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Clinical Trial Results:
Randomized, Double-Blind, Multicenter, Phase III Study Comparing the Efficacy and Safety of Retosiban Versus Placebo for Women in Spontaneous Preterm Labor

Summary
EudraCT number	2014-003326-41
Trial protocol	GB IT
Global end of trial date	24 Jul 2017

Results information
Results version number	v5(current)
This version publication date	30 Aug 2018
First version publication date	07 Feb 2018
Other versions	v1 , v2 , v3 , v4
Version creation reason

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

200719

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline

Sponsor organisation address

980 Great West Road, Brentford, Middlesex, United Kingdom,

Public contact

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

Scientific contact

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000162-PIP20-16

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

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

Yes

Analysis stage

Final

Date of interim/final analysis

06 Nov 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

24 Jul 2017

Was the trial ended prematurely?

Yes

Main objective of the trial

To demonstrate the superiority of retosiban to prolong pregnancy and improve neonatal outcomes compared with placebo

Protection of trial subjects

Not applicable

Background therapy

Evidence for comparator

Actual start date of recruitment

29 Feb 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 3

Country: Number of subjects enrolled

Japan: 8

Country: Number of subjects enrolled

United States: 14

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

NEWBORN-1 was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study to investigate efficacy and safety of retosiban in female participants aged 12 to 45 years with an uncomplicated singleton pregnancy in preterm labor with intact membranes between 24 0/7 and 33 6/7 weeks gestation. The study was conducted in 3 countries.

Screening details

Twenty-five participants were randomly assigned to study treatments: 12 participants to retosiban intravenous (IV) infusion and 13 participants to matched placebo IV infusion. Two participants randomized to retosiban arm did not receive study treatment. The study was terminated early due to feasibility of recruiting the study in a timely manner.

Number of subjects started

Intermediate milestone: Number of subjects

Treated: 23

Number of subjects completed

Reason: Number of subjects

Randomized and not treated: 2

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

Are arms mutually exclusive

Yes

Placebo

Arm description

Placebo was 0.9 percent sodium chloride infusion matched for retosiban volume, IV loading dose over 5 minutes and continuous infusion rate including dose increase in participants with an inadequate response any time after first hour of treatment.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Placebo was 0.9 percent sodium chloride matched for retosiban loading dose and continuous infusion rates.

Retosiban

Arm description

Arm type

Experimental

Investigational medicinal product name

Retosiban

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Retosiban was available as a clear, colorless solution for infusion at a concentration of 15 milligrams per milliliter (mg/mL).

Number of subjects in period 1 ^[1]	Placebo	Retosiban
Started	13	10
Completed	13	10

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: Two participants randomized to retosiban arm did not receive study treatment due to labor progression.

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Reporting group title

Retosiban

Reporting group description

Reporting group values	Placebo	Retosiban	Total
Number of subjects	13	10
Age categorical
Units: Subjects
Age continuous
Maternal intent-to-treat (ITT) Population comprised of all mothers randomly assigned to treatment who have been exposed to study treatment irrespective of their compliance to the planned course of treatment.
Units: years
arithmetic mean (standard deviation)	26.5 ± 6.78	27.7 ± 6.73	-
Gender categorical
Maternal intent-to-treat (ITT) Population comprised of all mothers randomly assigned to treatment who have been exposed to study treatment irrespective of their compliance to the planned course of treatment.
Units: Subjects
Female	13	10	23
Male	0	0	0
Race/Ethnicity, Customized
Maternal intent-to-treat (ITT) Population comprised of all mothers randomly assigned to treatment who have been exposed to study treatment irrespective of their compliance to the planned course of treatment.
Units: Subjects
African American/African Heritage	2	2	4
Asian-Central/South Asian Heritage	0	1	1
Asian-East Asian Heritage	1	0	1
Asian-Japanese Heritage	4	2	6
Asian-South East Asian Heritage	1	0	1
White-White/Caucasian/European Heritage	5	5	10

End points

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Reporting group title

Placebo

Reporting group description

Reporting group title

Retosiban

Reporting group description

Subject analysis set title

Retosiban

Subject analysis set type

Safety analysis

Subject analysis set description

Participants were administered 6 milligram (mg) IV loading dose of retosiban over 5 minutes followed by a 6 milligram per hour (mg/hour) continuous infusion of retosiban over 48 hours. Participants with an inadequate response any time after first hour of treatment were administered another 6 mg retosiban loading dose followed by 12 mg/hour continuous infusion for remainder of 48-hour treatment period. Data is a combined data set. Data is presented for 10 participants from retosiban arm of study 200719 (NCT02377466) and 43 participants from retosiban arm of study 200721 (NCT02292771). Actual total participants analyzed is 53 and not 10. 53 cannot be added due to system limitation.

Primary: Time to delivery or treatment failure, whichever occurs first

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End point title

Time to delivery or treatment failure, whichever occurs first ^[1]

End point description

Time to delivery or treatment failure is the number of days from the first dose of study treatment until delivery or treatment failure whichever occurs first. Treatment failure is defined as the administration of any putative tocolytic medication for treatment of preterm labor or as prophylaxis of preterm labor. Maternal intent-to-treat (ITT) Population comprised of all mothers randomly assigned to treatment who have been exposed to study treatment irrespective of their compliance to the planned course of treatment. The mean number of days to delivery or treatment failure along with standard deviation has been presented. Statistical analysis was not performed due to early termination of the study and resultant small sample size.

End point type

Primary

End point timeframe

Up to 17 weeks

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analysis was not performed due to early termination of the study and resultant small sample size.

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[2]	10 ^[3]
Units: Days
arithmetic mean (standard deviation)
Days	11.10 ± 14.987	18.91 ± 22.993

Notes
[2] - Maternal ITT Population
[3] - Maternal ITT Population

No statistical analyses for this end point

Primary: Number of neonates with any diagnosis from the neonatal morbidity and mortality composite component

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End point title

Number of neonates with any diagnosis from the neonatal morbidity and mortality composite component ^[4]

End point description

The neonatal composite endpoint was determined from review of medical records and included the following components: fetal or neonatal death, respiratory distress syndrome (RDS), bronchopulmonary dysplasia, necrotizing enterocolitis or isolated perforation, sepsis based on positive blood culture with clinical features of sepsis, meningitis based on positive results for cerebrospinal fluid culture performed as part of infection workup, retinopathy of prematurity, intraventricular hemorrhage (IVH), white matter injury and cerebellar hemorrhage. Neonates with any of the composite component has been presented. Statistical analysis was not performed due to early termination of study and resultant small sample size. Neonatal ITT Population comprised of all neonates whose mothers were the randomized participants who have been exposed to study treatment, that is, mothers from the ITT Population.

End point type

Primary

End point timeframe

Up to 28 days after the estimated date of delivery (EDD) of 40 0/7 weeks

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analysis was not performed due to early termination of the study and resultant small sample size.

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[5]	10 ^[6]
Units: Participants
Participants	4	2

Notes
[5] - Neonatal ITT Population
[6] - Neonatal ITT Population

No statistical analyses for this end point

Secondary: Time to delivery

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End point title

Time to delivery

End point description

The time to delivery was calculated as the days between the delivery and start time of the study treatment infusion using the formula: Time to delivery (days) = (date and time of delivery minus date and time of start of infusion) divided by (24 multiplied by 60). The mean number of days to delivery along with standard deviation has been presented.

End point type

Secondary

End point timeframe

Up to 17 weeks

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[7]	10 ^[8]
Units: Days
arithmetic mean (standard deviation)
Days	16.32 ± 18.595	19.18 ± 22.770

Notes
[7] - Maternal ITT Population
[8] - Maternal ITT Population

No statistical analyses for this end point

Secondary: Number of participants with births prior to 37 0/7 Weeks gestation

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End point title

Number of participants with births prior to 37 0/7 Weeks gestation

End point description

Gestational age at birth (weeks) is defined as the gestational age when the baby is born. Participants were considered to have delivered prior to 37 0/7 weeks, that is preterm, if the gestational age at birth is less than 37 0/7 weeks. The number of participants who delivered prior to 37 0/7 weeks gestation has been presented.

End point type

Secondary

End point timeframe

Up to 13 weeks

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[9]	10 ^[10]
Units: Participants
Participants	9	8

Notes
[9] - Maternal ITT Population
[10] - Maternal ITT Population

No statistical analyses for this end point

Secondary: Number of participants with births at term

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End point title

Number of participants with births at term

End point description

Participants were considered to have delivered at term if the gestational age was >=37 0/7. The number of participants who delivered at term, that is, 37 0/7 to 41 6/7 weeks gestation has been presented.

End point type

Secondary

End point timeframe

Up to 17 weeks

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[11]	10 ^[12]
Units: Participants
Participants	4	2

Notes
[11] - Maternal ITT Population
[12] - Maternal ITT Population

No statistical analyses for this end point

Secondary: Length of neonatal hospital stay

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End point title

Length of neonatal hospital stay

End point description

The length of stay was collected from medical records and was calculated as the days between the delivery date and time and discharge date and time.

End point type

Secondary

End point timeframe

Up to 28 days post EDD of 40 0/7 weeks gestation

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[13]	10 ^[14]
Units: Days
arithmetic mean (standard deviation)
Days	37.50 ± 34.537	26.05 ± 32.689

Notes
[13] - Neonatal ITT Population
[14] - Neonatal ITT Population

No statistical analyses for this end point

Secondary: Number of participants with births prior to 35 0/7 weeks gestation

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End point title

Number of participants with births prior to 35 0/7 weeks gestation

End point description

The number of participants who delivered prior to 35 0/7 weeks gestation has been presented.

End point type

Secondary

End point timeframe

Up to 11 weeks

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[15]	10 ^[16]
Units: Participants
Participants	9	7

Notes
[15] - Maternal ITT Population
[16] - Maternal ITT Population

No statistical analyses for this end point

Secondary: Number of participants with births prior to 32 0/7 weeks gestation

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End point title

Number of participants with births prior to 32 0/7 weeks gestation

End point description

The number of participants who delivered prior to 32 0/7 weeks gestation has been presented. Only those maternal participants who were randomized prior to 32 0/7 week's gestation and delivered were included.

End point type

Secondary

End point timeframe

Up to 8 weeks

End point values	Placebo	Retosiban
Number of subjects analysed	9 ^[17]	6 ^[18]
Units: Participants
Participants	6	2

Notes
[17] - Maternal ITT Population
[18] - Maternal ITT Population

No statistical analyses for this end point

Secondary: Number of participants with births prior to 28 0/7 weeks gestation

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End point title

Number of participants with births prior to 28 0/7 weeks gestation

End point description

The number of participants who delivered prior to 28 0/7 weeks gestation has been presented. Only those maternal participants who were randomized prior to 28 0/7 week's gestation and delivered were included.

End point type

Secondary

End point timeframe

Up to 4 weeks

End point values	Placebo	Retosiban
Number of subjects analysed	2 ^[19]	2 ^[20]
Units: Participants
Participants	2	1

Notes
[19] - Maternal ITT Population
[20] - Maternal ITT Population

No statistical analyses for this end point

Secondary: Number of participants with births at <=7 days from the first study treatment

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End point title

Number of participants with births at <=7 days from the first study treatment

End point description

The number of participants who delivered in less than or equal to 7 days from first dose of study treatment has been presented.

End point type

Secondary

End point timeframe

Up to 7 days

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[21]	10 ^[22]
Units: Participants
Participants	5	5

Notes
[21] - Maternal ITT Population
[22] - Maternal ITT Population

No statistical analyses for this end point

Secondary: Number of participants with births at <=48 hours from the first study treatment

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End point title

Number of participants with births at <=48 hours from the first study treatment

End point description

The number of participants who delivered in less than or equal to 48 hours from first dose of study treatment has been presented.

End point type

Secondary

End point timeframe

Up to 48 hours

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[23]	10 ^[24]
Units: Participants
Participants	3	3

Notes
[23] - Maternal ITT Population
[24] - Maternal ITT Population

No statistical analyses for this end point

Secondary: Number of participants with births at <=24 hours from the first study treatment

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End point title

Number of participants with births at <=24 hours from the first study treatment

End point description

The number of participants who delivered in less than or equal to 24 hours from first dose of study treatment has been presented.

End point type

Secondary

End point timeframe

Up to 24 hours

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[25]	10 ^[26]
Units: Participants
Participants	3	1

Notes
[25] - Maternal ITT Population
[26] - Maternal ITT Population

No statistical analyses for this end point

Secondary: Number of neonates with any of the co-primary composite neonatal morbidity and mortality, excluding RDS

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End point title

Number of neonates with any of the co-primary composite neonatal morbidity and mortality, excluding RDS

End point description

The neonatal composite endpoint was determined from review of medical records and included the following components: fetal or neonatal death, RDS, bronchopulmonary dysplasia, necrotizing enterocolitis or isolated perforation, sepsis based on positive blood culture with clinical features of sepsis, meningitis based on positive results for cerebrospinal fluid culture performed as part of infection workup, retinopathy of prematurity, IVH, white matter injury and cerebellar hemorrhage. The number of neonates with any co-primary composite neonatal morbidity and mortality component, excluding RDS has been presented.

End point type

Secondary

End point timeframe

Up to 28 weeks after EDD (40 weeks gestation)

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[27]	10 ^[28]
Units: Participants
Participants	3	0

Notes
[27] - Neonatal ITT Population
[28] - Neonatal ITT Population

No statistical analyses for this end point

Secondary: Number of neonates with each individual component of the composite neonatal morbidity and mortality

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End point title

Number of neonates with each individual component of the composite neonatal morbidity and mortality

End point description

The neonatal composite endpoint was determined from review of medical records and included the following components: fetal or neonatal death, RDS, bronchopulmonary dysplasia, necrotizing enterocolitis or isolated perforation, sepsis based on positive blood culture with clinical features of sepsis, meningitis based on positive results for cerebrospinal fluid culture performed as part of infection workup, retinopathy of prematurity, IVH, white matter injury and cerebellar hemorrhage. The number of neonates with each individual component of the composite component has been presented.

End point type

Secondary

End point timeframe

Up to 28 days after the EDD of 40 0/7 weeks

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[29]	10 ^[30]
Units: Participants
Fetal Death	0	0
Neonatal Death	0	0
RDS	3	2
Bronchopulmonary dysplasia	3	0
Necrotizing enterocolitis or Isolated Perforation	0	0
Sepsis	0	0
Meningitis	0	0
Retinopathy of prematurity	0	0
IVH	0	0
White Matter Injury	0	0
Cerebellar Hemorrhage	0	0

Notes
[29] - Neonatal ITT Population
[30] - Neonatal ITT Population

No statistical analyses for this end point

Secondary: Number of neonatal participants with admission to a particular hospital unit

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End point title

Number of neonatal participants with admission to a particular hospital unit

End point description

Neonatal healthcare resource utilization was collected from review of medical records. The number of neonatal participants who were admitted to a particular hospital unit that is, level III (or higher) intensive neonatal care (NICU), Intensive care unit (ICU), general ward, Level I - Basic Neonatal care, Well born nursery (SCBU) and Level II-Special Care Newborn nursery high dependency (NHDU) has been summarized. Neonatal Safety Population consisted of neonates whose mothers received study treatment.

End point type

Secondary

End point timeframe

Up to 28 days post EDD (40 0/7 weeks gestation)

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[31]	10 ^[32]
Units: Participants
Level III (or higher) NICU	5	6
Intensive care unit	0	1
General Ward	2	2
Level II-Special Care NHDU	0	1
Missing	1	0
Multiple ward type	5	0

Notes
[31] - Neonatal Safety Population
[32] - Neonatal Safety Population

No statistical analyses for this end point

Secondary: Length of stay in specialized care unit

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End point title

Length of stay in specialized care unit

End point description

Neonatal healthcare resource utilization was collected from review of medical records. The length of stay in a specialized care unit (NICU or ICU) has been presented for neonatal participants with admission to ICU or NICU.

End point type

Secondary

End point timeframe

Up to 28 days post EDD (40 0/7 weeks gestation)

End point values	Placebo	Retosiban
Number of subjects analysed	10 ^[33]	7 ^[34]
Units: Days
arithmetic mean (standard deviation)
Days	40.34 ± 35.475	35.60 ± 35.308

Notes
[33] - Neonatal Safety Population
[34] - Neonatal Safety Population

No statistical analyses for this end point

Secondary: Number of newborn participants with hospital readmission

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End point title

Number of newborn participants with hospital readmission

End point description

Newborn hospital readmission following hospitalization for birth was collected from the newborn's medical records. The number of newborn participants who had readmission to hospital is presented.

End point type

Secondary

End point timeframe

Up to 28 days of EDD (40 0/7 weeks gestation)

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[35]	10 ^[36]
Units: Participants
Participants	0	0

Notes
[35] - Neonatal Safety Population
[36] - Neonatal Safety Population

No statistical analyses for this end point

Secondary: Length of stay following readmission to hospital

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End point title

Length of stay following readmission to hospital

End point description

Newborn hospital readmission following hospitalization for birth was collected from the newborn's medical records. Length of stay in hospital following readmission is presented for neonates.

End point type

Secondary

End point timeframe

Up to 28 days after EDD (40 0/7 weeks gestation)

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[37]	10 ^[38]
Units: Days
median (full range (min-max))
Days	0 (0 to 0)	0 (0 to 0)

Notes
[37] - Neonatal Safety Population
[38] - Neonatal Safety Population

No statistical analyses for this end point

Secondary: Number of participants with ambulatory surgery

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End point title

Number of participants with ambulatory surgery

End point description

Information regarding participants who had ambulatory surgery was collected from the newborn medical records. The number of neonatal participants with ambulatory surgery is presented.

End point type

Secondary

End point timeframe

Up to 28 days post EDD (40 0/7 weeks gestation)

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[39]	10 ^[40]
Units: Participants
Participants	0	0

Notes
[39] - Neonatal Safety Population
[40] - Neonatal Safety Population

No statistical analyses for this end point

Secondary: Time to treatment failure

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End point title

Time to treatment failure

End point description

Treatment failure is defined as the administration of any putative tocolytic medication for treatment of preterm labor or as prophylaxis of preterm labor. Time to treatment failure is the number of days from the first dose of study treatment until treatment failure. The mean number of days to delivery or treatment failure along with standard deviation has been presented. Only those maternal participants with treatment failure were included in the analysis. 99999 indicates standard deviation could not be calculated as only one participant was analyzed.

End point type

Secondary

End point timeframe

Up to 17 weeks

End point values	Placebo	Retosiban
Number of subjects analysed	4 ^[41]	1 ^[42]
Units: Days
arithmetic mean (standard deviation)
Days	1.141 ± 1.4307	0.899 ± 99999

Notes
[41] - Maternal ITT Population
[42] - Maternal ITT Population

No statistical analyses for this end point

Secondary: Number of participants who received any putative tocolytic

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End point title

Number of participants who received any putative tocolytic

End point description

A putative tocolytic medication was the medication administered for active preterm labor or as prevention of preterm labor and included calcium channel blockers, nonsteroidal anti-inflammatory drugs, or beta agonists, or magnesium sulfate doses that exceeded prespecified IV loading doses, infusion rates, or total duration of administration.

End point type

Secondary

End point timeframe

Up to 17 weeks

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[43]	10 ^[44]
Units: Participants
Participants	4	1

Notes
[43] - Maternal Safety Population
[44] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Number of participants with subsequent preterm labor

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End point title

Number of participants with subsequent preterm labor

End point description

The participants who had not delivered after 48 hours post-infusion were contacted to determine if they had delivered or experienced any subsequent episodes of preterm labor. A subsequent episode of preterm labor was only recorded if the participant reported it to the Principal Investigator during one of the telephone follow-up calls but did not then go on to immediately deliver. However, if labor started and led to immediate delivery, then the only data collected would be the pre-specified delivery data and thus would not be counted as a subsequent episode of preterm labor. The number of participants who had a subsequent episode of preterm labor after administration of the study treatment has been presented. Maternal Safety Population comprised of all maternal participants randomly assigned to treatment who have been exposed to study treatment.

End point type

Secondary

End point timeframe

Up to 11 weeks

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[45]	10 ^[46]
Units: Participants
Participants	1	1

Notes
[45] - Maternal Safety Population
[46] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Number of maternal participants with adverse events (AEs) and serious adverse events (SAEs)

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End point title

Number of maternal participants with adverse events (AEs) and serious adverse events (SAEs)

End point description

An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; important medical events that mey require medical or surgical intervention to prevent one of the other outcomes described before; is associated with liver injury and impaired liver function. The number of maternal participants who experienced at least one AE and one SAE has been presented.

End point type

Secondary

End point timeframe

Up to 6 weeks after delivery

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[47]	10 ^[48]
Units: Participants
AEs	6	6
SAEs	0	0

Notes
[47] - Maternal Safety Population
[48] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Change from Baseline in diastolic blood pressure (DBP) and systolic blood pressure (SBP)

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End point title

Change from Baseline in diastolic blood pressure (DBP) and systolic blood pressure (SBP)

End point description

SBP and DBP were measured with participants in a semirecumbent or seated position. SBP and DBP were measured during inpatient randomized treatment phase (15 to 30 minutes, 4 to 8 hours, and 20 to 24 hours after the start of the infusion, at the end of the infusion) and at the post-infusion assessment. Baseline is the last available assessment prior to first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

End point type

Secondary

End point timeframe

Baseline and up to 9 days

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[49]	10 ^[50]
Units: millimeter of mercury (mmHg)
arithmetic mean (standard deviation)
DBP; Day 1: 15 to 30 minutes; n=13, 10	-3.2 ± 10.64	-6.8 ± 8.22
DBP; Day 1: 4 to 8 hours; n=11, 10	-9.0 ± 11.31	-7.0 ± 10.14
DBP; Day 1: 20 to 24 hours; n=10, 8	-13.1 ± 11.05	-6.5 ± 8.65
DBP; Day 2; n=11, 7	-10.2 ± 11.07	-4.0 ± 6.66
DBP; Post infusion assessment; n=9, 5	-6.6 ± 12.69	-2.8 ± 4.76
SBP; Day 1: 15 to 30 minutes; n=13, 10	-0.8 ± 7.50	-3.1 ± 10.40
SBP; Day 1: 4 to 8 hours; n=11, 10	-7.1 ± 13.09	-1.3 ± 9.06
SBP; Day 1: 20 to 24 hours; n=10, 8	-5.2 ± 12.47	2.6 ± 14.56
SBP; Day 2; n=11, 7	-4.5 ± 11.86	0.7 ± 10.21
SBP; Post infusion assessment; n=9, 5	-9.6 ± 8.69	-7.0 ± 8.22

Notes
[49] - Maternal Safety Population
[50] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Change from Baseline in heart rate

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End point title

Change from Baseline in heart rate

End point description

Heart rate was measured with the participants in a semirecumbent or seated position. Heart rate was measured during inpatient randomized treatment phase (15 to 30 minutes, 4 to 8 hours, and 20 to 24 hours after the start of the infusion, at the end of the infusion) and at the post-infusion assessment. Baseline is the last available assessment prior to first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

End point type

Secondary

End point timeframe

Baseline and up to 9 days

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[51]	10 ^[52]
Units: beats per minute
arithmetic mean (standard deviation)
Day 1: 15 to 30 minutes; n=13, 10	-5.1 ± 12.37	1.4 ± 8.13
Day 1: 4 to 8 hours; n=11, 10	-2.6 ± 10.82	-0.3 ± 8.12
Day 1: 20 to 24 hours; n=9, 8	-4.1 ± 10.61	6.5 ± 21.64
Day 2; n=11, 7	-5.6 ± 15.73	-3.6 ± 13.91
Post infusion assessment; n=9, 5	-6.1 ± 17.80	-3.8 ± 16.24

Notes
[51] - Maternal Safety Population
[52] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Change from Baseline in temperature

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End point title

Change from Baseline in temperature

End point description

Temperature was measured with the participants in a semirecumbent or seated position. Temperature was measured during inpatient randomized treatment phase (15 to 30 minutes, 4 to 8 hours, and 20 to 24 hours after the start of the infusion, at the end of the infusion) and at the post-infusion assessment. Baseline is the last available assessment prior to first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

End point type

Secondary

End point timeframe

Baseline and up to 1 week

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[53]	10 ^[54]
Units: degree Celsius
arithmetic mean (standard deviation)
Day 1: 15 to 30 minutes; n=12, 9	-0.028 ± 0.4123	-0.111 ± 0.1900
Day 1: 4 to 8 hours; n=11, 10	0.087 ± 0.3947	-0.144 ± 0.3594
Day 1: 20 to 24 hours; n=10, 8	0.104 ± 0.5413	-0.043 ± 0.3174
Day 2; n=11, 7	0.105 ± 0.5067	0.051 ± 0.2062
Post-infusion assessment; n=9, 5	-0.136 ± 0.4668	0.072 ± 0.2234

Notes
[53] - Maternal Safety Population
[54] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Change from Baseline in respiratory rate

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End point title

Change from Baseline in respiratory rate

End point description

Respiratory rate was measured with the participants in a semirecumbent or seated position. Respiratory rate was measured during inpatient randomized treatment phase (15 to 30 minutes, 4 to 8 hours, and 20 to 24 hours after the start of the infusion, at the end of the infusion) and at the post-infusion assessment. Baseline is the last available assessment prior to first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

End point type

Secondary

End point timeframe

Baseline and up to 1 week

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[55]	10 ^[56]
Units: breaths per minute
arithmetic mean (standard deviation)
Day 1: 15 to 30 minutes; n=11, 8	0.5 ± 3.45	-1.1 ± 2.90
Day 1: 4 to 8 hours; n=8, 9	1.1 ± 3.83	-1.1 ± 2.15
Day 1: 20 to 24 hours; n=9, 7	0.3 ± 2.35	-1.0 ± 2.77
Day 2; n=10, 6	0.9 ± 4.01	0.0 ± 1.79
Post infusion assessment; n=8, 4	0.4 ± 4.27	0.5 ± 2.52

Notes
[55] - Maternal Safety Population
[56] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Change from Baseline in hematocrit levels

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End point title

Change from Baseline in hematocrit levels

End point description

Blood samples were collected for the evaluation of change in hematocrit levels from Baseline. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

End point type

Secondary

End point timeframe

Baseline and up to 1 week

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[57]	10 ^[58]
Units: Proportion of red blood cells in blood
arithmetic mean (standard deviation)
Day 2; n=9, 3	-0.0343 ± 0.04324	-0.0470 ± 0.02773
Post-infusion assessment; n=7, 5	-0.0090 ± 0.02900	-0.0078 ± 0.02928

Notes
[57] - Maternal Safety Population
[58] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Change from Baseline in hemoglobin and Erythrocyte Mean Corpuscular hemoglobin Concentration (MCHC)

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End point title

Change from Baseline in hemoglobin and Erythrocyte Mean Corpuscular hemoglobin Concentration (MCHC)

End point description

Blood samples were collected for the evaluation of change in hemoglobin levels and MCHC from Baseline. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

End point type

Secondary

End point timeframe

Baseline and up to 1 week

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[59]	10 ^[60]
Units: grams per liter (g/L)
arithmetic mean (standard deviation)
Hemoglobin; Day 2; n=9, 3	-11.2 ± 11.20	-15.7 ± 6.66
Hemoglobin; Post-infusion assessment; n=7, 5	-1.0 ± 9.76	-1.6 ± 8.79
MCHC; Day 2; n=9, 3	-0.3 ± 17.27	-2.7 ± 10.97
MCHC; Post-infusion assessment; n=7, 5	5.0 ± 8.52	2.6 ± 5.41

Notes
[59] - Maternal Safety Population
[60] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Change from Baseline in basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelets and leukocytes count

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End point title

Change from Baseline in basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelets and leukocytes count

End point description

Blood samples were collected for the evaluation of change in basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelets and leukocytes count. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

End point type

Secondary

End point timeframe

Baseline and up to 1 week

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[61]	10 ^[62]
Units: Billion cells per liter (L)
arithmetic mean (standard deviation)
Basophils; Day 2; n=9, 3	-0.003 ± 0.0132	0.000 ± 0.0458
Basophils; post-infusion assessment; n=7, 5	0.003 ± 0.0160	0.058 ± 0.1103
Eosinophils; Day 2; n=9, 3	0.004 ± 0.0938	-0.063 ± 0.0513
Eosinophils; post-infusion assessment; 7, 5	0.064 ± 0.1321	-0.044 ± 0.1328
Lymphocytes; Day 2; n=9, 3	0.323 ± 0.6117	0.877 ± 0.1914
Lymphocytes; post-infusion assessment; 7, 5	0.253 ± 1.0579	1.006 ± 1.4223
Monocytes; Day 2; n=9, 3	0.008 ± 0.3389	0.147 ± 0.5773
Monocytes; post-infusion assessment; 7, 5	0.141 ± 0.2535	-0.082 ± 0.4135
Neutrophils; Day 2; n=9, 3	2.744 ± 6.9362	-1.813 ± 3.3001
Neutrophils; post-infusion assessment; 7, 5	-2.246 ± 6.0323	-1.910 ± 2.8497
Platelets; Day 2; n=8, 3	-6.4 ± 47.42	-24.7 ± 32.58
Platelets; post-infusion assessment; 6, 5	-15.7 ± 60.48	-5.4 ± 33.34
Leukocytes; Day 2; n=9, 3	3.10 ± 6.720	-0.87 ± 2.914
Leukocytes; post-infusion assessment; 7, 5	-1.76 ± 5.358	-0.98 ± 2.645

Notes
[61] - Maternal Safety Population
[62] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Change from Baseline in erythrocyte mean corpuscular volume (MCV) and mean platelet volume (MPV)

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End point title

Change from Baseline in erythrocyte mean corpuscular volume (MCV) and mean platelet volume (MPV)

End point description

Blood samples were collected for the evaluation of change in MCV and MPV from Baseline. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

End point type

Secondary

End point timeframe

Baseline and up to 1 week

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[63]	10 ^[64]
Units: femtoliter (fL)
arithmetic mean (standard deviation)
MCV; Day 2; n=9, 3	0.4 ± 2.79	1.7 ± 4.73
MCV; Post-infusion assessment; n=7, 5	-1.9 ± 1.77	-0.8 ± 1.30
MPV; Day 2; n=8, 3	-0.11 ± 0.455	-0.20 ± 0.436
MPV; Post-infusion assessment; n=6, 5	0.02 ± 0.833	0.48 ± 1.026

Notes
[63] - Maternal Safety Population
[64] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Change from Baseline in erythrocyte level

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End point title

Change from Baseline in erythrocyte level

End point description

Blood samples were collected for the evaluation of change in erythrocyte level from Baseline. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

End point type

Secondary

End point timeframe

Baseline and up to 1 week

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[65]	10 ^[66]
Units: Trillion cells per liter
arithmetic mean (standard deviation)
Day 2; n=9, 3	-0.39 ± 0.423	-0.53 ± 0.153
Post-infusion assessment; n=7, 5	-0.03 ± 0.330	-0.02 ± 0.303

Notes
[65] - Maternal Safety Population
[66] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Change from Baseline in alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT) and lactate dehydrogenase (LDH) levels

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End point title

Change from Baseline in alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT) and lactate dehydrogenase (LDH) levels

End point description

Blood samples were collected for the evaluation of change in ALP, ALT, AST, GGT and LDH from Baseline. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

End point type

Secondary

End point timeframe

Baseline and up to 1 week

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[67]	10 ^[68]
Units: International Units per liter (IU/L)
arithmetic mean (standard deviation)
ALP; Day 2; n=9, 5	-17.3 ± 17.56	-11.8 ± 6.46
ALP; post-infusion assessment; n=8, 6	6.6 ± 31.14	-2.8 ± 14.08
ALT; Day 2; n=9, 5	3.9 ± 19.60	4.4 ± 10.64
ALT; post-infusion assessment; n=8, 6	-8.8 ± 20.04	2.5 ± 5.50
AST; Day 2; n=9, 5	4.4 ± 15.69	2.0 ± 10.20
AST; post-infusion assessment; n=8, 6	-9.1 ± 13.05	-0.5 ± 7.45
GGT; Day 2; n=9, 5	-0.9 ± 1.69	-0.8 ± 1.30
GGT; post-infusion assessment; n=7, 5	4.4 ± 2.57	0.4 ± 2.07
LDH; Day 2; n=9, 5	-6.7 ± 33.51	-26.4 ± 31.86
LDH; post-infusion assessment; n=7, 5	-8.1 ± 21.93	-7.6 ± 31.76

Notes
[67] - Maternal Safety Population
[68] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Change from Baseline in albumin and protein levels

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End point title

Change from Baseline in albumin and protein levels

End point description

Blood samples were collected for the evaluation of change in albumin and protein levels from Baseline. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

End point type

Secondary

End point timeframe

Baseline and up to 1 week

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[69]	10 ^[70]
Units: grams per liter (g/L)
arithmetic mean (standard deviation)
Albumin; Day 2; n=9, 5	-3.4 ± 3.68	-2.6 ± 1.67
Albumin; post-infusion assessment; n=7, 5	-1.3 ± 2.21	-1.0 ± 2.35
Protein; Day 2; n=9, 5	-5.8 ± 6.26	-5.4 ± 3.58
Protein; post-infusion assessment; n=7, 5	-2.4 ± 3.41	-1.8 ± 5.02

Notes
[69] - Maternal Safety Population
[70] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Change from Baseline in anion gap, calcium, chloride, carbon dioxide, glucose, potassium, magnesium, phosphate and sodium level

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End point title

Change from Baseline in anion gap, calcium, chloride, carbon dioxide, glucose, potassium, magnesium, phosphate and sodium level

End point description

Blood samples were collected for the evaluation of change from Baseline in levels of anion gap, calcium, chloride, carbon dioxide, glucose, potassium, magnesium, phosphate, and sodium. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

End point type

Secondary

End point timeframe

Baseline and up to 1 week

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[71]	10 ^[72]
Units: millimoles per liter (mmol/L)
arithmetic mean (standard deviation)
Anion Gap; Day 2; n=8, 4	0.0 ± 4.72	0.0 ± 1.83
Anion Gap; post-infusion assessment; n=7, 4	-1.6 ± 5.26	0.3 ± 2.22
Calcium; Day 2; n=9, 5	-0.042 ± 0.2833	-0.040 ± 0.1208
Calcium; post-infusion assessment; n=7, 5	0.091 ± 0.2052	-0.048 ± 0.1016
Chloride; Day 2; n=9, 5	1.0 ± 5.17	1.8 ± 2.17
Chloride; post-infusion assessment; n=7, 5	-0.7 ± 3.35	-0.6 ± 2.30
Carbon Dioxide; Day 2; n=9, 5	-0.2 ± 3.63	0.0 ± 2.35
Carbon Dioxide; post-infusion assessment; n=7, 5	2.3 ± 3.64	-0.2 ± 2.77
Glucose; Day 2; n=9, 5	1.47 ± 1.639	1.98 ± 1.064
Glucose; post-infusion assessment; n=7, 5	0.11 ± 2.497	0.28 ± 2.109
Potassium; Day 2; n=9, 5	-0.16 ± 0.394	0.10 ± 0.515
Potassium; post-infusion assessment; n=7, 5	-0.16 ± 0.237	0.10 ± 0.283
Magnesium; Day 2; n=9, 5	-0.411 ± 0.9476	-0.236 ± 0.5428
Magnesium; post-infusion assessment; n=7, 5	-0.449 ± 0.6473	-0.056 ± 0.6199
Phosphate; Day 2; n=9, 5	-0.133 ± 0.1768	0.030 ± 0.2928
Phosphate; post-infusion assessment; n=7, 5	0.021 ± 0.2018	0.110 ± 0.1557
Sodium; Day 2; n=9, 5	1.4 ± 2.96	0.4 ± 1.67
Sodium; post-infusion assessment; n=7, 5	0.1 ± 2.12	-0.8 ± 1.64

Notes
[71] - Maternal Safety Population
[72] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Change from Baseline in direct bilirubin, bilirubin, indirect bilirubin, creatinine and urate levels

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End point title

Change from Baseline in direct bilirubin, bilirubin, indirect bilirubin, creatinine and urate levels

End point description

Blood samples were collected for the evaluation of change from Baseline in levels of direct bilirubin, bilirubin, indirect bilirubin, creatinine and urate. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).

End point type

Secondary

End point timeframe

Baseline and up to 1 week

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[73]	10 ^[74]
Units: micromoles per liter (µmol/L)
arithmetic mean (standard deviation)
Direct Bilirubin; Day 2; n=9, 5	0.0 ± 1.00	-0.4 ± 0.89
Direct Bilirubin; post-infusion assessment; n=7, 5	0.3 ± 0.76	-0.4 ± 0.89
Bilirubin; Day 2; n=9, 5	-0.7 ± 1.41	-0.8 ± 1.10
Bilirubin; post-infusion assessment; n=8, 6	-0.3 ± 1.28	-2.0 ± 3.10
Indirect Bilirubin; Day 2; n=9, 5	-0.7 ± 1.41	-0.4 ± 1.67
Indirect Bilirubin; post-infusion assessment;n=7,5	-0.6 ± 1.51	-1.6 ± 3.85
Creatinine; Day 2; n=6, 3	-0.33 ± 6.812	2.37 ± 1.429
Creatinine; post-infusion assessment; n=6, 3	1.92 ± 5.075	-0.33 ± 2.695
Urate; Day 2; n=9, 5	1.1 ± 24.72	-22.0 ± 13.04
Urate; post-infusion assessment; n=7, 5	12.9 ± 24.30	-2.0 ± 40.25

Notes
[73] - Maternal Safety Population
[74] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Number of participants who discontinued study treatment due to clinical and laboratory toxicities

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End point title

Number of participants who discontinued study treatment due to clinical and laboratory toxicities

End point description

Number of maternal participants who discontinued study treatment due to clinical and laboratory toxicities is presented.

End point type

Secondary

End point timeframe

Up to 48 hours post-infusion

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[75]	10 ^[76]
Units: Participants
Participants	0	0

Notes
[75] - Maternal Safety Population
[76] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Number of maternal participants with a score of 12 or higher on the Edinburgh Postnatal Depression Scale (EPDS)

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End point title

Number of maternal participants with a score of 12 or higher on the Edinburgh Postnatal Depression Scale (EPDS)

End point description

The effect of preterm birth on maternal health status was assessed using the EPDS. The EPDS is a 10-item self-reported assessment of depression, validated for administration during both the antenatal and the post-natal periods. Items are rated on a 4-point variable Likert scale, ranging from 0 to 3. The total score was calculated by adding individual scores for each item and ranged from 0 to 30. A score of less than 8 indicates depression not likely; score of 9 to 11 indicates possible depression and a score of more than 12 indicates an increased probability of depression. Maternal participants were required to complete the EPDS at the maternal follow-up assessment 6 weeks post-delivery.

End point type

Secondary

End point timeframe

Up to 6 weeks post delivery

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[77]	10 ^[78]
Units: Participants
Participants	2	0

Notes
[77] - Maternal Safety Population
[78] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Number of maternal participants with AEs of special interest (AESI).

Top of page

End point title

Number of maternal participants with AEs of special interest (AESI).

End point description

Maternal AESI included: maternal death; chorioamnionitis and its complications (clinical chorioamnionitis, preterm premature rupture of membranes, endomyometritis, wound infection, pelvic abscess, bacteremia, septic shock, disseminated intravascular coagulation, and adult RDS); placental abruption; postpartum hemorrhage – postpartum hemorrhage and/or retained placenta and pulmonary edema. The number of participants with at least one AESI has been presented.

End point type

Secondary

End point timeframe

Up to 6 weeks post-delivery

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[79]	10 ^[80]
Units: Participants
Participants	0	1

Notes
[79] - Maternal Safety Population
[80] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Number of maternal participants with disease related AEs (DRE)

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End point title

Number of maternal participants with disease related AEs (DRE)

End point description

Maternal DREs included: signs and symptoms of labor discomfort (example, cramping, backache, muscle aches, nausea); subsequent episodes of preterm labor and hospitalization for delivery. The number of participants with at least one DRE has been presented.

End point type

Secondary

End point timeframe

Up to 6 weeks post-delivery

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[81]	10 ^[82]
Units: Participants
Participants	0	1

Notes
[81] - Maternal Safety Population
[82] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Number of fetal participants with AEs and SAEs prior to delivery

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End point title

Number of fetal participants with AEs and SAEs prior to delivery

End point description

An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; important medical events that may require medical or surgical intervention to prevent one of the other outcomes described before; is associated with liver injury and impaired liver function. Fetal AEs and SAEs included the adverse events that were experienced by the fetus prior to delivery. The number of participants who experienced at least one AE and one SAE has been presented.

End point type

Secondary

End point timeframe

Up to 17 weeks post-infusion

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[83]	10 ^[84]
Units: Participants
AE	3	5
SAE	0	1

Notes
[83] - Maternal Safety Population
[84] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Number of participants with fetal acidosis

Top of page

End point title

Number of participants with fetal acidosis

End point description

The number of participants with fetal acidosis is presented.

End point type

Secondary

End point timeframe

Up to 16 weeks

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[85]	10 ^[86]
Units: Participants
Participants	0	0

Notes
[85] - Maternal Safety Population
[86] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Number of participants with fetal AESI

Top of page

End point title

Number of participants with fetal AESI

End point description

Fetal AESI included: intrauterine fetal demise; category II or III fetal heart rate tracing; and fetal inflammatory response syndrome characterized by cord blood interleukin-6 >11 picogram per milliliter (pg/mL), funisitis, or chorionic vasculitis. The number of participants who experienced at least one AESI has been presented.

End point type

Secondary

End point timeframe

Up to 17 weeks

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[87]	10 ^[88]
Units: Participants
Participants	3	5

Notes
[87] - Maternal Safety Population
[88] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Neonatal APGAR Scores

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End point title

Neonatal APGAR Scores

End point description

APGAR is a quick test to assess the health of new born children. The test is performed at 1 and 5 minutes after birth. APGAR scale is determined by evaluating the new born on five categories (appearance, pulse, grimace, activity and respiration) on a scale from zero to two, then summing up the five values obtained. APGAR score ranges from 0 to 10 where a score of 7 and above is normal. The mean and standard deviation of APGAR scores at one minute and at five minutes of birth has been presented.

End point type

Secondary

End point timeframe

Up to 5 minutes after birth

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[89]	10 ^[90]
Units: Score on APGAR scale
arithmetic mean (standard deviation)
one minute at birth	7.3 ± 1.80	7.5 ± 1.78
five minutes at birth	8.5 ± 1.05	8.7 ± 1.06

Notes
[89] - Neonatal ITT Population
[90] - Neonatal ITT Population

No statistical analyses for this end point

Secondary: Weight of neonates

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End point title

Weight of neonates

End point description

The weight of neonates was obtained from the neonate birth record. The mean weight of neonates and standard deviation has been presented.

End point type

Secondary

End point timeframe

Up to 17 weeks

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[91]	10 ^[92]
Units: grams (g)
arithmetic mean (standard deviation)
grams (g)	2015.0 ± 805.67	2121.2 ± 681.31

Notes
[91] - Neonatal ITT Population
[92] - Neonatal ITT Population

No statistical analyses for this end point

Secondary: Head circumference of neonates

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End point title

Head circumference of neonates

End point description

The head circumference was determined from the neonate birth record.

End point type

Secondary

End point timeframe

Up to 17 weeks

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[93]	10 ^[94]
Units: centimeters (cm)
arithmetic mean (standard deviation)
centimeters (cm)	29.57 ± 2.791	30.13 ± 3.059

Notes
[93] - Neonatal ITT Population
[94] - Neonatal ITT Population

No statistical analyses for this end point

Secondary: Number of neonatal participants with AEs and SAEs

Top of page

End point title

Number of neonatal participants with AEs and SAEs

End point description

An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; important medical events that may require medical or surgical intervention to prevent one of the other outcomes described before; is associated with liver injury and impaired liver function. The number of participants who experienced at least one AE and one SAE has been presented. Neonatal Safety Population consisted of neonates whose mothers received randomized treatment.

End point type

Secondary

End point timeframe

Up to 28 days after the EDD of 40 weeks gestation

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[95]	10 ^[96]
Units: Participants
AEs	8	7
SAEs	3	5

Notes
[95] - Neonatal Safety Population
[96] - Neonatal Safety Population

No statistical analyses for this end point

Secondary: Number of neonatal participants with AESI

Top of page

End point title

Number of neonatal participants with AESI

End point description

Neonatal AESI included: Neonatal death; Asphyxia; Infections (early onset neonatal sepsis, septic shock, pneumonia, meningitis); RDS; Hypotension; IVH/periventricular leukomalacia; Bronchopulmonary dysplasia; Neonatal acidosis; Hyperbilirubinemia; Necrotizing enterocolitis; and Hypoxic ischemic encephalopathy. The number of neonatal participants who experienced at least one AESI has been presented.

End point type

Secondary

End point timeframe

Up to 28 days after EDD of 40 weeks gestation

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[97]	10 ^[98]
Units: Participants
Participants	8	5

Notes
[97] - Neonatal Safety Population
[98] - Neonatal Safety Population

No statistical analyses for this end point

Secondary: Number of neonatal participants with DRE

Top of page

End point title

Number of neonatal participants with DRE

End point description

The disease related neonatal events occurring in Infants born prior to 37 completed weeks included: apnea (severe), respiratory failure due to fatigue, hypoxia, or air leak from alveolar injury, patent ductus arteriosus, bradycardia, ventriculomegaly, cerebellar hemorrhage, hydrocephalus other than congenital, gastroesophageal reflux, aspiration pneumonia, anemia, retinopathy of prematurity (all stages), hearing disorder, temperature instability and hypoglycemia. The number of participants with at least one DRE has been presented.

End point type

Secondary

End point timeframe

Up to 28 days after EDD of 40 weeks gestation

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[99]	10 ^[100]
Units: Participants
Participants	4	2

Notes
[99] - Neonatal Safety Population
[100] - Neonatal Safety Population

No statistical analyses for this end point

Secondary: Maternal length of stay in hospital

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End point title

Maternal length of stay in hospital

End point description

Details on maternal health care resource use (both for hospitalizations related to preterm labor not resulting in a delivery and hospitalizations related to preterm labor/normal labor resulting in a delivery) associated with an episode of preterm labor, preterm delivery and normal term delivery (>= 37 weeks gestation) were collected from review of medical records. Length of hospital stay associated with hospital admission for preterm labor and normal term labor/term delivery is presented. One participant in the retosiban arm did not have hospitalization data; hence, was excluded from the analysis at delivery. Only participants with data available at the specified time points were analyzed (indicated by n=X) in category titles. 99999 for dispersion indicates standard deviation could not be calculated as only one participant was analyzed. 99999 for retosiban arm indicates data was not available as the number of participants analyzed was zero.

End point type

Secondary

End point timeframe

Up to 28 days post EDD (40 0/7 weeks gestation)

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[101]	10 ^[102]
Units: Days
arithmetic mean (standard deviation)
Preterm labor; n=1, 0	2.642 ± 99999	99999 ± 99999
Preterm delivery; n=9, 7	10.177 ± 11.9312	13.583 ± 20.7670
Normal term delivery; n=4, 2	3.719 ± 2.2309	4.635 ± 2.7616

Notes
[101] - Maternal Safety Population
[102] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Number of participants with hospital admissions related to preterm labor and preterm delivery

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End point title

Number of participants with hospital admissions related to preterm labor and preterm delivery

End point description

Maternal healthcare resource utilization associated with an episode of preterm labor and preterm delivery were collected from the review of medical records. One participant in the retosiban arm did not have hospitalization data; hence, was excluded from the analysis at delivery. The number of participants who had hospital admission for preterm labor and preterm delivery has been presented. Only those participants with data available at the specified time points were analyzed (indicated by n=X in category titles).

End point type

Secondary

End point timeframe

Up to 28 days after EDD (40 0/7 weeks of gestation)

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[103]	10 ^[104]
Units: Participants
Preterm labor; n=13, 10	1	0
Preterm delivery; n=13, 9	9	7

Notes
[103] - Maternal Safety Population
[104] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Number of participants admitted to particular hospital unit

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End point title

Number of participants admitted to particular hospital unit

End point description

Maternal healthcare resource utilization associated with an episode of preterm labor, preterm delivery and normal term delivery were collected from the review of medical records. The number of participants who were admitted to a particular hospital unit has been presented.

End point type

Secondary

End point timeframe

Up to 28 days post EDD (40 0/7 weeks gestation)

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[105]	10 ^[106]
Units: Participants
General ward	9	2
Private/Semi-private room	3	2
Labor and delivery	2	3
Labor and delivery to post-partum	0	1
Post-partum	0	1
Ward not specified	0	1
Labor ward	0	1
Antenatal ward	0	1
Postnatal ward	0	1

Notes
[105] - Maternal Safety Population
[106] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Number of participants with different modes of transportation to hospital

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End point title

Number of participants with different modes of transportation to hospital

End point description

The means by which the maternal participants were transported to the hospital i.e. ground ambulance/emergency vehicle (gr. amb/emer. veh), air ambulance, family member or other means were obtained from the review of medical records. The number of maternal participants with the corresponding mode of transportation is presented for preterm labor visit and delivery visit. Only those participants with data available at specified time points were analyzed (indicated by n=X in category titles). 99999 indicates data was not available as the number of participants analyzed is zero.

End point type

Secondary

End point timeframe

Up to 28 days post EDD (40 0/7 weeks gestation)

End point values	Placebo	Retosiban
Number of subjects analysed	13 ^[107]	10 ^[108]
Units: Participants
Preterm labor; gr. amb/emer. veh; n=1, 0	0	99999
Preterm labor; air ambulance; n=1, 0	0	99999
Preterm labor; family member; n=1, 0	1	99999
Preterm labor; other; n=1, 0	0	99999
Delivery; gr. amb/emer. veh; n=5, 5	2	1
Delivery; air ambulance; n=5, 5	0	0
Delivery; family member; n=5, 5	3	3
Delivery; other; n=5, 5	0	1
Preterm labor;<24 hour stay;gr. amb/emer.veh;n=1,0	0	99999
Preterm labor; <24 hour stay;air ambulance; n=1, 0	0	99999
Preterm labor; <24 hour stay;family member; n=1, 0	1	99999
Preterm labor; <24 hour stay;other; n=1, 0	0	99999

Notes
[107] - Maternal Safety Population
[108] - Maternal Safety Population

No statistical analyses for this end point

Secondary: Retosiban clearance

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End point title

Retosiban clearance

End point description

Maternal blood samples were collected at the indicated time points for pharmacokinetic analysis. Data is a combined data set. Data is presented for 10 participants from retosiban arm of study 200719 (NCT02377466) and 43 participants from retosiban arm of study 200721 (NCT02292771).

End point type

Secondary

End point timeframe

Day 1 (2 to 4 hours, 10 to 14 hours) and Day 2 (22 to 26 hours, and 48 to 54 hours) post-infusion

End point values	Retosiban
Number of subjects analysed	10 ^[109]
Units: Liters per hour
geometric mean (geometric coefficient of variation)
Liters per hour	83.4 ± 5.25

Notes
[109] - Maternal Safety Population. Number of participants is combined from 2 studies. Actual value is 53.

No statistical analyses for this end point

Secondary: Volume of distribution of retosiban

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End point title

Volume of distribution of retosiban

End point description

End point type

Secondary

End point timeframe

Day 1 (2 to 4 hours, 10 to 14 hours) and Day 2 (22 to 26 hours, and 48 to 54 hours) post-infusion

End point values	Retosiban
Number of subjects analysed	10 ^[110]
Units: Liters
geometric mean (geometric coefficient of variation)
Liters	68.6 ± 109

Notes
[110] - Maternal Safety Population. Number of participants is combined from 2 studies. Actual value is 53.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) will be collected from the start of study treatment and until the follow up contact (Up to 6 weeks after delivery).

Adverse event reporting additional description

SAEs and AEs were analyzed in Maternal Safety Population and Neonatal Safety Population which comprised of mothers randomly assigned to treatment who were exposed to study treatment and neonates whose mothers received randomized treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Placebo (Maternal)

Reporting group description

Reporting group title

Retosiban (Maternal)

Reporting group description

Reporting group title

Placebo (Fetal)

Reporting group description

Reporting group title

Retosiban (Fetal)

Reporting group description

Reporting group title

Placebo (Neonatal)

Reporting group description

Reporting group title

Retosiban (Neonatal)

Reporting group description

Serious adverse events	Placebo (Maternal)	Retosiban (Maternal)	Placebo (Fetal)	Retosiban (Fetal)	Placebo (Neonatal)	Retosiban (Neonatal)
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	1 / 10 (10.00%)	3 / 13 (23.08%)	5 / 10 (50.00%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events
Congenital, familial and genetic disorders
Ankyloglossia congenital
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Congenital hypothyroidism
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac arrest
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Umbilical cord prolapse
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	1 / 10 (10.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Inguinal hernia
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	2 / 10 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meconium plug syndrome
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Neonatal respiratory distress syndrome
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	2 / 13 (15.38%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Selective eating disorder
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Group B streptococcus neonatal sepsis
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tracheitis
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Placebo (Maternal)	Retosiban (Maternal)	Placebo (Fetal)	Retosiban (Fetal)	Placebo (Neonatal)	Retosiban (Neonatal)
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 13 (46.15%)	6 / 10 (60.00%)	3 / 13 (23.08%)	5 / 10 (50.00%)	8 / 13 (61.54%)	7 / 10 (70.00%)
Vascular disorders
Hypertension
subjects affected / exposed	1 / 13 (7.69%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Hypotension
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Pregnancy, puerperium and perinatal conditions
Oligohydramnios
subjects affected / exposed	1 / 13 (7.69%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Uterine contractions abnormal
subjects affected / exposed	0 / 13 (0.00%)	1 / 10 (10.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0
General disorders and administration site conditions
Oedema
subjects affected / exposed	0 / 13 (0.00%)	1 / 10 (10.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0
Pyrexia
subjects affected / exposed	0 / 13 (0.00%)	1 / 10 (10.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0
Granuloma
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Reproductive system and breast disorders
Oedema genital
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 13 (0.00%)	1 / 10 (10.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	0	0	0
Neonatal respiratory distress syndrome
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	2 / 13 (15.38%)	2 / 10 (20.00%)
occurrences all number	0	0	0	0	2	2
Bronchopulmonary dysplasia
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	3 / 13 (23.08%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	3	0
Pleural effusion
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Respiratory acidosis
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Tachypnoea
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Investigations
Blood calcium decreased
subjects affected / exposed	1 / 13 (7.69%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Blood glucose decreased
subjects affected / exposed	1 / 13 (7.69%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Liver function test increased
subjects affected / exposed	1 / 13 (7.69%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Body temperature fluctuation
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Vaccination complication
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Cardiac disorders
Foetal heart rate disorder
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	2 / 13 (15.38%)	5 / 10 (50.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	14	28	0	0
Foetal heart rate deceleration abnormality
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0
Nervous system disorders
Headache
subjects affected / exposed	1 / 13 (7.69%)	1 / 10 (10.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	1	0	0	0	0
Intraventricular haemorrhage
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Motor dysfunction
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 13 (7.69%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Thrombocytopenia
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Eye disorders
Conjunctival haemorrhage
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Gastrointestinal disorders
Constipation
subjects affected / exposed	1 / 13 (7.69%)	1 / 10 (10.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	1	0	0	0	0
Abdominal discomfort
subjects affected / exposed	1 / 13 (7.69%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Diarrhoea
subjects affected / exposed	1 / 13 (7.69%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Haemorrhoids
subjects affected / exposed	1 / 13 (7.69%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Inguinal hernia
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	2 / 13 (15.38%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	2	0
Haematochezia
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Necrotising colitis
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Vomiting
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Hepatobiliary disorders
Hyperbilirubinaemia neonatal
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	6 / 13 (46.15%)	4 / 10 (40.00%)
occurrences all number	0	0	0	0	6	4
Jaundice
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	1
Cholestasis
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	0 / 13 (0.00%)	1 / 10 (10.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0
Pruritus generalised
subjects affected / exposed	1 / 13 (7.69%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Dermatitis diaper
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Dry skin
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Intertrigo
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Seborrhoea
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Musculoskeletal and connective tissue disorders
Myalgia
subjects affected / exposed	1 / 13 (7.69%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Pain in extremity
subjects affected / exposed	1 / 13 (7.69%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Osteopenia
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Infections and infestations
Abscess limb
subjects affected / exposed	0 / 13 (0.00%)	1 / 10 (10.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0
Amniotic cavity infection
subjects affected / exposed	0 / 13 (0.00%)	1 / 10 (10.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0
Bacterial vulvovaginitis
subjects affected / exposed	0 / 13 (0.00%)	1 / 10 (10.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0
Kidney infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Viral upper respiratory tract infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0
Device related infection
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Oral candidiasis
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Metabolism and nutrition disorders
Feeding intolerance
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0
Hypoglycaemia
subjects affected / exposed	0 / 13 (0.00%)	0 / 10 (0.00%)	0 / 13 (0.00%)	0 / 10 (0.00%)	1 / 13 (7.69%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

13 Aug 2015

Amendment No. 1

14 Sep 2015

Amendment No. 2 Revise the guidance for administration of antenatal corticosteroids to read as follows: If not previously administered, antenatal corticosteroid treatment should be administered as either (1) two 12-mg doses of betamethasone given intramuscularly 24 hours apart or (2) four 6-mg doses of dexamethasone administered intramuscularly every 12 hours. A single rescue course of antenatal corticosteroids is permitted if the antecedent treatment was at least 7 days prior to study enrollment. Clarify in the Time and Events Table (footnote 15) that hematology, chemistry, and liver function tests will only be determined through a central laboratory at the screening, Day 2, and the face-to-face post-infusion assessment visits. Incorporate other administrative changes

19 Apr 2016

Amendment No.3 The following changes are reflected in the Country-Specific Protocol Amendment for Italy: Amend inclusion criteria 1 and 2 to specify that participants must be at least 18 years of age to participate in Study 200719. Text was revised throughout to reflect the change in the participant age criterion. Revise text throughout to indicate that participants recruited into Study 200719 in Italy must not be dosed with the investigational product until the results of their chemical parameters have been reviewed by the Investigator and no indicators of altered liver function (AST and ALT values and bilirubinemia) are apparent. This check for altered liver function must be carried out before the study drug is administered, i.e., before initiating randomized treatment.

20 Jun 2016

Amendment No.4

05 Jan 2017

Remove screening urine drug and alcohol tests. Remove requirement that investigator confirm uterine contraction rate and cervical dilation after randomization and just before study drug administration. Add that after randomization and prior to study drug administration investigators will re-assess that tocolytic therapy is still indicated, according to their medical discretion. Clarify that an abdominal ultrasound to assess fetal growth is needed at Screening unless the most recent ultrasound is within 3 weeks (21 days) before the date of randomization. Update the list of maternal disease-related events to clarify the reporting process for events of subsequent preterm labor and hospitalization for delivery that are not worse than expected. Add that the amniotic fluid index should be measured using the 4-quadrant method. Incorporate other administrative changes.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: Randomized, Double-Blind, Multicenter, Phase III Study Comparing the Efficacy and Safety of Retosiban Versus Placebo for Women in Spontaneous Preterm Labor

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Time to delivery or treatment failure, whichever occurs first

Primary: Time to delivery or treatment failure, whichever occurs first

Primary: Number of neonates with any diagnosis from the neonatal morbidity and mortality composite component

Primary: Number of neonates with any diagnosis from the neonatal morbidity and mortality composite component

Secondary: Time to delivery

Secondary: Time to delivery

Secondary: Number of participants with births prior to 37 0/7 Weeks gestation

Secondary: Number of participants with births prior to 37 0/7 Weeks gestation

Secondary: Number of participants with births at term

Secondary: Number of participants with births at term

Secondary: Length of neonatal hospital stay

Secondary: Length of neonatal hospital stay

Secondary: Number of participants with births prior to 35 0/7 weeks gestation

Secondary: Number of participants with births prior to 35 0/7 weeks gestation

Secondary: Number of participants with births prior to 32 0/7 weeks gestation

Secondary: Number of participants with births prior to 32 0/7 weeks gestation

Secondary: Number of participants with births prior to 28 0/7 weeks gestation

Secondary: Number of participants with births prior to 28 0/7 weeks gestation

Secondary: Number of participants with births at <=7 days from the first study treatment

Secondary: Number of participants with births at <=7 days from the first study treatment

Secondary: Number of participants with births at <=48 hours from the first study treatment

Secondary: Number of participants with births at <=48 hours from the first study treatment

Secondary: Number of participants with births at <=24 hours from the first study treatment

Secondary: Number of participants with births at <=24 hours from the first study treatment

Secondary: Number of neonates with any of the co-primary composite neonatal morbidity and mortality, excluding RDS

Secondary: Number of neonates with any of the co-primary composite neonatal morbidity and mortality, excluding RDS

Secondary: Number of neonates with each individual component of the composite neonatal morbidity and mortality

Secondary: Number of neonates with each individual component of the composite neonatal morbidity and mortality

Secondary: Number of neonatal participants with admission to a particular hospital unit

Secondary: Number of neonatal participants with admission to a particular hospital unit

Secondary: Length of stay in specialized care unit

Secondary: Length of stay in specialized care unit

Secondary: Number of newborn participants with hospital readmission

Secondary: Number of newborn participants with hospital readmission

Secondary: Length of stay following readmission to hospital

Secondary: Length of stay following readmission to hospital

Secondary: Number of participants with ambulatory surgery

Secondary: Number of participants with ambulatory surgery

Secondary: Time to treatment failure

Secondary: Time to treatment failure

Secondary: Number of participants who received any putative tocolytic

Secondary: Number of participants who received any putative tocolytic

Secondary: Number of participants with subsequent preterm labor

Secondary: Number of participants with subsequent preterm labor

Secondary: Number of maternal participants with adverse events (AEs) and serious adverse events (SAEs)

Secondary: Number of maternal participants with adverse events (AEs) and serious adverse events (SAEs)

Secondary: Change from Baseline in diastolic blood pressure (DBP) and systolic blood pressure (SBP)

Secondary: Change from Baseline in diastolic blood pressure (DBP) and systolic blood pressure (SBP)

Secondary: Change from Baseline in heart rate

Secondary: Change from Baseline in heart rate

Secondary: Change from Baseline in temperature

Secondary: Change from Baseline in temperature

Secondary: Change from Baseline in respiratory rate

Secondary: Change from Baseline in respiratory rate

Secondary: Change from Baseline in hematocrit levels

Secondary: Change from Baseline in hematocrit levels

Secondary: Change from Baseline in hemoglobin and Erythrocyte Mean Corpuscular hemoglobin Concentration (MCHC)

Secondary: Change from Baseline in hemoglobin and Erythrocyte Mean Corpuscular hemoglobin Concentration (MCHC)

Secondary: Change from Baseline in basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelets and leukocytes count

Secondary: Change from Baseline in basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelets and leukocytes count

Secondary: Change from Baseline in erythrocyte mean corpuscular volume (MCV) and mean platelet volume (MPV)

Secondary: Change from Baseline in erythrocyte mean corpuscular volume (MCV) and mean platelet volume (MPV)

Secondary: Change from Baseline in erythrocyte level

Secondary: Change from Baseline in erythrocyte level

Secondary: Change from Baseline in alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT) and lactate dehydrogenase (LDH) levels

Secondary: Change from Baseline in alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT) and lactate dehydrogenase (LDH) levels

Secondary: Change from Baseline in albumin and protein levels

Secondary: Change from Baseline in albumin and protein levels

Secondary: Change from Baseline in anion gap, calcium, chloride, carbon dioxide, glucose, potassium, magnesium, phosphate and sodium level

Secondary: Change from Baseline in anion gap, calcium, chloride, carbon dioxide, glucose, potassium, magnesium, phosphate and sodium level

Clinical Trial Results:
Randomized, Double-Blind, Multicenter, Phase III Study Comparing the Efficacy and Safety of Retosiban Versus Placebo for Women in Spontaneous Preterm Labor