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Clinical Trial Results:
PANSAID – PAracetamol and NSAID in combination: A randomised, blinded, parallel 4-group clinical trial

Summary
EudraCT number	2015-002239-16
Trial protocol	DK
Global end of trial date	01 Jan 2018

Results information
Results version number	v1(current)
This version publication date	07 Jan 2021
First version publication date	07 Jan 2021
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

SM2-KHT-2015

ISRCTN number

US NCT number

NCT02571361

WHO universal trial number (UTN)

Sponsor organisation name

Departement of Anaesthesiology, Næstved Hospital

Sponsor organisation address

Ringstedgade 61, Næstved, Denmark, 4700

Public contact

Department of Anaesthesiology Daniel Hägi-Pedersen, Næstved Hospital, +45 21517167, dhag@regionsjaelland.dk

Scientific contact

Department of Anaesthesiology Daniel Hägi-Pedersen, Næstved Hospital, +45 21517167, dhag@regionsjaelland.dk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

01 Jan 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

01 Jan 2018

Global end of trial reached?

Yes

Global end of trial date

01 Jan 2018

Was the trial ended prematurely?

Main objective of the trial

The objective of this trial is to investigate the analgesic effects and safety of paracetamol and ibuprofen and their combination in different dosages after THA

Protection of trial subjects

Subjects received a Patient Controlled Analgesia Pump with morphine, where they could steer their own pain treatment. Thus reducing patients discomfort in trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Dec 2015

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy, Scientific research

Long term follow-up duration

1 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Denmark: 556

Worldwide total number of subjects

556

EEA total number of subjects

556

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

208

From 65 to 84 years

335

85 years and over

Subject disposition

Top of page

Recruitment details

Screening details

All patients planned for total hip arthroplasty

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

Blinding of trial medication, thus tablets were sealed in opaque hard capsules.

Are arms mutually exclusive

Yes

Treatment A

Arm description

Paracetamol 1g + ibuprofen 400 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Arm type

Active comparator

Investigational medicinal product name

Pinex

Investigational medicinal product code

Other name

paracetamol

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Paracetamol 1g orally starting1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Investigational medicinal product name

Ibumetin

Investigational medicinal product code

Other name

Ibumetin

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Ibuprofen 400 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Treatment B

Arm description

Paracetamol 1g + placebo orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Arm type

Active comparator

Investigational medicinal product name

Pinex

Investigational medicinal product code

Other name

paracetamol

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Paracetamol 1g orally starting1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

1 capsule placebo orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Treatment C

Arm description

Placebo + ibuprofen 400 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Arm type

Active comparator

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

2 capsules placebo orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Investigational medicinal product name

Ibumetin

Investigational medicinal product code

Other name

Ibumetin

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Ibuprofen 400 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Treatment D

Arm description

Paracetamol 0,5 g + ibuprofen 200 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Arm type

Active comparator

Investigational medicinal product name

Pinex

Investigational medicinal product code

Other name

paracetamol

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Paracetamol 0,5 g orally starting1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Investigational medicinal product name

Ibumetin

Investigational medicinal product code

Other name

Ibumetin

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Ibuprofen 200 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Number of subjects in period 1	Treatment A	Treatment B	Treatment C	Treatment D
Started	136	142	139	139
Completed	136	142	139	139

Baseline characteristics

Top of page

Reporting group title

Treatment A

Reporting group description

Paracetamol 1g + ibuprofen 400 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Reporting group title

Treatment B

Reporting group description

Paracetamol 1g + placebo orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Reporting group title

Treatment C

Reporting group description

Placebo + ibuprofen 400 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Reporting group title

Treatment D

Reporting group description

Paracetamol 0,5 g + ibuprofen 200 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Reporting group values	Treatment A	Treatment B	Treatment C	Treatment D	Total
Number of subjects	136	142	139	139	556
Age categorical
Units: Subjects
Adults (18-64 years)					0
From 65-84 years					0
85 years and over					0
Age continuous
Units: years
arithmetic mean (standard deviation)	67 ( 10 )	67 ( 10 )	67 ( 11 )	66 ( 10 )	-
Gender categorical
Units: Subjects
Female	68	66	67	76	277
Male	68	76	72	63	279
ASA-score
American Society of Anaesthesiologists Physical Status Classification System
Units: Subjects
ASA 1	34	44	44	43	165
ASA 2	87	84	80	84	335
ASA 3	15	14	15	12	56
Anesthesia
Type of Anesthesia
Units: Subjects
Spinal with sedation	65	70	66	69	270
Spinal	39	42	43	27	151
General	29	20	24	38	111
Conversion of spinal to general	3	10	6	5	24
Prior use of paracetamol
Use of paracetamol prior to the operation.
Units: Subjects
No use	53	52	51	51	207
As needed	29	24	24	22	99
Daily use	54	66	64	66	250
Prior use of NSAID
Use of NSAID prior to the operation.
Units: Subjects
No use	72	77	74	72	295
As needed	21	18	16	21	76
Daily use	43	47	49	46	185
Prior use of codeine
Use of codeine prior to the operation
Units: Subjects
No use	134	141	136	137	548
As needed	1	0	1	1	3
Daily use	1	1	2	1	5
Prior use of tramadol
Use of tramadol prior to the operation.
Units: Subjects
No use	121	127	125	122	495
As needed	5	6	6	8	25
Daily use	10	9	8	9	36
Type of surgery
Units: Subjects
No cement	122	129	127	122	500
Cement	2	3	2	4	11
Hybrid	12	10	10	13	45
Height
Units: cm
arithmetic mean (standard deviation)	172 ( 9 )	172 ( 8 )	172 ( 9 )	171 ( 9 )	-
Weight
Units: kg
arithmetic mean (standard deviation)	83 ( 16 )	82 ( 15 )	80 ( 15 )	81 ( 16 )	-
BMI
Body Mass Index
Units: kg/squaremeter
arithmetic mean (standard deviation)	27.7 ( 4.3 )	27.4 ( 4.1 )	26.8 ( 3.9 )	27.6 ( 4.7 )	-
Bupivacaine, SA
Bupivacaine dose for spinal anesthesia (SA)
Units: mg
arithmetic mean (standard deviation)	12 ( 2 )	12 ( 2 )	12 ( 2 )	12 ( 2 )	-
Sufentanil used if general anesthesia
Sufentanil dose prior to end of surgery
Units: micorgram
arithmetic mean (standard deviation)	24 ( 7 )	20 ( 9 )	21 ( 8 )	21 ( 8 )	-
Duration of surgery
Units: minute
arithmetic mean (standard deviation)	54 ( 19 )	51 ( 14 )	53 ( 18 )	53 ( 15 )	-

End points

Top of page

Reporting group title

Treatment A

Reporting group description

Paracetamol 1g + ibuprofen 400 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Reporting group title

Treatment B

Reporting group description

Paracetamol 1g + placebo orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Reporting group title

Treatment C

Reporting group description

Placebo + ibuprofen 400 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Reporting group title

Treatment D

Reporting group description

Paracetamol 0,5 g + ibuprofen 200 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Primary: Morphine consumption the first 24 hours postoperatively

Top of page

End point title

Morphine consumption the first 24 hours postoperatively

End point description

Total need for morphine administered as BOTH patient controlled analgesia (PCA) for the first 24 hours postoperatively AND supplemental morphine administered at the post-anaesthesia unit the first hour postoperatively. Bolus 2.0 mg; lockout: 10 min

End point type

Primary

End point timeframe

0-24 hours postoperatively

End point values	Treatment A	Treatment B	Treatment C	Treatment D
Number of subjects analysed	136	141	137	137
Units: miligram
median (confidence interval 99.6%)	20 (0 to 148)	36 (0 to 166)	26 (2 to 139)	28 (2 to 145)

Comparison of 24.hour morphine consumption, A vs B

Statistical analysis description

Pair-wise comparison of the groups.

Comparison groups

Treatment A v Treatment B

Number of subjects included in analysis

277

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[1]

Method

Van Elteren

Parameter type

Median difference (final values)

Point estimate

-16

Confidence interval

level

99.6%

sides

2-sided

lower limit

-24

upper limit

-6.5

Notes
[1] - P-value for this anlysis is corrected for co-primary outcome and 6 possible comparisons. P=0.0042.

Comparison of 24.hour morphine consumption, A vs C

Statistical analysis description

Pair-wise comparison of the groups.

Comparison groups

Treatment A v Treatment C

Number of subjects included in analysis

273

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002 ^[2]

Method

Van Elteren

Parameter type

Median difference (final values)

Point estimate

-6

Confidence interval

level

99.6%

sides

2-sided

lower limit

-16

upper limit

-2

Notes
[2] - P-value for this anlysis is corrected for co-primary outcome and 6 possible comparisons. P=0.0042.

Comparison of 24.hour morphine consumption, A vs D

Statistical analysis description

Pair-wise comparison of the groups.

Comparison groups

Treatment A v Treatment D

Number of subjects included in analysis

273

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.005 ^[3]

Method

Van Elteren

Parameter type

Median difference (final values)

Point estimate

-8

Confidence interval

level

99.6%

sides

2-sided

lower limit

-16

upper limit

Notes
[3] - P-value for this anlysis is corrected for co-primary outcome and 6 possible comparisons. P=0.0042.

Comparison of 24.hour morphine consumption,B vs C

Statistical analysis description

Pair-wise comparison of the groups.

Comparison groups

Treatment B v Treatment C

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0044 ^[4]

Method

Van Elteren

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

99.6%

sides

2-sided

lower limit

-2

upper limit

Notes
[4] - P-value for this anlysis is corrected for co-primary outcome and 6 possible comparisons. P=0.0042.

Comparison of 24.hour morphine consumption,B vs D

Statistical analysis description

Pair-wise comparison of the groups.

Comparison groups

Treatment B v Treatment D

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001 ^[5]

Method

Van Elteren

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

99.6%

sides

2-sided

lower limit

-1

upper limit

Notes
[5] - P-value for this anlysis is corrected for co-primary outcome and 6 possible comparisons. P=0.0042.

Comparison of 24.hour morphine consumption, C vs D

Statistical analysis description

Pair-wise comparison of the groups.

Comparison groups

Treatment D v Treatment C

Number of subjects included in analysis

274

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.81 ^[6]

Method

Van Elteren

Parameter type

Median difference (final values)

Point estimate

-2

Confidence interval

level

99.6%

sides

2-sided

lower limit

-7

upper limit

Notes
[6] - P-value for this anlysis is corrected for co-primary outcome and 6 possible comparisons. P=0.0042.

Primary: Proportion of patients with 1 or more modified SAEs from the surgery to 90 days postoperatively

Top of page

End point title

Proportion of patients with 1 or more modified SAEs from the surgery to 90 days postoperatively

End point description

End point type

Primary

End point timeframe

Surgery to 90 days postoperatively.

End point values	Treatment A	Treatment B	Treatment C	Treatment D
Number of subjects analysed	136	142	139	139
Units: Number of SAE	20	15	20	18

Comparsion of porpotions of SAE

Statistical analysis description

To investigate harm of ibuprofen, patients in the 3 groups randomized to receive ibuprofen (Treatment A + C + D) were compared with patients in the paracetamol-alone group (Treatment B) for the modified SAE outcome.

Comparison groups

Treatment A v Treatment B v Treatment C v Treatment D

Number of subjects included in analysis

556

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.18 ^[7]

Method

Generalized estimating equations

Parameter type

Risk ratio (RR)

Point estimate

1.44

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.79

upper limit

2.64

Notes
[7] - P-value is corrected for co-primary outcome. P=0.025.

Proportions of modified SAEs

Statistical analysis description

Proportion of patients with 1 or more modified SAEs from the surgery to 90 days postoperatively. To investigate harm of ibuprofen, patients in the 3 groups randomized to receive ibuprofen were compared with patients in the paracetamol-alone group for the modified SAE outcome. A + C + D vs B

Comparison groups

Treatment A v Treatment B v Treatment C v Treatment D

Number of subjects included in analysis

556

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.18 ^[8]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

1.44

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.79

upper limit

2.64

Notes
[8] - Level of significance corrected, due to co-primary outcome to p= 0.025

Secondary: Pain scores, with mobilization at 6 h

Top of page

End point title

Pain scores, with mobilization at 6 h

End point description

End point type

Secondary

End point timeframe

6 hours postoperatively.

End point values	Treatment A	Treatment B	Treatment C	Treatment D
Number of subjects analysed	136	141	137	137
Units: mm
arithmetic mean (confidence interval 99.2%)	45 (39 to 51)	52 (47 to 58)	50 (44 to 55)	53 (48 to 58)

Comparison pain scores 6 h, mob, A vs B

Statistical analysis description

Comparison of the pain scores 6 hours postoperatively, with mobilization.

Comparison groups

Treatment A v Treatment B

Number of subjects included in analysis

277

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.03 ^[9]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

-7

Confidence interval

level

99.2%

sides

2-sided

lower limit

-15

upper limit

Notes
[9] - The statistically significance level i corrected for multiple comparisons til p=0.0084

Comparison pain scores 6 h, mob, A vs D

Statistical analysis description

Comparison of the pain scores 6 hours postoperatively, with mobilization.

Comparison groups

Treatment A v Treatment D

Number of subjects included in analysis

273

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.01 ^[10]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

-8

Confidence interval

level

99.2%

sides

2-sided

lower limit

-15

upper limit

Notes
[10] - The statistically significance level i corrected for multiple comparisons til p=0.0084

Comparison pain scores 6 h, mob, B vs C

Statistical analysis description

Comparison of the pain scores 6 hours postoperatively, with mobilization.

Comparison groups

Treatment B v Treatment C

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.34 ^[11]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

99.2%

sides

2-sided

lower limit

-5

upper limit

Notes
[11] - The statistically significance level i corrected for multiple comparisons til p=0.0084

Comparison pain scores 6 h, mob, B vs D

Statistical analysis description

Comparison of the pain scores 6 hours postoperatively, with mobilization.

Comparison groups

Treatment D v Treatment B

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.86 ^[12]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

-1

Confidence interval

level

99.2%

sides

2-sided

lower limit

-8

upper limit

Notes
[12] - The statistically significance level i corrected for multiple comparisons til p=0.0084

Comparison pain scores 6 h, mob, C vs D

Statistical analysis description

Comparison of the pain scores 6 hours postoperatively, with mobilization.

Comparison groups

Treatment D v Treatment C

Number of subjects included in analysis

274

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.23 ^[13]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

-3

Confidence interval

level

99.2%

sides

2-sided

lower limit

-11

upper limit

Notes
[13] - The statistically significance level i corrected for multiple comparisons til p=0.0084

Comparison pain scores 6 h, mob, A vs C

Statistical analysis description

Comparison of the pain scores 6 hours postoperatively, with mobilization.

Comparison groups

Treatment A v Treatment C

Number of subjects included in analysis

273

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.17 ^[14]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

-4

Confidence interval

level

99.2%

sides

2-sided

lower limit

-12

upper limit

Notes
[14] - The statistically significance level i corrected for multiple comparisons til p=0.0084

Secondary: Pain scores, at rest 6 hours

Top of page

End point title

Pain scores, at rest 6 hours

End point description

End point type

Secondary

End point timeframe

6 hours postoperatively

End point values	Treatment A	Treatment B	Treatment C	Treatment D
Number of subjects analysed	136	141	137	137
Units: mm
arithmetic mean (confidence interval 99.2%)	32 (27 to 37)	39 (34 to 44)	37 (32 to 42)	36 (31 to 41)

Comparison of pain scores, at rest 6 hours, A vs B

Statistical analysis description

Comparison of pain scores, 6 hours postoperatively at rest.

Comparison groups

Treatment A v Treatment B

Number of subjects included in analysis

277

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.005 ^[15]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

-8

Confidence interval

level

99.2%

sides

2-sided

lower limit

-15

upper limit

Notes
[15] - Statistical significance level corrected for multiple comparison to p=0.0084.

Comparison of pain scores, at rest 6 hours, A vs C

Statistical analysis description

Comparison of pain scores, 6 hours postoperatively at rest.

Comparison groups

Treatment A v Treatment C

Number of subjects included in analysis

273

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.05 ^[16]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

-5

Confidence interval

level

99.2%

sides

2-sided

lower limit

-12

upper limit

Notes
[16] - Statistical significance level corrected for multiple comparison to p=0.0084.

Comparison of pain scores, at rest 6 hours, A vs D

Statistical analysis description

Comparison of pain scores, 6 hours postoperatively at rest.

Comparison groups

Treatment A v Treatment D

Number of subjects included in analysis

273

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.08 ^[17]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

-5

Confidence interval

level

99.2%

sides

2-sided

lower limit

-11

upper limit

Notes
[17] - Statistical significance level corrected for multiple comparison to p=0.0084.

Comparison of pain scores, at rest 6 hours, B vs C

Statistical analysis description

Comparison of pain scores, 6 hours postoperatively at rest.

Comparison groups

Treatment B v Treatment C

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.38 ^[18]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

99.2%

sides

2-sided

lower limit

-5

upper limit

Notes
[18] - Statistical significance level corrected for multiple comparison to p=0.0084.

Comparison of pain scores, at rest 6 hours, B vs D

Statistical analysis description

Comparison of pain scores, 6 hours postoperatively at rest.

Comparison groups

Treatment B v Treatment D

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.25 ^[19]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

99.2%

sides

2-sided

lower limit

-4

upper limit

Notes
[19] - Statistical significance level corrected for multiple comparison to p=0.0084.

Comparison of pain scores, at rest 6 hours, C vs D

Statistical analysis description

Comparison of pain scores, 6 hours postoperatively at rest.

Comparison groups

Treatment D v Treatment C

Number of subjects included in analysis

274

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.81 ^[20]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

99.2%

sides

2-sided

lower limit

-6

upper limit

Notes
[20] - Statistical significance level corrected for multiple comparison to p=0.0084.

Secondary: Pain scores with mobilization at 24 hours

Top of page

End point title

Pain scores with mobilization at 24 hours

End point description

End point type

Secondary

End point timeframe

24 hours postoperatively

End point values	Treatment A	Treatment B	Treatment C	Treatment D
Number of subjects analysed	136	141	137	137
Units: mm
arithmetic mean (confidence interval 99.2%)	37 (32 to 43)	49 (43 to 54)	45 (39 to 51)	46 (40 to 51)

Comparison of pain scores, with mob 24 h, A vs B

Statistical analysis description

Comparison of pain scores with mobilization 24 hours postoperatively.

Comparison groups

Treatment A v Treatment B

Number of subjects included in analysis

277

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[21]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

-11

Confidence interval

level

99.2%

sides

2-sided

lower limit

-19

upper limit

-3

Notes
[21] - Statistical significance level corrected for multiple comparison to p=0.0084.

Comparison of pain scores, with mob 24 h, A vs C

Statistical analysis description

Comparison of pain scores with mobilization 24 hours postoperatively.

Comparison groups

Treatment A v Treatment C

Number of subjects included in analysis

273

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.009 ^[22]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

-8

Confidence interval

level

99.2%

sides

2-sided

lower limit

-15

upper limit

Notes
[22] - Statistical significance level corrected for multiple comparison to p=0.0084.

Comparison of pain scores, with mob 24 h, A vs D

Statistical analysis description

Comparison of pain scores with mobilization 24 hours postoperatively.

Comparison groups

Treatment A v Treatment D

Number of subjects included in analysis

273

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.005 ^[23]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

-8

Confidence interval

level

99.2%

sides

2-sided

lower limit

-16

upper limit

Notes
[23] - Statistical significance level corrected for multiple comparison to p=0.0084.

Comparison of pain scores, with mob 24 h, B vs C

Statistical analysis description

Comparison of pain scores with mobilization 24 hours postoperatively.

Comparison groups

Treatment B v Treatment C

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.24 ^[24]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

99.2%

sides

2-sided

lower limit

-4

upper limit

Notes
[24] - Statistical significance level corrected for multiple comparison to p=0.0084.

Comparison of pain scores, with mob 24 h, B vs D

Statistical analysis description

Comparison of pain scores with mobilization 24 hours postoperatively.

Comparison groups

Treatment B v Treatment D

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.32 ^[25]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

99.2%

sides

2-sided

lower limit

-5

upper limit

Notes
[25] - Statistical significance level corrected for multiple comparison to p=0.0084.

Comparison of pain scores, with mob 24 h, C vs D

Statistical analysis description

Comparison of pain scores with mobilization 24 hours postoperatively.

Comparison groups

Treatment D v Treatment C

Number of subjects included in analysis

274

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.86 ^[26]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

-1

Confidence interval

level

99.2%

sides

2-sided

lower limit

-8

upper limit

Notes
[26] - Statistical significance level corrected for multiple comparison to p=0.0084.

Secondary: Pain scores at rest at 24 hours

Top of page

End point title

Pain scores at rest at 24 hours

End point description

End point type

Secondary

End point timeframe

24 hours postoperatively.

End point values	Treatment A	Treatment B	Treatment C	Treatment D
Number of subjects analysed	136	141	137	137
Units: mm
arithmetic mean (confidence interval 99.2%)	13 (10 to 17)	24 (19 to 29)	21 (16 to 26)	19 (15 to 23)

Comparison of pain scores, at rest 24 h, A vs B

Statistical analysis description

Comparison of pain scores at rest 24 hours postoperatively.

Comparison groups

Treatment A v Treatment B

Number of subjects included in analysis

277

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[27]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

-11

Confidence interval

level

99.2%

sides

2-sided

lower limit

-17

upper limit

-5

Notes
[27] - Statistical significance level corrected for multiple comparison to p=0.0084.

Comparison of pain scores, at rest 24 h, A vs C

Statistical analysis description

Comparison of pain scores at rest 24 hours postoperatively.

Comparison groups

Treatment A v Treatment C

Number of subjects included in analysis

273

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001 ^[28]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

-8

Confidence interval

level

99.2%

sides

2-sided

lower limit

-13

upper limit

-2

Notes
[28] - Statistical significance level corrected for multiple comparison to p=0.0084.

Comparison of pain scores, at rest 24 h, A vs D

Statistical analysis description

Comparison of pain scores at rest 24 hours postoperatively.

Comparison groups

Treatment A v Treatment D

Number of subjects included in analysis

273

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004 ^[29]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

-6

Confidence interval

level

99.2%

sides

2-sided

lower limit

-11

upper limit

Notes
[29] - Statistical significance level corrected for multiple comparison to p=0.0084.

Comparison of pain scores, at rest 24 h, B vs C

Statistical analysis description

Comparison of pain scores at rest 24 hours postoperatively.

Comparison groups

Treatment B v Treatment C

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.21 ^[30]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

99.2%

sides

2-sided

lower limit

-4

upper limit

Notes
[30] - Statistical significance level corrected for multiple comparison to p=0.0084.

Comparison of pain scores, at rest 24 h, B vs D

Statistical analysis description

Comparison of pain scores at rest 24 hours postoperatively.

Comparison groups

Treatment B v Treatment D

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.04 ^[31]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

99.2%

sides

2-sided

lower limit

-2

upper limit

Notes
[31] - Statistical significance level corrected for multiple comparison to p=0.0084.

Comparison of pain scores, at rest 24 h, C vs D

Statistical analysis description

Comparison of pain scores at rest 24 hours postoperatively.

Comparison groups

Treatment D v Treatment C

Number of subjects included in analysis

274

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.46 ^[32]

Method

Generalized estimating equation (GEE)

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

99.2%

sides

2-sided

lower limit

-4

upper limit

Notes
[32] - Statistical significance level corrected for multiple comparison to p=0.0084.

Secondary: Adverse events in the first 24 h

Top of page

End point title

Adverse events in the first 24 h

End point description

End point type

Secondary

End point timeframe

The first 24 hours postoperatively.

End point values	Treatment A	Treatment B	Treatment C	Treatment D
Number of subjects analysed	136	141	137	137
Units: Adverse events	20	23	22	21

Comparison of AE in the first 24 hours, A vs B

Statistical analysis description

Mean difference (RR) of adverse events in the first 24 hours.

Comparison groups

Treatment A v Treatment B

Number of subjects included in analysis

277

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.73 ^[33]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.91

Confidence interval

level

99.2%

sides

2-sided

lower limit

0.43

upper limit

1.91

Notes
[33] - Statistical significance level corrected for multiple comparison to p=0.0084.

Comparison of AE in the first 24 hours, A vs C

Statistical analysis description

Mean difference (RR) of adverse events in the first 24 hours.

Comparison groups

Treatment A v Treatment C

Number of subjects included in analysis

273

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8 ^[34]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.93

Confidence interval

level

99.2%

sides

2-sided

lower limit

0.44

upper limit

1.98

Notes
[34] - Statistical significance level corrected for multiple comparison to p=0.0084.

Comparison of AE in the first 24 hours, A vs D

Statistical analysis description

Mean difference (RR) of adverse events in the first 24 hours.

Comparison groups

Treatment A v Treatment D

Number of subjects included in analysis

273

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.94 ^[35]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

1.02

Confidence interval

level

99.2%

sides

2-sided

lower limit

0.47

upper limit

2.22

Notes
[35] - Statistical significance level corrected for multiple comparison to p=0.0084.

Comparison of AE in the first 24 hours, B vs C

Statistical analysis description

Mean difference (RR) of adverse events in the first 24 hours.

Comparison groups

Treatment B v Treatment C

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.93 ^[36]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

1.02

Confidence interval

level

99.2%

sides

2-sided

lower limit

0.5

upper limit

2.11

Notes
[36] - Statistical significance level corrected for multiple comparison to p=0.0084.

Comparison of AE in the first 24 hours, B vs D

Statistical analysis description

Mean difference (RR) of adverse events in the first 24 hours.

Comparison groups

Treatment B v Treatment D

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.67 ^[37]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

1.13

Confidence interval

level

99.2%

sides

2-sided

lower limit

0.53

upper limit

2.37

Notes
[37] - Statistical significance level corrected for multiple comparison to p=0.0084.

Comparison of AE in the first 24 hours, C vs D

Statistical analysis description

Mean difference (RR) of adverse events in the first 24 hours.

Comparison groups

Treatment D v Treatment C

Number of subjects included in analysis

274

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.74 ^[38]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

1.1

Confidence interval

level

99.2%

sides

2-sided

lower limit

0.52

upper limit

2.34

Notes
[38] - Statistical significance level corrected for multiple comparison to p=0.0084.

Other pre-specified: Nausea, 6 hours %

Top of page

End point title

Nausea, 6 hours %

End point description

End point type

Other pre-specified

End point timeframe

Surgery to 24 hours postoperatively.

End point values	Treatment A	Treatment B	Treatment C	Treatment D
Number of subjects analysed	135	139	130	134
Units: mild, moderat, severe nausea	22	32	19	28

Comparison nausea 6 hours, A vs B

Statistical analysis description

Comparison of the proportions of nausea 6 hours postoperatively.

Comparison groups

Treatment A v Treatment B

Number of subjects included in analysis

274

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.17 ^[39]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.71

Confidence interval

level

95%

sides

2-sided

lower limit

0.43

upper limit

1.15

Notes
[39] - Significance level p= 0.05

Comparison nausea 6 hours, A vs C

Statistical analysis description

Comparison of the proportions of nausea 6 hours postoperatively.

Comparison groups

Treatment A v Treatment C

Number of subjects included in analysis

265

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.82 ^[40]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

1.07

Confidence interval

level

95%

sides

2-sided

lower limit

0.61

upper limit

1.86

Notes
[40] - Significance level p= 0.05

Comparison nausea 6 hours, A vs D

Statistical analysis description

Comparison of the proportions of nausea 6 hours postoperatively.

Comparison groups

Treatment A v Treatment D

Number of subjects included in analysis

269

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.33 ^[41]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.78

Confidence interval

level

95%

sides

2-sided

lower limit

0.47

upper limit

1.29

Notes
[41] - Significance level p= 0.05

Comparison nausea 6 hours, B vs C

Statistical analysis description

Comparison of the proportions of nausea 6 hours postoperatively.

Comparison groups

Treatment B v Treatment C

Number of subjects included in analysis

269

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.11 ^[42]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

1.51

Confidence interval

level

95%

sides

2-sided

lower limit

0.91

upper limit

2.5

Notes
[42] - Significance level p= 0.05

Comparison nausea 6 hours, B vs D

Statistical analysis description

Comparison of the proportions of nausea 6 hours postoperatively.

Comparison groups

Treatment B v Treatment D

Number of subjects included in analysis

273

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.67 ^[43]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

1.72

Notes
[43] - Significance level p= 0.05

Comparison nausea 6 hours, C vs D

Statistical analysis description

Comparison of the proportions of nausea 6 hours postoperatively.

Comparison groups

Treatment D v Treatment C

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.24 ^[44]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.73

Confidence interval

level

95%

sides

2-sided

lower limit

0.43

upper limit

1.23

Notes
[44] - Significance level p= 0.05

Other pre-specified: Nausea, 24 hours postoperatively

Top of page

End point title

Nausea, 24 hours postoperatively

End point description

End point type

Other pre-specified

End point timeframe

24 hours postoperatively.

End point values	Treatment A	Treatment B	Treatment C	Treatment D
Number of subjects analysed	134	137	132	135
Units: mild, moderate, severe nausea	17	33	30	38

Comparison nausea 24 hours, A vs B

Statistical analysis description

Comparison of proportions of nausea at 24 hours postoperatively.

Comparison groups

Treatment A v Treatment B

Number of subjects included in analysis

271

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.019 ^[45]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.53

Confidence interval

level

95%

sides

2-sided

lower limit

0.31

upper limit

0.9

Notes
[45] - Level of significance p = 0.05.

Comparison nausea 24 hours, A vs C

Statistical analysis description

Comparison of proportions of nausea at 24 hours postoperatively.

Comparison groups

Treatment A v Treatment C

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.036 ^[46]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.56

Confidence interval

level

95%

sides

2-sided

lower limit

0.32

upper limit

0.96

Notes
[46] - Level of significance p = 0.05.

Comparison nausea 24 hours, A vs D

Statistical analysis description

Comparison of proportions of nausea at 24 hours postoperatively.

Comparison groups

Treatment A v Treatment D

Number of subjects included in analysis

269

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003 ^[47]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.45

Confidence interval

level

95%

sides

2-sided

lower limit

0.27

upper limit

0.76

Notes
[47] - Level of significance p = 0.05.

Comparison nausea 24 hours, B vs C

Statistical analysis description

Comparison of proportions of nausea at 24 hours postoperatively.

Comparison groups

Treatment B v Treatment C

Number of subjects included in analysis

269

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.79 ^[48]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

1.06

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

1.63

Notes
[48] - Level of significance p = 0.05.

Comparison nausea 24 hours, B vs D

Statistical analysis description

Comparison of proportions of nausea at 24 hours postoperatively.

Comparison groups

Treatment B v Treatment D

Number of subjects included in analysis

272

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.45 ^[49]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.86

Confidence interval

level

95%

sides

2-sided

lower limit

0.57

upper limit

1.28

Notes
[49] - Level of significance p = 0.05.

Comparison nausea 24 hours, C vs D

Statistical analysis description

Comparison of proportions of nausea at 24 hours postoperatively.

Comparison groups

Treatment D v Treatment C

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.31 ^[50]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.81

Confidence interval

level

95%

sides

2-sided

lower limit

0.53

upper limit

1.22

Notes
[50] - Level of significance p = 0.05.

Other pre-specified: Sedation 6 hours postoperatively

Top of page

End point title

Sedation 6 hours postoperatively

End point description

End point type

Other pre-specified

End point timeframe

6 hours postoperatively

End point values	Treatment A	Treatment B	Treatment C	Treatment D
Number of subjects analysed	135	138	130	132
Units: mild, moderate, severe sedation	33	51	27	38

Comparison sedation 6 hours, A vs B

Statistical analysis description

Comparison of proportions of sedation 6 hours postoperatively.

Comparison groups

Treatment A v Treatment B

Number of subjects included in analysis

273

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.028 ^[51]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.66

Confidence interval

level

95%

sides

2-sided

lower limit

0.46

upper limit

0.96

Notes
[51] - Level of significance p = 0.05

Comparison sedation 6 hours, A vs C

Statistical analysis description

Comparison of proportions of sedation 6 hours postoperatively.

Comparison groups

Treatment A v Treatment C

Number of subjects included in analysis

265

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.48 ^[52]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

1.18

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

1.84

Notes
[52] - Level of significance p = 0.05

Comparison sedation 6 hours, A vs D

Statistical analysis description

Comparison of proportions of sedation 6 hours postoperatively.

Comparison groups

Treatment A v Treatment D

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.42 ^[53]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.85

Confidence interval

level

95%

sides

2-sided

lower limit

0.57

upper limit

1.27

Notes
[53] - Level of significance p = 0.05

Comparison sedation 6 hours, B vs C

Statistical analysis description

Comparison of proportions of sedation 6 hours postoperatively.

Comparison groups

Treatment B v Treatment C

Number of subjects included in analysis

268

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.005 ^[54]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

1.78

Confidence interval

level

95%

sides

2-sided

lower limit

1.19

upper limit

2.66

Notes
[54] - Level of significance p = 0.05

Comparison sedation 6 hours, B vs D

Statistical analysis description

Comparison of proportions of sedation 6 hours postoperatively.

Comparison groups

Treatment B v Treatment D

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.16 ^[55]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

1.28

Confidence interval

level

95%

sides

2-sided

lower limit

0.91

upper limit

1.81

Notes
[55] - Level of significance p = 0.05

Comparison sedation 6 hours, C vs D

Statistical analysis description

Comparison of proportions of sedation 6 hours postoperatively.

Comparison groups

Treatment D v Treatment C

Number of subjects included in analysis

262

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.14 ^[56]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.72

Confidence interval

level

95%

sides

2-sided

lower limit

0.47

upper limit

1.11

Notes
[56] - Level of significance p = 0.05

Other pre-specified: Sedation, 24 hours postoperatively

Top of page

End point title

Sedation, 24 hours postoperatively

End point description

End point type

Other pre-specified

End point timeframe

24 hours postoperatively.

End point values	Treatment A	Treatment B	Treatment C	Treatment D
Number of subjects analysed	134	137	132	135
Units: mild, moderate, severe sedation	44	58	47	57

Comparison sedation 24 hours, A vs B

Statistical analysis description

Comaprison of proportions of sedation 24 hours postoperatively.

Comparison groups

Treatment A v Treatment B

Number of subjects included in analysis

271

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.019 ^[57]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.53

Confidence interval

level

95%

sides

2-sided

lower limit

0.31

upper limit

0.9

Notes
[57] - Level of significance p = 0.05

Comparison sedation 24 hours, A vs C

Statistical analysis description

Comaprison of proportions of sedation 24 hours postoperatively.

Comparison groups

Treatment A v Treatment C

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.036 ^[58]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.56

Confidence interval

level

95%

sides

2-sided

lower limit

0.32

upper limit

0.96

Notes
[58] - Level of significance p = 0.05

Comparison sedation 24 hours, A vs D

Statistical analysis description

Comaprison of proportions of sedation 24 hours postoperatively.

Comparison groups

Treatment A v Treatment D

Number of subjects included in analysis

269

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003 ^[59]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.45

Confidence interval

level

95%

sides

2-sided

lower limit

0.27

upper limit

0.76

Notes
[59] - Level of significance p = 0.05

Comparison sedation 24 hours, B vs C

Statistical analysis description

Comaprison of proportions of sedation 24 hours postoperatively.

Comparison groups

Treatment B v Treatment C

Number of subjects included in analysis

269

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.79 ^[60]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

1.06

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

1.63

Notes
[60] - Level of significance p = 0.05

Comparison sedation 24 hours, B vs D

Statistical analysis description

Comaprison of proportions of sedation 24 hours postoperatively.

Comparison groups

Treatment B v Treatment D

Number of subjects included in analysis

272

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.45 ^[61]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.86

Confidence interval

level

95%

sides

2-sided

lower limit

0.57

upper limit

1.28

Notes
[61] - Level of significance p = 0.05

Comparison sedation 24 hours, C vs D

Statistical analysis description

Comaprison of proportions of sedation 24 hours postoperatively.

Comparison groups

Treatment D v Treatment C

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.31 ^[62]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.81

Confidence interval

level

95%

sides

2-sided

lower limit

0.53

upper limit

1.22

Notes
[62] - Level of significance p = 0.05

Other pre-specified: Dizziness, 6 hours postoperatively

Top of page

End point title

Dizziness, 6 hours postoperatively

End point description

End point type

Other pre-specified

End point timeframe

6 hours postoperatively.

End point values	Treatment A	Treatment B	Treatment C	Treatment D
Number of subjects analysed	135	139	130	133
Units: mild, moderate, severe dizziness	19	35	26	32

Comparison dizziness 6 hours, A vs B

Statistical analysis description

Comparison of proportions of dizziness 6 hours postoperatively.

Comparison groups

Treatment A v Treatment B

Number of subjects included in analysis

274

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.024 ^[63]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.56

Confidence interval

level

95%

sides

2-sided

lower limit

0.34

upper limit

0.93

Notes
[63] - Level of significance p = 0.05

Comparison dizziness 6 hours, A vs C

Statistical analysis description

Comparison of proportions of dizziness 6 hours postoperatively.

Comparison groups

Treatment A v Treatment C

Number of subjects included in analysis

265

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2 ^[64]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

0.41

upper limit

1.21

Notes
[64] - Level of significance p = 0.05

Comparison dizziness 6 hours, A vs D

Statistical analysis description

Comparison of proportions of dizziness 6 hours postoperatively.

Comparison groups

Treatment A v Treatment D

Number of subjects included in analysis

268

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.041 ^[65]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.58

Confidence interval

level

95%

sides

2-sided

lower limit

0.35

upper limit

0.98

Notes
[65] - Level of significance p = 0.05

Comparison dizziness 6 hours, B vs C

Statistical analysis description

Comparison of proportions of dizziness 6 hours postoperatively.

Comparison groups

Treatment B v Treatment C

Number of subjects included in analysis

269

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.31 ^[66]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

1.26

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

1.97

Notes
[66] - Level of significance p = 0.05

Comparison dizziness 6 hours, B vs D

Statistical analysis description

Comparison of proportions of dizziness 6 hours postoperatively.

Comparison groups

Treatment B v Treatment D

Number of subjects included in analysis

272

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.83 ^[67]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

1.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

1.59

Notes
[67] - Level of significance p = 0.05

Comparison dizziness 6 hours, C vs D

Statistical analysis description

Comparison of proportions of dizziness 6 hours postoperatively.

Comparison groups

Treatment D v Treatment C

Number of subjects included in analysis

263

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.43 ^[68]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.83

Confidence interval

level

95%

sides

2-sided

lower limit

0.53

upper limit

1.31

Notes
[68] - Level of significance p = 0.05

Other pre-specified: Dizziness, 24 hours postoperatively

Top of page

End point title

Dizziness, 24 hours postoperatively

End point description

End point type

Other pre-specified

End point timeframe

24 hours postoperatively.

End point values	Treatment A	Treatment B	Treatment C	Treatment D
Number of subjects analysed	134	137	132	135
Units: mild, moderate, severe dizziness	26	32	38	37

Comparison dizziness 24 hours, A vs B

Statistical analysis description

Comparison of proportions of dizziness 24 hours postoperatively.

Comparison groups

Treatment A v Treatment B

Number of subjects included in analysis

271

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.43 ^[69]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.83

Confidence interval

level

95%

sides

2-sided

lower limit

0.52

upper limit

1.32

Notes
[69] - Level of significance p = 0.05.

Comparison dizziness 24 hours, A vs C

Statistical analysis description

Comparison of proportions of dizziness 24 hours postoperatively.

Comparison groups

Treatment A v Treatment C

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.77 ^[70]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.44

upper limit

1.04

Notes
[70] - Level of significance p = 0.05.

Comparison dizziness 24 hours, A vs D

Statistical analysis description

Comparison of proportions of dizziness 24 hours postoperatively.

Comparison groups

Treatment A v Treatment D

Number of subjects included in analysis

269

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.13 ^[71]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.71

Confidence interval

level

95%

sides

2-sided

lower limit

0.46

upper limit

1.1

Notes
[71] - Level of significance p = 0.05.

Comparison dizziness 24 hours, B vs C

Statistical analysis description

Comparison of proportions of dizziness 24 hours postoperatively.

Comparison groups

Treatment B v Treatment C

Number of subjects included in analysis

269

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.31 ^[72]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.81

Confidence interval

level

95%

sides

2-sided

lower limit

0.54

upper limit

1.22

Notes
[72] - Level of significance p = 0.05.

Comparison dizziness 24 hours, B vs D

Statistical analysis description

Comparison of proportions of dizziness 24 hours postoperatively.

Comparison groups

Treatment B v Treatment D

Number of subjects included in analysis

272

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.44 ^[73]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

0.85

Confidence interval

level

95%

sides

2-sided

lower limit

0.57

upper limit

1.28

Notes
[73] - Level of significance p = 0.05.

Copy of Comparison dizziness 24 hours, C vs D

Statistical analysis description

Comparison of proportions of dizziness 24 hours postoperatively.

Comparison groups

Treatment D v Treatment C

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8 ^[74]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

1.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

1.54

Notes
[74] - Level of significance p = 0.05.

Other pre-specified: Vomiting, first 24 hours postoperatively.

Top of page

End point title

Vomiting, first 24 hours postoperatively.

End point description

End point type

Other pre-specified

End point timeframe

First 24 hours postoperatively.

End point values	Treatment A	Treatment B	Treatment C	Treatment D
Number of subjects analysed	136	141	137	137
Units: number of vomiting	0	0	0	0

Comparison of vomiting, first 24 hours, A vs B

Statistical analysis description

Comparison of vomiting, the first 24 hours postoperatively.

Comparison groups

Treatment A v Treatment B

Number of subjects included in analysis

277

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.47

Method

Generalized estimating equation (GEE)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Comparison of vomiting, first 24 hours, A vs C

Statistical analysis description

Comparison of vomiting, the first 24 hours postoperatively.

Comparison groups

Treatment A v Treatment C

Number of subjects included in analysis

273

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.96

Method

Generalized estimating equation (GEE)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Comparison of vomiting, first 24 hours, A vs D

Statistical analysis description

Comparison of vomiting, the first 24 hours postoperatively.

Comparison groups

Treatment A v Treatment D

Number of subjects included in analysis

273

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2

Method

Generalized estimating equation (GEE)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Comparison of vomiting, first 24 hours, B vs C

Statistical analysis description

Comparison of vomiting, the first 24 hours postoperatively.

Comparison groups

Treatment B v Treatment C

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.36

Method

Generalized estimating equation (GEE)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Comparison of vomiting, first 24 hours, B vs D

Statistical analysis description

Comparison of vomiting, the first 24 hours postoperatively.

Comparison groups

Treatment B v Treatment D

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.55

Method

Generalized estimating equation (GEE)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Comparison of vomiting, first 24 hours, C vs D

Statistical analysis description

Comparison of vomiting, the first 24 hours postoperatively.

Comparison groups

Treatment D v Treatment C

Number of subjects included in analysis

274

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.13

Method

Generalized estimating equation (GEE)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Other pre-specified: Ondansetron use first 24 hours

Top of page

End point title

Ondansetron use first 24 hours

End point description

End point type

Other pre-specified

End point timeframe

First 24 hours postoperatively.

End point values	Treatment A	Treatment B	Treatment C	Treatment D
Number of subjects analysed	136	140	136	139
Units: mg
median (inter-quartile range (Q1-Q3))	0 (0 to 4)	0 (0 to 4)	0 (0 to 4)	0 (0 to 5)

Comparsion of ondansetron use, first 24 h, A vs B

Statistical analysis description

Comparison of the use of ondansetron, the first 24 hours postoperatively.

Comparison groups

Treatment A v Treatment B

Number of subjects included in analysis

276

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.09 ^[75]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Notes
[75] - Level of significance p = 0.05

Comparsion of ondansetron use, first 24 h, A vs C

Statistical analysis description

Comparison of the use of ondansetron, the first 24 hours postoperatively.

Comparison groups

Treatment A v Treatment C

Number of subjects included in analysis

272

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.86 ^[76]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Notes
[76] - Level of significance p = 0.05

Comparsion of ondansetron use, first 24 h, A vs D

Statistical analysis description

Comparison of the use of ondansetron, the first 24 hours postoperatively.

Comparison groups

Treatment D v Treatment A

Number of subjects included in analysis

275

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2 ^[77]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Notes
[77] - Level of significance p = 0.05

Comparsion of ondansetron use, first 24 h, B vs C

Statistical analysis description

Comparison of the use of ondansetron, the first 24 hours postoperatively.

Comparison groups

Treatment B v Treatment C

Number of subjects included in analysis

276

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.15 ^[78]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Notes
[78] - Level of significance p = 0.05

Comparsion of ondansetron use, first 24 h, B vs D

Statistical analysis description

Comparison of the use of ondansetron, the first 24 hours postoperatively.

Comparison groups

Treatment B v Treatment D

Number of subjects included in analysis

279

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.73 ^[79]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Notes
[79] - Level of significance p = 0.05

Comparsion of ondansetron use, first 24 h, C vs D

Statistical analysis description

Comparison of the use of ondansetron, the first 24 hours postoperatively.

Comparison groups

Treatment D v Treatment C

Number of subjects included in analysis

275

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.05 ^[80]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Notes
[80] - Level of significance p = 0.05

Other pre-specified: Blood loss

Top of page

End point title

Blood loss

End point description

Exploratory outcome

End point type

Other pre-specified

End point timeframe

Peroperative blood loss.

End point values	Treatment A	Treatment B	Treatment C	Treatment D
Number of subjects analysed	132	137	136	134
Units: ml
median (inter-quartile range (Q1-Q3))	300 (200 to 415)	300 (200 to 470)	265 (177.5 to 400)	287.5 (165 to 400)

Comparison blood loss, A vs B

Statistical analysis description

Comparsion of peroperative blood loss in ml.

Comparison groups

Treatment A v Treatment B

Number of subjects included in analysis

269

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9 ^[81]

Method

Generalized estimating equation (GEE)

Parameter type

Risk ratio (RR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-60

upper limit

52.5

Notes
[81] - Level of Significance p = 0.05

Comparison blood loss, A vs C

Statistical analysis description

Comparsion of peroperative blood loss in ml.

Comparison groups

Treatment A v Treatment C

Number of subjects included in analysis

268

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.29 ^[82]

Method

Generalized estimating equation (GEE)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-25

upper limit

Notes
[82] - Level of Significance p = 0.05

Comparison blood loss, A vs D

Statistical analysis description

Comparsion of peroperative blood loss in ml.

Comparison groups

Treatment A v Treatment D

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.36 ^[83]

Method

Generalized estimating equation (GEE)

Parameter type

Median difference (final values)

Point estimate

12.5

Confidence interval

level

95%

sides

2-sided

lower limit

-50

upper limit

Notes
[83] - Level of Significance p = 0.05

Comparison blood loss, B vs C

Statistical analysis description

Comparsion of peroperative blood loss in ml.

Comparison groups

Treatment B v Treatment C

Number of subjects included in analysis

273

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.19 ^[84]

Method

Generalized estimating equation (GEE)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-20

upper limit

100

Notes
[84] - Level of Significance p = 0.05

Comparison blood loss, B vs D

Statistical analysis description

Comparsion of peroperative blood loss in ml.

Comparison groups

Treatment B v Treatment D

Number of subjects included in analysis

271

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.37 ^[85]

Method

Generalized estimating equation (GEE)

Parameter type

Median difference (final values)

Point estimate

12.5

Confidence interval

level

95%

sides

2-sided

lower limit

-50

upper limit

Notes
[85] - Level of Significance p = 0.05

Comparison blood loss,v C vs D

Statistical analysis description

Comparsion of peroperative blood loss in ml.

Comparison groups

Treatment D v Treatment C

Number of subjects included in analysis

270

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.85 ^[86]

Method

Generalized estimating equation (GEE)

Parameter type

Median difference (final values)

Point estimate

-22.5

Confidence interval

level

95%

sides

2-sided

lower limit

-75

upper limit

Notes
[86] - Level of Significance p = 0.05

Other pre-specified: Days alive and outside hospital, days

Top of page

End point title

Days alive and outside hospital, days

End point description

Exploratory outcome

End point type

Other pre-specified

End point timeframe

Days alive and outside hospital, days

End point values	Treatment A	Treatment B	Treatment C	Treatment D
Number of subjects analysed	134	141	138	138
Units: days
median (inter-quartile range (Q1-Q3))	89 (88 to 89)	88 (88 to 89)	88 (88 to 89)	88 (88 to 89)

Median differences, days alive and outside, A vs B

Statistical analysis description

Median differences of days alive and outside of hospital.

Comparison groups

Treatment A v Treatment B

Number of subjects included in analysis

275

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.46 ^[87]

Method

Generalized estimating equation (GEE)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Notes
[87] - Level of significance p = 0.05.

Median differences, days alive and outside, A vs C

Statistical analysis description

Median differences of days alive and outside of hospital.

Comparison groups

Treatment A v Treatment C

Number of subjects included in analysis

272

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.13 ^[88]

Method

Generalized estimating equation (GEE)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Notes
[88] - Level of significance p = 0.05.

Median differences, days alive and outside, A vs D

Statistical analysis description

Median differences of days alive and outside of hospital.

Comparison groups

Treatment A v Treatment D

Number of subjects included in analysis

272

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.55 ^[89]

Method

Generalized estimating equation (GEE)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Notes
[89] - Level of significance p = 0.05.

Median differences, days alive and outside, B vs C

Statistical analysis description

Median differences of days alive and outside of hospital.

Comparison groups

Treatment B v Treatment C

Number of subjects included in analysis

279

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.69 ^[90]

Method

Generalized estimating equation (GEE)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Notes
[90] - Level of significance p = 0.05.

Median differences, days alive and outside, B vs D

Statistical analysis description

Median differences of days alive and outside of hospital.

Comparison groups

Treatment B v Treatment D

Number of subjects included in analysis

279

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.94 ^[91]

Method

Generalized estimating equation (GEE)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Notes
[91] - Level of significance p = 0.05.

Median differences, days alive and outside, C vs D

Statistical analysis description

Median differences of days alive and outside of hospital.

Comparison groups

Treatment D v Treatment C

Number of subjects included in analysis

276

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.56 ^[92]

Method

Generalized estimating equation (GEE)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

Notes
[92] - Level of significance p = 0.05.

Adverse events

Top of page

Timeframe for reporting adverse events

From operation to 90 days postoperatively.

Assessment type

Systematic

Dictionary name

ICH-GCP

Dictionary version

Revision 2

Reporting group title

Treatment A

Reporting group description

Paracetamol 1g + ibuprofen 400 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Reporting group title

Treatment B

Reporting group description

Paracetamol 1g + placebo orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Reporting group title

Treatment C

Reporting group description

Placebo + ibuprofen 400 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Reporting group title

Treatment D

Reporting group description

Paracetamol 0,5 g + ibuprofen 200 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

Serious adverse events	Treatment A	Treatment B	Treatment C	Treatment D
Total subjects affected by serious adverse events
subjects affected / exposed	25 / 136 (18.38%)	15 / 142 (10.56%)	20 / 139 (14.39%)	18 / 139 (12.95%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Investigations
Unknown
subjects affected / exposed	5 / 136 (3.68%)	4 / 142 (2.82%)	3 / 139 (2.16%)	2 / 139 (1.44%)
occurrences causally related to treatment / all	0 / 5	0 / 4	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep venous thrombosis (CVT)
subjects affected / exposed	1 / 136 (0.74%)	0 / 142 (0.00%)	2 / 139 (1.44%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 136 (0.74%)	1 / 142 (0.70%)	0 / 139 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Mechanical problems with the prosthesis
subjects affected / exposed	5 / 136 (3.68%)	4 / 142 (2.82%)	3 / 139 (2.16%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 5	0 / 4	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiological
subjects affected / exposed	1 / 136 (0.74%)	1 / 142 (0.70%)	3 / 139 (2.16%)	3 / 139 (2.16%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Delirium
subjects affected / exposed	0 / 136 (0.00%)	0 / 142 (0.00%)	0 / 139 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 136 (0.00%)	0 / 142 (0.00%)	0 / 139 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Low hemoglobin
subjects affected / exposed	2 / 136 (1.47%)	0 / 142 (0.00%)	0 / 139 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 136 (0.00%)	0 / 142 (0.00%)	0 / 139 (0.00%)	2 / 139 (1.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Dyspepsia
subjects affected / exposed	1 / 136 (0.74%)	0 / 142 (0.00%)	0 / 139 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 136 (0.74%)	0 / 142 (0.00%)	0 / 139 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 136 (0.00%)	0 / 142 (0.00%)	0 / 139 (0.00%)	2 / 139 (1.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pneumonia
subjects affected / exposed	1 / 136 (0.74%)	0 / 142 (0.00%)	2 / 139 (1.44%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal
subjects affected / exposed	1 / 136 (0.74%)	0 / 142 (0.00%)	0 / 139 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Fracture, not anatomical related
subjects affected / exposed	0 / 136 (0.00%)	0 / 142 (0.00%)	1 / 139 (0.72%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Surgical site infection
subjects affected / exposed	5 / 136 (3.68%)	4 / 142 (2.82%)	5 / 139 (3.60%)	4 / 139 (2.88%)
occurrences causally related to treatment / all	0 / 5	0 / 4	0 / 5	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infection, not anatomical related
subjects affected / exposed	1 / 136 (0.74%)	1 / 142 (0.70%)	1 / 139 (0.72%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Treatment A	Treatment B	Treatment C	Treatment D
Total subjects affected by non serious adverse events
subjects affected / exposed	20 / 136 (14.71%)	23 / 142 (16.20%)	22 / 139 (15.83%)	21 / 139 (15.11%)
Cardiac disorders
Bradycardia
subjects affected / exposed	0 / 136 (0.00%)	0 / 142 (0.00%)	0 / 139 (0.00%)	1 / 139 (0.72%)
occurrences all number	0	0	0	1
Low blood pressure
subjects affected / exposed	0 / 136 (0.00%)	0 / 142 (0.00%)	3 / 139 (2.16%)	0 / 139 (0.00%)
occurrences all number	0	0	3	0
Surgical and medical procedures
Hot flush when using PCA-morphine
subjects affected / exposed	0 / 136 (0.00%)	0 / 142 (0.00%)	2 / 139 (1.44%)	1 / 139 (0.72%)
occurrences all number	0	0	2	1
Leaking from surgical site
subjects affected / exposed	0 / 136 (0.00%)	1 / 142 (0.70%)	1 / 139 (0.72%)	0 / 139 (0.00%)
occurrences all number	0	1	1	0
Transfer to an other hospital
subjects affected / exposed	0 / 136 (0.00%)	0 / 142 (0.00%)	1 / 139 (0.72%)	0 / 139 (0.00%)
occurrences all number	0	0	1	0
Vasovagal episode during anesthesia
subjects affected / exposed	0 / 136 (0.00%)	0 / 142 (0.00%)	0 / 139 (0.00%)	1 / 139 (0.72%)
occurrences all number	0	0	0	1
Nervous system disorders
Confusion
subjects affected / exposed	2 / 136 (1.47%)	3 / 142 (2.11%)	4 / 139 (2.88%)	1 / 139 (0.72%)
occurrences all number	2	3	4	1
Headache
subjects affected / exposed	0 / 136 (0.00%)	0 / 142 (0.00%)	1 / 139 (0.72%)	0 / 139 (0.00%)
occurrences all number	0	0	1	0
Sleep disorder
subjects affected / exposed	1 / 136 (0.74%)	2 / 142 (1.41%)	1 / 139 (0.72%)	0 / 139 (0.00%)
occurrences all number	1	2	1	0
Vasovagal episode during mobilization
subjects affected / exposed	1 / 136 (0.74%)	3 / 142 (2.11%)	1 / 139 (0.72%)	0 / 139 (0.00%)
occurrences all number	1	3	1	0
Blood and lymphatic system disorders
Low hemoglobin
subjects affected / exposed	3 / 136 (2.21%)	0 / 142 (0.00%)	2 / 139 (1.44%)	2 / 139 (1.44%)
occurrences all number	3	0	2	2
Gastrointestinal disorders
Dyspepsia
subjects affected / exposed	3 / 136 (2.21%)	4 / 142 (2.82%)	1 / 139 (0.72%)	5 / 139 (3.60%)
occurrences all number	3	4	1	5
Incontinence (stool)
subjects affected / exposed	0 / 136 (0.00%)	0 / 142 (0.00%)	0 / 139 (0.00%)	1 / 139 (0.72%)
occurrences all number	0	0	0	1
Nausea
subjects affected / exposed	0 / 136 (0.00%)	1 / 142 (0.70%)	0 / 139 (0.00%)	1 / 139 (0.72%)
occurrences all number	0	1	0	1
Ructus
subjects affected / exposed	0 / 136 (0.00%)	0 / 142 (0.00%)	0 / 139 (0.00%)	1 / 139 (0.72%)
occurrences all number	0	0	0	1
Dry mouth
subjects affected / exposed	0 / 136 (0.00%)	1 / 142 (0.70%)	0 / 139 (0.00%)	1 / 139 (0.72%)
occurrences all number	0	1	0	1
Skin and subcutaneous tissue disorders
Itching, PCA
subjects affected / exposed	7 / 136 (5.15%)	5 / 142 (3.52%)	3 / 139 (2.16%)	2 / 139 (1.44%)
occurrences all number	7	5	3	2
Renal and urinary disorders
Hematuria
subjects affected / exposed	1 / 136 (0.74%)	0 / 142 (0.00%)	0 / 139 (0.00%)	0 / 139 (0.00%)
occurrences all number	1	0	0	0
Elevated creatinin
subjects affected / exposed	0 / 136 (0.00%)	0 / 142 (0.00%)	1 / 139 (0.72%)	1 / 139 (0.72%)
occurrences all number	0	0	1	1
Endocrine disorders
Low potassium
subjects affected / exposed	0 / 136 (0.00%)	0 / 142 (0.00%)	0 / 139 (0.00%)	1 / 139 (0.72%)
occurrences all number	0	0	0	1
Musculoskeletal and connective tissue disorders
Fall
subjects affected / exposed	1 / 136 (0.74%)	0 / 142 (0.00%)	0 / 139 (0.00%)	0 / 139 (0.00%)
occurrences all number	1	0	0	0
Not mobilized
subjects affected / exposed	0 / 136 (0.00%)	1 / 142 (0.70%)	0 / 139 (0.00%)	1 / 139 (0.72%)
occurrences all number	0	1	0	1
Shivering
subjects affected / exposed	0 / 136 (0.00%)	1 / 142 (0.70%)	0 / 139 (0.00%)	0 / 139 (0.00%)
occurrences all number	0	1	0	0
Syncope during mobilization
subjects affected / exposed	1 / 136 (0.74%)	0 / 142 (0.00%)	0 / 139 (0.00%)	0 / 139 (0.00%)
occurrences all number	1	0	0	0
Infections and infestations
Fever
subjects affected / exposed	0 / 136 (0.00%)	1 / 142 (0.70%)	1 / 139 (0.72%)	0 / 139 (0.00%)
occurrences all number	0	1	1	0
Product issues
Pain when using PCA-morphine
subjects affected / exposed	0 / 136 (0.00%)	0 / 142 (0.00%)	0 / 139 (0.00%)	1 / 139 (0.72%)
occurrences all number	0	0	0	1

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

http://www.ncbi.nlm.nih.gov/pubmed/30747964
http://www.ncbi.nlm.nih.gov/pubmed/31648374
http://www.ncbi.nlm.nih.gov/pubmed/32270482

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Clinical trials

Clinical Trial Results: PANSAID – PAracetamol and NSAID in combination: A randomised, blinded, parallel 4-group clinical trial

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Morphine consumption the first 24 hours postoperatively

Primary: Morphine consumption the first 24 hours postoperatively

Primary: Proportion of patients with 1 or more modified SAEs from the surgery to 90 days postoperatively

Primary: Proportion of patients with 1 or more modified SAEs from the surgery to 90 days postoperatively

Secondary: Pain scores, with mobilization at 6 h

Secondary: Pain scores, with mobilization at 6 h

Secondary: Pain scores, at rest 6 hours

Secondary: Pain scores, at rest 6 hours

Secondary: Pain scores with mobilization at 24 hours

Secondary: Pain scores with mobilization at 24 hours

Secondary: Pain scores at rest at 24 hours

Secondary: Pain scores at rest at 24 hours

Secondary: Adverse events in the first 24 h

Secondary: Adverse events in the first 24 h

Other pre-specified: Nausea, 6 hours %

Other pre-specified: Nausea, 6 hours %

Other pre-specified: Nausea, 24 hours postoperatively

Other pre-specified: Nausea, 24 hours postoperatively

Other pre-specified: Sedation 6 hours postoperatively

Other pre-specified: Sedation 6 hours postoperatively

Other pre-specified: Sedation, 24 hours postoperatively

Other pre-specified: Sedation, 24 hours postoperatively

Other pre-specified: Dizziness, 6 hours postoperatively

Other pre-specified: Dizziness, 6 hours postoperatively

Other pre-specified: Dizziness, 24 hours postoperatively

Other pre-specified: Dizziness, 24 hours postoperatively

Other pre-specified: Vomiting, first 24 hours postoperatively.

Other pre-specified: Vomiting, first 24 hours postoperatively.

Other pre-specified: Ondansetron use first 24 hours

Other pre-specified: Ondansetron use first 24 hours

Other pre-specified: Blood loss

Other pre-specified: Blood loss

Other pre-specified: Days alive and outside hospital, days

Other pre-specified: Days alive and outside hospital, days

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
PANSAID – PAracetamol and NSAID in combination: A randomised, blinded, parallel 4-group clinical trial