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Clinical Trial Results:
A randomized, controlled multi-centre parallel group study to assess the efficacy and safety of multiple doses of a topically applied combination containing diclofenac 2% + capsaicin 0.075% (2 g formulation per application; 2-times daily for 5 days) compared to placebo, as well as to diclofenac 2% and capsaicin 0.075% in patients with acute back or neck pain

Summary
EudraCT number	2015-000404-25
Trial protocol	DE
Global end of trial date	21 Jul 2017

Results information
Results version number	v1(current)
This version publication date	04 Aug 2018
First version publication date	04 Aug 2018
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

1358.1

ISRCTN number

US NCT number

NCT02700815

WHO universal trial number (UTN)

Sponsor organisation name

Boehringer Ingelheim

Sponsor organisation address

Binger Strasse 173, Ingelheim am Rhein, Germany, 55216

Public contact

QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com

Scientific contact

QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.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?

Analysis stage

Final

Date of interim/final analysis

19 Oct 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

13 Jul 2017

Global end of trial reached?

Yes

Global end of trial date

21 Jul 2017

Was the trial ended prematurely?

Main objective of the trial

The objective was to compare the efficacy of a combination of topical diclofenac (2%) + capsaicin (0.075%) (diclofenac + capsaicin) versus placebo, diclofenac alone (2%), and capsaicin alone (0.075%) in the treatment of acute back or neck pain, and to assess the safety and tolerability of the combination of diclofenac and capsaicin in comparison to gels with diclofenac alone or capsaicin alone.

Protection of trial subjects

All patients were informed that they were free to withdraw their consent at any time during the study without penalty or prejudice. The patients were informed that their personal trial related data would be considered confidential and used by BI in accordance with the local data protection laws. The level of disclosure was explained to the patients. The patients were also informed that their medical records could be examined by Clinical Quality Assurance auditors appointed by BI, by members of the appropriate IEC/IRB, and by inspectors from regulatory authorities. Confidentiality of patient data was ensured by the use of depersonalised patient identification codes (patient numbers). The terms and conditions of the insurance cover were available to the investigator and the patients in the Investigator Site File (ISF).

Background therapy

Evidence for comparator

Actual start date of recruitment

17 May 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 693

Country: Number of subjects enrolled

Russian Federation: 64

Worldwide total number of subjects

757

EEA total number of subjects

693

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)

664

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This was a randomised, placebo- and active treatment-controlled, double-blind, parallel-group study. Out of 757 enrolled patients with acute back or neck pain, 746 were randomised and treated with 4 topical treatments administered twice daily for 4 to 7 days.

Screening details

All subjects were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that all subjects met all inclusion/exclusion criteria. Subjects were not to be entered to trial if any of the specific entry criteria were not met.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Assessor

Are arms mutually exclusive

Yes

Placebo Gel

Arm description

Patients were topically applied matching Placebo 2 gram (g) gel, twice daily with 12 ± 4 hours (h) between applications.

Arm type

Placebo

Investigational medicinal product name

Placebo Gel

Investigational medicinal product code

Other name

Pharmaceutical forms

Gel

Routes of administration

Topical use

Dosage and administration details

Topical application of matching Placebo 2 gram (g) gel, twice daily with 12 ± 4 hours (h) between applications.

Capsaicin (0.075%) Gel

Arm description

Patients were topically applied Capsaicin 2 g gel (1.5 milligram (mg) Capsaicin), twice daily with 12 ± 4 hours (h) between applications.

Arm type

Experimental

Investigational medicinal product name

Capsaicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Gel

Routes of administration

Topical use

Dosage and administration details

Topically application of Capsaicin 2 g gel (1.5 milligram (mg) Capsaicin), twice daily with 12 ± 4 hours (h) between applications.

Diclofenac (2%) Gel

Arm description

Patients were topically applied Diclofenac 2 g gel (40 milligram (mg) Diclofenac), twice daily with 12 ± 4 hours (h) between applications.

Arm type

Experimental

Investigational medicinal product name

Diclofenac

Investigational medicinal product code

Other name

Pharmaceutical forms

Gel

Routes of administration

Topical use

Dosage and administration details

Topically application of Diclofenac 2 g gel (40 milligram (mg) Diclofenac), twice daily with 12 ± 4 hours (h) between applications.

Diclofenac (2%) +Capsaicin (0.075%) Gel

Arm description

Patients were topically applied Diclofenac + Capsaicin 2 g gel (40 mg diclofenac, 1.5 mg capsaicin), twice daily with 12 ± 4 hours (h) between applications.

Arm type

Experimental

Investigational medicinal product name

Diclofenac

Investigational medicinal product code

Other name

Pharmaceutical forms

Gel

Routes of administration

Topical use

Dosage and administration details

Topical application of Diclofenac + Capsaicin 2 g gel (40 mg diclofenac, 1.5 mg capsaicin), twice daily with 12 ± 4 hours (h) between applications.

Investigational medicinal product name

Capsaicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Gel

Routes of administration

Topical use

Dosage and administration details

Topical application of Diclofenac + Capsaicin 2 g gel (40 mg diclofenac, 1.5 mg capsaicin), twice daily with 12 ± 4 hours (h) between applications.

Number of subjects in period 1 ^[1]	Placebo Gel	Capsaicin (0.075%) Gel	Diclofenac (2%) Gel	Diclofenac (2%) +Capsaicin (0.075%) Gel
Started	75	223	223	225
Completed	74	216	219	218
Not completed	1	7	4	7
Consent withdrawn by subject	-	-	1	-
Adverse event, non-fatal	-	6	2	3
Refusal to continue medication	-	1	-	1
Lost to follow-up	1	-	-	1
Lack of efficacy	-	-	1	2

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication.

Baseline characteristics

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Reporting group title

Placebo Gel

Reporting group description

Patients were topically applied matching Placebo 2 gram (g) gel, twice daily with 12 ± 4 hours (h) between applications.

Reporting group title

Capsaicin (0.075%) Gel

Reporting group description

Patients were topically applied Capsaicin 2 g gel (1.5 milligram (mg) Capsaicin), twice daily with 12 ± 4 hours (h) between applications.

Reporting group title

Diclofenac (2%) Gel

Reporting group description

Patients were topically applied Diclofenac 2 g gel (40 milligram (mg) Diclofenac), twice daily with 12 ± 4 hours (h) between applications.

Reporting group title

Diclofenac (2%) +Capsaicin (0.075%) Gel

Reporting group description

Patients were topically applied Diclofenac + Capsaicin 2 g gel (40 mg diclofenac, 1.5 mg capsaicin), twice daily with 12 ± 4 hours (h) between applications.

Reporting group values	Placebo Gel	Capsaicin (0.075%) Gel	Diclofenac (2%) Gel	Diclofenac (2%) +Capsaicin (0.075%) Gel	Total
Number of subjects	75	223	223	225	746
Age categorical
Units: Subjects
Age Continuous
Age of all patients included in the trial. Treated Set (TS): All randomised patients who used at least 1 dose of study medication were included in the TS. Patients who received the wrong treatment were analysed within the planned (randomised) treatment group in the efficacy analysis and within the actual treatment group in the safety analysis (TS, as treated).
Units: years
arithmetic mean (standard deviation)	45.3 ( 14.78 )	43.2 ( 15.42 )	44.0 ( 15.96 )	44.2 ( 15.49 )	-
Sex: Female, Male
Gender distribution of all patients included in the trial. TS was used to assess gender of all patients.
Units: Subjects
Female	44	128	136	136	444
Male	31	95	87	89	302
Race (NIH/OMB)
Race of all patients included in the trial. TS was used to assess race of all patients.
Units: Subjects
American Indian or Alaska Native	0	1	0	1	2
Asian	2	3	0	2	7
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	0	1	1	3	5
White	73	216	218	216	723
More than one race	0	2	4	3	9
Unknown or Not Reported	0	0	0	0	0
Ethnicity (NIH/OMB)
Ethnicity of all patients included in the trial. TS was used to assess ethnicity of all patients.
Units: Subjects
Hispanic or Latino	0	3	3	3	9
Not Hispanic or Latino	75	220	220	222	737
Unknown or Not Reported	0	0	0	0	0
Country
The list of countries from which the respective number of patients had been enrolled. TS was used to assess country of participation of all patients.
Units: Subjects
Germany\|	69	205	205	205	684
Russia\|	6	18	18	20	62
Application site
Pain on Movement (POM) was assessed by patients on performance of standardized, muscle group specific movements measured using a VAS on application sites. Back and Neck were defined as application sites for this study. Acute back and neck pain was studied in this trial. Number of patients with either neck or back as an application site were presented here. TS was used to assess application site of all patients.
Units: Subjects
Neck\|	45	126	129	130	430
Back\|	30	97	94	95	316
Pain on movement of worst procedure (POMwp)
POM was used to assess pain measurement for back and neck. The standard movements have been established for which the measurement was taken. POMwp was the POM measure that gave the highest score at baseline; i.e. POM of worst procedure. Pain intensity was assessed at rest after standing in an upright position relatively motionless for 1 minute. The pain was evaluated by asking patient 'How would you rate your pain right now?' and by using a visual analogue scale (VAS) ranging from 0-10 cm wherein 0 cm = no pain to 10 cm = worst pain possible. TS was used to assess POMwp of all patients.
Units: Unit on scale from 0 to 10
arithmetic mean (standard deviation)	7.20 ( 1.246 )	7.22 ( 1.157 )	7.29 ( 1.274 )	7.28 ( 1.148 )	-

End points

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Reporting group title

Placebo Gel

Reporting group description

Patients were topically applied matching Placebo 2 gram (g) gel, twice daily with 12 ± 4 hours (h) between applications.

Reporting group title

Capsaicin (0.075%) Gel

Reporting group description

Patients were topically applied Capsaicin 2 g gel (1.5 milligram (mg) Capsaicin), twice daily with 12 ± 4 hours (h) between applications.

Reporting group title

Diclofenac (2%) Gel

Reporting group description

Patients were topically applied Diclofenac 2 g gel (40 milligram (mg) Diclofenac), twice daily with 12 ± 4 hours (h) between applications.

Reporting group title

Diclofenac (2%) +Capsaicin (0.075%) Gel

Reporting group description

Patients were topically applied Diclofenac + Capsaicin 2 g gel (40 mg diclofenac, 1.5 mg capsaicin), twice daily with 12 ± 4 hours (h) between applications.

Primary: Change in POM between baseline and Day 2 evening, 1 hour after drug application

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End point title

Change in POM between baseline and Day 2 evening, 1 hour after drug application

End point description

POM was used to assess pain measurement for back and neck. The standardized movements have been established for which the measurement was taken. POMwp was the POM measure that gave highest score at baseline i.e. POM of worst procedure. Pain intensity was assessed at rest after standing in an upright position motionless for 1 min. The pain was evaluated by asking patient How would you rate your pain right now? and by using a visual analogue scale (VAS) ranging from 0-10 cm wherein 0 cm = no pain to 10 cm = worst pain possible. Results presented here are adjusted mean change from baseline and standard error for POMwp in centimeters (cm).Full analysis set (FAS): All patients in treated set with a baseline value pre application for POMwp at Visit 1 and at least 1 POMwp value during assessment times at Visit 1 (Day 1 morning 1h after application), Visit 2 (Day 2, morning 1h after application), Visit 3 (Day 2 evening before application) or Visit 3 (Day 2 evening 1h after application)

End point type

Primary

End point timeframe

Baseline and Day 2

End point values	Placebo Gel	Capsaicin (0.075%) Gel	Diclofenac (2%) Gel	Diclofenac (2%) +Capsaicin (0.075%) Gel
Number of subjects analysed	75 ^[1]	222 ^[2]	222 ^[3]	225 ^[4]
Units: Centimeter (cm)
least squares mean (standard error)	-2.45 ( 0.252 )	-3.26 ( 0.160 )	-2.33 ( 0.160 )	-3.05 ( 0.159 )

Notes
[1] - FAS
[2] - FAS
[3] - FAS
[4] - FAS

Statistical analysis 1

Statistical analysis description

A Mixed Model Repeat Measures (MMRM) analysis was used to compare change in POMwp from baseline between placebo and combination therapy diclofenac + capsaicin.

Comparison groups

Placebo Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

300

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

= 0.0303

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-1.15

upper limit

-0.06

Variability estimate

Standard error of the mean

Dispersion value

0.277

Notes
[5] - MMRM model included fixed effects of treatment, country, application site (back/neck), time and fixed covariates of baseline POMwp and baseline POMwp by time interaction. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical analysis 2

Statistical analysis description

A Mixed Model Repeat Measures (MMRM) analysis was used to compare change in POMwp from baseline between capsaicin and combination therapy diclofenac + capsaicin.

Comparison groups

Capsaicin (0.075%) Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

447

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

P-value

= 0.2886

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.21

Confidence interval

level

95%

sides

2-sided

lower limit

-0.18

upper limit

0.6

Variability estimate

Standard error of the mean

Dispersion value

0.197

Notes
[6] - MMRM model included fixed effects of treatment, country, application site (back/neck), time and fixed covariates of baseline POMwp and baseline POMwp by time interaction. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical analysis 3

Statistical analysis description

A Mixed Model Repeat Measures (MMRM) analysis was used to compare change in POMwp from baseline between diclofenac and combination therapy diclofenac + capsaicin.

Comparison groups

Diclofenac (2%) Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

447

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

= 0.0003

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.72

Confidence interval

level

95%

sides

2-sided

lower limit

-1.1

upper limit

-0.33

Variability estimate

Standard error of the mean

Dispersion value

0.197

Notes
[7] - MMRM model included fixed effects of treatment, country, application site (back/neck), time and fixed covariates of baseline POMwp and baseline POMwp by time interaction. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Secondary: POMwp area under the curve (AUC) calculated from 0 to 72 hours (h) (POMwp AUC(0-72 h))

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End point title

POMwp area under the curve (AUC) calculated from 0 to 72 hours (h) (POMwp AUC(0-72 h))

End point description

This is a key secondary endpoint. AUC for POMwp calculated from 0 to 72 h that is for first three treatment days using the trapezoidal rule divided by the observation time. The results presented here are adjusted mean and standard error for POMwp AUC (0-72 h) in centimeters (cm). TS was used to assess POMwp AUC.

End point type

Secondary

End point timeframe

First 3 treatment days

End point values	Placebo Gel	Capsaicin (0.075%) Gel	Diclofenac (2%) Gel	Diclofenac (2%) +Capsaicin (0.075%) Gel
Number of subjects analysed	75 ^[8]	223 ^[9]	223 ^[10]	225 ^[11]
Units: cm
least squares mean (standard error)	4.62 ( 0.213 )	3.95 ( 0.145 )	4.81 ( 0.145 )	4.25 ( 0.143 )

Notes
[8] - TS
[9] - TS
[10] - TS
[11] - TS

Statistical analysis 1

Statistical analysis description

An analysis of covariance (ANCOVA) was used to compare POMwp AUC(0-72 h) between placebo and combination therapy diclofenac + capsaicin

Comparison groups

Placebo Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

300

Analysis specification

Pre-specified

Analysis type

superiority ^[12]

P-value

= 0.0956

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-0.37

Confidence interval

level

95%

sides

2-sided

lower limit

-0.8

upper limit

0.07

Variability estimate

Standard error of the mean

Dispersion value

0.221

Notes
[12] - ANCOVA includes treatment, country, and application site (back/neck) as fixed effects, and baseline POMwp as a continuous covariate. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical analysis 2

Statistical analysis description

An analysis of covariance (ANCOVA) was used to compare POMwp AUC(0-72 h) between capsaicin and combination therapy diclofenac + capsaicin

Comparison groups

Capsaicin (0.075%) Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

448

Analysis specification

Pre-specified

Analysis type

superiority ^[13]

P-value

= 0.0564

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.01

upper limit

0.61

Variability estimate

Standard error of the mean

Dispersion value

0.157

Notes
[13] - ANCOVA includes treatment, country, and application site (back/neck) as fixed effects, and baseline POMwp as a continuous covariate. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical analysis 3

Statistical analysis description

An analysis of covariance (ANCOVA) was used to compare POMwp AUC(0-72 h) between diclofenac and combination therapy diclofenac + capsaicin

Comparison groups

Diclofenac (2%) Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

448

Analysis specification

Pre-specified

Analysis type

superiority ^[14]

P-value

= 0.0004

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-0.56

Confidence interval

level

95%

sides

2-sided

lower limit

-0.87

upper limit

-0.25

Variability estimate

Standard error of the mean

Dispersion value

0.157

Notes
[14] - ANCOVA includes treatment, country, and application site (back/neck) as fixed effects, and baseline POMwp as a continuous covariate. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Secondary: POMwp Area under the curve (AUC) calculated from 0 to 120 hours (h) (POMwp AUC(0-120 h))

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End point title

POMwp Area under the curve (AUC) calculated from 0 to 120 hours (h) (POMwp AUC(0-120 h))

End point description

This is a key secondary endpoint. AUC for POMwp calculated from 0 to 120 h that is for first five treatment days using the trapezoidal rule divided by the observation time. The results presented here are adjusted mean and standard error for POMwp AUC (0-120 h) in centimeters (cm). TS was used to assess POMwp AUC.

End point type

Secondary

End point timeframe

First 5 treatment days

End point values	Placebo Gel	Capsaicin (0.075%) Gel	Diclofenac (2%) Gel	Diclofenac (2%) +Capsaicin (0.075%) Gel
Number of subjects analysed	75 ^[15]	223 ^[16]	223 ^[17]	225 ^[18]
Units: cm
least squares mean (standard error)	3.92 ( 0.230 )	3.10 ( 0.156 )	4.10 ( 0.156 )	3.41 ( 0.154 )

Notes
[15] - TS
[16] - TS
[17] - TS
[18] - TS

Statistical analysis 1

Statistical analysis description

An analysis of covariance (ANCOVA) was used to compare POMwp AUC(0-120 h) between placebo and combination therapy diclofenac + capsaicin

Comparison groups

Placebo Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

300

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

P-value

= 0.0347

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-0.97

upper limit

-0.04

Variability estimate

Standard error of the mean

Dispersion value

0.238

Notes
[19] - ANCOVA includes treatment, country, and application site (back/neck) as fixed effects, and baseline POMwp as a continuous covariate. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical analysis 2

Statistical analysis description

An analysis of covariance (ANCOVA) was used to compare POMwp AUC(0-120 h) between capsaicin and combination therapy diclofenac + capsaicin

Comparison groups

Capsaicin (0.075%) Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

448

Analysis specification

Pre-specified

Analysis type

superiority ^[20]

P-value

= 0.0622

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

0.32

Confidence interval

level

95%

sides

2-sided

lower limit

-0.02

upper limit

0.65

Variability estimate

Standard error of the mean

Dispersion value

0.169

Notes
[20] - ANCOVA includes treatment, country, and application site (back/neck) as fixed effects, and baseline POMwp as a continuous covariate. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical analysis 3

Statistical analysis description

An analysis of covariance (ANCOVA) was used to compare POMwp AUC(0-120 h) between diclofenac and combination therapy diclofenac + capsaicin

Comparison groups

Diclofenac (2%) Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

448

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-0.68

Confidence interval

level

95%

sides

2-sided

lower limit

-1.01

upper limit

-0.35

Variability estimate

Standard error of the mean

Dispersion value

0.169

Notes
[21] - ANCOVA includes treatment, country, and application site (back/neck) as fixed effects, and baseline POMwp as a continuous covariate. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Secondary: Number of patients with decrease in POMwp of at least 30% from baseline

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End point title

Number of patients with decrease in POMwp of at least 30% from baseline

End point description

This outcome measures the pattern of number of patients with a decrease in POMwp of at least 30% from baseline at 1 hour after dosing on Day 2 evening. TS was used to assess decrease in POMwp.

End point type

Secondary

End point timeframe

Baseline and day 2

End point values	Placebo Gel	Capsaicin (0.075%) Gel	Diclofenac (2%) Gel	Diclofenac (2%) +Capsaicin (0.075%) Gel
Number of subjects analysed	75 ^[22]	223 ^[23]	223 ^[24]	225 ^[25]
Units: Participants	34	150	107	134

Notes
[22] - TS
[23] - TS
[24] - TS
[25] - TS

Statistical analysis 1

Statistical analysis description

A logistic regression was used to compare change in number of patients with a decrease in POMwp of at least 30% from baseline between placebo and combination therapy diclofenac + capsaicin. The likelihood-ratio test was used to test for differences between treatments.

Comparison groups

Placebo Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

300

Analysis specification

Pre-specified

Analysis type

superiority ^[26]

P-value

= 0.0202

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.882

Confidence interval

level

95%

sides

2-sided

lower limit

1.1

upper limit

3.21

Notes
[26] - Logistic regression model include country and application site as covariates. Odds ratio was calculated as combination treatment/individual treatment.

Statistical analysis 2

Statistical analysis description

A logistic regression was used to compare change in number of patients with a decrease in POMwp of at least 30% from baseline between capsaicin and combination therapy diclofenac + capsaicin. The likelihood-ratio test was used to test for differences between treatments.

Comparison groups

Capsaicin (0.075%) Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

448

Analysis specification

Pre-specified

Analysis type

superiority ^[27]

P-value

= 0.1206

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.732

Confidence interval

level

95%

sides

2-sided

lower limit

0.49

upper limit

1.09

Notes
[27] - Logistic regression model include country and application site as covariates. Odds ratio was calculated as combination treatment/individual treatment.

Statistical analysis 3

Statistical analysis description

A logistic regression was used to compare change in number of patients with a decrease in POMwp of at least 30% from baseline between diclofenac and combination therapy diclofenac + capsaicin. The likelihood-ratio test was used to test for differences between treatments.

Comparison groups

Diclofenac (2%) Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

448

Analysis specification

Pre-specified

Analysis type

superiority ^[28]

P-value

= 0.0122

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.629

Confidence interval

level

95%

sides

2-sided

lower limit

1.11

upper limit

2.39

Notes
[28] - Logistic regression model include country and application site as covariates. Odds ratio was calculated as combination treatment/individual treatment.

Secondary: Number of patients with decrease in POMwp of at least 50% from baseline

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End point title

Number of patients with decrease in POMwp of at least 50% from baseline

End point description

This outcome measures the pattern of number of patients with a decrease in POMwp of at least 50% from baseline at 1 hour after dosing on Day 2 evening. TS was used to assess decrease in POMwp.

End point type

Secondary

End point timeframe

Baseline and day 2

End point values	Placebo Gel	Capsaicin (0.075%) Gel	Diclofenac (2%) Gel	Diclofenac (2%) +Capsaicin (0.075%) Gel
Number of subjects analysed	75 ^[29]	223 ^[30]	223 ^[31]	225 ^[32]
Units: Participants	20	95	50	85

Notes
[29] - TS
[30] - TS
[31] - TS
[32] - TS

Statistical analysis 1

Statistical analysis description

A logistic regression was used to compare change in number of patients with a decrease in POMwp of at least 50% from baseline between placebo and combination therapy diclofenac + capsaicin. The likelihood-ratio test was used to test for differences between treatments.

Comparison groups

Placebo Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

300

Analysis specification

Pre-specified

Analysis type

superiority ^[33]

P-value

= 0.0643

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.729

Confidence interval

level

95%

sides

2-sided

lower limit

0.97

upper limit

3.09

Notes
[33] - Logistic regression model include country and application site as covariates. Odds ratio was calculated as combination treatment/individual treatment.

Statistical analysis 2

Statistical analysis description

A logistic regression was used to compare change in number of patients with a decrease in POMwp of at least 50% from baseline between capsaicin and combination therapy diclofenac + capsaicin. The likelihood-ratio test was used to test for differences between treatments.

Comparison groups

Capsaicin (0.075%) Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

448

Analysis specification

Pre-specified

Analysis type

superiority ^[34]

P-value

= 0.3479

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.833

Confidence interval

level

95%

sides

2-sided

lower limit

0.57

upper limit

1.22

Notes
[34] - Logistic regression model include country and application site as covariates. Odds ratio was calculated as combination treatment/individual treatment.

Statistical analysis 3

Statistical analysis description

A logistic regression was used to compare change in number of patients with a decrease in POMwp of at least 50% from baseline between diclofenac and combination therapy diclofenac + capsaicin. The likelihood-ratio test was used to test for differences between treatments.

Comparison groups

Diclofenac (2%) Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

448

Analysis specification

Pre-specified

Analysis type

superiority ^[35]

P-value

= 0.0004

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

2.125

Confidence interval

level

95%

sides

2-sided

lower limit

1.4

upper limit

3.22

Notes
[35] - Logistic regression model include country and application site as covariates. Odds ratio was calculated as combination treatment/individual treatment.

Secondary: Change from baseline in POMwp (cm) at Day 6 morning

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End point title

Change from baseline in POMwp (cm) at Day 6 morning

End point description

Pain on movement (POM) was used to assess pain measurement for back and neck pain. The standardized movements have been established for which the measurement was taken. POMwp was the POM measure that gave the highest score at baseline; i.e. POM of worst procedure. Pain intensity was assessed at rest after standing in an upright position relatively motionless for 1 minute. The pain was evaluated by asking patient 'How would you rate your pain right now?' and by using a visual analogue scale (VAS) ranging from 0-10 cm wherein 0 cm = no pain to 10 cm = worst pain possible. The results presented here are adjusted mean change from baseline and standard error for POMwp in centimeters (cm). TS was used to assess change fom baseline in POMwp.

End point type

Secondary

End point timeframe

Baseline and Day 6

End point values	Placebo Gel	Capsaicin (0.075%) Gel	Diclofenac (2%) Gel	Diclofenac (2%) +Capsaicin (0.075%) Gel
Number of subjects analysed	75 ^[36]	223 ^[37]	223 ^[38]	225 ^[39]
Units: cm
least squares mean (standard error)	-3.83 ( 0.282 )	-5.08 ( 0.175 )	-3.77 ( 0.175 )	-4.88 ( 0.174 )

Notes
[36] - TS
[37] - TS
[38] - TS
[39] - TS

Statistical analysis 1

Statistical analysis description

A Mixed Model Repeat Measures (MMRM) analysis was used to compare change in POMwp from baseline between placebo and combination therapy diclofenac + capsaicin.

Comparison groups

Placebo Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

300

Analysis specification

Pre-specified

Analysis type

superiority ^[40]

P-value

= 0.0008

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-1.05

Confidence interval

level

95%

sides

2-sided

lower limit

-1.67

upper limit

-0.44

Variability estimate

Standard error of the mean

Dispersion value

0.313

Notes
[40] - MMRM model included fixed effects of treatment, country, application site (back/neck), time and fixed covariates of baseline POMwp and baseline POMwp by time interaction. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical analysis 2

Statistical analysis description

A Mixed Model Repeat Measures (MMRM) analysis was used to compare change in POMwp from baseline between capsaicin and combination therapy diclofenac + capsaicin.

Comparison groups

Capsaicin (0.075%) Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

448

Analysis specification

Pre-specified

Analysis type

superiority ^[41]

P-value

= 0.3726

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.24

upper limit

0.64

Variability estimate

Standard error of the mean

Dispersion value

0.223

Notes
[41] - MMRM model included fixed effects of treatment, country, application site (back/neck), time and fixed covariates of baseline POMwp and baseline POMwp by time interaction. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical analysis 3

Statistical analysis description

A Mixed Model Repeat Measures (MMRM) analysis was used to compare change in POMwp from baseline between diclofenac and combination therapy diclofenac + capsaicin.

Comparison groups

Diclofenac (2%) Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

448

Analysis specification

Pre-specified

Analysis type

superiority ^[42]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-1.12

Confidence interval

level

95%

sides

2-sided

lower limit

-1.56

upper limit

-0.68

Variability estimate

Standard error of the mean

Dispersion value

0.223

Notes
[42] - MMRM model included fixed effects of treatment, country, application site (back/neck), time and fixed covariates of baseline POMwp and baseline POMwp by time interaction. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Secondary: Change from baseline in pressure algometry (PA) at day 2 evening before drug application

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End point title

Change from baseline in pressure algometry (PA) at day 2 evening before drug application

End point description

PA is a method described to determine pressure pain threshold (PPT) by applying controlled pressure to a given body point. The results presented here are adjusted mean change from baseline and standard error for PA. TS was used to assess change from baseline in PA.

End point type

Secondary

End point timeframe

Baseline and Day 2

End point values	Placebo Gel	Capsaicin (0.075%) Gel	Diclofenac (2%) Gel	Diclofenac (2%) +Capsaicin (0.075%) Gel
Number of subjects analysed	75 ^[43]	223 ^[44]	223 ^[45]	225 ^[46]
Units: Newton/centimeter square (N/cm^2)
least squares mean (standard error)	3.89 ( 0.795 )	3.46 ( 0.526 )	3.00 ( 0.530 )	3.77 ( 0.526 )

Notes
[43] - TS
[44] - TS
[45] - TS
[46] - TS

Statistical analysis 1

Statistical analysis description

A Mixed Model Repeat Measures (MMRM) analysis was used to compare change in PA from baseline between placebo and combination therapy diclofenac + capsaicin.

Comparison groups

Placebo Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

300

Analysis specification

Pre-specified

Analysis type

superiority ^[47]

P-value

= 0.881

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-1.78

upper limit

1.53

Variability estimate

Standard error of the mean

Dispersion value

0.844

Notes
[47] - MMRM model included fixed effects of treatment, country, application site (back/neck), time and fixed covariates of baseline PA and baseline PA by time interaction. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical analysis 2

Statistical analysis description

A Mixed Model Repeat Measures (MMRM) analysis was used to compare change in PA from baseline between capsaicin and combination therapy diclofenac + capsaicin.

Comparison groups

Capsaicin (0.075%) Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

448

Analysis specification

Pre-specified

Analysis type

superiority ^[48]

P-value

= 0.6094

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.31

Confidence interval

level

95%

sides

2-sided

lower limit

-0.87

upper limit

1.49

Variability estimate

Standard error of the mean

Dispersion value

0.601

Notes
[48] - MMRM model included fixed effects of treatment, country, application site (back/neck), time and fixed covariates of baseline PA and baseline PA by time interaction. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical analysis 3

Statistical analysis description

A Mixed Model Repeat Measures (MMRM) analysis was used to compare change in PA from baseline between diclofenac and combination therapy diclofenac + capsaicin.

Comparison groups

Diclofenac (2%) Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

448

Analysis specification

Pre-specified

Analysis type

superiority ^[49]

P-value

= 0.2047

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.76

Confidence interval

level

95%

sides

2-sided

lower limit

-0.42

upper limit

1.95

Variability estimate

Standard error of the mean

Dispersion value

0.602

Notes
[49] - MMRM model included fixed effects of treatment, country, application site (back/neck), time and fixed covariates of baseline PA and baseline PA by time interaction. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Secondary: Change from baseline in pressure algometry (PA) at day 6 morning

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End point title

Change from baseline in pressure algometry (PA) at day 6 morning

End point description

End point type

Secondary

End point timeframe

Baseline and Day 6

End point values	Placebo Gel	Capsaicin (0.075%) Gel	Diclofenac (2%) Gel	Diclofenac (2%) +Capsaicin (0.075%) Gel
Number of subjects analysed	75 ^[50]	223 ^[51]	223 ^[52]	225 ^[53]
Units: Newton/centimeter square (N/cm^2)
least squares mean (standard error)	8.01 ( 1.199 )	9.38 ( 0.737 )	7.64 ( 0.740 )	9.66 ( 0.737 )

Notes
[50] - TS
[51] - TS
[52] - TS
[53] - TS

Statistical analysis 1

Statistical analysis description

A Mixed Model Repeat Measures (MMRM) analysis was used to compare change in PA from baseline between placebo and combination therapy diclofenac + capsaicin.

Comparison groups

Placebo Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

300

Analysis specification

Pre-specified

Analysis type

superiority ^[54]

P-value

= 0.2193

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

1.65

Confidence interval

level

95%

sides

2-sided

lower limit

-0.98

upper limit

4.27

Variability estimate

Standard error of the mean

Dispersion value

1.339

Notes
[54] - MMRM model included fixed effects of treatment, country, application site (back/neck), time and fixed covariates of baseline PA and baseline PA by time interaction. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical analysis 2

Statistical analysis description

A Mixed Model Repeat Measures (MMRM) analysis was used to compare change in PA from baseline between capsaicin and combination therapy diclofenac + capsaicin.

Comparison groups

Capsaicin (0.075%) Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

448

Analysis specification

Pre-specified

Analysis type

superiority ^[55]

P-value

= 0.7672

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.28

Confidence interval

level

95%

sides

2-sided

lower limit

-1.58

upper limit

2.15

Variability estimate

Standard error of the mean

Dispersion value

0.949

Notes
[55] - MMRM model included fixed effects of treatment, country, application site (back/neck), time and fixed covariates of baseline PA and baseline PA by time interaction. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical analysis 3

Statistical analysis description

A Mixed Model Repeat Measures (MMRM) analysis was used to compare change in PA from baseline between diclofenac and combination therapy diclofenac + capsaicin.

Comparison groups

Diclofenac (2%) Gel v Diclofenac (2%) +Capsaicin (0.075%) Gel

Number of subjects included in analysis

448

Analysis specification

Pre-specified

Analysis type

superiority ^[56]

P-value

= 0.0339

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

2.02

Confidence interval

level

95%

sides

2-sided

lower limit

0.15

upper limit

3.88

Variability estimate

Standard error of the mean

Dispersion value

0.95

Notes
[56] - MMRM model included fixed effects of treatment, country, application site (back/neck), time and fixed covariates of baseline PA and baseline PA by time interaction. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Adverse events

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Timeframe for reporting adverse events

From first drug administration until 2 days after the last drug administration, i.e. up to 8 days.

Adverse event reporting additional description

An adverse event (AE) was defined as any untoward medical occurrence, including an exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a pharmaceutical product. The event did not necessarily have to have a causal relationship with this treatment. TS (as treated) has been used for assessment of AEs.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.1

Reporting group title

Placebo Gel

Reporting group description

Patients were topically applied with matching Placebo 2 gram (g) gel, twice daily with 12 ± 4 hours (h) between applications.

Reporting group title

Capsaicin (0.075%) Gel

Reporting group description

Patients were topically applied with Capsaicin 2 g gel (1.5 milligram (mg) Capsaicin), twice daily with 12 ± 4 hours (h) between applications.

Reporting group title

Diclofenac (2%) Gel

Reporting group description

Patients were topically applied with Diclofenac 2 g gel (40 milligram (mg) Diclofenac), twice daily with 12 ± 4 hours (h) between applications.

Reporting group title

Diclofenac (2%) +Capsaicin (0.075%) Gel

Reporting group description

Patients were topically applied with Diclofenac + Capsaicin 2 g gel (40 mg diclofenac, 1.5 mg capsaicin), twice daily with 12 ± 4 hours (h) between applications.

Serious adverse events	Placebo Gel	Capsaicin (0.075%) Gel	Diclofenac (2%) Gel	Diclofenac (2%) +Capsaicin (0.075%) Gel
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 75 (0.00%)	0 / 223 (0.00%)	0 / 223 (0.00%)	0 / 225 (0.00%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0

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

Non-serious adverse events	Placebo Gel	Capsaicin (0.075%) Gel	Diclofenac (2%) Gel	Diclofenac (2%) +Capsaicin (0.075%) Gel
Total subjects affected by non serious adverse events
subjects affected / exposed	4 / 75 (5.33%)	29 / 223 (13.00%)	7 / 223 (3.14%)	26 / 225 (11.56%)
General disorders and administration site conditions
Burning sensation
subjects affected / exposed	0 / 75 (0.00%)	16 / 223 (7.17%)	1 / 223 (0.45%)	12 / 225 (5.33%)
occurrences all number	0	17	1	15
Skin and subcutaneous tissue disorders
Skin burning sensation
subjects affected / exposed	0 / 75 (0.00%)	7 / 223 (3.14%)	2 / 223 (0.90%)	12 / 225 (5.33%)
occurrences all number	0	9	2	13
Infections and infestations
Nasopharyngitis
subjects affected / exposed	4 / 75 (5.33%)	9 / 223 (4.04%)	4 / 223 (1.79%)	3 / 225 (1.33%)
occurrences all number	4	9	4	3

More information

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Were there any global substantial amendments to the protocol? Yes

21 Jun 2016

With the introduction of this amendment, in addition to some changes in responsibilities, clarifications, correction of typographical errors, and minor revisions for consistency within the CTP or to avoid repetitions, the following changes were made: 1.The trigger point for AP was revised from ≤2.5 N/cm2 to ≤25 N/cm2 2.The description of the formulation of study medication was changed from a semisolid formulation to a gel 3.The endpoints number of patients with a decrease in POMWP from baseline of at least 30% and 50%, respectively, to the timepoint before drug application in the morning of Day 2 (Visit 2) were revised since no POM assessment was scheduled at this timepoint 4.An analysis of the primary endpoint including an additional variable for analgesic use was added

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.

A possible limitation of this study design related to the warming effect that is attributable to the topical application of capsaicin, which could potentially have led to inadvertent unblinding of treatment assignments in the study.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in POM between baseline and Day 2 evening, 1 hour after drug application

Primary: Change in POM between baseline and Day 2 evening, 1 hour after drug application

Secondary: POMwp area under the curve (AUC) calculated from 0 to 72 hours (h) (POMwp AUC(0-72 h))

Secondary: POMwp area under the curve (AUC) calculated from 0 to 72 hours (h) (POMwp AUC(0-72 h))

Secondary: POMwp Area under the curve (AUC) calculated from 0 to 120 hours (h) (POMwp AUC(0-120 h))

Secondary: POMwp Area under the curve (AUC) calculated from 0 to 120 hours (h) (POMwp AUC(0-120 h))

Secondary: Number of patients with decrease in POMwp of at least 30% from baseline

Secondary: Number of patients with decrease in POMwp of at least 30% from baseline

Secondary: Number of patients with decrease in POMwp of at least 50% from baseline

Secondary: Number of patients with decrease in POMwp of at least 50% from baseline

Secondary: Change from baseline in POMwp (cm) at Day 6 morning

Secondary: Change from baseline in POMwp (cm) at Day 6 morning

Secondary: Change from baseline in pressure algometry (PA) at day 2 evening before drug application

Secondary: Change from baseline in pressure algometry (PA) at day 2 evening before drug application

Secondary: Change from baseline in pressure algometry (PA) at day 6 morning

Secondary: Change from baseline in pressure algometry (PA) at day 6 morning

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Cyprus
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Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
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Slovenia
Spain
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Outside EU/EEA