of overall status integrates the effect of the treatment on pain, side effects, and the patient's expectation of pain relief. It is made using a 7-point categorical scale (1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; 7 = very much worse)
Pain Intensity Score (11-point PINRS) After 6 Weeks of Maintenance Treatment	6 weeks	The Pain Intensity Score is an 11-point pain intensity numerical rating scale ranging from 0: no pain to 10: worst possible pain
Time to Response	12 weeks	Response was defined as a decrease of ≥1 point in an 11-point PINRS (11-point pain intensity numerical rating scale ranging from 0: no pain to 10: worst possible pain) from baseline to the last visit. The time to response was estimated using Kaplan-Meier analysis and a 95% CI for the median time was calculated.
Discontinuation Due to Lack of Efficacy	12 weeks	The number of patients who discontinued due to lack of efficacy was reported.
Discontinuation Due to Adverse Events	12 weeks	The number of patients who discontinued due to adverse events (AEs). An AE is defined as any untoward medical event that occurs during the course of a clinical investigation in which a patient is administered a pharmaceutical or other therapeutic product. Its occurrence does not necessarily imply a causal relationship with the treatment.
Physician Global Impression of Change at the End of the Study (Week 12 or Time of Discontinuation)	week 12	This assessment of overall impression of study drug is made using a 7-point categorical scale (1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; 7 = very much worse)

Participant flow

Participants by arm

Arm	Count
1 Tramadol Once A Day	432
2 Placebo	214
Total	646

Withdrawals & dropouts

Period	Reason	FG000	FG001
Double-blind Phase	Administrative reason	1	3
Double-blind Phase	Adverse Event	44	11
Double-blind Phase	Lack of Efficacy	34	22
Double-blind Phase	Physician Decision	4	7
Double-blind Phase	Withdrawal by Subject	23	6
Open-label Phase	Administrative reason	1	0
Open-label Phase	Adverse Event	225	0
Open-label Phase	Did not complete wash-out period	12	0
Open-label Phase	enrolled in error (immediately D/C)	1	0
Open-label Phase	Lack of Efficacy	28	0
Open-label Phase	Physician Decision	20	0
Open-label Phase	Protocol Violation	47	0
Open-label Phase	Withdrawal by Subject	48	0

Baseline characteristics

Characteristic	1 Tramadol Once A Day	2 Placebo	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	180 Participants	98 Participants	278 Participants
Age, Categorical Between 18 and 65 years	252 Participants	116 Participants	368 Participants
Age Continuous	61.8 years STANDARD_DEVIATION 9	62.3 years STANDARD_DEVIATION 8.9	62.0 years STANDARD_DEVIATION 9
Sex: Female, Male Female	275 Participants	133 Participants	408 Participants
Sex: Female, Male Male	157 Participants	81 Participants	238 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	136 / —	29 / —
serious Total, serious adverse events	9 / —	1 / —

Outcome results

Primary

Pain Intensity Score as Measured by the 11-point Pain Intensity-Numerical Rating Scale Score at the End of the Study (Week 12 or Time of Discontinuation)

The Pain Intensity Score is an 11-point pain intensity numerical rating scale ranging from 0: no pain to 10: worst possible pain. The mean score at the end of the study (week 12 or time of discontinuation) was calculated.

Time frame: 12 weeks