Clinical Trial Results:
A randomised, double-blind, parallel groups, placebo-controlled, multi-centre study assessing the effects of a selective oxytocin antagonist (barusiban) and a mixed oxytocin antagonist – vasopressin V1a antagonist (atosiban) administered intravenously on luteal phase uterine contractions in oocyte donors supplemented with vaginal progesterone

Trial information Top of page
Trial identification
Sponsor protocol code	FE 200440 CS09
Additional study identifiers
ISRCTN number	-
US NCT number	NCT00587327
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Ferring Pharmaceuticals A/S
Sponsor organisation address	Kay Fiskers Plads 11, Copenhagen S, Denmark, 2300
Public contact	Clinical Development Support, Ferring Pharmaceuticals, DK0-Disclosure@ferring.com
Scientific contact	Clinical Development Support, Ferring Pharmaceuticals, DK0-Disclosure@ferring.com
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	11 Sep 2008
Is this the analysis of the primary completion data?	Yes
Primary completion date	26 May 2008
Global end of trial reached?	Yes
Global end of trial date	11 Sep 2008
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	To evaluate the effects of barusiban and atosiban compared to placebo on luteal phase uterine contractions in oocyte donors supplemented with progesterone
Protection of trial subjects	The trial was performed in accordance with the Declaration of Helsinki and its amendments in force at the initiation of the trial.
Background therapy	Progesterone (utrogestan), as non-investigational medicinal product (NIMP), was dispensed to subjects who were screened and included in the trial.
Evidence for comparator	This was a randomised controlled trial with placebo as the comparator to adequately document the efficacy and safety of barusiban and atosiban. A placebo group was justified for this trial as there is no therapy available for this indication.
Actual start date of recruitment	13 Nov 2007
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Belgium: 33
Country: Number of subjects enrolled	Czech Republic: 53
Country: Number of subjects enrolled	Spain: 39
Worldwide total number of subjects	125
EEA total number of subjects	125
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	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)	125
From 65 to 84 years	0
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	A total of 5 sites randomised subjects into the trial : 1 in Belgium, 2 in Spain, and 2 in Czech Republic.
Pre-assignment
Screening details	A total of 129 subjects were screened in the trial, of whom 125 subjects were randomised: 41 to barusiban, 42 to atosiban and 42 to placebo.
Period 1
Period 1 title	Overall period
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Double blind
Roles blinded	Subject, Investigator, Monitor, Data analyst, Carer, Assessor
Arms
Are arms mutually exclusive	Yes
Arm title	Barusiban
Arm description	Subjects randomised to barusiban investigational medicinal product (IMP) were included in this group.
Arm type	Experimental
Investigational medicinal product name	Barusiban
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for injection
Routes of administration	Intravenous use
Dosage and administration details	Subjects received barusiban (Intravenous [IV] bolus 9 mg followed by an IV infusion of 2.16 mg/h). The IV bolus volume was 0.9 mL administered over 1 minute and the infusion rate was 24 mL/h for approximately 4 hours. Total amount of exposure to barusiban was 17.64 mg (9.0 mg bolus + 8.64 mg infused).
Arm title	Atosiban
Arm description	Subjects randomised to atosiban IMP were included in this group.
Arm type	Experimental
Investigational medicinal product name	Atosiban
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for injection
Routes of administration	Intravenous use
Dosage and administration details	Subjects received atosiban (IV bolus 6.75 mg followed by an IV infusion of 18 mg/h). The IV bolus volume was 0.9 mL administered over 1 minute and the infusion rate was 24 mL/h for approximately 4 hours. Total amount of exposure to atosiban was 78.75 mg (6.75 mg bolus + 72.0 mg infused).
Arm title	Placebo
Arm description	Subjects randomised to placebo IMP were included in this group.
Arm type	Placebo
Investigational medicinal product name	Placebo
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for injection
Routes of administration	Intravenous use
Dosage and administration details	Subjects received IV bolus of saline (sodium chloride 0.9%) followed by an IV infusion of saline. The IV bolus volume was 0.9 mL administered over 1 minute and the infusion rate was 24 mL/h for approximately 4 hours.
Number of subjects in period 1 Barusiban Atosiban Placebo Started 41 42 42 Completed 41 41 42 Not completed 0 1 0      Adverse event, non-fatal - 1 -

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Barusiban
Reporting group description	Subjects randomised to barusiban investigational medicinal product (IMP) were included in this group.
Reporting group title	Atosiban
Reporting group description	Subjects randomised to atosiban IMP were included in this group.
Reporting group title	Placebo
Reporting group description	Subjects randomised to placebo IMP were included in this group.
Reporting group values Barusiban Atosiban Placebo Total Number of subjects 41 42 42 125 Age categorical Data are presented for the ITT analysis set. Units: Subjects     In utero 0 0 0 0     Preterm newborn infants (gestational age < 37 wks) 0 0 0 0     Newborns (0-27 days) 0 0 0 0     Infants and toddlers (28 days-23 months) 0 0 0 0     Children (2-11 years) 0 0 0 0     Adolescents (12-17 years) 0 0 0 0     Adults (18-64 years) 41 42 42 125     From 65-84 years 0 0 0 0     85 years and over 0 0 0 0 Gender categorical Units: Subjects     Female 41 42 42 125     Male 0 0 0 0
Subject analysis sets
Subject analysis set title	Intention-to-treat (ITT) analysis set
Subject analysis set type	Intention-to-treat
Subject analysis set description	All randomised and exposed subjects providing data on the frequency of uterine contractions 3 hours after start of dosing were included in this analysis set.
Subject analysis set title	Per Protocol (PP) analysis set
Subject analysis set type	Per protocol
Subject analysis set description	All subjects in the ITT analysis set except those who met any of the criteria considered as major protocol deviations were included in this analysis set.
Subject analysis set title	Safety Analysis Set
Subject analysis set type	Safety analysis
Subject analysis set description	All randomised and exposed subjects were included in this analysis set.
Subject analysis sets values Intention-to-treat (ITT) analysis set Per Protocol (PP) analysis set Safety Analysis Set Number of subjects 117 112 125 Age categorical Data are presented for the ITT analysis set. Units: Subjects     In utero 0 0 0     Preterm newborn infants (gestational age < 37 wks) 0 0 0     Newborns (0-27 days) 0 0 0     Infants and toddlers (28 days-23 months) 0 0 0     Children (2-11 years) 0 0 0     Adolescents (12-17 years) 0 0 0     Adults (18-64 years) 117 112 125     From 65-84 years 0 0 0     85 years and over 0 0 0 Age continuous Units:      ( ) ( ) ( ) Gender categorical Units: Subjects     Female 117 112 125     Male 0 0 0

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Barusiban
Reporting group description	Subjects randomised to barusiban investigational medicinal product (IMP) were included in this group.
Reporting group title	Atosiban
Reporting group description	Subjects randomised to atosiban IMP were included in this group.
Reporting group title	Placebo
Reporting group description	Subjects randomised to placebo IMP were included in this group.
Subject analysis set title	Intention-to-treat (ITT) analysis set
Subject analysis set type	Intention-to-treat
Subject analysis set description	All randomised and exposed subjects providing data on the frequency of uterine contractions 3 hours after start of dosing were included in this analysis set.
Subject analysis set title	Per Protocol (PP) analysis set
Subject analysis set type	Per protocol
Subject analysis set description	All subjects in the ITT analysis set except those who met any of the criteria considered as major protocol deviations were included in this analysis set.
Subject analysis set title	Safety Analysis Set
Subject analysis set type	Safety analysis
Subject analysis set description	All randomised and exposed subjects were included in this analysis set.

End points Top of page

Primary: Frequency of uterine contractions at 3 hours after start of dosing Top of page
End point title	Frequency of uterine contractions at 3 hours after start of dosing
End point description	Data are presented for the ITT analysis set.
End point type	Primary
End point timeframe	At 3 hours after start of dosing.
End point values Barusiban Atosiban Placebo Number of subjects analysed 38 36 36 Units: contractions/min     arithmetic mean (standard deviation) 2.72 ( 0.991 ) 2.81 ( 0.947 ) 3.14 ( 1.11 )
Statistical analysis title	Frequency at 3 hours- atosiban vs placebo
Statistical analysis description	Analysis of contraction frequency at 3 hours after start of dosing was done using analysis of variance (ANOVA) on the ITT analysis set.
Comparison groups	Placebo v Atosiban
Number of subjects included in analysis	72
Analysis specification	Pre-specified
Analysis type	superiority
P-value	= 0.166
Method	t-test, 2-sided
Parameter type	Mean difference (final values)
Point estimate	-0.335
Confidence interval
level	95%
sides	2-sided
lower limit	-0.811
upper limit	0.141
Statistical analysis title	Frequency at 3 hours- barusiban vs placebo
Statistical analysis description	Analysis of contraction frequency at 3 hours after start of dosing was done using analysis of variance (ANOVA) on the ITT analysis set.
Comparison groups	Placebo v Barusiban
Number of subjects included in analysis	74
Analysis specification	Pre-specified
Analysis type	superiority
P-value	= 0.075
Method	t-test, 2-sided
Parameter type	Mean difference (final values)
Point estimate	-0.426
Confidence interval
level	95%
sides	2-sided
lower limit	-0.896
upper limit	0.043

Primary: Frequency of uterine contractions at 3 hours after start of dosing Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	Overall Treatment Period
Adverse event reporting additional description	Treatment-emergent adverse events (TEAEs) were presented and evaluated by treatment groups. Data were presented for safety analysis set.
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	10.1
Reporting groups
Reporting group title	Barusiban
Reporting group description	Subjects randomised to barusiban IMP were included in this group.
Reporting group title	Atosiban
Reporting group description	Subjects randomised to atosiban IMP were included in this group.
Reporting group title	Placebo
Reporting group description	Subjects randomised to placebo IMP were included in this group.
Serious adverse events Barusiban Atosiban Placebo Total subjects affected by serious adverse events      subjects affected / exposed 0 / 41 (0.00%) 0 / 42 (0.00%) 0 / 42 (0.00%)      number of deaths (all causes) 0 0 0      number of deaths resulting from adverse events 0 0 0
Frequency threshold for reporting non-serious adverse events: 0%
Non-serious adverse events Barusiban Atosiban Placebo Total subjects affected by non serious adverse events      subjects affected / exposed 3 / 41 (7.32%) 1 / 42 (2.38%) 3 / 42 (7.14%) Nervous system disorders Headache      subjects affected / exposed 1 / 41 (2.44%) 0 / 42 (0.00%) 1 / 42 (2.38%)      occurrences all number 1 0 1 Syncope vasovagal      subjects affected / exposed 0 / 41 (0.00%) 1 / 42 (2.38%) 0 / 42 (0.00%)      occurrences all number 0 1 0 General disorders and administration site conditions Injection site erythema      subjects affected / exposed 1 / 41 (2.44%) 0 / 42 (0.00%) 0 / 42 (0.00%)      occurrences all number 1 0 0 Gastrointestinal disorders Nausea      subjects affected / exposed 1 / 41 (2.44%) 0 / 42 (0.00%) 0 / 42 (0.00%)      occurrences all number 1 0 0 Reproductive system and breast disorders Ovarian hyperstimulation syndrome      subjects affected / exposed 0 / 41 (0.00%) 0 / 42 (0.00%) 1 / 42 (2.38%)      occurrences all number 0 0 1 Skin and subcutaneous tissue disorders Eczema      subjects affected / exposed 0 / 41 (0.00%) 0 / 42 (0.00%) 1 / 42 (2.38%)      occurrences all number 0 0 1 Infections and infestations Influenza      subjects affected / exposed 1 / 41 (2.44%) 0 / 42 (0.00%) 0 / 42 (0.00%)      occurrences all number 1 0 0

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date	Amendment
29 May 2008	Two protocol changes were introduced in this amendment: the inclusion of a new secondary endpoint, and addition of uterine description and transvaginal ultrasound quality parameters.
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
None reported

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