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Clinical Trial Results:
A Randomized, Double-Blind, Single-Dose, Parallel, Placebo-Controlled Pivotal Trial to Confirm the Efficacy of a Fixed Dose Combination (FDC) Tablet of Naproxen Sodium and Caffeine to Effectively Alleviate Postsurgical Dental Pain

Summary
EudraCT number	2022-003274-22
Trial protocol	Outside EU/EEA
Global end of trial date	29 Jan 2024

Results information
Results version number	v1(current)
This version publication date	25 Jul 2024
First version publication date	25 Jul 2024
Other versions

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

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Trial information

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Sponsor protocol code

BAY2880376 / 22093

ISRCTN number

US NCT number

NCT05485805

WHO universal trial number (UTN)

Sponsor organisation name

Bayer HealthCare LLC, Consumer Health

Sponsor organisation address

100 Bayer Boulevard, Whippany, United States,

Public contact

Bayer Clinical Trials Contact, Bayer AG, clinical-trials-contact@bayer.com

Scientific contact

Bayer Clinical Trials Contact, Bayer AG, clinical-trials-contact@bayer.com

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?

Yes

Analysis stage

Final

Date of interim/final analysis

29 Mar 2024

Is this the analysis of the primary completion data?

Yes

Primary completion date

25 Jan 2024

Global end of trial reached?

Yes

Global end of trial date

29 Jan 2024

Was the trial ended prematurely?

Main objective of the trial

To compare a single oral dose of the FDC relative to naproxen sodium 220mg, Caffeine 100 mg and placebo.

Protection of trial subjects

The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.

Background therapy

Evidence for comparator

Actual start date of recruitment

21 Sep 2022

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 541

Worldwide total number of subjects

541

EEA total number of subjects

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)

258

Adults (18-64 years)

283

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The clinical study was conducted at a single study site in the United States between 21 September 2022 (first subject first visit) and 29 January 2024 (last subject last visit).

Screening details

A total of 750 participants were screened at a single study center in the United States. 541 participants were randomly assigned to study intervention.

Period 1 title

overall (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Naproxen sodium/ Caffeine 220/65 mg

Arm description

Participants received one tablet of the fixed dose combination Naproxen sodium/Caffeine 220/65 mg and one tablet of placebo.

Arm type

Experimental

Investigational medicinal product name

Naproxen sodium/Caffeine 220/65 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

administration as 1 table single dose

Naproxen sodium/Caffeine 2x220/65 mg

Arm description

Participants received two tablets of the fixed dose combination Naproxen sodium/Caffeine 220/65 mg.

Arm type

Experimental

Investigational medicinal product name

Naproxen sodium/Caffeine 220/65 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

administration as one table single dose

Naproxen sodium 220 mg

Arm description

Participants received one tablet of Naproxen sodium 220 mg and one tablet of placebo.

Arm type

Experimental

Investigational medicinal product name

Naproxen sodium 220 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

administration as one single tablet Naproxen sodium 220 mg

Caffeine 100 mg

Arm description

Participants received one tablet Caffeine 100 mg one one tablet of placebo.

Arm type

Experimental

Investigational medicinal product name

Caffeine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Caffeine 100 mg 1 tablet as single dose

Placebo

Arm description

Participants received two tablets of placebo.

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

two tablets of placebo as single dose

Number of subjects in period 1	Naproxen sodium/ Caffeine 220/65 mg	Naproxen sodium/Caffeine 2x220/65 mg	Naproxen sodium 220 mg	Caffeine 100 mg	Placebo
Started	147	148	147	50	49
Completed	145	144	142	49	47
Not completed	2	4	5	1	2
Consent withdrawn by subject	1	2	2	-	2
Adverse event, non-fatal	-	1	-	-	-
Lost to follow-up	1	1	3	1	-

Baseline characteristics

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Reporting group title

Naproxen sodium/ Caffeine 220/65 mg

Reporting group description

Participants received one tablet of the fixed dose combination Naproxen sodium/Caffeine 220/65 mg and one tablet of placebo.

Reporting group title

Naproxen sodium/Caffeine 2x220/65 mg

Reporting group description

Participants received two tablets of the fixed dose combination Naproxen sodium/Caffeine 220/65 mg.

Reporting group title

Naproxen sodium 220 mg

Reporting group description

Participants received one tablet of Naproxen sodium 220 mg and one tablet of placebo.

Reporting group title

Caffeine 100 mg

Reporting group description

Participants received one tablet Caffeine 100 mg one one tablet of placebo.

Reporting group title

Placebo

Reporting group description

Participants received two tablets of placebo.

Reporting group values	Naproxen sodium/ Caffeine 220/65 mg	Naproxen sodium/Caffeine 2x220/65 mg	Naproxen sodium 220 mg	Caffeine 100 mg	Placebo	Total
Number of subjects	147	148	147	50	49	541
Age categorical
Units: Subjects
In utero						0
Preterm newborn infants (gestational age < 37 wks)						0
Newborns (0-27 days)						0
Infants and toddlers (28 days-23 months)						0
Children (2-11 years)						0
Adolescents (12-17 years)						0
Adults (18-64 years)						0
From 65-84 years						0
85 years and over						0
Age continuous
Units: years
arithmetic mean (standard deviation)	18.3 ( 2.13 )	18.1 ( 1.99 )	18.1 ( 1.84 )	17.7 ( 1.82 )	17.9 ( 2.05 )	-
Gender categorical
Units: Subjects
Female	61	70	67	22	23	243
Male	86	78	80	28	26	298

End points

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Reporting group title

Naproxen sodium/ Caffeine 220/65 mg

Reporting group description

Participants received one tablet of the fixed dose combination Naproxen sodium/Caffeine 220/65 mg and one tablet of placebo.

Reporting group title

Naproxen sodium/Caffeine 2x220/65 mg

Reporting group description

Participants received two tablets of the fixed dose combination Naproxen sodium/Caffeine 220/65 mg.

Reporting group title

Naproxen sodium 220 mg

Reporting group description

Participants received one tablet of Naproxen sodium 220 mg and one tablet of placebo.

Reporting group title

Caffeine 100 mg

Reporting group description

Participants received one tablet Caffeine 100 mg one one tablet of placebo.

Reporting group title

Placebo

Reporting group description

Participants received two tablets of placebo.

Primary: Sum of pain intensity difference (SPID) over 8 hours post-dose

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End point title

Sum of pain intensity difference (SPID) over 8 hours post-dose

End point description

End point type

Primary

End point timeframe

Up to 8 hours post-dose

End point values	Naproxen sodium/ Caffeine 220/65 mg	Naproxen sodium/Caffeine 2x220/65 mg	Naproxen sodium 220 mg	Caffeine 100 mg	Placebo
Number of subjects analysed	147	148	147	50	49
Units: Points on scale
least squares mean (standard error)	31.293 ( 1.441 )	37.242 ( 1.436 )	31.082 ( 1.443 )	5.146 ( 2.470 )	8.622 ( 2.521 )

group 1 vs group 2

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium/Caffeine 2x220/65 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.004

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

-5.95

Confidence interval

level

95%

sides

2-sided

lower limit

-9.946

upper limit

-1.954

group 2 vs group 3

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.003

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

6.161

Confidence interval

level

95%

sides

2-sided

lower limit

2.161

upper limit

10.161

group 3 vs group 4

Comparison groups

Caffeine 100 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

25.936

Confidence interval

level

95%

sides

2-sided

lower limit

20.317

upper limit

31.556

group 4 vs group 5

Comparison groups

Caffeine 100 mg v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.325

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

-3.476

Confidence interval

level

95%

sides

2-sided

lower limit

-10.41

upper limit

3.457

group 1 vs group 3

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

294

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.918

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

0.211

Confidence interval

level

95%

sides

2-sided

lower limit

-3.798

upper limit

4.22

group 2 vs group 4

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Caffeine 100 mg

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

32.097

Confidence interval

level

95%

sides

2-sided

lower limit

26.484

upper limit

37.71

group 3 vs group 5

Comparison groups

Naproxen sodium 220 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

22.46

Confidence interval

level

95%

sides

2-sided

lower limit

16.753

upper limit

28.166

group 1 vs group 4

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Caffeine 100 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

26.147

Confidence interval

level

95%

sides

2-sided

lower limit

20.529

upper limit

31.765

group 2 vs group 5

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Placebo

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

28.62

Confidence interval

level

95%

sides

2-sided

lower limit

22.921

upper limit

34.32

group 1 vs group 5

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

22.671

Confidence interval

level

95%

sides

2-sided

lower limit

16.966

upper limit

28.375

Secondary: Sum of pain intensity differences from 0 to 2, 4, 6, 12 and 24 hours post-dose

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End point title

Sum of pain intensity differences from 0 to 2, 4, 6, 12 and 24 hours post-dose

End point description

End point type

Secondary

End point timeframe

from 0 to 2, 4, 6, 12 and 24 hours post-dose

End point values	Naproxen sodium/ Caffeine 220/65 mg	Naproxen sodium/Caffeine 2x220/65 mg	Naproxen sodium 220 mg	Caffeine 100 mg	Placebo
Number of subjects analysed	147	148	147	50	49
Units: Points on scale
least squares mean (standard error)
0-2 hours post-dose	7.347 ( 0.341 )	8.950 ( 0.340 )	7.973 ( 0.341 )	1.876 ( 0.585 )	1.567 ( 0.597 )
0-4 hours post-dose	15.899 ( 0.688 )	19.210 ( 0.686 )	16.627 ( 0.689 )	2.924 ( 1.179 )	3.982 ( 1.204 )
0-6 hours post-dose	23.851 ( 1.057 )	28.632 ( 1.053 )	24.381 ( 1.058 )	4.024 ( 1.812 )	6.308 ( 1.849 )
0-12 hours post-dose	44.207 ( 2.266 )	51.737 ( 2.258 )	42.907 ( 2.268 )	7.003 ( 3.883 )	13.455 ( 3.964 )
0-24 hours post-dose	77.596 ( 4.949 )	83.884 ( 4.930 )	72.796 ( 4.953 )	12.533 ( 8.481 )	28.400 ( 8.656 )

group 1 vs group 2

Statistical analysis description

0-2 hours post-dose

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium/Caffeine 2x220/65 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

-1.602

Confidence interval

level

95%

sides

2-sided

lower limit

-2.548

upper limit

-0.656

group 2 vs group 3

Statistical analysis description

0-2 hours post-dose

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

P-value

= 0.043

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

0.976

Confidence interval

level

95%

sides

2-sided

lower limit

0.029

upper limit

1.923

group 3 vs group 4

Statistical analysis description

0-2 hours post-dose

Comparison groups

Naproxen sodium 220 mg v Caffeine 100 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

6.097

Confidence interval

level

95%

sides

2-sided

lower limit

4.766

upper limit

7.427

group 4 vs group 5

Statistical analysis description

0-2 hours post-dose

Comparison groups

Caffeine 100 mg v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.711

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

0.31

Confidence interval

level

95%

sides

2-sided

lower limit

-1.332

upper limit

1.951

group 1 vs group 3

Statistical analysis description

0-2 hours post-dose

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

294

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.196

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

-0.626

Confidence interval

level

95%

sides

2-sided

lower limit

-1.575

upper limit

0.323

group 2 vs group 4

Statistical analysis description

0-2 hours post-dose

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Caffeine 100 mg

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

7.073

Confidence interval

level

95%

sides

2-sided

lower limit

5.744

upper limit

8.402

group 3 vs group 5

Statistical analysis description

0-2 hours post-dose

Comparison groups

Naproxen sodium 220 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

6.406

Confidence interval

level

95%

sides

2-sided

lower limit

5.055

upper limit

7.757

group 1 vs group 4

Statistical analysis description

0-2 hours post-dose

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Caffeine 100 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

5.471

Confidence interval

level

95%

sides

2-sided

lower limit

4.141

upper limit

6.801

group 2 vs group 5

Statistical analysis description

0-2 hours post-dose

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Placebo

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

7.383

Confidence interval

level

95%

sides

2-sided

lower limit

6.033

upper limit

8.732

group 1 vs group 5

Statistical analysis description

0-2 hours post-dose

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

5.78

Confidence interval

level

95%

sides

2-sided

lower limit

4.43

upper limit

7.131

Secondary: Total pain relief (TOTPAR) from 0 to 2, 4, 6, 8, 12 and 24 hours post-dose

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End point title

Total pain relief (TOTPAR) from 0 to 2, 4, 6, 8, 12 and 24 hours post-dose

End point description

End point type

Secondary

End point timeframe

up to 24 hours post-dose

End point values	Naproxen sodium/ Caffeine 220/65 mg	Naproxen sodium/Caffeine 2x220/65 mg	Naproxen sodium 220 mg	Caffeine 100 mg	Placebo
Number of subjects analysed	147	148	147	50	49
Units: Points on scale
least squares mean (standard error)
0-2 hours post-dose	3.284 ( 0.114 )	3.870 ( 0.114 )	3.417 ( 0.115 )	1.047 ( 0.196 )	1.216 ( 0.200 )
0-4 hours post-dose	7.781 ( 0.287 )	9.118 ( 0.286 )	8.102 ( 0.287 )	2.120 ( 0.492 )	3.168 ( 0.502 )
0-6 hours post-dose	12.098 ( 0.465 )	14.061 ( 0.464 )	12.420 ( 0.466 )	3.228 ( 0.798 )	4.870 ( 0.814 )
0-8 hours post-dose	16.227 ( 0.645 )	18.625 ( 0.642 )	16.225 ( 0.645 )	4.327 ( 1.105 )	6.552 ( 1.128 )
0-12 hours post-dose	23.512 ( 1.029 )	26.461 ( 1.026 )	22.767 ( 1.030 )	6.264 ( 1.764 )	9.700 ( 1.801 )
0-24 hours post-dose	41.596 ( 2.281 )	43.908 ( 2.272 )	39.127 ( 2.283 )	12.047 ( 3.909 )	18.975 ( 3.990 )

group 1 vs group 2

Statistical analysis description

0-2 hours post-dose

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium/Caffeine 2x220/65 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

-0.586

Confidence interval

level

95%

sides

2-sided

lower limit

-0.903

upper limit

-0.269

Variability estimate

Standard error of the mean

group 2 vs group 3

Statistical analysis description

0-2 hours post-dose

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.005

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

0.454

Confidence interval

level

95%

sides

2-sided

lower limit

0.136

upper limit

0.771

Variability estimate

Standard error of the mean

group 3 vs group 4

Statistical analysis description

0-2 hours post-dose

Comparison groups

Naproxen sodium 220 mg v Caffeine 100 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

2.369

Confidence interval

level

95%

sides

2-sided

lower limit

1.923

upper limit

2.815

Variability estimate

Standard error of the mean

group 4 vs group 5

Statistical analysis description

0-2 hours post-dose

Comparison groups

Caffeine 100 mg v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.548

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

-0.169

Confidence interval

level

95%

sides

2-sided

lower limit

-0.719

upper limit

0.382

Variability estimate

Standard error of the mean

group 1 vs group 3

Statistical analysis description

0-2 hours post-dose

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

294

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.415

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

-0.132

Confidence interval

level

95%

sides

2-sided

lower limit

-0.451

upper limit

0.186

Variability estimate

Standard error of the mean

group 2 vs group 4

Statistical analysis description

0-2 hours post-dose

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Caffeine 100 mg

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

2.823

Confidence interval

level

95%

sides

2-sided

lower limit

2.377

upper limit

3.268

Variability estimate

Standard error of the mean

group 3 vs group 5

Statistical analysis description

0-2 hours post-dose

Comparison groups

Naproxen sodium 220 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

2.201

Confidence interval

level

95%

sides

2-sided

lower limit

1.748

upper limit

2.654

Variability estimate

Standard error of the mean

group 1 vs group 4

Statistical analysis description

0-2 hours post-dose

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Caffeine 100 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

2.237

Confidence interval

level

95%

sides

2-sided

lower limit

1.791

upper limit

2.683

Variability estimate

Standard error of the mean

group 2 vs group 5

Statistical analysis description

0-2 hours post-dose

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Placebo

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

2.654

Confidence interval

level

95%

sides

2-sided

lower limit

2.202

upper limit

3.106

Variability estimate

Standard error of the mean

group 1 vs group 5

Statistical analysis description

0-2 hours post-dose

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Placebo

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

2.068

Confidence interval

level

95%

sides

2-sided

lower limit

1.615

upper limit

2.521

Variability estimate

Standard error of the mean

group 1 vs group 2

Statistical analysis description

0-4 hours post-dose

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium/Caffeine 2x220/65 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

-1.338

Confidence interval

level

95%

sides

2-sided

lower limit

-2.133

upper limit

-0.542

Variability estimate

Standard error of the mean

group 2 vs group 3

Statistical analysis description

0-4 hours post-dose

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.012

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

1.016

Confidence interval

level

95%

sides

2-sided

lower limit

0.22

upper limit

1.813

Variability estimate

Standard error of the mean

group 3 vs group 4

Statistical analysis description

0-4 hours post-dose

Comparison groups

Naproxen sodium 220 mg v Caffeine 100 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

5.982

Confidence interval

level

95%

sides

2-sided

lower limit

4.864

upper limit

7.101

Variability estimate

Standard error of the mean

group 4 vs group 5

Statistical analysis description

0-4 hours post-dose

Comparison groups

Caffeine 100 mg v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.136

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

-1.048

Confidence interval

level

95%

sides

2-sided

lower limit

-2.428

upper limit

0.332

Variability estimate

Standard error of the mean

group 1 vs group 3

Statistical analysis description

0-4 hours post-dose

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

294

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.43

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

-0.321

Confidence interval

level

95%

sides

2-sided

lower limit

-1.119

upper limit

0.477

Variability estimate

Standard error of the mean

group 2 vs group 4

Statistical analysis description

0-4 hours post-dose

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Caffeine 100 mg

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

6.999

Confidence interval

level

95%

sides

2-sided

lower limit

5.881

upper limit

8.116

Variability estimate

Standard error of the mean

group 3 vs group 5

Statistical analysis description

0-4 hours post-dose

Comparison groups

Naproxen sodium 220 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

4.934

Confidence interval

level

95%

sides

2-sided

lower limit

3.798

upper limit

6.07

Variability estimate

Standard error of the mean

group 1 vs group 4

Statistical analysis description

0-4 hours post-dose

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Caffeine 100 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

5.661

Confidence interval

level

95%

sides

2-sided

lower limit

4.543

upper limit

6.779

Variability estimate

Standard error of the mean

group 2 vs group 5

Statistical analysis description

0-4 hours post-dose

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Placebo

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

5.951

Confidence interval

level

95%

sides

2-sided

lower limit

4.816

upper limit

7.085

Variability estimate

Standard error of the mean

group 1 vs group 5

Statistical analysis description

0-4 hours post-dose

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

4.613

Confidence interval

level

95%

sides

2-sided

lower limit

3.478

upper limit

5.749

Variability estimate

Standard error of the mean

group 1 vs group 2

Statistical analysis description

0-6 hours post-dose

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium/Caffeine 2x220/65 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.003

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

-1.963

Confidence interval

level

95%

sides

2-sided

lower limit

-3.254

upper limit

-0.673

Variability estimate

Standard error of the mean

group 2 vs group 3

Statistical analysis description

0-6 hours post-dose

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.013

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

1.641

Confidence interval

level

95%

sides

2-sided

lower limit

0.35

upper limit

2.933

Variability estimate

Standard error of the mean

group 3 vs group 4

Statistical analysis description

0-6 hours post-dose

Comparison groups

Naproxen sodium 220 mg v Caffeine 100 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

9.191

Confidence interval

level

95%

sides

2-sided

lower limit

7.377

upper limit

11.006

Variability estimate

Standard error of the mean

group 4 vs group 5

Statistical analysis description

0-6 hours post-dose

Comparison groups

Caffeine 100 mg v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.15

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

-1.642

Confidence interval

level

95%

sides

2-sided

lower limit

-3.881

upper limit

0.597

Variability estimate

Standard error of the mean

group 1 vs group 3

Statistical analysis description

0-6 hours post-dose

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

294

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.625

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

-0.322

Confidence interval

level

95%

sides

2-sided

lower limit

-1.617

upper limit

0.972

Variability estimate

Standard error of the mean

group 2 vs group 4

Statistical analysis description

0-6 hours post-dose

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Caffeine 100 mg

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

10.833

Confidence interval

level

95%

sides

2-sided

lower limit

9.02

upper limit

12.645

Variability estimate

Standard error of the mean

group 3 vs group 5

Statistical analysis description

0-6 hours post-dose

Comparison groups

Naproxen sodium 220 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

7.55

Confidence interval

level

95%

sides

2-sided

lower limit

5.707

upper limit

9.392

Variability estimate

Standard error of the mean

group 1 vs group 4

Statistical analysis description

0-6 hours post-dose

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Caffeine 100 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

8.869

Confidence interval

level

95%

sides

2-sided

lower limit

7.055

upper limit

10.683

Variability estimate

Standard error of the mean

group 2 vs group 5

Statistical analysis description

0-6 hours post-dose

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Placebo

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

9.191

Confidence interval

level

95%

sides

2-sided

lower limit

7.351

upper limit

11.031

Variability estimate

Standard error of the mean

group 1 vs group 5

Statistical analysis description

0-6 hours post-dose

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

7.228

Confidence interval

level

95%

sides

2-sided

lower limit

5.386

upper limit

9.07

Variability estimate

Standard error of the mean

group 1 vs group 2

Statistical analysis description

0-8 hours post-dose

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium/Caffeine 2x220/65 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.009

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

-2.398

Confidence interval

level

95%

sides

2-sided

lower limit

-4.185

upper limit

-0.61

Variability estimate

Standard error of the mean

group 2 vs group 3

Statistical analysis description

0-8 hours post-dose

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.009

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

2.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.61

upper limit

4.189

Variability estimate

Standard error of the mean

group 3 vs group 4

Statistical analysis description

0-8 hours post-dose

Comparison groups

Naproxen sodium 220 mg v Caffeine 100 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

11.898

Confidence interval

level

95%

sides

2-sided

lower limit

9.384

upper limit

14.412

Variability estimate

Standard error of the mean

group 4 vs group 5

Statistical analysis description

0-8 hours post-dose

Comparison groups

Caffeine 100 mg v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.159

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

-2.225

Confidence interval

level

95%

sides

2-sided

lower limit

-5.327

upper limit

0.877

Variability estimate

Standard error of the mean

group 1 vs group 3

Statistical analysis description

0-8 hours post-dose

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

294

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.998

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

0.002

Confidence interval

level

95%

sides

2-sided

lower limit

-1.792

upper limit

1.795

Variability estimate

Standard error of the mean

group 2 vs group 4

Statistical analysis description

0-8 hours post-dose

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Caffeine 100 mg

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

14.298

Confidence interval

level

95%

sides

2-sided

lower limit

11.787

upper limit

16.809

Variability estimate

Standard error of the mean

group 3 vs group 5

Statistical analysis description

0-8 hours post-dose

Comparison groups

Naproxen sodium 220 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

9.673

Confidence interval

level

95%

sides

2-sided

lower limit

7.12

upper limit

12.226

Variability estimate

Standard error of the mean

group 1 vs group 4

Statistical analysis description

0-8 hours post-dose

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Caffeine 100 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

11.9

Confidence interval

level

95%

sides

2-sided

lower limit

9.387

upper limit

14.413

Variability estimate

Standard error of the mean

group 2 vs group 5

Statistical analysis description

0-8 hours post-dose

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Placebo

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

12.073

Confidence interval

level

95%

sides

2-sided

lower limit

9.523

upper limit

14.623

Variability estimate

Standard error of the mean

group 1 vs group 5

Statistical analysis description

0-8 hours post-dose

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

9.675

Confidence interval

level

95%

sides

2-sided

lower limit

7.123

upper limit

12.227

Variability estimate

Standard error of the mean

group 1 vs group 2

Statistical analysis description

0-12 hours post-dose

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium/Caffeine 2x220/65 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.043

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

-2.949

Confidence interval

level

95%

sides

2-sided

lower limit

-5.803

upper limit

-0.095

Variability estimate

Standard error of the mean

group 2 vs group 3

Statistical analysis description

0-12 hours post-dose

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.011

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

3.694

Confidence interval

level

95%

sides

2-sided

lower limit

0.837

upper limit

6.55

Variability estimate

Standard error of the mean

group 3 vs group 4

Statistical analysis description

0-12 hours post-dose

Comparison groups

Naproxen sodium 220 mg v Caffeine 100 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

16.504

Confidence interval

level

95%

sides

2-sided

lower limit

12.49

upper limit

20.517

Variability estimate

Standard error of the mean

group 4 vs group 5

Statistical analysis description

0-12 hours post-dose

Comparison groups

Caffeine 100 mg v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.173

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

-3.437

Confidence interval

level

95%

sides

2-sided

lower limit

-8.389

upper limit

1.515

Variability estimate

Standard error of the mean

group 1 vs group 3

Statistical analysis description

0-12 hours post-dose

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

294

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.61

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

0.744

Confidence interval

level

95%

sides

2-sided

lower limit

-2.119

upper limit

3.608

Variability estimate

Standard error of the mean

group 2 vs group 4

Statistical analysis description

0-12 hours post-dose

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Caffeine 100 mg

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

20.197

Confidence interval

level

95%

sides

2-sided

lower limit

16.189

upper limit

24.206

Variability estimate

Standard error of the mean

group 3 vs group 5

Statistical analysis description

0-12 hours post-dose

Comparison groups

Naproxen sodium 220 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

13.067

Confidence interval

level

95%

sides

2-sided

lower limit

8.992

upper limit

17.143

Variability estimate

Standard error of the mean

group 2 vs group 4

Statistical analysis description

0-12 hours post-dose

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Caffeine 100 mg

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

17.248

Confidence interval

level

95%

sides

2-sided

lower limit

13.236

upper limit

21.261

Variability estimate

Standard error of the mean

group 2 vs group 5

Statistical analysis description

0-12 hours post-dose

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Placebo

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

16.761

Confidence interval

level

95%

sides

2-sided

lower limit

12.69

upper limit

20.831

Variability estimate

Standard error of the mean

Copy of group 1 vs group 5

Statistical analysis description

0-12 hours post-dose

Comparison groups

Placebo v Naproxen sodium/ Caffeine 220/65 mg

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

13.812

Confidence interval

level

95%

sides

2-sided

lower limit

9.738

upper limit

17.886

Variability estimate

Standard error of the mean

group 1 vs group 2

Statistical analysis description

0-24 hours post-dose

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium/Caffeine 2x220/65 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.473

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

-2.312

Confidence interval

level

95%

sides

2-sided

lower limit

-8.635

upper limit

4.011

Variability estimate

Standard error of the mean

group 3 vs group 4

Statistical analysis description

0-24 hours post-dose

Comparison groups

Naproxen sodium 220 mg v Caffeine 100 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

27.08

Confidence interval

level

95%

sides

2-sided

lower limit

18.188

upper limit

35.973

Variability estimate

Standard error of the mean

group 4 vs group 5

Statistical analysis description

0-24 hours post-dose

Comparison groups

Caffeine 100 mg v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.215

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

-6.928

Confidence interval

level

95%

sides

2-sided

lower limit

-17.9

upper limit

4.044

Variability estimate

Standard error of the mean

group 1 vs group 3

Statistical analysis description

0-24 hours post-dose

Comparison groups

Naproxen sodium 220 mg v Naproxen sodium/ Caffeine 220/65 mg

Number of subjects included in analysis

294

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.445

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

2.468

Confidence interval

level

95%

sides

2-sided

lower limit

-3.876

upper limit

8.813

Variability estimate

Standard error of the mean

group 3 vs group 5

Statistical analysis description

0-24 hours post-dose

Comparison groups

Naproxen sodium 220 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

20.152

Confidence interval

level

95%

sides

2-sided

lower limit

11.122

upper limit

29.183

Variability estimate

Standard error of the mean

group 2 vs group 5

Statistical analysis description

0-24 hours post-dose

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Placebo

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

24.933

Confidence interval

level

95%

sides

2-sided

lower limit

15.914

upper limit

33.952

Variability estimate

Standard error of the mean

group 1 vs group 5

Statistical analysis description

0-24 hours post-dose

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Geometric LS means

Point estimate

22.621

Confidence interval

level

95%

sides

2-sided

lower limit

13.594

upper limit

31.648

Variability estimate

Standard error of the mean

Secondary: Time to first use of rescue medication

Top of page

End point title

Time to first use of rescue medication

End point description

End point type

Secondary

End point timeframe

Up to 24 hours post-dose

End point values	Naproxen sodium/ Caffeine 220/65 mg	Naproxen sodium/Caffeine 2x220/65 mg	Naproxen sodium 220 mg	Caffeine 100 mg	Placebo
Number of subjects analysed	147 ^[1]	148 ^[2]	147 ^[3]	50	49
Units: Hours
median (confidence interval 95%)	99999 (17.33 to 99999)	99999 (14.08 to 99999)	19.72 (11.08 to 99999)	2.07 (1.72 to 2.75)	2.65 (1.67 to 7.28)

Notes
[1] - “"99999" in data entry fields stands for "Not determined” as the value cannot be measured.
[2] - “"99999" in data entry fields stands for "Not determined” as the value cannot be measured.
[3] - “"99999" in data entry fields stands for "Not determined” as the value cannot be measured.

group 1 vs group 2

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium/Caffeine 2x220/65 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.963

Method

ANCOVA

Confidence interval

group 2 vs group 3

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.118

Method

ANCOVA

Confidence interval

group 3 vs group 4

Comparison groups

Naproxen sodium 220 mg v Caffeine 100 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Confidence interval

group 4 vs group 5

Comparison groups

Caffeine 100 mg v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.244

Method

ANCOVA

Confidence interval

group 1 vs group 3

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

294

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.139

Method

ANCOVA

Confidence interval

group 2 vs group 4

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

294

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Confidence interval

group 3 vs group 5

Comparison groups

Naproxen sodium 220 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Confidence interval

group 1 vs group 4

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Caffeine 100 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Confidence interval

group 2 vs group 5

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Placebo

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Confidence interval

group 1 vs group 5

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Confidence interval

Secondary: The cumulative proportion of participants taking rescue medication over the 24 hour period

Top of page

End point title

The cumulative proportion of participants taking rescue medication over the 24 hour period

End point description

End point type

Secondary

End point timeframe

Up to 24 hours post-dose

End point values	Naproxen sodium/ Caffeine 220/65 mg	Naproxen sodium/Caffeine 2x220/65 mg	Naproxen sodium 220 mg	Caffeine 100 mg	Placebo
Number of subjects analysed	147	148	147	50	49
Units: proportion
number (not applicable)
0.5 hour	0	0	0	0	0
less or equal 1 hour	0.007	0	0.007	0.04	0.02
less or equal 1.5 hour	0.027	0.007	0.007	0.3	0.2
less or equal 2 hours	0.1	0.034	0.048	0.4	0.5
less or equal 3 hours	0.1	0.1	0.1	0.7	0.5
less or equal 4hours	0.2	0.1	0.1	0.7	0.6
less or equal 5 hours	0.2	0.1	0.1	0.7	0.6
less or equal 6 hours	0.2	0.1	0.2	0.8	0.6
less or equal 7 hours	0.2	0.1	0.2	0.8	0.6
less or equal 8 hours	0.2	0.1	0.3	0.8	0.6
less or equal 9 hours	0.3	0.2	0.3	0.8	0.7
less or equal 10 hours	0.3	0.2	0.4	0.8	0.7
less or equal 11 hours	0.4	0.3	0.4	0.8	0.7
less or equal 12 hours	0.4	0.3	0.4	0.8	0.7
less or equal 14 hours	0.4	0.4	0.4	0.8	0.7
less or equal 16 hours	0.4	0.4	0.5	0.8	0.7
less or equal 18 hours	0.4	0.4	0.5	0.8	0.7
less or equal 20 hours	0.4	0.4	0.5	0.8	0.7
less or equal 22 hours	0.4	0.4	0.5	0.8	0.7
less or equal 24 hours	0.4	0.4	0.5	0.8	0.7

No statistical analyses for this end point

Secondary: Time to first perceptible relief measured by a stopwatch

Top of page

End point title

Time to first perceptible relief measured by a stopwatch

End point description

End point type

Secondary

End point timeframe

Up to 24 hours post-dose

End point values	Naproxen sodium/ Caffeine 220/65 mg	Naproxen sodium/Caffeine 2x220/65 mg	Naproxen sodium 220 mg	Caffeine 100 mg	Placebo
Number of subjects analysed	147	148	147	50	49 ^[4]
Units: Hours
median (confidence interval 95%)	0.39 (0.33 to 0.42)	0.35 (0.32 to 0.41)	0.35 (0.32 to 0.39)	0.60 (0.42 to 4.13)	1.93 (0.51 to 99999)

Notes
[4] - “99999" in data entry fields stands for "Not determined” as the value cannot be measured.

group 1 vs group 2

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium/Caffeine 2x220/65 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.647

Method

ANCOVA

Confidence interval

group 2 vs group 3

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.714

Method

ANCOVA

Confidence interval

group 4 vs group 5

Comparison groups

Caffeine 100 mg v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.065

Method

ANCOVA

Confidence interval

group 1 vs group 3

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

294

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.742

Method

ANCOVA

Confidence interval

group 2 vs group 4

Comparison groups

Caffeine 100 mg v Naproxen sodium/Caffeine 2x220/65 mg

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Confidence interval

group 3 vs group 5

Comparison groups

Naproxen sodium 220 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Confidence interval

group 1 vs group 4

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Caffeine 100 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Confidence interval

group 2 vs group 5

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Placebo

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Confidence interval

group 1 vs group 5

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Confidence interval

Secondary: Time to meaningful relief measured by a stopwatch

Top of page

End point title

Time to meaningful relief measured by a stopwatch

End point description

End point type

Secondary

End point timeframe

Up to 24 hours post-dose

End point values	Naproxen sodium/ Caffeine 220/65 mg	Naproxen sodium/Caffeine 2x220/65 mg	Naproxen sodium 220 mg	Caffeine 100 mg	Placebo
Number of subjects analysed	147	148	147	50 ^[5]	49
Units: Hours
median (confidence interval 95%)	0.83 (0.71 to 0.92)	0.76 (0.67 to 0.85)	0.79 (0.67 to 0.93)	99999 (2.24 to 99999)	5.63 (2.11 to 5.78)

Notes
[5] - “99999" in data entry fields stands for "Not determined” as the value cannot be measured.

group 1 vs group 2

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium/Caffeine 2x220/65 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.162

Method

ANCOVA

Confidence interval

group 2 vs group 3

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.319

Method

ANCOVA

Confidence interval

group 3 vs group 4

Comparison groups

Naproxen sodium 220 mg v Caffeine 100 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Confidence interval

group 4 vs group 5

Comparison groups

Caffeine 100 mg v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.343

Method

ANCOVA

Confidence interval

group 2 vs group 4

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Caffeine 100 mg

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Confidence interval

group 3 vs group 5

Comparison groups

Naproxen sodium 220 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Confidence interval

group 1 vs group 4

Comparison groups

Caffeine 100 mg v Naproxen sodium/ Caffeine 220/65 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Confidence interval

group 2 vs group 5

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Placebo

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Confidence interval

group 1 vs group 5

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Confidence interval

Secondary: Time to first perceptible relief confirmed by meaningful relief defined as the time to perceptible pain relief

Top of page

End point title

Time to first perceptible relief confirmed by meaningful relief defined as the time to perceptible pain relief

End point description

End point type

Secondary

End point timeframe

Up to 24 hours post-dose

End point values	Naproxen sodium/ Caffeine 220/65 mg	Naproxen sodium/Caffeine 2x220/65 mg	Naproxen sodium 220 mg	Caffeine 100 mg	Placebo
Number of subjects analysed	147	148	147	50 ^[6]	49
Units: Hours
median (confidence interval 95%)	0.83 (0.71 to 0.92)	0.76 (0.67 to 0.85)	0.79 (0.67 to 0.93)	99999 (2.24 to 99999)	5.63 (2.11 to 5.78)

Notes
[6] - “99999" in data entry fields stands for "Not determined” as the value cannot be measured.

group 1 vs group 2

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium/Caffeine 2x220/65 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.162

Method

ANCOVA

Confidence interval

group 2 vs group 3

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.319

Method

ANCOVA

Confidence interval

group 3 vs group 4

Comparison groups

Naproxen sodium 220 mg v Caffeine 100 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Confidence interval

group 4 vs group 45

Comparison groups

Caffeine 100 mg v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.343

Method

ANCOVA

Confidence interval

Copy of group 1 vs group 3

Comparison groups

Naproxen sodium 220 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.772

Method

ANCOVA

Confidence interval

group 2 vs group 4

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Caffeine 100 mg

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Confidence interval

group 3 vs group 5

Comparison groups

Naproxen sodium 220 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Confidence interval

group 1 vs group 4

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Caffeine 100 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Confidence interval

group 2 vs group 5

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Placebo

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Confidence interval

group 1 vs group 5

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Confidence interval

Secondary: Pain intensity difference (PID)

Top of page

End point title

Pain intensity difference (PID)

End point description

End point type

Secondary

End point timeframe

up to 24 hours post-dose

End point values	Naproxen sodium/ Caffeine 220/65 mg	Naproxen sodium/Caffeine 2x220/65 mg	Naproxen sodium 220 mg	Caffeine 100 mg	Placebo
Number of subjects analysed	147	148	147	50	49
Units: Points on scale
arithmetic mean (standard deviation)
Baseline	7.6 ( 1.22 )	7.6 ( 1.20 )	7.8 ( 1.21 )	7.7 ( 1.39 )	7.7 ( 0.99 )
0.5 hours post-dose	1.8 ( 1.89 )	2.3 ( 1.91 )	2.4 ( 1.98 )	1.0 ( 1.38 )	0.6 ( 1.18 )
1 hour post-dose	3.4 ( 2.40 )	4.3 ( 2.18 )	3.7 ( 2.23 )	0.8 ( 1.67 )	0.7 ( 1.89 )
1.5 hours post-dose	4.0 ( 2.40 )	4.9 ( 2.13 )	4.3 ( 2.27 )	0.6 ( 1.68 )	0.6 ( 2.17 )
2 hours post-dose	4.4 ( 2.56 )	5.2 ( 2.12 )	4.7 ( 2.30 )	0.7 ( 1.99 )	0.9 ( 2.48 )
3 hours post-dose	4.3 ( 2.55 )	5.2 ( 2.28 )	4.4 ( 2.45 )	0.4 ( 1.94 )	1.1 ( 2.64 )
4 hours post-dose	4.2 ( 2.54 )	5.1 ( 2.47 )	4.3 ( 2.65 )	0.6 ( 2.19 )	1.4 ( 2.99 )
5 hours post-dose	4.0 ( 2.55 )	4.8 ( 2.46 )	4.1 ( 2.73 )	0.5 ( 2.11 )	1.2 ( 2.84 )
6 hours post-dose	3.9 ( 2.60 )	4.6 ( 2.48 )	3.8 ( 2.74 )	0.6 ( 2.34 )	1.2 ( 3.01 )
7 hours post-dose	3.8 ( 2.61 )	4.4 ( 2.56 )	3.5 ( 2.80 )	0.6 ( 2.30 )	1.2 ( 2.94 )
8 hours post-dose	3.6 ( 2.63 )	4.1 ( 2.60 )	3.3 ( 2.88 )	0.6 ( 2.30 )	1.2 ( 3.00 )
9 hours post dose	3.5 ( 2.72 )	3.9 ( 2.68 )	3.3 ( 2.96 )	0.6 ( 2.47 )	1.3 ( 3.15 )
10 hours post-dose	3.3 ( 2.78 )	3.8 ( 2.81 )	3.1 ( 3.03 )	0.4 ( 2.25 )	1.3 ( 3.24 )
11 hours post-dose	3.1 ( 2.84 )	3.6 ( 2.86 )	2.9 ( 3.02 )	0.4 ( 2.34 )	1.2 ( 3.23 )
12 hours post-dose	2.9 ( 2.90 )	3.2 ( 2.90 )	2.8 ( 3.07 )	0.4 ( 2.29 )	1.3 ( 3.32 )
14 hours post-dose	2.9 ( 2.97 )	2.9 ( 3.01 )	2.6 ( 3.04 )	0.4 ( 2.20 )	1.3 ( 3.32 )
16 hours post-dose	2.6 ( 2.99 )	2.7 ( 2.85 )	2.4 ( 3.04 )	0.4 ( 2.27 )	1.2 ( 3.21 )
18 hours post-dose	2.7 ( 3.05 )	2.6 ( 2.83 )	2.4 ( 3.02 )	0.4 ( 2.27 )	1.2 ( 3.22 )
20 hours post-dose	2.7 ( 3.07 )	2.6 ( 2.81 )	2.5 ( 3.06 )	0.4 ( 2.33 )	1.2 ( 3.28 )
22 hours post-dose	2.8 ( 3.19 )	2.7 ( 2.85 )	2.6 ( 3.14 )	0.5 ( 2.55 )	1.4 ( 3.51 )
24 hours post-dose	2.9 ( 3.19 )	2.8 ( 2.92 )	2.6 ( 3.20 )	0.6 ( 2.62 )	1.5 ( 3.63 )

No statistical analyses for this end point

Secondary: Pain relief score

Top of page

End point title

Pain relief score

End point description

Pain Relief Score (PRS): 0 = No Relief; 1 = A Little Relief; 2 = Some Relief; 3 = A Lot of Relief; 4 = Complete Relief.

End point type

Secondary

End point timeframe

Up to 24 hours post-dose

End point values	Naproxen sodium/ Caffeine 220/65 mg	Naproxen sodium/Caffeine 2x220/65 mg	Naproxen sodium 220 mg	Caffeine 100 mg	Placebo
Number of subjects analysed	147	148	147	50	49
Units: Points on scale
arithmetic mean (standard deviation)
0.5 hours post-dose	1.3 ( 0.93 )	1.5 ( 1.01 )	1.5 ( 0.97 )	0.7 ( 0.72 )	0 ( 0.65 )
1 hour post-dose	2.0 ( 1.04 )	2.4 ( 0.9 )	2.1 ( 0.99 )	0.7 ( 0.9 )	0.8 ( 0.96 )
1.5 hours post-dose	2.3 ( 1.07 )	2.6 ( 0.87 )	2.3 ( 0.94 )	0.6 ( 0.88 )	0.8 ( 1.04 )
2 hours post-dose	2.3 ( 1.13 )	2.7 ( 0.93 )	2.5 ( 0.99 )	0.7 ( 0.95 )	0.9 ( 1.17 )
3 hours post-dose	2.3 ( 1.19 )	2.7 ( 1.06 )	2.4 ( 1.11 )	0.5 ( 0.93 )	1.0 ( 1.25 )
4 hours post-dose	2.2 ( 1.2 )	2.6 ( 1.18 )	2.3 ( 1.2 )	0.6 ( 0.99 )	1.0 ( 1.35 )
5 hours post-dose	2.1 ( 1.24 )	2.5 ( 1.13 )	2.3 ( 1.28 )	0.5 ( 1.03 )	0.8 ( 1.17 )
6 hours post-dose	2.2 ( 1.26 )	2.5 ( 1.12 )	2.1 ( 1.28 )	0.6 ( 1.07 )	0.9 ( 1.3 )
7 hours post-dose	2.1 ( 1.27 )	2.3 ( 1.16 )	2.0 ( 1.28 )	0.6 ( 1.07 )	0.9 ( 1.28 )
8 hours post-dose	2.1 ( 1.28 )	2.2 ( 1.23 )	1.8 ( 1.36 )	0.5 ( 1.03 )	0.8 ( 1.21 )
9 hours post-dose	2.0 ( 1.33 )	2.1 ( 1.28 )	1.8 ( 1.39 )	0.5 ( 1.02 )	0.8 ( 1.28 )
10 hours post-dose	1.9 ( 1.35 )	2.1 ( 1.35 )	1.7 ( 1.42 )	0.5 ( 1.05 )	0.8 ( 1.31 )
11 hours post-dose	1.8 ( 1.38 )	2.0 ( 1.41 )	1.6 ( 1.45 )	0.5 ( 1.07 )	0.8 ( 1.34 )
12 hours post-dose	1.7 ( 1.4 )	1.8 ( 1.46 )	1.5 ( 1.47 )	0.5 ( 1.07 )	0.8 ( 1.34 )
14 hours post-dose	1.6 ( 1.44 )	1.6 ( 1.51 )	1.4 ( 1.46 )	0.5 ( 1.03 )	0.8 ( 1.29 )
16 hours post-dose	1.5 ( 1.45 )	1.5 ( 1.46 )	1.3 ( 1.44 )	0.5 ( 1.03 )	0.7 ( 1.25 )
18 hours post-dose	1.5 ( 1.45 )	1.4 ( 1.44 )	1.3 ( 1.43 )	0.5 ( 1.03 )	0.7 ( 1.25 )
20 hours post-dose	1.5 ( 1.44 )	1.4 ( 1.44 )	1.3 ( 1.46 )	0.5 ( 1.03 )	0.8 ( 1.31 )
22 hours post-dose	1.5 ( 1.51 )	1.5 ( 1.50 )	1.4 ( 1.51 )	0.5 ( 1.18 )	0.9 ( 1.46 )
24 hours post-dose	1.6 ( 1.53 )	1.6 ( 1.51 )	1.4 ( 1.56 )	0.5 ( 1.22 )	0.9 ( 1.51 )

No statistical analyses for this end point

Secondary: Peak pain intensity difference (PID)

Top of page

End point title

Peak pain intensity difference (PID)

End point description

End point type

Secondary

End point timeframe

Up to 24 hours post-dose

End point values	Naproxen sodium/ Caffeine 220/65 mg	Naproxen sodium/Caffeine 2x220/65 mg	Naproxen sodium 220 mg	Caffeine 100 mg	Placebo
Number of subjects analysed	147	148	147	50	49
Units: Points on scale
least squares mean (standard error)	6.12 ( 0.11 )	6.26 ( 0.11 )	6.22 ( 0.11 )	6.30 ( 0.18 )	6.33 ( 0.19 )

group 1 vs group 2

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium/Caffeine 2x220/65 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.334

Method

ANCOVA

Parameter type

geometric LS mean square

Point estimate

-0.14

Confidence interval

level

95%

sides

2-sided

lower limit

-0.44

upper limit

0.15

Variability estimate

Standard error of the mean

group 2 vs group 3

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.783

Method

ANCOVA

Parameter type

geometric LS mean square

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.25

upper limit

0.33

Variability estimate

Standard error of the mean

group 3 vs group 4

Comparison groups

Naproxen sodium 220 mg v Caffeine 100 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.687

Method

ANCOVA

Parameter type

geometric LS mean square

Point estimate

-0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

0.33

Variability estimate

Standard error of the mean

group 4 vs group 5

Comparison groups

Caffeine 100 mg v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.927

Method

ANCOVA

Parameter type

geometric LS mean square

Point estimate

-0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.53

upper limit

0.49

Variability estimate

Standard error of the mean

group 1 vs group 3

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Naproxen sodium 220 mg

Number of subjects included in analysis

294

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.492

Method

ANCOVA

Parameter type

geometric LS mean square

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

0.19

Variability estimate

Standard error of the mean

group 2 vs group 4

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Caffeine 100 mg

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.836

Method

ANCOVA

Parameter type

geometric LS mean square

Point estimate

-0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.46

upper limit

0.37

Variability estimate

Standard error of the mean

group 3 vs group 5

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.611

Method

ANCOVA

Parameter type

geometric LS mean square

Point estimate

-0.11

Confidence interval

level

95%

sides

2-sided

lower limit

-0.53

upper limit

0.31

Variability estimate

Standard error of the mean

group 1 vs group 4

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Caffeine 100 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.371

Method

ANCOVA

Parameter type

geometric LS mean square

Point estimate

-0.19

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

0.22

Variability estimate

Standard error of the mean

group 2 vs group 5

Comparison groups

Naproxen sodium/Caffeine 2x220/65 mg v Placebo

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.752

Method

ANCOVA

Parameter type

geometric LS mean square

Point estimate

-0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.49

upper limit

0.35

Variability estimate

Standard error of the mean

group 1 vs group 5

Comparison groups

Naproxen sodium/ Caffeine 220/65 mg v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.321

Method

ANCOVA

Parameter type

geometric LS mean square

Point estimate

-0.21

Confidence interval

level

95%

sides

2-sided

lower limit

-0.63

upper limit

0.21

Variability estimate

Standard error of the mean

Secondary: Number of participants with certain peak pain relief score

Top of page

End point title

Number of participants with certain peak pain relief score

End point description

Number of participants with pain relief score 4, 3, 2, 1

End point type

Secondary

End point timeframe

Up to 24 hours post-dose

End point values	Naproxen sodium/ Caffeine 220/65 mg	Naproxen sodium/Caffeine 2x220/65 mg	Naproxen sodium 220 mg	Caffeine 100 mg	Placebo
Number of subjects analysed	147	148	147	50	49
Units: participants
Pain relief score 4	31	47	36	15	15
Pain relief score 3	101	85	102	31	29
Pain relief score 2	14	15	9	4	5
Pain relief score 1	1	1	0	0	0

No statistical analyses for this end point

Secondary: Cumulative percent of participants with ‘at least a 2-point PID’ over time

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End point title

Cumulative percent of participants with ‘at least a 2-point PID’ over time

End point description

End point type

Secondary

End point timeframe

Up to 24 hours post-dose

End point values	Naproxen sodium/ Caffeine 220/65 mg	Naproxen sodium/Caffeine 2x220/65 mg	Naproxen sodium 220 mg	Caffeine 100 mg	Placebo
Number of subjects analysed	147	148	147	50	49
Units: percentage
number (not applicable)
0.5 hour post-dose	50.3	62.8	60.5	32.0	18.4
less or equal 1 hour	78.2	86.5	86.4	40.0	26.5
less or equal 1.5 hour	87.1	94.6	92.5	46.0	40.8
less or equal 2 hours	92.5	98.0	94.6	64.0	71.4
less or equal 3 hours	98.0	99.3	98.0	86.0	87.8
less or equal 4 hours	98.6	99.3	99.3	94.0	95.9
less or equal 5 hours	98.6	99.3	99.3	98.0	98.0
less or equal 6 hours	99.3	99.3	99.3	100	98.0
less or equal 7 hours	99.3	99.3	99.3	100	98.0
less or equal 8 hours	99.3	99.3	100	100	98.0
less or equal 9 hours	99.3	99.3	100	100	98.0
less or equal 10 hours	99.3	99.3	100	100	98.0
less or equal 11 hours	99.3	99.3	100	100	98.0
less or equal 12 hours	100	99.3	100	100	98.0
less or equal 14 hours	100	99.3	100	100	98.0
less or equal 16 hours	100	99.3	100	100	98.0
less or equal 18 hours	100	99.3	100	100	98.0
less or equal 20 hours	100	99.3	100	100	98.0
less or equal 22 hours	100	99.3	100	100	98.0
less or equal 24 hours	100	99.3	100	100	98.0

No statistical analyses for this end point

Secondary: Global assessment of pain relief of the investigational product

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End point title

Global assessment of pain relief of the investigational product

End point description

Number of participants with overall rating poor, fair, good, very good, excellent 24 hour post-dose

End point type

Secondary

End point timeframe

24 hours post-dose

End point values	Naproxen sodium/ Caffeine 220/65 mg	Naproxen sodium/Caffeine 2x220/65 mg	Naproxen sodium 220 mg	Caffeine 100 mg	Placebo
Number of subjects analysed	147	148	147	50	49
Units: participants
poor	16	5	11	26	27
fair	10	12	12	10	5
good	35	23	38	8	3
very good	56	69	58	5	9
excellent	30	37	28	1	3

No statistical analyses for this end point

Secondary: Number of participants with adverse events

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End point title

Number of participants with adverse events

End point description

End point type

Secondary

End point timeframe

Up to 5 days post-dose

End point values	Naproxen sodium/ Caffeine 220/65 mg	Naproxen sodium/Caffeine 2x220/65 mg	Naproxen sodium 220 mg	Caffeine 100 mg	Placebo
Number of subjects analysed	147	148	147	50	49
Units: participants	28	18	27	7	7

No statistical analyses for this end point

Secondary: Number of participants with significant changes in vital signs since baseline

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End point title

Number of participants with significant changes in vital signs since baseline

End point description

End point type

Secondary

End point timeframe

Up to 5 days post-dose

End point values	Naproxen sodium/ Caffeine 220/65 mg	Naproxen sodium/Caffeine 2x220/65 mg	Naproxen sodium 220 mg	Caffeine 100 mg	Placebo
Number of subjects analysed	147	148	147	50	49
Units: participants
Bradycardia	1	1	0	0	0
Tachycardia	1	0	3	0	0
Hypertension	2	0	0	0	0
Hypotension	1	3	4	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

AEs were considered treatment-emergent if they had started or worsened after the first dose of the investigational medicinal product (IMP) until 2-5 after end of treatment

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

Fixed Dose Combination

Reporting group description

Fixed Dose Combination of Naproxen Sodium 220 mg and Caffeine 65 mg

Reporting group title

Fixed Dose Combination

Reporting group description

Fixed Dose Combination of twice Naproxen Sodium 220 mg and Caffeine 65 mg

Reporting group title

Placebo

Reporting group description

Placebo

Reporting group title

Caffeine

Reporting group description

Caffeine 100 mg

Reporting group title

Naproxen Sodium

Reporting group description

Naproxen sodium 220 mg

Serious adverse events	Fixed Dose Combination	Fixed Dose Combination	Placebo	Caffeine	Naproxen Sodium
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 147 (0.00%)	0 / 148 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 147 (0.00%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Fixed Dose Combination	Fixed Dose Combination	Placebo	Caffeine	Naproxen Sodium
Total subjects affected by non serious adverse events
subjects affected / exposed	19 / 147 (12.93%)	11 / 148 (7.43%)	4 / 49 (8.16%)	3 / 50 (6.00%)	23 / 147 (15.65%)
Injury, poisoning and procedural complications
Wound haemorrhage
subjects affected / exposed	0 / 147 (0.00%)	1 / 148 (0.68%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 147 (0.00%)
occurrences all number	0	1	0	0	0
Vascular disorders
Hypertension
subjects affected / exposed	2 / 147 (1.36%)	0 / 148 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 147 (0.00%)
occurrences all number	2	0	0	0	0
Hypotension
subjects affected / exposed	1 / 147 (0.68%)	1 / 148 (0.68%)	0 / 49 (0.00%)	0 / 50 (0.00%)	3 / 147 (2.04%)
occurrences all number	1	1	0	0	3
Thrombosis
subjects affected / exposed	0 / 147 (0.00%)	0 / 148 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	2 / 147 (1.36%)
occurrences all number	0	0	0	0	2
Cardiac disorders
Bradycardia
subjects affected / exposed	1 / 147 (0.68%)	0 / 148 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 147 (0.00%)
occurrences all number	1	0	0	0	0
Tachycardia
subjects affected / exposed	1 / 147 (0.68%)	0 / 148 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	3 / 147 (2.04%)
occurrences all number	1	0	0	0	3
Nervous system disorders
Dizziness
subjects affected / exposed	3 / 147 (2.04%)	2 / 148 (1.35%)	1 / 49 (2.04%)	0 / 50 (0.00%)	7 / 147 (4.76%)
occurrences all number	4	2	1	0	7
Headache
subjects affected / exposed	4 / 147 (2.72%)	0 / 148 (0.00%)	3 / 49 (6.12%)	1 / 50 (2.00%)	1 / 147 (0.68%)
occurrences all number	4	0	3	2	1
Syncope
subjects affected / exposed	0 / 147 (0.00%)	2 / 148 (1.35%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 147 (0.00%)
occurrences all number	0	2	0	0	0
General disorders and administration site conditions
Chills
subjects affected / exposed	0 / 147 (0.00%)	0 / 148 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 147 (0.68%)
occurrences all number	0	0	0	0	1
Pain
subjects affected / exposed	1 / 147 (0.68%)	0 / 148 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 147 (0.00%)
occurrences all number	1	0	0	0	0
Pyrexia
subjects affected / exposed	1 / 147 (0.68%)	0 / 148 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 147 (0.00%)
occurrences all number	1	0	0	0	0
Ear and labyrinth disorders
Deafness
subjects affected / exposed	0 / 147 (0.00%)	1 / 148 (0.68%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 147 (0.00%)
occurrences all number	0	1	0	0	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 147 (0.00%)	1 / 148 (0.68%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 147 (0.00%)
occurrences all number	0	1	0	0	0
Abdominal pain upper
subjects affected / exposed	1 / 147 (0.68%)	0 / 148 (0.00%)	0 / 49 (0.00%)	1 / 50 (2.00%)	0 / 147 (0.00%)
occurrences all number	1	0	0	1	0
Constipation
subjects affected / exposed	0 / 147 (0.00%)	0 / 148 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 147 (0.68%)
occurrences all number	0	0	0	0	1
Dyspepsia
subjects affected / exposed	1 / 147 (0.68%)	1 / 148 (0.68%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 147 (0.00%)
occurrences all number	1	1	0	0	0
Nausea
subjects affected / exposed	1 / 147 (0.68%)	6 / 148 (4.05%)	0 / 49 (0.00%)	0 / 50 (0.00%)	5 / 147 (3.40%)
occurrences all number	1	7	0	0	5
Toothache
subjects affected / exposed	1 / 147 (0.68%)	0 / 148 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 147 (0.00%)
occurrences all number	1	0	0	0	0
Vomiting
subjects affected / exposed	0 / 147 (0.00%)	0 / 148 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	9 / 147 (6.12%)
occurrences all number	0	0	0	0	12
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 147 (0.00%)	0 / 148 (0.00%)	0 / 49 (0.00%)	1 / 50 (2.00%)	0 / 147 (0.00%)
occurrences all number	0	0	0	1	0
Oropharyngeal pain
subjects affected / exposed	0 / 147 (0.00%)	0 / 148 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	2 / 147 (1.36%)
occurrences all number	0	0	0	0	2
Skin and subcutaneous tissue disorders
Hyperhidrosis
subjects affected / exposed	0 / 147 (0.00%)	1 / 148 (0.68%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 147 (0.00%)
occurrences all number	0	1	0	0	0
Rash
subjects affected / exposed	1 / 147 (0.68%)	0 / 148 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 147 (0.00%)
occurrences all number	1	0	0	0	0
Musculoskeletal and connective tissue disorders
Myalgia
subjects affected / exposed	0 / 147 (0.00%)	0 / 148 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 147 (0.68%)
occurrences all number	0	0	0	0	1
Infections and infestations
Alveolar osteitis
subjects affected / exposed	4 / 147 (2.72%)	0 / 148 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 147 (0.68%)
occurrences all number	4	0	0	0	1
Candida infection
subjects affected / exposed	0 / 147 (0.00%)	0 / 148 (0.00%)	1 / 49 (2.04%)	0 / 50 (0.00%)	0 / 147 (0.00%)
occurrences all number	0	0	1	0	0
Post procedural infection
subjects affected / exposed	0 / 147 (0.00%)	0 / 148 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 147 (0.68%)
occurrences all number	0	0	0	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

28 Apr 2022

The randomization schedule was changed from 2:2:2:1:1 to 3:3:3:1:1

07 Nov 2022

• Specified that at the timepoints of 16, 18, and 20 hours for Pain Intensity Difference (PID), Pain Relief scores, Pain Intensity NRS, and Categorical Pain Relief, the assessments would be performed only if the participant was awake; • Added a secondary endpoint of ‘time and cumulative proportion of achieving complete pain relief’. This endpoint was to be analyzed similarly as for the time to first use of rescue medication. Cumulative percent of participants with ‘at least a 2 point PID’ and cumulative percent of participants achieving complete pain relief were to be plotted over time and were to be analyzed using Chi-square tests; • Changed the exclusion criterion of Nicotine containing products from ‘midnight prior to surgery until discharge’ to ‘from 24 hours prior to surgery until discharge’; • Added a timepoint for vital sign measurement at 12 hours post-dose. Further clarifications and adjustments

13 Mar 2023

• Added a window period for vital signs measurements; • Added a window period for participants who did not meet the randomization criteria within 4.5 hours from last suture or 14:30 hours.

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

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Clinical trials

Clinical Trial Results: A Randomized, Double-Blind, Single-Dose, Parallel, Placebo-Controlled Pivotal Trial to Confirm the Efficacy of a Fixed Dose Combination (FDC) Tablet of Naproxen Sodium and Caffeine to Effectively Alleviate Postsurgical Dental Pain

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Sum of pain intensity difference (SPID) over 8 hours post-dose

Primary: Sum of pain intensity difference (SPID) over 8 hours post-dose

Secondary: Sum of pain intensity differences from 0 to 2, 4, 6, 12 and 24 hours post-dose

Secondary: Sum of pain intensity differences from 0 to 2, 4, 6, 12 and 24 hours post-dose

Secondary: Total pain relief (TOTPAR) from 0 to 2, 4, 6, 8, 12 and 24 hours post-dose

Secondary: Total pain relief (TOTPAR) from 0 to 2, 4, 6, 8, 12 and 24 hours post-dose

Secondary: Time to first use of rescue medication

Secondary: Time to first use of rescue medication

Secondary: The cumulative proportion of participants taking rescue medication over the 24 hour period

Secondary: The cumulative proportion of participants taking rescue medication over the 24 hour period

Secondary: Time to first perceptible relief measured by a stopwatch

Secondary: Time to first perceptible relief measured by a stopwatch

Secondary: Time to meaningful relief measured by a stopwatch

Secondary: Time to meaningful relief measured by a stopwatch

Secondary: Time to first perceptible relief confirmed by meaningful relief defined as the time to perceptible pain relief

Secondary: Time to first perceptible relief confirmed by meaningful relief defined as the time to perceptible pain relief

Secondary: Pain intensity difference (PID)

Secondary: Pain intensity difference (PID)

Secondary: Pain relief score

Secondary: Pain relief score

Secondary: Peak pain intensity difference (PID)

Secondary: Peak pain intensity difference (PID)

Secondary: Number of participants with certain peak pain relief score

Secondary: Number of participants with certain peak pain relief score

Secondary: Cumulative percent of participants with ‘at least a 2-point PID’ over time

Secondary: Cumulative percent of participants with ‘at least a 2-point PID’ over time

Secondary: Global assessment of pain relief of the investigational product

Secondary: Global assessment of pain relief of the investigational product

Secondary: Number of participants with adverse events

Secondary: Number of participants with adverse events

Secondary: Number of participants with significant changes in vital signs since baseline

Secondary: Number of participants with significant changes in vital signs since baseline

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Randomized, Double-Blind, Single-Dose, Parallel, Placebo-Controlled Pivotal Trial to Confirm the Efficacy of a Fixed Dose Combination (FDC) Tablet of Naproxen Sodium and Caffeine to Effectively Alleviate Postsurgical Dental Pain