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Clinical Trial Results:
A PHASE III, MULTICENTRE, INTERNATIONAL, RANDOMISED, DOUBLE-BLIND, DOUBLE-DUMMY, PARALLEL-GROUP, PLACEBO AND ACTIVE COMPARATORCONTROLLED CLINICAL TRIAL TO EVALUATE THE ANALGESIC EFFICACY AND SAFETY OF IBUPROFEN ARGININE/TRAMADOL 400/37.5 MG COMPARED WITH IBUPROFEN ARGININE 400 MG ALONE, TRAMADOL 50 MG ALONE AND PLACEBO IN PATIENTS WITH MODERATE TO SEVERE PAIN AFTER NON-ONCOLOGICAL ABDOMINAL HYSTERECTOMY

Summary
EudraCT number	2014-004081-21
Trial protocol	ES
Global end of trial date	21 Apr 2016

Results information
Results version number	v1(current)
This version publication date	07 Jul 2022
First version publication date	07 Jul 2022
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

FMLD-IOTRA-20_FIIIB

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

FARMALIDER S.A.

Sponsor organisation address

C/ La Granja Nº 1, Alcobendas (Madrid), Spain, 28108

Public contact

Medical department, FARMALIDER, Medical department, FARMALIDER, 34 916612335, farmalider@farmalider.com

Scientific contact

Medical department, FARMALIDER, Medical department, FARMALIDER, 34 916612335, farmalider@farmalider.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

21 Apr 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

21 Apr 2016

Global end of trial reached?

Yes

Global end of trial date

21 Apr 2016

Was the trial ended prematurely?

Main objective of the trial

To evaluate the analgesic efficacy at multiple doses of the fixed combination of ibuprofen (arginine) and tramadol hydrochloride versus each ingredient separately and placebo, in oral administration, in patients with moderate to severe pain after partial or total non-oncological abdominal hysterectomy.

Protection of trial subjects

The protocol and amedments were checked and approved by Clinical Research Ethics Committee of the Hospital de Getafe, Madrid as Reference CEIC and by the local CEICs of each of the participating centers. This study was conducted in accordance with the latest version of the Declaration of Helsinki (Fortaleza, 2013, www.wma.net), International Conference of Harmonisation Good Clinical Practice standards (GCP/ICH), and European and local legislation.

Background therapy

Evidence for comparator

Actual start date of recruitment

27 Jan 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 217

Country: Number of subjects enrolled

Hungary: 159

Worldwide total number of subjects

376

EEA total number of subjects

376

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)

376

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 533 patients were included in the study, of which 157 could not be randomized for different reasons, the most frequent being failure to achieve VAS≥ 4 cm after the post-surgical period according to the protocol. 376 patients were randomized into the 4 study groups.

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

Blinding implementation details

Due to the different pharmaceutical forms of the investigational products, two pharmaceutcal forms of placebo, granules and drops, were necessary.

Are arms mutually exclusive

Yes

Treatment 1 (Ibuprofen - Tramadol)

Arm description

Arm type

Experimental

Investigational medicinal product name

Ibuprofen/ Tramadol

Investigational medicinal product code

Other name

Experimental

Pharmaceutical forms

Granules for oral solution

Routes of administration

Oral use

Dosage and administration details

Dose: 1 sachet All treatments being administered orally. The regimen of administration of the medication was 1 dose every 6 hours from the time of randomisation.

Investigational medicinal product name

Placebo B

Investigational medicinal product code

Other name

Pharmaceutical forms

Granules for oral solution

Routes of administration

Oral use

Dosage and administration details

Dose: 1 sachet All treatments were administered orally. The regimen of administration of the medication was 1 dose every 6 hours from the time of randomisation.

Investigational medicinal product name

Placebo C

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral drops, solution

Routes of administration

Oral use

Dosage and administration details

Dose: 0,5 ml (20 drops) All treatments were administered orally. The regimen of administration of the medication was 1 dose every 6 hours from the time of randomisation.

Treatment 2 (Ibuprofen (arginine))

Arm description

Arm type

Active comparator

Investigational medicinal product name

Ibuprofen (arginine)

Investigational medicinal product code

Other name

Reference A

Pharmaceutical forms

Granules for oral solution

Routes of administration

Oral use

Dosage and administration details

Dose: 1 sachet ibuprofen (arginine) All treatments being administered orally. The regimen of administration of the medication was 1 dose every 6 hours from the time of randomisation.

Investigational medicinal product name

Placebo A

Investigational medicinal product code

Other name

Pharmaceutical forms

Granules for oral solution

Routes of administration

Oral use

Dosage and administration details

Dose: 1 sachet All treatments being administered orally. The regimen of administration of the medication was 1 dose every 6 hours from the time of randomisation.

Investigational medicinal product name

Placebo C

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral drops, solution

Routes of administration

Oral use

Dosage and administration details

Dose: 0,5 ml (20 drops) All treatments being administered orally. The regimen of administration of the medication was 1 dose every 6 hours from the time of randomisation.

Treatment 3 (Tramadol)

Arm description

Arm type

Active comparator

Investigational medicinal product name

Tramadol

Investigational medicinal product code

Other name

Reference B

Pharmaceutical forms

Oral drops, solution

Routes of administration

Oral use

Dosage and administration details

Dose: 0,5 ml (20 drops) All treatments being administered orally. The regimen of administration of the medication was 1 dose every 6 hours from the time of randomisation.

Investigational medicinal product name

Placebo B

Investigational medicinal product code

Other name

Pharmaceutical forms

Granules for oral solution

Routes of administration

Oral use

Dosage and administration details

Dose: 1 sachet All treatments were administered orally. The regimen of administration of the medication was 1 dose every 6 hours from the time of randomisation.

Investigational medicinal product name

Placebo A

Investigational medicinal product code

Other name

Pharmaceutical forms

Granules for oral solution

Routes of administration

Oral use

Dosage and administration details

Dose: 1 sachet All treatments being administered orally. The regimen of administration of the medication was 1 dose every 6 hours from the time of randomisation.

Treatment 4 (Placebo)

Arm description

Arm type

Placebo

Investigational medicinal product name

Placebo A

Investigational medicinal product code

Other name

Pharmaceutical forms

Granules for oral solution

Routes of administration

Oral use

Dosage and administration details

Dose: 1 sachet All treatments being administered orally. The regimen of administration of the medication was 1 dose every 6 hours from the time of randomisation.

Investigational medicinal product name

Placebo B

Investigational medicinal product code

Other name

Pharmaceutical forms

Granules for oral solution

Routes of administration

Oral use

Dosage and administration details

Dose: 1 sachet All treatments were administered orally. The regimen of administration of the medication was 1 dose every 6 hours from the time of randomisation.

Investigational medicinal product name

Placebo C

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral drops, solution

Routes of administration

Oral use

Dosage and administration details

Dose: 0,5 ml (20 drops) All treatments being administered orally. The regimen of administration of the medication was 1 dose every 6 hours from the time of randomisation.

Number of subjects in period 1	Treatment 1 (Ibuprofen - Tramadol)	Treatment 2 (Ibuprofen (arginine))	Treatment 3 (Tramadol)	Treatment 4 (Placebo)
Started	91	94	98	93
Completed	74	59	57	42
Not completed	17	35	41	51
Consent withdrawn by subject	1	2	2	4
Physician decision	-	-	-	1
Adverse event, non-fatal	3	4	4	1
Other reasons	13	29	35	45

Baseline characteristics

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Reporting group title

Overall Study

Reporting group description

Reporting group values	Overall Study	Total
Number of subjects	376	376
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	376	376
From 65-84 years	0	0
85 years and over	0	0
Gender categorical
Units: Subjects
Female	376	376

End points

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Reporting group title

Treatment 1 (Ibuprofen - Tramadol)

Reporting group description

Reporting group title

Treatment 2 (Ibuprofen (arginine))

Reporting group description

Reporting group title

Treatment 3 (Tramadol)

Reporting group description

Reporting group title

Treatment 4 (Placebo)

Reporting group description

Primary: Pain intensity 24 hours after the start of the treatment.

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End point title

Pain intensity 24 hours after the start of the treatment.

End point description

The primary efficacy variable for this was the pain intensity score as measured by a visual analogue scale (VAS) and evaluated by the patient 24 hours after the first dose of the treatment.

End point type

Primary

End point timeframe

Over 24 hours after first dose

End point values	Treatment 1 (Ibuprofen - Tramadol)	Treatment 2 (Ibuprofen (arginine))	Treatment 3 (Tramadol)	Treatment 4 (Placebo)
Number of subjects analysed	91	91	95	92
Units: cm
median (standard error)	2.9 ( 2.5 )	3.6 ( 2.7 )	4.1 ( 2.7 )	5.2 ( 3.1 )

ANCOVA analysis of pain intensity T1 and T2

Comparison groups

Treatment 1 (Ibuprofen - Tramadol) v Treatment 2 (Ibuprofen (arginine))

Number of subjects included in analysis

182

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0804

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

0.1

ANCOVA analysis of pain intensity T 1 and T3

Comparison groups

Treatment 1 (Ibuprofen - Tramadol) v Treatment 3 (Tramadol)

Number of subjects included in analysis

186

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0036

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

-0.4

ANCOVA analysis of pain intensity T1 and T4

Comparison groups

Treatment 1 (Ibuprofen - Tramadol) v Treatment 4 (Placebo)

Number of subjects included in analysis

183

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-2.2

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

-1.4

Adverse events

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Timeframe for reporting adverse events

SAE reporting requirements for all patients from randomisation to 30 days after last administered dose of study medication.

Adverse event reporting additional description

Safety analysis was performed on 384 randomised patients.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

Treatment 1 (Ibuprofen - Tramadol)

Reporting group description

Reporting group title

Treatment 2 (Ibuprofen (arginine))

Reporting group description

Reporting group title

Treatment 3 (Tramadol)

Reporting group description

Reporting group title

Treatment 4 (Placebo)

Reporting group description

Serious adverse events	Treatment 1 (Ibuprofen - Tramadol)	Treatment 2 (Ibuprofen (arginine))	Treatment 3 (Tramadol)	Treatment 4 (Placebo)
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 92 (3.26%)	2 / 97 (2.06%)	9 / 99 (9.09%)	10 / 96 (10.42%)
number of deaths (all causes)	0	0	1	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Endometrial adenocarcinoma
subjects affected / exposed	1 / 92 (1.09%)	0 / 97 (0.00%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Glioblastoma
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Endometrial stromal sarcoma
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cervix carcinoma stage 0
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	0 / 99 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Borderline ovarian tumour
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	0 / 99 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Wound haemorrhage
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ureteric injury
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound dehiscence
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	0 / 99 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suture-related complication
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	0 / 99 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haematoma
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	1 / 99 (1.01%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Abscess drainage
subjects affected / exposed	1 / 92 (1.09%)	0 / 97 (0.00%)	0 / 99 (0.00%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Leukocytosis
subjects affected / exposed	0 / 92 (0.00%)	1 / 97 (1.03%)	0 / 99 (0.00%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound secretion
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal wall haematoma
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	1 / 92 (1.09%)	0 / 97 (0.00%)	0 / 99 (0.00%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 92 (0.00%)	1 / 97 (1.03%)	0 / 99 (0.00%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Vaginal haematoma
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	0 / 99 (0.00%)	2 / 96 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Ureteric obstruction
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	0 / 99 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Vulval abscess
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	1 / 92 (1.09%)	0 / 97 (0.00%)	0 / 99 (0.00%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	0 / 99 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	0 / 99 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Treatment 1 (Ibuprofen - Tramadol)	Treatment 2 (Ibuprofen (arginine))	Treatment 3 (Tramadol)	Treatment 4 (Placebo)
Total subjects affected by non serious adverse events
subjects affected / exposed	31 / 92 (33.70%)	29 / 97 (29.90%)	31 / 99 (31.31%)	23 / 96 (23.96%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign gastrointestinal neoplasm
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences all number	0	0	1	0
Vascular disorders
Hot flush
subjects affected / exposed	0 / 92 (0.00%)	1 / 97 (1.03%)	0 / 99 (0.00%)	0 / 96 (0.00%)
occurrences all number	0	1	0	0
Thrombosis
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences all number	0	0	1	0
Surgical and medical procedures
Protein C increased
subjects affected / exposed	0 / 92 (0.00%)	1 / 97 (1.03%)	0 / 99 (0.00%)	0 / 96 (0.00%)
occurrences all number	0	1	0	0
Removal of foreign body from throat
subjects affected / exposed	1 / 92 (1.09%)	0 / 97 (0.00%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences all number	1	0	1	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences all number	0	0	1	0
Pain
subjects affected / exposed	0 / 92 (0.00%)	1 / 97 (1.03%)	0 / 99 (0.00%)	0 / 96 (0.00%)
occurrences all number	0	1	0	0
thoracic pain
subjects affected / exposed	1 / 92 (1.09%)	0 / 97 (0.00%)	0 / 99 (0.00%)	1 / 96 (1.04%)
occurrences all number	1	0	0	1
Malaise
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	0 / 99 (0.00%)	1 / 96 (1.04%)
occurrences all number	0	0	0	1
Discomfort
subjects affected / exposed	1 / 92 (1.09%)	0 / 97 (0.00%)	0 / 99 (0.00%)	0 / 96 (0.00%)
occurrences all number	1	0	0	0
Pyrexia
subjects affected / exposed	1 / 92 (1.09%)	7 / 97 (7.22%)	3 / 99 (3.03%)	8 / 96 (8.33%)
occurrences all number	1	7	3	8
Drug tolerance increased
subjects affected / exposed	1 / 92 (1.09%)	0 / 97 (0.00%)	0 / 99 (0.00%)	0 / 96 (0.00%)
occurrences all number	1	0	0	0
Social circumstances
Tattoo
subjects affected / exposed	1 / 92 (1.09%)	0 / 97 (0.00%)	0 / 99 (0.00%)	0 / 96 (0.00%)
occurrences all number	1	0	0	0
Reproductive system and breast disorders
Vaginal haemorrhage
subjects affected / exposed	0 / 92 (0.00%)	1 / 97 (1.03%)	0 / 99 (0.00%)	1 / 96 (1.04%)
occurrences all number	0	1	0	1
Vaginal discharge
subjects affected / exposed	1 / 92 (1.09%)	0 / 97 (0.00%)	0 / 99 (0.00%)	0 / 96 (0.00%)
occurrences all number	1	0	0	0
Vulvovaginal pruritus
subjects affected / exposed	1 / 92 (1.09%)	0 / 97 (0.00%)	0 / 99 (0.00%)	0 / 96 (0.00%)
occurrences all number	1	0	0	0
Respiratory, thoracic and mediastinal disorders
Catarrh
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	0 / 99 (0.00%)	1 / 96 (1.04%)
occurrences all number	0	0	0	1
Nasal congestion
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	0 / 99 (0.00%)	1 / 96 (1.04%)
occurrences all number	0	0	0	1
Cough
subjects affected / exposed	1 / 92 (1.09%)	1 / 97 (1.03%)	1 / 99 (1.01%)	1 / 96 (1.04%)
occurrences all number	1	1	1	1
Psychiatric disorders
Insomnia
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences all number	0	0	1	0
Injury, poisoning and procedural complications
Anaemia postoperative
subjects affected / exposed	0 / 92 (0.00%)	1 / 97 (1.03%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences all number	0	1	1	0
Subcutaneous haematoma
subjects affected / exposed	0 / 92 (0.00%)	1 / 97 (1.03%)	0 / 99 (0.00%)	0 / 96 (0.00%)
occurrences all number	0	1	0	0
Seroma
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	0 / 99 (0.00%)	1 / 96 (1.04%)
occurrences all number	0	0	0	1
Wound dehiscence
subjects affected / exposed	1 / 92 (1.09%)	0 / 97 (0.00%)	1 / 99 (1.01%)	1 / 96 (1.04%)
occurrences all number	1	0	1	1
Post procedural haematoma
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	0 / 99 (0.00%)	1 / 96 (1.04%)
occurrences all number	0	0	0	1
Wound secretion
subjects affected / exposed	1 / 92 (1.09%)	0 / 97 (0.00%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences all number	1	0	1	0
Nervous system disorders
Headache
subjects affected / exposed	0 / 92 (0.00%)	2 / 97 (2.06%)	5 / 99 (5.05%)	3 / 96 (3.13%)
occurrences all number	0	2	5	3
Paraesthesia
subjects affected / exposed	0 / 92 (0.00%)	1 / 97 (1.03%)	0 / 99 (0.00%)	0 / 96 (0.00%)
occurrences all number	0	1	0	0
Dizziness
subjects affected / exposed	4 / 92 (4.35%)	1 / 97 (1.03%)	5 / 99 (5.05%)	1 / 96 (1.04%)
occurrences all number	4	1	6	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	6 / 92 (6.52%)	5 / 97 (5.15%)	5 / 99 (5.05%)	2 / 96 (2.08%)
occurrences all number	6	5	5	2
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 92 (0.00%)	1 / 97 (1.03%)	0 / 99 (0.00%)	1 / 96 (1.04%)
occurrences all number	0	1	0	1
Eye disorders
Halo vision
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	0 / 99 (0.00%)	1 / 96 (1.04%)
occurrences all number	0	0	0	1
Gastrointestinal disorders
Abdominal pain lower
subjects affected / exposed	2 / 92 (2.17%)	1 / 97 (1.03%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences all number	2	1	1	0
Abdominal pain upper
subjects affected / exposed	0 / 92 (0.00%)	1 / 97 (1.03%)	1 / 99 (1.01%)	1 / 96 (1.04%)
occurrences all number	0	1	1	1
Constipation
subjects affected / exposed	2 / 92 (2.17%)	0 / 97 (0.00%)	0 / 99 (0.00%)	0 / 96 (0.00%)
occurrences all number	2	0	0	0
Incisional hernia
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	0 / 99 (0.00%)	1 / 96 (1.04%)
occurrences all number	0	0	0	1
Flatulence
subjects affected / exposed	1 / 92 (1.09%)	3 / 97 (3.09%)	2 / 99 (2.02%)	2 / 96 (2.08%)
occurrences all number	1	3	2	2
Nausea
subjects affected / exposed	3 / 92 (3.26%)	4 / 97 (4.12%)	5 / 99 (5.05%)	5 / 96 (5.21%)
occurrences all number	3	4	5	5
Gastrointestinal motility disorder
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences all number	0	0	1	0
Vomiting
subjects affected / exposed	5 / 92 (5.43%)	1 / 97 (1.03%)	4 / 99 (4.04%)	3 / 96 (3.13%)
occurrences all number	5	1	4	3
Diarrhoea
subjects affected / exposed	0 / 92 (0.00%)	2 / 97 (2.06%)	0 / 99 (0.00%)	0 / 96 (0.00%)
occurrences all number	0	2	0	0
Abdominal pain
subjects affected / exposed	1 / 92 (1.09%)	1 / 97 (1.03%)	1 / 99 (1.01%)	1 / 96 (1.04%)
occurrences all number	1	1	1	1
Abdominal wall haematoma
subjects affected / exposed	0 / 92 (0.00%)	1 / 97 (1.03%)	0 / 99 (0.00%)	0 / 96 (0.00%)
occurrences all number	0	1	0	0
Skin and subcutaneous tissue disorders
Dermatitis contact0
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences all number	0	0	1	0
Ecchymosis
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	0 / 99 (0.00%)	1 / 96 (1.04%)
occurrences all number	0	0	0	1
Erythema
subjects affected / exposed	1 / 92 (1.09%)	0 / 97 (0.00%)	0 / 99 (0.00%)	1 / 96 (1.04%)
occurrences all number	1	0	0	1
Urticaria
subjects affected / exposed	0 / 92 (0.00%)	1 / 97 (1.03%)	0 / 99 (0.00%)	0 / 96 (0.00%)
occurrences all number	0	1	0	0
Decubitus ulcer
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences all number	0	0	1	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	2 / 99 (2.02%)	1 / 96 (1.04%)
occurrences all number	0	0	2	1
Bladder spasm
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences all number	0	0	1	0
Incontinence
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences all number	0	0	1	0
Micturition urgency
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	0 / 99 (0.00%)	1 / 96 (1.04%)
occurrences all number	0	0	0	1
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 92 (0.00%)	1 / 97 (1.03%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences all number	0	1	1	0
Infections and infestations
Vulvovaginal candidiasis
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	0 / 99 (0.00%)	1 / 96 (1.04%)
occurrences all number	0	0	0	1
Cystitis
subjects affected / exposed	0 / 92 (0.00%)	0 / 97 (0.00%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences all number	0	0	1	0
Pharyngitis
subjects affected / exposed	1 / 92 (1.09%)	0 / 97 (0.00%)	0 / 99 (0.00%)	0 / 96 (0.00%)
occurrences all number	1	0	0	0
Urinary tract infection
subjects affected / exposed	1 / 92 (1.09%)	0 / 97 (0.00%)	1 / 99 (1.01%)	1 / 96 (1.04%)
occurrences all number	1	0	1	1
Wound infection staphylococcal
subjects affected / exposed	1 / 92 (1.09%)	0 / 97 (0.00%)	0 / 99 (0.00%)	0 / 96 (0.00%)
occurrences all number	1	0	0	0
Postoperative wound infection
subjects affected / exposed	2 / 92 (2.17%)	1 / 97 (1.03%)	1 / 99 (1.01%)	0 / 96 (0.00%)
occurrences all number	2	1	1	0
Metabolism and nutrition disorders
Hypoglycaemia
subjects affected / exposed	0 / 92 (0.00%)	1 / 97 (1.03%)	0 / 99 (0.00%)	0 / 96 (0.00%)
occurrences all number	0	1	0	0

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

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

None reported

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Subject disposition

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Baseline characteristics

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End points

Primary: Pain intensity 24 hours after the start of the treatment.

Primary: Pain intensity 24 hours after the start of the treatment.

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

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