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

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02311881
• Collaborator: (none)
• Enrollment: 960
• Locations: 56
• Arms: 3
• Duration (Months): 13
• Patients Per Site: 17.1
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Pain	Drug: Paracetamol 1000 mg SR tablets; Drug: Paracetamol 665 mg SR tablets; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 960 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: An Efficacy and Safety Study of Sustained-release Paracetamol in Subjects With Osteoarthritis
• Study Start Date: Jan 1, 2015
• Actual Primary Completion Date: Feb 1, 2016
• Actual Study Completion Date: Feb 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Paracetamol 2000 mg twice daily (BID) 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; 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.
Active Comparator: Paracetamol 1330 mg thrice daily (TID) 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; 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.
Placebo Comparator: Placebo 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; 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.

Outcome Measures

Primary Outcome Measures

1. Time-weighted Mean Change From Baseline in Western Ontario McMaster (WOMAC) Pain Through Week 12 of Treatment [Baseline up to week 12]

   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).

Secondary Outcome Measures

1. Time Weighted Mean Change From Baseline in WOMAC Physical Function Through Week 12 of Treatment [Baseline up to Week 12]

   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).

2. Time Weighted Mean Change From Baseline in WOMAC Stiffness Through Week 12 of Treatment [Baseline up to week 12]

   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).

3. Time-weighted Mean Change From Baseline in WOMAC Total Index Through Week 12 of Treatment [Baseline up to week 12]

   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.

4. Mean Change From Baseline in Global Patient Assessment of Arthritis (GPAOA) [Baseline, Week 4, Week 8, Week 12]

   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.

5. Number of Participants Classified as Responder [Baseline, Week 12]

   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.

6. Mean Change From Baseline in Daily Pain, Daily Stiffness and Pain/Stiffness (Composite) at Week 12 [Baseline, 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.

7. Mean Number of Rescue Medication Pills Taken Per Day up to 12 Weeks [every 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.

8. Mean Change From Baseline in Chronic Pain Sleep Inventory (CPSI) [Baseline, Week 4, Week 8, Week 12]

   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).

9. Patient Global Assessment of Response to Therapy (PGART) [Week 4, Week 8, Week 12]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Birmingham	Alabama	United States	35242
2	GSK Investigational Site	Huntsville	Alabama	United States	35801
3	GSK Investigational Site	Chandler	Arizona	United States	85224
4	GSK Investigational Site	Tucson	Arizona	United States	85712
5	GSK Investigational Site	Tucson	Arizona	United States	85745
6	GSK Investigational Site	Anaheim	California	United States	92801
7	GSK Investigational Site	Carmichael	California	United States	95608
8	GSK Investigational Site	Fresno	California	United States	93702
9	GSK Investigational Site	North Hollywood	California	United States	91606-1559
10	GSK Investigational Site	San Diego	California	United States	92103
11	GSK Investigational Site	Brandon	Florida	United States	33511
12	GSK Investigational Site	Clearwater	Florida	United States	33756
13	GSK Investigational Site	Edgewater	Florida	United States	32132
14	GSK Investigational Site	Hialeah	Florida	United States	33012
15	GSK Investigational Site	Hialeah	Florida	United States	33016
16	GSK Investigational Site	Homestead	Florida	United States	33030
17	GSK Investigational Site	Jupiter	Florida	United States	33458
18	GSK Investigational Site	Miami	Florida	United States	33155
19	GSK Investigational Site	Miami	Florida	United States	33173
20	GSK Investigational Site	Miami	Florida	United States	33185
21	GSK Investigational Site	Oldsmar	Florida	United States	34677
22	GSK Investigational Site	Orlando	Florida	United States	32806
23	GSK Investigational Site	Oviedo	Florida	United States	32765
24	GSK Investigational Site	Port Orange	Florida	United States	32127
25	GSK Investigational Site	South Miami	Florida	United States	33143
26	GSK Investigational Site	West Palm Beach	Florida	United States	33409
27	GSK Investigational Site	Savannah	Georgia	United States	31406
28	GSK Investigational Site	Chicago	Illinois	United States	60640
29	GSK Investigational Site	Evanston	Illinois	United States	60201
30	GSK Investigational Site	Prairie Village	Kansas	United States	66206
31	GSK Investigational Site	Wichita	Kansas	United States	67203
32	GSK Investigational Site	Crestview Hills	Kentucky	United States	41017
33	GSK Investigational Site	New Orleans	Louisiana	United States	70115
34	GSK Investigational Site	Watertown	Massachusetts	United States	02472
35	GSK Investigational Site	Saint Louis	Missouri	United States	63139
36	GSK Investigational Site	Bellevue	Nebraska	United States	68005
37	GSK Investigational Site	Omaha	Nebraska	United States	68134
38	GSK Investigational Site	Las Vegas	Nevada	United States	89119
39	GSK Investigational Site	Brooklyn	New York	United States	11230
40	GSK Investigational Site	Buffalo	New York	United States	14223
41	GSK Investigational Site	Hartsdale	New York	United States
42	GSK Investigational Site	Hickory	North Carolina	United States	28601
43	GSK Investigational Site	Cincinnati	Ohio	United States	45227
44	GSK Investigational Site	Cincinnati	Ohio	United States	45242
45	GSK Investigational Site	Cincinnati	Ohio	United States	45255
46	GSK Investigational Site	Dayton	Ohio	United States	45424
47	GSK Investigational Site	Toledo	Ohio	United States	43623
48	GSK Investigational Site	Oklahoma	Oklahoma	United States	73119
49	GSK Investigational Site	Altoona	Pennsylvania	United States	16602
50	GSK Investigational Site	Duncansville	Pennsylvania	United States	16635
51	GSK Investigational Site	Smithfield	Pennsylvania	United States	15478
52	GSK Investigational Site	Mount Pleasant	South Carolina	United States	29464
53	GSK Investigational Site	Dallas	Texas	United States	75230
54	GSK Investigational Site	Plano	Texas	United States	75075
55	GSK Investigational Site	San Antonio	Texas	United States	78209
56	GSK Investigational Site	San Antonio	Texas	United States	78229

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT02311881
• Other Study ID Numbers: 202195; RH02448
• First Posted: Dec 9, 2014
• Last Update Posted: Apr 7, 2017
• Last Verified: Feb 1, 2017

• Additional relevant MeSH terms: Osteoarthritis; Acetaminophen

Study Results

Participant Flow

Recruitment Details	This study was conducted in 57 centers in United States.
Pre-assignment Detail	A total of 1531 participants were screened for study. Out of which only 960 participants who completed screening visit & took part in wash-out period were enrolled. Out of 960 enrolled participants, only 708 were randomized. 252 were not randomized because they did not fulfill specific inclusion criterion measured at the end of the wash-out period.

Arm/Group Title	Paracetamol 2000 mg Twice Daily (BID)	Paracetamol 1330 mg Thrice Daily (TID)	Placebo
Arm/Group Description	Participants were instructed to take two active paracetamol 1000 milligram (mg) sustained release (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 milliliter [mL]) of water/dose for 12 weeks.	Participants were 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.	Participants were 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.
Period Title: Overall Study
STARTED	235	236	237
Safety Population	234	236	237
COMPLETED	200	193	196
NOT COMPLETED	35	43	41

Baseline Characteristics

Arm/Group Title	Paracetamol 2000 mg Twice Daily (BID)	Paracetamol 1330 mg Thrice Daily (TID)	Placebo	Total
Arm/Group Description	Participants were 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.	Participants were 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.	Participants were 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.	Total of all reporting groups
Overall Participants	234	236	237	707
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	60.27 (8.544)	60.47 (8.410)	61.46 (8.187)	60.73 (8.385)
Sex: Female, Male (Count of Participants)
Female	146 62.4%	147 62.3%	150 63.3%	443 62.7%
Male	88 37.6%	89 37.7%	87 36.7%	264 37.3%
Race/Ethnicity, Customized (number of participants) [Number]
Hispanic or Latino	77 32.9%	81 34.3%	95 40.1%	253 35.8%
Not Hispanic or Latino	157 67.1%	155 65.7%	142 59.9%	454 64.2%

Outcome Measures

1. Primary Outcome

Title	Time-weighted Mean Change From Baseline in Western Ontario McMaster (WOMAC) Pain Through Week 12 of Treatment
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Paracetamol 2000 mg Twice Daily (BID)	Paracetamol 1330 mg Thrice Daily (TID)	Placebo
Arm/Group Description	Participants were 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.	Participants were 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.	Participants were 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.
Measure Participants	224	225	227
Least Squares Mean (Standard Error) [millimeter(mm)]	-28.25 (1.697)	-25.89 (1.714)	-25.74 (1.713)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Paracetamol 2000 mg Twice Daily (BID), Placebo
	Comments	H0: There is no significant difference in mean change from baseline through week 12 of WOMAC Pain between twice daily Paracetamol 1000 mg SR tablets and placebo. H1: There is a significant difference in mean change from baseline through week 12 of WOMAC Pain between twice daily Paracetamol 1000 mg SR tablets and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1626
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-2.51
	Confidence Interval	(2-Sided) 95%; -6.037 to 1.016
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS treatment means from mixed model analysis of covariance with treatment, target joint and center pools as fixed effects and baseline as a covariate.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Paracetamol 2000 mg Twice Daily (BID), Paracetamol 1330 mg Thrice Daily (TID)
	Comments	H0: Difference in mean change from baseline through week 12 of WOMAC Pain between Paracetamol 1000 mg SR tablet and Paracetamol 665 mg SR tablet is ≤ - 5.3 (inferiority). H1: Difference in mean change from baseline through week 12 of WOMAC Pain between Paracetamol 1000 mg SR tablet and Paracetamol 665 mg SR tablet is > - 5.3 (noninferiority).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Paracetamol 2000mg BID is non-inferior to Paracetamol 1330mg TID if the upper bound of the 95% confidence Interval is less than 5.3.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-2.36
	Confidence Interval	(2-Sided) 95%; -5.894 to 1.166
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS treatment means from mixed model analysis of covariance with treatment, target joint and center pools as fixed effects and baseline as a covariate.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Paracetamol 1330 mg Thrice Daily (TID), Placebo
	Comments	H0: There is no significant difference in mean change from baseline through week 12 of WOMAC Pain between Paracetamol 665 mg SR tablets and placebo. H1: There is a significant difference in mean change from baseline through week 12 of WOMAC Pain between Paracetamol 665 mg SR tablets and placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9352
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -3.687 to 3.394
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS treatment means from mixed model analysis of covariance with treatment, target joint and center pools as fixed effects and baseline as a covariate.

2. Secondary Outcome

Title	Time Weighted Mean Change From Baseline in WOMAC Physical Function Through Week 12 of Treatment
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Paracetamol 2000 mg Twice Daily (BID)	Paracetamol 1330 mg Thrice Daily (TID)	Placebo
Arm/Group Description	Participants were 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.	Participants were 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.	Participants were 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.
Measure Participants	224	225	227
Mean (Standard Deviation) [mm]	-28.24 (21.341)	-26.23 (22.028)	-26.68 (20.137)

3. Secondary Outcome

Title	Time Weighted Mean Change From Baseline in WOMAC Stiffness Through Week 12 of Treatment
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Paracetamol 2000 mg Twice Daily (BID)	Paracetamol 1330 mg Thrice Daily (TID)	Placebo
Arm/Group Description	Participants were 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.	Participants were 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.	Participants were 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.
Measure Participants	224	225	227
Mean (Standard Deviation) [mm]	-27.68 (21.579)	-25.61 (22.238)	-26.16 (21.554)

4. Secondary Outcome

Title	Time-weighted Mean Change From Baseline in WOMAC Total Index Through Week 12 of Treatment
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Paracetamol 2000 mg Twice Daily (BID)	Paracetamol 1330 mg Thrice Daily (TID)	Placebo
Arm/Group Description	Participants were 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.	Participants were 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.	Participants were 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.
Measure Participants	224	225	227
Mean (Standard Deviation) [mm]	-0.28 (0.209)	-0.26 (0.217)	-0.27 (0.200)

5. Secondary Outcome

Title	Mean Change From Baseline in Global Patient Assessment of Arthritis (GPAOA)
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Paracetamol 2000 mg Twice Daily (BID)	Paracetamol 1330 mg Thrice Daily (TID)	Placebo
Arm/Group Description	Participants were 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.	Participants were 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.	Participants were 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.
Measure Participants	224	225	227
At Baseline	68.23 (16.965)	69.20 (16.607)	69.79 (16.734)
At Week 4	39.34 (20.605)	41.46 (22.330)	42.93 (21.856)
Change from baseline at Week 4	-29.02 (22.343)	-27.78 (26.398)	-26.83 (24.229)
At Week 8	36.08 (22.662)	37.62 (23.523)	39.09 (21.858)
Change from baseline at Week 8	-32.51 (24.429)	-31.15 (28.064)	-31.00 (23.649)
At Week 12	32.41 (23.737)	36.04 (23.848)	35.44 (20.546)
Change from baseline at Week 12	-36.15 (26.192)	-33.04 (29.547)	-34.31 (25.521)

6. Secondary Outcome

Title	Number of Participants Classified as Responder
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Paracetamol 2000 mg Twice Daily (BID)	Paracetamol 1330 mg Thrice Daily (TID)	Placebo
Arm/Group Description	Participants were 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.	Participants were 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.	Participants were 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.
Measure Participants	224	225	227
Number [participants]	157 67.1%	148 62.7%	159 67.1%

7. Secondary Outcome

Title	Mean Change From Baseline in Daily Pain, Daily Stiffness and Pain/Stiffness (Composite) at Week 12
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Paracetamol 2000 mg Twice Daily (BID)	Paracetamol 1330 mg Thrice Daily (TID)	Placebo
Arm/Group Description	Participants were 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.	Participants were 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.	Participants were 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.
Measure Participants	224	225	227
Pain at Baseline (n= 224, 225, 227)	6.39 (1.902)	6.27 (1.942)	6.63 (1.774)
Pain at Week 12(n= 176, 175, 177)	3.80 (2.454)	3.80 (2.197)	3.82 (2.056)
Pain, Change at Week 12 (n= 176, 175, 177)	-2.54 (2.301)	-2.49 (2.457)	-2.91 (2.442)
Stiffness at Baseline (n= 224, 225, 227)	6.20 (2.015)	6.13 (1.908)	6.38 (1.842)
Stiffness at Week 12(n= 176, 175, 177)	3.56 (2.383)	3.63 (2.246)	3.72 (2.145)
Stiffness, Change at Week 12(n= 176, 175, 177	-2.56 (2.227)	-2.44 (2.361)	-2.76 (2.500)
Composite at Baseline (n= 224, 225, 227)	6.30 (1.883)	6.20 (1.817)	6.51 (1.729)
Composite at Week 12(n= 176, 175, 177)	3.68 (2.361)	3.71 (2.150)	3.77 (2.043)
Composite, Change at Week 12(n= 176, 175, 177	-2.55 (2.209)	-2.46 (2.347)	-2.83 (2.410)

8. Secondary Outcome

Title	Mean Number of Rescue Medication Pills Taken Per Day up to 12 Weeks
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Paracetamol 2000 mg Twice Daily (BID)	Paracetamol 1330 mg Thrice Daily (TID)	Placebo
Arm/Group Description	Participants were 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.	Participants were 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.	Participants were 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.
Measure Participants	224	225	227
Mean (Standard Deviation) [number of rescue medication pills/day]	0.356 (1.7910)	0.200 (0.8052)	0.337 (1.1254)

9. Secondary Outcome

Title	Mean Change From Baseline in Chronic Pain Sleep Inventory (CPSI)
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Paracetamol 2000 mg Twice Daily (BID)	Paracetamol 1330 mg Thrice Daily (TID)	Placebo
Arm/Group Description	Participants were 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.	Participants were 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.	Participants were 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.
Measure Participants	224	225	227
At Baseline, CPSI-1	60.40 (26.089)	57.77 (27.705)	61.30 (25.500)
At Baseline, CPSI-3	59.21 (26.980)	57.19 (28.829)	60.50 (25.532)
At Baseline, CPSI-4	58.49 (27.759)	56.94 (28.834)	61.30 (25.773)
At Baseline, Sleep Problems Index	59.36 (25.886)	57.26 (27.384)	61.04 (24.156)
At Week 4, CPSI-1	32.32 (25.396)	29.23 (26.718)	34.01 (24.701)
At Week 4, Change in CPSI-1	-27.87 (24.563)	-27.61 (28.248)	-27.44 (26.746)
At Week 4, CPSI-3	32.54 (26.437)	28.94 (27.232)	32.75 (24.833)
At Week 4, Change in CPSI-3	-26.63 (25.621)	-27.51 (28.497)	-27.69 (26.257)
At Week 4, CPSI-4	31.70 (25.667)	28.85 (26.365)	33.80 (25.749)
At Week 4, Change in CPSI-4	-26.55 (25.230)	-27.52 (28.135)	-27.47 (27.265)
At Week 4, Sleep Problems Index	32.16 (24.845)	28.96 (26.102)	33.52 (24.004)
At Week 4, Change in Sleep Problems Index	-27.04 (23.458)	-27.59 (26.860)	-27.53 (24.930)
At Week 8, CPSI-1	30.53 (26.672)	29.22 (26.468)	30.84 (24.277)
At Week 8, Change in CPSI-1	-29.98 (26.601)	-27.45 (28.842)	-31.34 (25.290)
At Week 8, CPSI-3	30.25 (27.329)	29.45 (27.286)	29.71 (24.478)
At Week 8, Change at CPSI-3	-29.16 (27.321)	-26.91 (28.210)	-30.83 (25.892)
At Week 8, CPSI-4	30.33 (26.856)	29.12 (27.444)	31.02 (24.625)
At Week 8, Change at CPSI-4	-28.19 (27.359)	-26.78 (29.961)	-30.11 (25.874)
At Week 8, Sleep Problems Index	30.33 (26.206)	29.20 (26.533)	30.50 (23.868)
At Week 8, Change in Sleep Problems Index	-29.15 (25.838)	-27.11 (27.784)	-30.78 (24.315)
At Week 12, CPSI-1	26.73 (25.302)	26.90 (25.288)	27.64 (21.977)
At Week 12, Change in CPSI-1	-33.12 (27.859)	-30.17 (30.532)	-34.43 (25.975)
At Week 12, CPSI-3	26.95 (25.124)	26.63 (25.684)	27.42 (21.827)
At Week 12, Change in CPSI-3	-32.23 (29.228)	-29.99 (29.859)	-33.01 (27.116)
At Week 12, CPSI-4	27.26 (25.887)	26.85 (25.812)	27.79 (22.581)
At Week 12, Change in CPSI-4	-30.90 (29.052)	-29.73 (30.967)	-32.97 (27.357)
At Week 12, Sleep Problems Index	26.96 (24.709)	26.72 (25.135)	27.61 (21.593)
At Week 12, Change in Sleep Problems Index	-32.11 (27.489)	-30.03 (29.275)	-33.48 (25.485)

10. Secondary Outcome

Title	Patient Global Assessment of Response to Therapy (PGART)
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Paracetamol 2000 mg Twice Daily (BID)	Paracetamol 1330 mg Thrice Daily (TID)	Placebo
Arm/Group Description	Participants were 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.	Participants were 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.	Participants were 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.
Measure Participants	224	225	227
At Week 4 (n=197, 188, 202)	2.50 (0.867)	2.43 (0.871)	2.25 (0.900)
At Week 8(n=196, 184, 192)	2.58 (0.852)	2.40 (0.998)	2.44 (0.958)
At Week 12(n=189, 182, 181)	2.62 (0.870)	2.46 (1.022)	2.43 (1.045)

Adverse Events

Time Frame	throughout the study completion (up to 408 days)
Arm/Group Title	Paracetamol 2000 mg Twice Daily (BID)		Paracetamol 1330 mg Thrice Daily (TID)		Placebo
Arm/Group Description	Participants were 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.		Participants were 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.		Participants were 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.
All Cause Mortality
	Paracetamol 2000 mg Twice Daily (BID)		Paracetamol 1330 mg Thrice Daily (TID)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Paracetamol 2000 mg Twice Daily (BID)		Paracetamol 1330 mg Thrice Daily (TID)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/234 (1.7%)		5/236 (2.1%)		0/237 (0%)
Gastrointestinal disorders
ABDOMINAL PAIN	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
General disorders
CHEST PAIN	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
Hepatobiliary disorders
CHOLELITHIASIS	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
Injury, poisoning and procedural complications
GUN SHOT WOUND	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
MULTIPLE INJURIES	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
Metabolism and nutrition disorders
DEHYDRATION	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
COLON CANCER	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
OESOPHAGEAL CARCINOMA	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
Nervous system disorders
CEREBROVASCULAR ACCIDENT	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
Other (Not Including Serious) Adverse Events
	Paracetamol 2000 mg Twice Daily (BID)		Paracetamol 1330 mg Thrice Daily (TID)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	67/234 (28.6%)		69/236 (29.2%)		51/237 (21.5%)
Blood and lymphatic system disorders
RED BLOOD CELL ABNORMALITY	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
Cardiac disorders
ARTERIOSCLEROSIS CORONARY ARTERY	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
CORONARY ARTERY DISEASE	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
CORONARY ARTERY STENOSIS	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
Ear and labyrinth disorders
TINNITUS	1/234 (0.4%)		1/236 (0.4%)		1/237 (0.4%)
VERTIGO	0/234 (0%)		0/236 (0%)		1/237 (0.4%)
Eye disorders
DRY EYE	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
Gastrointestinal disorders
NAUSEA	8/234 (3.4%)		5/236 (2.1%)		4/237 (1.7%)
DIARRHOEA	6/234 (2.6%)		7/236 (3%)		2/237 (0.8%)
FLATULENCE	4/234 (1.7%)		0/236 (0%)		1/237 (0.4%)
DYSPEPSIA	3/234 (1.3%)		3/236 (1.3%)		0/237 (0%)
ABDOMINAL DISCOMFORT	2/234 (0.9%)		2/236 (0.8%)		4/237 (1.7%)
ABDOMINAL PAIN UPPER	2/234 (0.9%)		0/236 (0%)		0/237 (0%)
DRY MOUTH	2/234 (0.9%)		1/236 (0.4%)		1/237 (0.4%)
VOMITING	2/234 (0.9%)		2/236 (0.8%)		2/237 (0.8%)
ABDOMINAL PAIN	1/234 (0.4%)		1/236 (0.4%)		0/237 (0%)
ABDOMINAL PAIN LOWER	1/234 (0.4%)		1/236 (0.4%)		0/237 (0%)
CONSTIPATION	1/234 (0.4%)		6/236 (2.5%)		2/237 (0.8%)
DENTAL CARIES	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
HAEMATOCHEZIA	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
ODYNOPHAGIA	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
ABDOMINAL DISTENSION	0/234 (0%)		2/236 (0.8%)		0/237 (0%)
FAECES DISCOLOURED	0/234 (0%)		1/236 (0.4%)		1/237 (0.4%)
GASTROOESOPHAGEAL REFLUX DISEASE	0/234 (0%)		0/236 (0%)		1/237 (0.4%)
General disorders
FATIGUE	3/234 (1.3%)		0/236 (0%)		2/237 (0.8%)
ASTHENIA	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
CHEST PAIN	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
CHILLS	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
OEDEMA PERIPHERAL	1/234 (0.4%)		1/236 (0.4%)		2/237 (0.8%)
PERIPHERAL SWELLING	1/234 (0.4%)		0/236 (0%)		1/237 (0.4%)
INFLUENZA LIKE ILLNESS	0/234 (0%)		0/236 (0%)		1/237 (0.4%)
PYREXIA	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
Hepatobiliary disorders
CHOLELITHIASIS	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
Immune system disorders
RUBBER SENSITIVITY	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
Infections and infestations
GASTROENTERITIS	6/234 (2.6%)		1/236 (0.4%)		1/237 (0.4%)
UPPER RESPIRATORY TRACT INFECTION	5/234 (2.1%)		3/236 (1.3%)		2/237 (0.8%)
BRONCHITIS	1/234 (0.4%)		1/236 (0.4%)		1/237 (0.4%)
CONJUNCTIVITIS	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
INFLUENZA	1/234 (0.4%)		2/236 (0.8%)		2/237 (0.8%)
NASOPHARYNGITIS	1/234 (0.4%)		3/236 (1.3%)		2/237 (0.8%)
SINUSITIS	1/234 (0.4%)		1/236 (0.4%)		4/237 (1.7%)
ACUTE SINUSITIS	0/234 (0%)		0/236 (0%)		1/237 (0.4%)
CELLULITIS	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
DIVERTICULITIS	0/234 (0%)		0/236 (0%)		1/237 (0.4%)
FOLLICULITIS	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
FUNGAL INFECTION	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
GASTROENTERITIS VIRAL	0/234 (0%)		2/236 (0.8%)		1/237 (0.4%)
LOWER RESPIRATORY TRACT INFECTION	0/234 (0%)		0/236 (0%)		1/237 (0.4%)
PNEUMONIA	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
TOOTH ABSCESS	0/234 (0%)		0/236 (0%)		1/237 (0.4%)
URINARY TRACT INFECTION	0/234 (0%)		0/236 (0%)		2/237 (0.8%)
VIRAL UPPER RESPIRATORY TRACT INFECTION	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
Injury, poisoning and procedural complications
CONTUSION	1/234 (0.4%)		2/236 (0.8%)		0/237 (0%)
ANIMAL BITE	1/234 (0.4%)		1/236 (0.4%)		0/237 (0%)
TENDON RUPTURE	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
GUN SHOT WOUND	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
JOINT INJURY	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
LIGAMENT SPRAIN	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
MULTIPLE INJURIES	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
PATELLA FRACTURE	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
RIB FRACTURE	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED	7/234 (3%)		4/236 (1.7%)		0/237 (0%)
PROSTATIC SPECIFIC ANTIGEN INCREASED	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
BLOOD PRESSURE INCREASED	0/234 (0%)		1/236 (0.4%)		1/237 (0.4%)
HEPATIC ENZYME INCREASED	0/234 (0%)		3/236 (1.3%)		0/237 (0%)
HEPATITIS C VIRUS TEST POSITIVE	0/234 (0%)		0/236 (0%)		1/237 (0.4%)
LIVER FUNCTION TEST INCREASED	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
LYMPHOCYTE COUNT INCREASED	0/234 (0%)		0/236 (0%)		1/237 (0.4%)
WHITE BLOOD CELL COUNT INCREASED	0/234 (0%)		0/236 (0%)		1/237 (0.4%)
Metabolism and nutrition disorders
DEHYDRATION	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
Musculoskeletal and connective tissue disorders
BACK PAIN	2/234 (0.9%)		3/236 (1.3%)		1/237 (0.4%)
PAIN IN EXTREMITY	3/234 (1.3%)		0/236 (0%)		1/237 (0.4%)
MUSCLE SPASMS	2/234 (0.9%)		0/236 (0%)		1/237 (0.4%)
MYALGIA	2/234 (0.9%)		0/236 (0%)		0/237 (0%)
ARTHRALGIA	1/234 (0.4%)		3/236 (1.3%)		1/237 (0.4%)
JOINT SWELLING	1/234 (0.4%)		1/236 (0.4%)		0/237 (0%)
MUSCULOSKELETAL CHEST PAIN	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
MUSCULOSKELETAL PAIN	1/234 (0.4%)		0/236 (0%)		2/237 (0.8%)
TENDONITIS	1/234 (0.4%)		2/236 (0.8%)		0/237 (0%)
JOINT STIFFNESS	0/234 (0%)		0/236 (0%)		1/237 (0.4%)
OSTEOARTHRITIS	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
COLON CANCER	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
OESOPHAGEAL CARCINOMA	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
UTERINE LEIOMYOMA	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
Nervous system disorders
HEADACHE	5/234 (2.1%)		5/236 (2.1%)		5/237 (2.1%)
DIZZINESS	3/234 (1.3%)		3/236 (1.3%)		1/237 (0.4%)
TENSION HEADACHE	2/234 (0.9%)		0/236 (0%)		0/237 (0%)
CEREBROVASCULAR ACCIDENT	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
DYSGEUSIA	0/234 (0%)		0/236 (0%)		1/237 (0.4%)
PARAESTHESIA	0/234 (0%)		0/236 (0%)		1/237 (0.4%)
Psychiatric disorders
INSOMNIA	1/234 (0.4%)		1/236 (0.4%)		0/237 (0%)
Renal and urinary disorders
NEPHROLITHIASIS	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
RENAL FAILURE	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
URINE FLOW DECREASED	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
POLLAKIURIA	0/234 (0%)		2/236 (0.8%)		1/237 (0.4%)
RENAL PAIN	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
URINARY INCONTINENCE	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
URINARY RETENTION	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
URINE ODOUR ABNORMAL	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
Reproductive system and breast disorders
HYDROMETRA	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
MENORRHAGIA	0/234 (0%)		0/236 (0%)		1/237 (0.4%)
PROSTATOMEGALY	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
VULVOVAGINAL DRYNESS	0/234 (0%)		0/236 (0%)		1/237 (0.4%)
Respiratory, thoracic and mediastinal disorders
OROPHARYNGEAL PAIN	2/234 (0.9%)		2/236 (0.8%)		0/237 (0%)
DRY THROAT	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
DYSPNOEA	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
NASAL CONGESTION	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
SINUS CONGESTION	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
CHRONIC OBSTRUCTIVE PULMONARY DISEASE	0/234 (0%)		0/236 (0%)		1/237 (0.4%)
COUGH	0/234 (0%)		0/236 (0%)		1/237 (0.4%)
RHINORRHOEA	0/234 (0%)		1/236 (0.4%)		0/237 (0%)
Skin and subcutaneous tissue disorders
RASH	2/234 (0.9%)		0/236 (0%)		0/237 (0%)
PRURITUS	1/234 (0.4%)		2/236 (0.8%)		0/237 (0%)
URTICARIA	1/234 (0.4%)		0/236 (0%)		0/237 (0%)
DIABETIC FOOT	0/234 (0%)		0/236 (0%)		1/237 (0.4%)
MILIARIA	0/234 (0%)		0/236 (0%)		1/237 (0.4%)
Vascular disorders
HYPERTENSION	6/234 (2.6%)		2/236 (0.8%)		1/237 (0.4%)
HOT FLUSH	1/234 (0.4%)		0/236 (0%)		0/237 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.