A 12-Week Efficacy Study of Paracetamol 1000mg Sustained-release Tablets in Patients With Osteoarthritis

Study Overview
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Brief Summary
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The purpose of the study is to determine whether paracetamol 1000 mg sustained-release (SR) tablets administered orally, twice daily are effective and safe in the treatment of patients with osteoarthritis of the knee or hip.

Official Title
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An Efficacy and Safety Study of Sustained-release Paracetamol in Subjects With Osteoarthritis

Conditions
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Pain

Intervention / Treatment
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* Drug: Paracetamol 1000 mg SR tablets
* Drug: Paracetamol 665 mg SR tablets
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants between 40 and 80 years of age Diagnosis of moderate to moderately-severe osteoarthritis (OA) of either the knee or hip with respect to the following: Pain in one knee/hip over 3 months immediately before screening visit Use of non steroidal anti-inflammatory drugs (NSAIDs), acetaminophen (paracetamol) or any other analgesic for 3 or more days per week for at least 3 months prior to screening visit Clinical diagnosis of osteoarthritis of knee/hip for minimum 6 month duration prior to screening visit Therapeutic benefit with acetaminophen use with a score of ≥ 1 on 5-point categorical scale Radiological evidence of ≥ Grade 2 osteoarthritis according to Kellgren-Lawrence radiographic criteria Increased WOMAC Pain Subscale score of at least 20 % following untreated run-in period Moderate to moderately-severe self-reported pain on a 5-point categorical scale following untreated run-in period Historical self-reported positive therapeutic benefit with paracetamol use for osteoarthritis pain relief Exclusion Criteria: History of surgery or major trauma to the study joint Clinically significant signs or symptoms of inflammation upon completion of run-in period Required ongoing use of analgesic therapy for other indications, anticoagulants, psychotherapeutic agents, aspirin at daily doses greater than 325 mg, statin-class hypolipidemic agents at doses that have not been stabilized, or other treatments know to interfere with pain perception History of hepatic or renal or liver or biliary disease or gastrointestinal surgery Participants with alanine aminotransferase (ALT) >2 times Upper Limit Normal (2xULN) and bilirubin > 1.5 times Upper Limit Normal (1.5xULN) (However, if direct bilirubin is <35% and fractioned, isolated bilirubin >1.5xULN is acceptable) Other arthritis type, fibromyalgia or collagen vascular disease or secondary OA of study joint or chronic pain condition

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Paracetamol 2000 mg twice daily (BID)<br>Participants will be instructed to take two active paracetamol 1000 mg SR tablets twice daily (with 10-12 hours between adjacent doses) and two placebo to match paracetamol 665 mg SR tablets thrice daily (with 6-8 hours between adjacent doses) orally with approximately 8 ounces (  240 mL) of water/dose for 12 weeks. | Drug: Paracetamol 1000 mg SR tablets<br>* Two paracetamol 1000 mg SR tablets administered orally two times a day plus two placebo-matched paracetamol 665 mg SR tablets administered orally three times a day for 12 weeks.<br>|
| Active Comparator: Paracetamol 1330 mg thrice daily (TID)<br>Participants will be instructed to take two active paracetamol 665 mg SR tablets orally thrice daily (with 6-8 hours between adjacent doses) and two placebo to match paracetamol 1000 mg SR tablets orally twice daily (with 10-12 hours between adjacent doses) orally with approximately 8 ounces (  240 mL) of water/dose for 12 weeks. | Drug: Paracetamol 665 mg SR tablets<br>* Two paracetamol 665 mg SR tablets administered orally three times a day plus two placebo-matched paracetamol 1000 mg SR tablets administered orally two times a day for 12 weeks.<br>|
| Placebo Comparator: Placebo<br>Participants will be instructed to take two placebo to match paracetamol 1000 mg SR tablets twice daily (with 10-12 hours between adjacent doses) and two placebo to match paracetamol 665 mg SR tablets thrice daily (with 6-8 hours between adjacent doses) orally with approximately 8 ounces (  240 mL) of water/dose for 12 weeks. | Drug: Placebo<br>* Two placebo-matched paracetamol 665 mg SR tablets administered orally three times a day plus two placebo-matched paracetamol 1000 mg SR tablets administered orally two times a day for 12 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-weighted Mean Change From Baseline in Western Ontario McMaster (WOMAC) Pain Through Week 12 of Treatment | The WOMAC Osteoarthritis Index is a 24-item questionnaire that assesses pain, physical function, and stiffness in the target joint. WOMAC Pain was measured using visual analogue scale (VAS) ranging from 0mm (no pain) to 100mm (extreme pain) at baseline and at week 1, 2, 4, 8, and 12. Lower values represent a better outcome. At each time point the assessment included 5 WOMAC Pain items: 1-walking on flat, 2-going up down stairs, 3-at night while in bed, 4-sitting or lying; 5-standing upright. Mean WOMAC Pain subscale score was calculated at each visit as the sum of 5 pain category scores divided by 5. Change from baseline was calculated for each visit as the mean WOMAC Pain subscale score minus the mean baseline WOMAC Pain subscale score. A negative change from Baseline indicated improvement. The time-weighted mean change was calculated as the area under the curve of change from baseline divided by the nominal time of the last on-therapy visit (week 12) from randomization (baseline). | Baseline up to week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time Weighted Mean Change From Baseline in WOMAC Physical Function Through Week 12 of Treatment | The WOMAC Osteoarthritis Index is a 24-item questionnaire that assesses pain, physical function, and stiffness in the target joint. WOMAC Physical function was measured using VAS ranging from 0mm (no difficulty) to 100mm (extreme difficulty) at baseline and at week 1, 2, 4, 8, and 12. Lower values represent a better outcome. At each time point the assessment included 17 WOMAC Physical function categories. Mean WOMAC Physical function was calculated for baseline and each time point (sum of scores for 17 physical function categories divided by 17). Change from baseline was calculated for each visit as mean WOMAC physical function subscale score minus mean baseline WOMAC physical function subscale score. A negative change from Baseline indicated improvement. The time-weighted mean change was calculated as the area under the curve of change from baseline divided by the nominal time of the last on-therapy visit (week 12) from randomization (baseline). | Baseline up to Week 12 | 
| Time Weighted Mean Change From Baseline in WOMAC Stiffness Through Week 12 of Treatment | The WOMAC Osteoarthritis Index is a 24-item questionnaire that assesses pain, physical function, and stiffness in the target joint. WOMAC stiffness was measured using VAS ranging from 0mm (no stiffness) to 100mm (maximum stiffness) at baseline and at week 1, 2, 4, 8, and 12. Lower values represent a better outcome. At each time point the assessment included 2 WOMAC stiffness categories: 1- after awakening in the morning; 2- later in the day. Mean WOMAC stiffness was calculated for baseline and each time point (sum of scores for 2 stiffness categories divided by 2). Change from baseline was calculated for each visit as mean WOMAC stiffness subscale score at specific time point minus mean WOMAC stiffness subscale score at baseline. A negative change from Baseline indicated improvement. The time-weighted mean change from baseline was calculated as area under the curve of change from baseline divided by nominal time of the last on-therapy visit (week 12) from randomization (baseline). | Baseline up to week 12 | 
| Time-weighted Mean Change From Baseline in WOMAC Total Index Through Week 12 of Treatment | The WOMAC Osteoarthritis Index is a 24-item questionnaire that assesses pain, physical function, and stiffness in the target joint. The Total Index Score included the WOMAC Pain Score (5 questions about pain where: 0=no pain to 100=extreme pain), the WOMAC Physical Function score (17 questions about the difficulty of daily activities where: 0=no difficulty to 100=extreme difficulty) and the WOMAC Stiffness Score (2 questions about stiffness where: 0=no stiffness to 100=extreme stiffness). WOMAC Total Index was calculated at baseline and each time point as sum of scores of all 24 WOMAC questions divided by 2400, ranging from 0 (no pain/difficulty/stiffness) to 1 (extreme pain/ difficulty/stiffness). Change from baseline was calculated as WOMAC Total Index at specific time point minus WOMAC Total Index at baseline. A negative change from Baseline indicated improvement. | Baseline up to week 12 | 
| Mean Change From Baseline in Global Patient Assessment of Arthritis (GPAOA) | Participants performed an instantaneous GPAOA via a 0-100mm VAS, ranging from 0 (best ever) to 100 (worst ever) with respect to With respect to your arthritis condition, how would you describe yourself now? GPAOA was calculated periodically during the 12 week treatment period. | Baseline, Week 4, Week 8, Week 12 | 
| Number of Participants Classified as Responder | A participant was considered a responder if his/her improvement from baseline (change from baseline at week 12) satisfied at least one of the two criteria high' or 'moderate' improvement as follows:- High improvement: 50% improvement from baseline in the last available WOMAC pain score or 60% improvement from baseline in the last available WOMAC physical function score. Moderate improvement: Fulfills two out of three criteria: 30% improvement from baseline in the last available WOMAC Pain score, 20% improvement from baseline in the last available WOMAC Physical Function score, 25% improvement from baseline in the last available GPAOA. | Baseline, Week 12 | 
| Mean Change From Baseline in Daily Pain, Daily Stiffness and Pain/Stiffness (Composite) at Week 12 | Participants assessed their daily pain and stiffness each morning (upon awakening) during the 12-week treatment period using an 11-point Numerical Rating Scale (NRS), ranging from 0 (no pain / no stiffness) to 10 (extreme pain / extreme stiffness). Composite daily pain/stiffness score was calculated as sum of scores of pain and stiffness each morning divided by 2, ranging from 0 (no pain/stiffness) to 10 (extreme pain/stiffness). The mean of pain, mean of stiffness, and mean pain /stiffness composite score was calculated. Change from baseline was calculated as the difference between Daily Pain, stiffness and composite score each morning with that at baseline and was presented per week. A negative change from Baseline indicated improvement. | Baseline, Week 12 | 
| Mean Number of Rescue Medication Pills Taken Per Day up to 12 Weeks | Participants recorded use of rescue medication daily in their patient diary. The mean number of doses of rescue medications taken per day during the 12-week treatment period was calculated. | every day up to 12 weeks | 
| Mean Change From Baseline in Chronic Pain Sleep Inventory (CPSI) | Chronic Pain Sleep Inventory (CPSI) was assessed, based on the three questions: CPSI-1-'Trouble falling asleep': How often the participant had trouble falling asleep? , CPSI-3-'Awakening due to pain at night': How often the subject was awakened by pain during the night, CPSI-4- Awakening due to pain in the morning': How often the participant was awakened by pain in the morning? The participants responded to these questions via 0-100mm VAS, ranging from 0 (never) to 100 (always). Sleep problem index (SPI) was calculated as mean of these three CPSI questions, ranging from 0 (never affected by pain during sleep) to 100 (always affected by pain during sleep). | Baseline, Week 4, Week 8, Week 12 | 
| Patient Global Assessment of Response to Therapy (PGART) | The PGART is a global assessment of the participant's response to therapy, was measured using on a 5 point Likert scale as follows: 0=None (no good at all, ineffective), 1= Poor (some effect, but unsatisfactory), 2= Fair (reasonable effect, but could be better), 3= Good (satisfactory effect with occasional episodes of pain and/or stiffness), 4= Excellent (ideal response, virtually pain-free). Mean PGART scores from 5 point Likert scale was calculated periodically (at Week 4, Week 8, Week 12) for the 12 week treatment period. | Week 4, Week 8, Week 12 |