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

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).

Time frame: Baseline up to week 12

Population: Modified intent to treat (mITT) population which included all participants included in the ITT population (included all randomized participants that received the study treatment \& had at least one post-baseline efficacy assessment), except participants randomized in a site where good clinical practice issues were identified.

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).

Time frame: Baseline, Week 4, Week 8, Week 12

Population: Analysis for this outcome was conducted on mITT population which included all participants included in the ITT population (included all randomized participants that received the study treatment \& had at least one post-baseline efficacy assessment), except participant randomized in a site where good clinical practice issues were identified.

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.

Time frame: Baseline, Week 12

Population: Analysis for this outcome was conducted on mITT population which included all participants included in the ITT population (included all randomized participants that received the study treatment \& had at least one post-baseline efficacy assessment), except participants randomized in a site where good clinical practices issues were identified.

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.

Time frame: Baseline, Week 4, Week 8, Week 12

Population: Analysis for this outcome was conducted on mITT population which included all participants included in the ITT population (included all randomized participants that received the study treatment \& had at least one post-baseline efficacy assessment), except participants randomized in a site where good clinical practice issues were identified.

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.

Time frame: every day up to 12 weeks

Population: Analysis for this outcome was conducted on mITT population which included all participants included in the ITT population (included all randomized participants that received the study treatment \& had at least one post-baseline efficacy assessment), except participant randomized in a site where good clinical practice issues were identified.

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.

Time frame: Baseline, Week 12

Population: Analysis for this outcome was conducted on mITT population which included all participants included in the ITT population (included all randomized participants that received the study treatment \& had at least one post-baseline efficacy assessment), except participants randomized in a site where good clinical practice issues were identified.

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.

Time frame: Week 4, Week 8, Week 12

Population: Analysis for this outcome was conducted on mITT population which included all participants included in the ITT population (included all randomized participants that received the study treatment \& had at least one post-baseline efficacy assessment), except participants randomized in a site where good clinical practice issues were identified.

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).

Time frame: Baseline up to Week 12

Population: Analysis for this outcome was conducted on mITT population which included all participants included in the ITT population (included all randomized participants that received the study treatment \& had at least one post-baseline efficacy assessment), except participants randomized in a site where good clinical practices issues were identified.

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).

Time frame: Baseline up to week 12

Population: Analysis for this outcome was conducted on mITT population which included all participants included in the ITT population (included all randomized participants that received the study treatment \& had at least one post-baseline efficacy assessment), except participants randomized in a site where good clinical practices issues were identified.

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.

Time frame: Baseline up to week 12

Population: Analysis for this outcome was conducted on mITT population which included all participants included in the ITT population (included all randomized participants that received the study treatment \& had at least one post-baseline efficacy assessment), except participants randomized in a site where good clinical practices issues were identified.