Abstract:
The present invention relates to the use of misoprostol for the induction of labour in a pregnant female, and in particular to the use of a sustained delivery device or insert containing substantially 200 μg misoprostol for intravaginal use. The use encompasses methods of therapy as well as compositions for use in such methods.

Description:
FIELD OF THE INVENTION 
       [0001]    The present invention relates to the use of misoprostol for the induction of labour in a pregnant female, and in particular to the use of a sustained delivery device or insert containing substantially 200 μg misoprostol for intravaginal use. The use encompasses methods of therapy as well as compositions for use in such methods. 
       BACKGROUND OF THE INVENTION 
       [0002]    The present invention relates to the use of misoprostol for the induction of labour in a pregnant female, and in particular the use of a sustained delivery device or insert containing substantially 200 μg misoprostol for intravaginal use. 
         [0003]    Misoprostol is a synthetic analogue of prostaglandin E 1 , and has been increasingly used for cervical ripening and labour induction administered both vaginally and orally. In some countries, it is available as a 100 μg or 200 μg tablet, which is quartered or halved and then placed in the vagina every four to six hours. However, splitting tablets does not provide adequate control of dosing of misoprostol, nor is drug release from the tablet fragments steady or well defined. 
         [0004]    Our patent application WO2004/029125 discloses a controlled release vaginal pessary comprising misoprostol in a cross-linked polyurethane polymer. Sustained release data in vitro is provided. Our patent application WO2006/013335 discloses that the long term storage properties of such misoprostol cross-linked polyurethane sustained release devices may be improved by maintaining the water content at a low level. 
         [0005]    A prostaglandin-containing vaginal pessary has been available for a number of years under the trade mark Propess/Cervidil. It contains 10 mg of the PGE2 prostaglandin dinoprostone in a cross-linked polyurethane matrix for sustained vaginal release. The pessary is contained within a net bag and has a retrieval cord or tape, allowing the pessary to be withdrawn once the desired dose has been administered or when the woman reaches an appropriate stage during labour. 
         [0006]    Cross-linked polyurethane formulations containing a prostaglandin are also disclosed in U.S. Pat. No. 4,931,288. 
         [0007]    Patents U.S. Pat. No. 6,642,278, US2004/044080 and WO2003/011301 disclose other background information. 
         [0008]    The normal gestation period in a human female is around 40 weeks. Induction of labour may be considered if the pregnancy progresses beyond the 40 week term without the baby being born. Generally, induction is considered if the pregnancy goes beyond the 41st or 42nd week. Induction may also be considered for a variety of other medical reasons. The so called “Bishop Score” and “Modified Bishop Score” are pre-labour scoring systems used to assess the progression of labour and/or to determine whether induction of labour will be required. The duration of labour is inversely correlated with the Modified Bishop Score; a score that exceeds 8 describes a patient most likely to achieve a successful vaginal birth. Modified Bishop Scores of less than 4 usually require that a cervical ripening method be used before other methods. The determination of a Bishop Score and/or Modified Bishop Score involves assessing certain factors including cervical dilation, length of cervix, cervical effacement, cervical consistency, cervical position, and foetal station. 
         [0009]    Induced labour tends to be more painful for the women and can lead to increased use of analgesics. It is also possible that induction may lead to an increased likelihood of caesarean section delivery for the baby. Medical reasons for the inducement of labour include hypertension or pre-eclampsia in the mother. However, induction may have adverse events, such as uterine tachysystole, foetal heart rate (FHR) irregularities, meconium in amniotic fluid, poor neonatal condition (Apgar score), postpartum haemorrhage, chorioamnionitis, diabetes and poor neonatal respiration. 
         [0010]    Misoprostol controlled release pessaries have been investigated for possible clinical use and results are disclosed in a number of references including Powers et al. Journal of Clinical Pharmacology 2008, 48: 26-34, Ewert et al., Obstet Gynecol 2006; 108: 1130-7, Wing et al., J Reprod Med 2008; 53: 695-696, Castaneda et al. American Jn of Obstet Gyneco 2005; 193; 1071-5, Rayburn et al., J Soc Gynecol Investig 2006; 13: 112-7, Pevzner et al, Obstet Gynecol 2009; 114: 261-7, Wing Obster Gynecol 2008; 112: 801-12, Wing et al., Obstet Gynecol 2011; 117: 533-41, Pevzner et al., Obstet Gynecol 2009; 114, 1315-21 and Pevzner et al., European J Obstet Gynecol and Repr Biology 2011: 156, 144-148. Results of clinical trials are also disclosed in our publication WO2011/156812, where the principal basis of comparison is absence of drug or escalating misoprostol dosage. Generally speaking, these studies show improved speed to vaginal delivery using misoprostol 200 μg pessaries without increased rate of caesarean delivery. 
         [0011]    The present application is based on the discovery of further surprising benefits of misoprostol—containing controlled release vaginal pessaries. 
       SUMMARY OF THE INVENTION 
       [0012]    Vaginal inserts containing 200 μg misoprostol may be used to induce labour in female subjects. The present invention is based on the finding that induction of labour by administration of vaginal inserts containing 200 μg misoprostol results in significant benefits (for example reduced labour associated adverse events/improved outcomes) which are not observed when labour is induced by administration of vaginal inserts containing 10 mg dinoprostone. These benefits and improved outcomes are described below. 
         [0013]    Accordingly, a first aspect of this invention provides a method of reducing
       (i) pre-delivery oxytocin use   (ii) the total dose of pre-delivery oxytocin administered;   (iii) the duration of pre-delivery oxytocin use; and   (iv) the maximum dose of oxytocin;       
 
         [0018]    after induction of labour in a female, the method comprising administering intravaginally to the female an insert comprising a cross-linked polyurethane reaction polyurethane product of a polyethylene glycol, a triol and a diisocyanate, the insert containing 200 μg misoprostol; 
         [0019]    reductions (i), (ii), (iii) and (iv) being reduced in comparison to the administration of said insert containing 10 mg dinoprostone. 
         [0020]    Inserts containing 200 μg misoprostol or 10 mg dinoprostone may also be referred to as containing a “dose reservoir”. For example, inserts containing 200 μg misoprostol may be said to comprise a “200 μg (dose) reservoir of misoprostol”. One of skill will appreciate that the phrase “dose reservoir” may be a reference to the total amount of a therapeutic agent contained within any given delivery device—for example a vaginal insert. Once deployed within a patient, a device may release therapeutic agent from the reservoir. The release may be defined as a controlled release where, for example, predetermined quantities of agent are released from the device over a predetermined period of time or at predetermined intervals. The release may further be defined as a “sustained release” where release of the therapeutic agent in maintained (at a constant or variable rate) throughout the period of deployment. 
         [0021]    Oxytocin is a naturally occurring hormone commonly used to induce labour. In the present case, a female to be induced for labour may be administered a single vaginal insert comprising misoprostol for a period of time determined by a clinician. For example, an insert comprising misoprostol may be administered for up to about 24 hours. If after the predetermined time there is no indication that the active phase of labour has begun, oxytocin may be administered. Oxytocin may be administered after completion of a 30-minute waiting period, the waiting period beginning with removal of the vaginal insert. 
         [0022]    Oxytocin may be dosed according to, for example, a dose regimen such as, for example a “low-dose” regimen. A starting dose of about 1 mU/min may be used and this may be increased to about 1-4 mU/min every 30 minutes if an active labour pattern has not established. The maximum dose of oxytocin administered may be 30 mU/min. 
         [0023]    If labour is induced using vaginal inserts containing 200 μg misoprostol and not 10 mg dinoprostone, significant reductions in the requirement for oxytocin, the duration of oxytocin use, the total oxytocin dose and maximum oxytocin dose are observed. 
         [0024]    The effect of a misoprostol containing insert is compared to a dinoprostone-containing insert in the same cross-linked polyurethane. The term “insert” refers to the polyurethane hydrogel sustained delivery device, which may be loaded with drug (misoprostol; or dinoprostone for comparison). The terms MVI or MVI200 refer to a formulated polyurethane insert containing 200 μg misoprostol. The term DVI refers to a formulated polyurethane insert containing 10 mg dinoprostone, which is used as the basis for comparison in the experimental data herein. The drug-containing insert may also be referred to as a pessary. In the experimental data herein the term “insert” is also used to include drug-loaded inserts. 
         [0025]    The insert may provide a sustained and/or controlled delivery of misoprostol vaginally to a female patient. Retrieval means may be provided for withdrawal of the insert as a desired time according to clinical need. 
         [0026]    A second aspect of this invention provides a method of reducing the time to delivery in a female induced for labour, said method comprising administering intravaginally to the female an insert comprising a cross-linked polyurethane reaction product of a polyethylene glycol, a triol and a diisocyanate, the insert containing 200 misoprostol; 
         [0027]    the reduced time to delivery, being reduced in comparison to the administration of said insert containing 10 mg dinoprostone. 
         [0028]    Delivery of a baby may be vaginally or by caesarean section. Vaginal delivery may be spontaneous or with instrumental assistance. Following induction of labour through administration of an insert containing 200 μg misoprostol, delivery of a baby may occur within about 24 hours or within about 12 hours. 
         [0029]    Delivery time may begin with the onset of labour which includes a latent and an active phase. As such, the observed reduction in time to delivery may occur as a consequence of a reduction in the duration of the latent and/or active phase of labour. It should be understood that an insert containing misoprostol may be removed at the onset of active labour. 
         [0030]    In addition to reducing the time to delivery, the present inventors have discovered that induction of labour through vaginal administration of an insert containing 200 μg misoprostol (as opposed to 10 mg dinoprostone) greatly increases the likelihood that a female will deliver the baby vaginally. Additionally, or alternatively, following induction of labour by administration of an insert containing 200 μg misoprostol, a vaginal delivery may occur within about 24 hours or within about 12 hours. 
         [0031]    Generally, the present invention relates to misoprostol-based inserts (for example MVI 200) for use in inducing labour, wherein induction of labour using misoprostol-based inserts confers benefits and/or a reduction in labour associated adverse events as compared to induction using dinoprostone based inserts (for example DVI). 
         [0032]    Induction of labour may be used in a number of clinical situations. By way of example, a female may be induced due to cholestatis, pre-eclampsia, premature rupture of membranes. Additionally, or alternatively, labour may be induced because of foetal macrosomia and/or intrauterine growth restriction. Labour may also be induced because the female is post term (nominally 40 weeks). For example, a post-term female may have been pregnant for anywhere between about 40 and 41 weeks or for a term equal to or greater than 41 weeks. 
         [0033]    In females induced for one or more of the abovementioned clinical situations, the inventors have identified a series of benefits associated with induction through administration of an insert containing 200 μg misoprostol, which benefits are not observed when labour is induced using an insert comprising 10 mg dinoprostone. 
         [0034]    The inventors have observed that in some of the clinical situations described herein, induction of labour using misoprostol as opposed to dinoprostone based inserts, resulted in reduced incidence of a category II foetal heart rate. A category II foetal heart rate may comprise heart rates which exhibit, for example, evidence of tachycardia, bradycardia, loss of or minimal variability, variable decelerations, and/or prolonged decelerations. 
         [0035]    Additionally, the inventors have observed that in some of the clinical situations described herein, induction of labour using misoprostol as opposed to dinoprostone based inserts, results in a reduced likelihood of a newborn being allocated an APGAR score 1 minute after birth of lower than 7. An APGAR (Appearance, Pulse, Grimace, Activity, Respiration) score is used as a means to quickly and reproducibly assess and report the health of a baby following delivery. An APGAR score may be recorded at 1 minute and 5 minutes postpartum. These scores may be referred to as the minute 1 and minute 5 APGAR scores. Generally, a score of 3 or below indicates that the baby is in a critical state whereas a score of between about 4 and about 6 indicates that the baby is only moderately critical. Babies allocated scores of 7 or above are generally regarded as normal. 
         [0036]    In some cases, instruments such as forceps or a ventouse are used to deliver a baby. In other cases, it may be necessary to deliver a baby by caesarean section. The inventors have discovered that in some of the clinical situations described herein, induction of labour using misoprostol as opposed to dinoprostone based inserts, resulted in a reduced requirement for instrumented vaginal delivery and/or caesarean delivery. 
         [0037]    In some of the clinical situations described herein, induction of labour using misoprostol as opposed to dinoprostone based inserts, resulted in a reduced tocolytic agent/drug use. A tocolytic agent/drug may be used to inhibit, suppress or reduce contractions during labour. Examples of tocolytic agents may include terbutaline or magnesium sulfate. 
         [0038]    In some of the clinical situations described herein, induction of labour using misoprostol as opposed to dinoprostone based inserts, resulted in reduced risk of postpartum haemorrhage. Postpartum haemorrhage may be characterised by any significant loss of blood by the female following birth. By way of example, the loss of greater than about 500 ml of blood following a vaginal delivery, or about 1000 ml of blood following caesarean section may be regarded as an occurrence of postpartum haemorrhage. Induction of labour may contribute as a risk factor for postpartum haemorrhage which is the most common cause of perinatal maternal death in the developed world and a major cause of maternal morbidity worldwide. As such, the induction of labour using vaginal inserts containing misoprostol—as opposed to dinoprostone may reduce the risk of the induced female suffering postpartum haemorrhage. 
         [0039]    In some of the clinical situations described herein, induction of labour using misoprostol as opposed to dinoprostone based inserts, resulted in a reduced risk of an induced female developing Chorioamnionitis. Chorioamnionitis is caused by a (bacterial) infection and results in inflammation of the amnion and/or chorion (the foetal membranes). Chorioamniontis is known to prolong labour. The signs and/or symptoms of chorioamnionitis may include, for example, a fever (temperature &gt;37.5° C.), uterine tenderness, purulent vaginal discharge and/or persistent maternal or foetal tachycardia. 
         [0040]    Any of the clinical situations described herein may cause foetal stress. Intrapartum resuscitation techniques may be used to reverse the hypoxic and acidosis states which may occur when a foetus becomes distressed during labour. In some of the clinical situations described herein, the inventors have observed that induction of labour using misoprostol as opposed to dinoprostone based inserts, resulted in a reduction in the use of intrapartum resuscitation techniques. 
         [0041]    Meconium is normally held within the foetus&#39; intestines but occasionally, and often when subjected to stress, the foetus will expel the meconium into the amniotic fluid. If the foetus inhales amniotic fluid contaminated with meconium, respiratory problems may ensue. The inventors have discovered that in certain clinical situations induction of labour using misoprostol as opposed to dinoprostone based inserts, resulted in a reduction in the risk that meconium is expelled by the foetus into the amniotic fluid. 
         [0042]    In some of the clinical situations described herein, the inventors have observed that following induction of labour using misoprostol as opposed to dinoprostone based inserts, the risk that a neonate required admission to an intensive care unit (ICU) was significantly reduced. 
         [0043]    In all aspects of this invention, the misoprostol-containing insert may be administered by introduction into the female at a point determined by the clinician. The insert may be left in-situ until the female enters the active phase of labour. Once the active phase of labour has begun, the misoprostol containing insert may be removed. The misoprostol-containing insert may not be left in situ for more than a period of time determined by a clinician. 
         [0044]    The female induced for labour may be nulliparous or parous. 
         [0045]    The female induced for labour may be hospitalised for the first time. 
         [0046]    The misoprostol-containing insert may be administered by introduction into the female at a time determined by the clinician. As such, the dosing period is the time from insertion of the drug-containing insert into the female to removal thereof. 
         [0047]    The present invention also relates to uses of the misoprostol-containing insert described herein. For example, the invention provides the misoprostol-containing insert for use in any of the methods described herein as well as misoprostol (for example 200 μg misoprostol) for use in the manufacture of medicaments for use in any of the methods described herein. The present invention may provide an insert comprising a cross-linked polyurethane reaction product of a polyethylene glycol, a triol and a diisocyanate and containing 200 μg misoprostol for use in any of the methods described herein. 
     
    
     
       DETAILED DESCRIPTION 
         [0048]    Experimental data will now be presented by way of example and with reference to the following figures which show: 
           [0049]      FIG. 1 : Kaplan-Meier Plot of Time to Vaginal Delivery (All Parity) 
           [0050]      FIG. 2 : Kaplan-Meier Plot of Time to Vaginal Delivery (Nulliparous Subjects) 
           [0051]      FIG. 3 : Kaplan-Meier Plot of Time to Vaginal Delivery (Parous Subjects) 
           [0052]      FIG. 4 : Kaplan-Meier Plot of Time to Any Delivery (All Parity) 
           [0053]      FIG. 5 : Kaplan-Meier Plot of Time to Active Labour (All Parity) 
       
    
    
     EXPERIMENTAL 
     Overall Study Design 
       [0054]    This was a Phase III, double-blind, randomised, multicentre study of approximately 1,350 subjects at or near term gestation requiring cervical ripening and induction of labour. 
         [0055]    Treatment consisted of administration of one randomly assigned MVI 200 or DVI. Nulliparous and parous subjects were randomised to their assigned treatments within their parity cohort in a double-blinded manner. The insert was to be kept in place for 24 hours unless events occurred that necessitated earlier removal (e.g., onset of active labour or intrapartum adverse event (AE)). Oxytocin was permitted after removal of the insert and completion of a 30-minute waiting period, if needed, to augment or induce labour. Enrollment was stratified by site and by parity, and randomization proceeded to ensure that approximately 60% nulliparous subjects and 40% parous subjects were enroled. 
       Detailed Design 
       [0056]    This Phase III study was a double-blind, randomised study comparing MVI 200 with DVI. DVI (Cervidil® [Forest Laboratories], Propess® [Ferring Pharmaceuticals]) is an appropriate comparator for MVI 200 because it is the most commonly used marketed cervical ripening product available in the US and because it is identical in appearance to the MVI, allowing the study to be double-blinded. DVI is labeled in the US for a single administration of a single dose with removal at 12 hours. However, there is an adequate amount of drug in the reservoir to allow continuous dosing via controlled release for up to 24 hours. Because of this, the product is approved in some European countries for administration up to 24 hours. The FDA agreed to allow dosing of up to 24 hours for the DVI during this study in order to maintain the blinded nature of the study. 
         [0057]    The study was randomised in order to prevent bias in the administration of different treatment groups and to attempt to have an even distribution of baseline characteristics across the arms of the study. 
         [0058]    Eligible subjects were randomised to receive one of the following treatments: MVI 200 or DVI 
         [0059]    Subjects were treated with one vaginal insert for up to 24 hours, one time only. 
         [0060]    Intravenous oxytocin was permitted, when required, at least 30 minutes following removal of the study drug assuming no contraindications and active labour not present. 
         [0061]    The MVI 200 and the DVI (Cervidil) were manufactured and released by Controlled Therapeutics (Scotland) Ltd. 
         [0062]    The MVI had three components:
       a hydrogel polymer base measuring approximately 30×10×0.8 mm   200 mcg reservoir of misoprostol released at a controlled rate   a retrieval tape consisting of inert woven polyester into which the polymer base was placed       
 
         [0066]    The DVI had three components:
       a hydrogel polymer base measuring approximately 30×10×0.8 mm   10 mg reservoir of dinoprostone released at approximately 0.3 mg/hour   a retrieval tape consisting of inert woven polyester into which the polymer base was placed.
 
Batch number information is provided in Table 1.
       
 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Investigational Drug (MVI and DVI) Batch Numbers 
               
             
          
           
               
                   
                 Investigational Drug/Dose 
                 Batch No. 
                 Expiry Date 
               
               
                   
                   
               
               
                   
                 MVI 200 mcg 
                 MS10006 
                 31 Jul. 2013 
               
               
                   
                 DVI 10 mg (Cervidil) 
                 MA10K02/1 
                 30 Jun. 2013 
               
               
                   
                   
               
             
          
         
       
     
         [0070]    For both the MVI and DVI, the polymer base was designed to absorb fluid from the vagina. As the polymer hydrates and swells, it creates a concentration gradient leading to a sustained release of misoprostol or dinoprostone for up to 24 hours. The polymer was a cross-linked polyurethane. 
         [0071]    The MVI and DVI study drug inserts and packaging were identical in appearance (double-blinded). Each study drug kit consisted of a foil sachet with a preprinted subject number detailed on the label. The subject number differentiated study drug intended for nulliparous subjects from that intended for parous subjects. A second self-adhesive label identical to that found on the study drug foil sachet was attached to the study drug foil label. The second self-adhesive label was placed on the study drug accountability form for that subject and kept with the study source documents. 
         [0072]    The study drug kits were stored in a freezer. If unopened study drug was not used following removal from the freezer, it could have been returned to the freezer for use at a later date. The study drug could have been removed from and returned to the freezer multiple times as long as it was unopened and the total cumulative time outside the freezer was not more than 24 hours. Any study drug remaining out of the freezer for more than a total of 24 hours was discarded and its destruction documented. 
       Selection and Timing of Dose for Each Patient 
       [0073]    Subjects were randomised to receive one of the following in a double-blind manner: MVI 200 or DVI. 
         [0074]    One randomised study drug was administered to each subject by the Investigator or qualified designee. The insert was placed high in the posterior vaginal fornix and positioned transversely. A minimal quantity of water-soluble lubricant could have been used to aid placement of the study drug. The insert was not pre-wetted or pre-swelled prior to insertion and obstetric cream was not used. 
         [0075]    The subject remained in bed for at least 30 minutes after insertion to ensure that sufficient time was provided for the insert to hydrate and start to swell. 
         [0076]    The subject was instructed to use caution when using the toilet or washing to avoid inadvertent removal of the insert. 
         [0077]    Subjects were treated with study drug for up to 24 hours. The study drug was removed before 24 hours if there was clinical concern for the wellbeing of mother or baby or if an adverse event (AE) occurred: 
         [0078]    If the study drug fell out of the vagina spontaneously or was mistakenly removed early, it was not replaced. At the time of removal, an obstetrician, midwife, obstetric nurse, or other qualified site staff removed the insert by gently pulling on the retrieval tape. 
       Oxytocin Use 
       [0079]    Oxytocin use was not permitted within 7 days prior to study drug administration and while the study drug was in situ. 
         [0080]    Intravenous oxytocin was permitted, when required, at least 30 minutes following removal of the study drug, assuming no contraindications and no active Labour. Earlier administration was permitted, if required, for treatment of an emergency situation. 
       Onset of Active Labour and Delivery 
       [0081]    The date and time of onset of active labour were to be recorded throughout the treatment period. Active labour was defined as progressive cervical dilatation to 4 cm with any frequency of contractions OR rhythmic, firm, adequate, quality uterine contractions causing progressive cervical change occurring at a frequency of three or more in 10 minutes and lasting 45 seconds or more. 
         [0082]    At time of delivery of neonate, the following were recorded:
       Mode of delivery (spontaneous vaginal, instrumented vaginal, or caesarean)
           If caesarean delivery, the reason for the caesarean delivery was recorded.   
           Date and time of delivery of neonate.       
 
       Adverse Events 
       [0086]    An AE was defined as any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and that does not necessarily have a causal relationship with this treatment. 
         [0087]    Subjects were questioned and observed for evidence of AEs, whether or not related to study drug. 
         [0088]    Adverse events were collected through hospital discharge following delivery. Adverse events that occurred during the labour and delivery (L&amp;D) period were categorised as intrapartum AEs. Following delivery, AEs were categorised as postpartum (maternal) or neonatal events. 
       Summaries of Adverse Event Incidence Rates 
       [0089]    Averse events were summarised by system organ class and preferred term for intrapartum, postpartum, and neonate events without regard to relationship to study drug. 
       Summary of Outcomes and Adverse Events of Special Interest 
       [0090]    Safety assessments were also summarised for Outcomes and AEs of Special 
         [0091]    Interest. Treatment groups were compared using Fisher&#39;s exact tests for each of these outcomes or events. However, there was no correction for multiplicity; therefore, p-values should be interpreted with caution. 
       Efficacy Results and Tabulations of Individual Patient Data 
     Analysis of Efficacy 
     Primary Efficacy Endpoint: Time to Vaginal Delivery During the First Hospitalisation 
       [0092]    Time to vaginal delivery during first hospitalisation was statistically significantly shorter for MVI 200 subjects (median 1292.00 minutes [21.5 hours]) compared with DVI subjects (median 1968.50 minutes [32.8 hours]) (p&lt;0.001). Time to vaginal delivery during first hospitalisation was also statistically significantly shorter in MVI 200 subjects compared with DVI subjects among the subsets of nulliparous subjects (p&lt;0.001) and parous subjects (p&lt;0.001). Kaplan Meier estimates of time to vaginal delivery are presented in Table 2. 
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Kaplan-Meier Estimates of Time to Vaginal 
               
               
                 Delivery (ITT/Safety Population) 
               
             
          
           
               
                 Time From Study Drug 
                   
                   
               
               
                 Administration to 
               
               
                 Vaginal Delivery 
                 MVI 200 
                 DVI 
               
               
                 (minutes) 
                 (N = 678) 
                 (N = 680) 
               
               
                   
               
               
                 Any parity 
                   
                   
               
               
                 N 
                 678    
                 680 
               
               
                 Median 
                 1292.00 (21.5 
                 1968.50 (32.8 
               
               
                   
                 hours) 
                 hours) 
               
               
                 95% CI 1   
                 (1200.00, 1402.00) 
                 (1812.00, 2093.00) 
               
               
                   
                 (20 hours, 23.4 
                 (30.2 hours, 34.9 
               
               
                   
                 hours) 
                 hours) 
               
               
                 p-value 1   
                 &lt;0.001 
               
               
                 Number (%) of censored 
                 181 (26.7)  
                 193 (28.4) 
               
               
                 subjects 2   
               
               
                 Caesarean delivery 
                 176 (26.0)  
                 184 (27.1) 
               
               
                 (imputed value: 6548 minutes) 
               
               
                 Discharged prior to delivery 
                 5 (0.7) 
                  9 (1.3) 
               
               
                 (imputed value: 4571 minutes) 
               
               
                 Nulliparous subjects 
               
               
                 N 
                 441    
                 451 
               
               
                 Median 
                 1750.00 (29.2 
                 2586.00 (43.1 
               
               
                   
                 hours) 
                 hours) 
               
               
                 95% CI 1   
                 (1524.00, 1963.00) 
                 (2272.00, 2926.00) 
               
               
                   
                 (25.4 hours, 32.7 
                 (37.9 hours, 48.8 
               
               
                   
                 hours) 
                 hours) 
               
               
                 p-value 1   
                 &lt;0.001 
               
               
                 Number (%) of censored 
                 156 (35.4)  
                 176 (39.0) 
               
               
                 subjects 2   
               
               
                 Caesarean delivery 
                 152 (34.5)  
                 168 (37.3) 
               
               
                 (imputed value: 6548 minutes) 
               
               
                 Discharged prior to delivery 
                 4 (0.9) 
                  8 (1.8) 
               
               
                 (imputed value: 4571 minutes) 
               
               
                 Parous subjects 
               
               
                 N 
                 237    
                 229 
               
               
                 Median 
                 802.00 (13.4 
                 1203.00 (20.1 
               
               
                   
                 hours) 
                 hours) 
               
               
                 95% CI 1   
                 (748.00, 885.00) 
                 (1065.00, 1368.00) 
               
               
                   
                 (12.5 hours, 14.75 
                 (17.75 hours, 22.8 
               
               
                   
                 hours) 
                 hours) 
               
               
                 p-value 1   
                 &lt;0.001 
               
               
                 Number (%) of censored 
                 25 (10.5) 
                 17 (7.4) 
               
               
                 subjects 2   
               
               
                 Caesarean delivery 
                 24 (10.1) 
                 16 (7.0) 
               
               
                 (imputed value: 4346 minutes) 
               
               
                 Discharged prior to delivery 
                 1 (0.4) 
                  1 (0.4) 
               
               
                 (imputed value: 1642 minutes) 
               
               
                   
               
               
                   1 Two-sided p-values and CIs were obtained from a Log-Rank Test 
               
               
                   2 Subjects who had a caesarean delivery during the first hospitalisation were censored using the longest time interval from study drug administration to caesarean delivery during the first hospitalisation, independent of treatment group. Subjects who, in their first hospitalisation, were discharged prior to delivery or withdrew consent prior to delivery were censored using the longest time interval from study drug administration to L&amp;D discharge, independent of treatment group. 
               
             
          
         
       
     
         [0093]    Time to caesarean delivery was significantly shorter for MVI 200 subjects (median 1431.5 minutes [23.9 hours]) compared with DVI subjects (median 2077.5 minutes [34.6 hours]) (p&lt;0.001). Time to caesarean delivery was also significantly shorter in MVI 200 subjects compared with DVI subjects among both nulliparous subjects (p&lt;0.001) and parous subjects (p&lt;0.001). The summary of time to caesarean delivery is presented in Table 3. 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 Summary of Time to Caesarean Delivery During 
               
               
                 First Hospitalisation (ITT/Safety Population) 
               
             
          
           
               
                 Time from Study Drug 
                   
                   
               
               
                 Administration to Caesarean 
               
               
                 Delivery During First 
               
               
                 Hospitalisation 
                 MVI 200 
                 DVI 
               
               
                 (minutes) 
                 (N = 678) 
                 (N = 680) 
               
               
                   
               
             
          
           
               
                 Any parity 
                   
                   
               
               
                 n 
                 176 
                 184 
               
               
                 Median 
                 1431.5 (23.9 
                 2077.5 (34.6 
               
               
                   
                 hours) 
                 hours) 
               
               
                 Minimum, maximum 
                 177, 6548 
                 182, 5618 
               
               
                   
                 (2.95 hours, 109.1 
                 (3.1 hours, 93.6 
               
               
                   
                 hours) 
                 hours) 
               
               
                 p-value 1   
                 &lt;0.001 
               
               
                 Nulliparous subjects 
               
               
                 n 
                 152 
                 168 
               
               
                 Median 
                 1516.0 (25.3 
                 2097.5 (35 
               
               
                   
                 hours) 
                 hours) 
               
               
                 Minimum, maximum 
                 263, 6548 
                 182, 5618 
               
               
                   
                 (4.4 hours, 109.1 
                 (3.1 hours, 93.6 
               
               
                   
                 hours) 
                 hours) 
               
               
                 p-value 1   
                 &lt;0.001 
               
               
                 Parous subjects 
               
               
                 n 
                 24 
                  16 
               
               
                 Median 
                 1235.5 (20.6 
                 1630.0 (27.2 
               
               
                   
                 hours) 
                 hours) 
               
               
                 Minimum, maximum 
                 177, 4346 
                 564, 3378 
               
               
                   
                 (2.95 hours, 72.4 
                 (9.4 hours, 56.3 
               
               
                   
                 hours) 
                 hours) 
               
               
                 p-value 1   
                 0.163 
               
               
                   
               
               
                   1 P-value based on a Wilcoxon Rank Sum test. 
               
             
          
         
       
     
       Time to Any Delivery (Vaginal or Caesarean) During the First Hospitalisation 
       [0094]    Time to any delivery mode (vaginal or caesarean) was significantly shorter in MVI 200 subjects (Kaplan Meier median 1096.50 minutes [18.3 hours]) compared with DVI subjects (Kaplan Meier median 1639.50 minutes [27.3 hours]) (p&lt;0.001). Time to any delivery was also significantly shorter in MVI 200 subjects compared with DVI subjects among both nulliparous subjects (p&lt;0.001) and parous subjects (p&lt;0.001). Kaplan Meier estimates of time to any delivery are presented Table 4. 
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 Kaplan-Meier Estimates of Time to Any 
               
               
                 Delivery (ITT/Safety Population) 
               
             
          
           
               
                 Time From Study Drug 
                   
                   
               
               
                 Administration to 
               
               
                 Any Delivery 
                 MVI 200 
                 DVI 
               
               
                 (minutes) 
                 (N = 678) 
                 (N = 680) 
               
               
                   
               
               
                 Any parity 
                   
                   
               
               
                 N 
                 678    
                 680 
               
               
                 Median 
                 1096.50 (18.3 
                 1639.50 (27.3 
               
               
                   
                 hours) 
                 hours) 
               
               
                 95% CI 1   
                 (1031.00, 1170.00) 
                 (1573.00, 1731.00) 
               
               
                   
                 (17.1 hours, 19.5 
                 (26.2 hours, 28.9 
               
               
                   
                 hours) 
                 hours) 
               
               
                 p-value 1   
                 &lt;0.001 
               
               
                 Number (%) of censored 
                 5 (0.7) 
                 9 (1.3) 
               
               
                 subjects 2   
               
               
                 Discharged prior to delivery 
                 5 (0.7) 
                 9 (1.3) 
               
               
                 (imputed value: 4571 minutes) 
               
               
                 Nulliparous subjects 
               
               
                 N 
                 441    
                 451 
               
               
                 Median 
                 1304.00 (21.7 
                 1882.00 (31.4 
               
               
                   
                 hours) 
                 hours) 
               
               
                 95% CI 1   
                 (1203.00, 1376.00) 
                 (1764.00, 2016.00) 
               
               
                   
                 (20.1 hours, 23 
                 (29.4 hours, 33.6 
               
               
                   
                 hours) 
                 hours) 
               
               
                 p-value 1   
                 &lt;0.001 
               
               
                 Number (%) of censored 
                 4 (0.9) 
                 8 (1.8) 
               
               
                 subjects 2   
               
               
                 Discharged prior to delivery 
                 4 (0.9) 
                 8 (1.8) 
               
               
                 (imputed value: 4571 minutes) 
               
               
                 Parous subjects 
               
               
                 N 
                 237    
                 229 
               
               
                 Median 
                 777.00 (12.95 
                 1155.00 (19.25 
               
               
                   
                 hours) 
                 hours) 
               
               
                 95% CI 1   
                 (732.00, 823.00) 
                 (1040.00, 1321.00) 
               
               
                   
                 (12.2 hours, 13.7 
                 (17.3 hours, 22 
               
               
                   
                 hours) 
                 hours) 
               
               
                 p-value 1   
                 &lt;0.001 
               
               
                 Number (%) of censored 
                 1 (0.4) 
                 1 (0.4) 
               
               
                 subjects 2   
               
               
                 Discharged prior to delivery 
                 1 (0.4) 
                 1 (0.4) 
               
               
                 (imputed value: 1642 minutes) 
               
               
                   
               
               
                   1 Two-sided p-values and CIs were obtained from a Log-Rank Test. 
               
               
                   2 Subjects who did not deliver during their first hospitalisation were censored using the longest time interval from study drug administration to L&amp;D discharge, independent of treatment group. 
               
             
          
         
       
     
         [0095]    The Kaplan-Meier plot of time to any delivery during the first hospitalisation is presented in  FIG. 4  (all parity). Kaplan-Meier plots of time to vaginal delivery (all parity), time to vaginal delivery (nulliparous subjects) and time to vaginal delivery (parous subjects) are presented in  FIGS. 1, 2 and 3 . 
       Time to Active Labour (or Duration of Latent Labour) During the First Hospitalisation 
       [0096]    Active labour was defined as progressive cervical dilatation to 4 cm with any frequency of contractions OR rhythmic, firm, adequate, quality uterine contractions causing progressive cervical change occurring at a frequency of three or more in 10 minutes and lasting 45 seconds or more. 
         [0097]    Time to active labour was significantly shorter in MVI 200 subjects (median 726.50 minutes [12.1 hours]) compared to DVI subjects (median 1116.50 minutes [18.6 hours]) (p&lt;0.001). Time to active labour was also significantly shorter in MVI 200 subjects compared with DVI subjects among both nulliparous subjects (p&lt;0.001) and parous subjects (p&lt;0.001). Kaplan-Meier estimates of time to active labour are presented in Table 5. 
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                 Kaplan-Meier Estimates of Time to Active 
               
               
                 Labour (ITT/Safety Population) 
               
             
          
           
               
                 Time From Study Drug 
                   
                   
               
               
                 Administration to 
               
               
                 Active Labour 
                 MVI 200 
                 DVI 
               
               
                 (minutes) 
                 (N = 678) 
                 (N = 680) 
               
               
                   
               
               
                 Any parity 
                   
                   
               
               
                 N 
                 678    
                 680 
               
               
                 Median 
                 726.50 (12.1 
                 1116.50 (18.6 
               
               
                   
                 hours) 
                 hours) 
               
               
                 95% CI 1   
                 (719.00, 773.00) 
                 (1083.00, 1352.00) 
               
               
                   
                 (12 hours, 12.9 
                 (18.1 hours, 22.5 
               
               
                   
                 hours) 
                 hours) 
               
               
                 p-value 1   
                 &lt;0.001 
               
               
                 Number (%) of censored 
                 47 (6.9)  
                 54 (7.9)  
               
               
                 subjects 2   
               
               
                 Discharged without active labour 
                 42 (6.2)  
                 45 (6.6)  
               
               
                 (imputed value: 5618 minutes) 
               
               
                 Discharged prior to active labour 
                 5 (0.7) 
                 9 (1.3) 
               
               
                 (imputed value: 4571 minutes) 
               
               
                 Nulliparous subjects 
               
               
                 N 
                 441    
                 451 
               
               
                 Median 
                 885.00 (14.8 
                 1444.00 (24.1 
               
               
                   
                 hours) 
                 hours) 
               
               
                 95% CI 1   
                 (810.00, 948.00) 
                 (1352.00, 1558.00) 
               
               
                   
                 (13.5 hours, 15.8 
                 (22.5 hours, 26 
               
               
                   
                 hours) 
                 hours) 
               
               
                 p-value 1   
                 &lt;0.001 
               
               
                 Number (%) of censored 
                 41 (9.3)  
                 50 (11.1) 
               
               
                 subjects 2   
               
               
                 Discharged without active labour 
                 37 (8.4)  
                 42 (9.3)  
               
               
                 (imputed value: 5618 minutes) 
               
               
                 Discharged prior to active labour 
                 4 (0.9) 
                 8 (1.8) 
               
               
                 (imputed value: 4571 minutes) 
               
               
                 Parous subjects 
               
               
                 N 
                 237    
                 229 
               
               
                 Median 
                 579.00 (9.7 
                 780.00 (13 
               
               
                   
                 hours) 
                 hours) 
               
               
                 95% CI 1   
                 (535.00, 616.00) 
                 (715.00, 913.00) 
               
               
                   
                 (8.92 hours, 10.3 
                 (11.9 hours, 15.2 
               
               
                   
                 hours) 
                 hours) 
               
               
                 p-value 1   
                 &lt;0.001 
               
               
                 Number (%) of censored 
                 6 (2.5) 
                 4 (1.7) 
               
               
                 subjects 2   
               
               
                 Discharged without active labour 
                 5 (2.1) 
                 3 (1.3) 
               
               
                 (imputed value: 1451 minutes) 
               
               
                 Discharged prior to active labour 
                 1 (0.4) 
                 1 (0.4) 
               
               
                 (imputed value: 1642 minutes) 
               
               
                   
               
               
                   1 Two-sided p-values and CIs were obtained from a Log-Rank Test. 
               
               
                   2 Subjects who did not go into active labour during the first hospitalisation were censored using the longest time interval from study drug administration to delivery during the first hospitalisation, independent of treatment group. Subjects who, in their first hospitalisation, were discharged prior to delivery or withdrew consent prior to delivery were censored using the longest time interval from study drug administration to L&amp;D discharge, independent of treatment group. 
               
             
          
         
       
     
         [0098]    A Kaplan-Meier plot of time to active labour (all parity) is presented in  FIG. 5   
       Incidence of Pre-Delivery Oxytocin Use During the First Hospitalisation 
       [0099]    The percentages of subjects requiring pre-delivery oxytocin, pre-delivery oxytocin total dose, duration of pre-delivery oxytocin use, and maximum dose/minute were all lower in the MVI 200 treatment group compared with the DVI treatment group (p&lt;0.001 ; Table 6). 
         [0100]    The statistically significant treatment differences (p≦0.001) were also observed among nulliparous subjects and among parous subjects for these oxytocin parameters. 
       Duration of Pre-Delivery Oxytocin Administration for Subjects Who Delivered During First Hospitalisation 
       [0101]    The percentage of subjects requiring pre-delivery oxytocin was lower for MVI 200 subjects (47.4%/48.1%*) compared with DVI subjects (73.9%/74.1%*) (p&lt;0.001) (Table 6). Compared with DVI subjects, MVI 200 subjects had a lower total dose (mean 6.53/4.4*units vs. 8.29 units; p&lt;0.001), shorter duration (mean 498.6/500.6*minutes [8.31/8.34*hours] vs. 657.3/486.62*minutes [10.96/8.11*hours]; p&lt;0.001), and lower maximum dose/minute (mean 10.6 vs. 14.1 mU; p&lt;0.001) of pre-delivery oxytocin (Table 6). Note: * denotes data from a revised analysis of raw data used to obtain the preliminary data (a). 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                 Pre-Delivery Oxytocin Use During First Hospitalisation (ITT/Safety Population) 
               
             
          
           
               
                   
                 MVI 200 
                 MVI 200 
                 DVI 
                 DVI 
               
               
                   
                 (N = 678) a   
                 (N = 678)* 
                 (N = 680) a   
                 (N = 680) a   
               
               
                   
                   
               
             
          
           
               
                 Subjects who delivered during first 
                 673    
                 673 
                 671   
                 671 
               
               
                 hospitalisation 
               
               
                 Subjects requiring pre-delivery 
               
               
                 oxytocin 1   
               
               
                 n (%) 
                 319 (47.4) 
                  324 (48.1) 
                  496 (73.9) 
                  497 (74.1) 
               
               
                 95% CI 2   
                 (43.57%, 51.25%)  
                 (44.24%, 51.92%) 
                 (70.42%, 77.20%)  
                 70.58%, 77.35%)     
               
               
                 p-value 3   
                 &lt;0.001 
                 &lt;0.001 
               
               
                 Pre-delivery oxytocin total dose 
                   
                 320 
                   
                 496 
               
               
                 (units) 
               
               
                 Mean (SD) 
                  4.4 (6.53) 
                  4.4 (6.52) 
                  7.2 (8.29) 
                  7.2 (8.29) 
               
               
                 Median 
                 1.9  
                 1.9 
                  4.4 
                    4.4 
               
               
                 Minimum, maximum 
                 0, 48 
                 0.48 
                 0, 50 
                 0, 50 
               
               
                 p-value 4   
                 &lt;0.001 
                 &lt;0.001 
               
               
                 Duration of pre-delivery oxytocin 
                   
                 321 
               
               
                 use (minutes) 
               
               
                 Mean (SD) 
                  498.6 (451.63) 
                  500.6 (452.08) 
                  657.3 (487.11) 
                  657.2 (486.62) 
               
               
                 Median 
                 385.0   
                 385.0 
                 544.5 
                   545.0 
               
               
                 Minimum, maximum 
                  1, 2625 
                   1, 2625 
                  5, 3217 
                  5, 3217 
               
               
                 p-value 4   
                 &lt;0.001 
                 &lt;0.001 
               
               
                 Maximum dose/minute (mU) 
                   
                 321 
                   
                 497 
               
               
                 Mean (SD) 
                 10.6 (8.64) 
                 10.6 (8.66) 
                 14.1 (8.97) 
                 14.1 (8.96) 
               
               
                 Median 
                 8.0  
                 8.0 
                  12.0 
                   12.0 
               
               
                 Minimum, maximum 
                 1, 42 
                  1, 42 
                 1, 42 
                 1, 42 
               
               
                 p-value 4   
                 &lt;0.001 
                 &lt;0.001 
               
               
                   
               
               
                   1 Percentage based on subjects who delivered or received oxytocin during first hospitalisation. 
               
               
                   2 95% exact binomial CI. 
               
               
                   3 Two-sided p-values were obtained from Fisher&#39;s exact tests. 
               
               
                   4 Two-sided p-values were obtained from one-way ANOVA models. 
               
               
                 *denotes data from a revised analysis of raw data used to obtain the preliminary data a . 
               
             
          
         
       
     
       Incidence of Vaginal Delivery Within 12 Hours of Study Drug Administration 
       [0102]    A higher percentage of subjects in the MVI 200 treatment group had vaginal delivery within 12 hours of study drug administration than in the DVI treatment group (19.76% vs. 8.38%, p&lt;0.001; Table 7). The treatment group difference was also statistically significant among nulliparous subjects (p&lt;0.001) and parous subjects (p&lt;0.001). 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 7 
               
             
             
               
                   
               
               
                 Incidence of Vaginal Delivery Within 12 Hours of Study Drug Administration (ITT/Safety Population) 
               
             
          
           
               
                   
                 MVI 200 
                 MVI 200 
                 DVI 
                 DVI 
               
               
                   
                 (N = 678) a   
                 (N = 678)* 
                 (N = 680) a   
                 (N = 680)* 
               
               
                   
                   
               
             
          
           
               
                 Any parity 
                 370 
                 678 
                 231 
                 680 
               
               
                 Within 12 hours, n (%) 
                 134 (19.76)  
                 134 (19.76)  
                 57 (8.38)  
                 57 (8.38)  
               
               
                 95% CI 1   
                 (16.83%, 22.96%) 
                 (16.83%, 22.96%) 
                  (6.41%, 10.72%) 
                  (6.41%, 10.72%) 
               
               
                 p-value 2   
                    &lt;0.001 
                    &lt;0.001 
               
               
                 Number of subjects with 
                 497 
                 499 
                 487 
                 491 
               
               
                 vaginal delivery 
               
               
                 Delivered within 12 
                 134 (26.96)  
                 134 (26.85)  
                 57 (11.70) 
                 57 (11.61) 
               
               
                 hours, n (%) 3   
               
               
                 Nulliparous 
                 185 
                 441 
                  97 
                 451 
               
               
                 Within 12 hours, n (%) 
                 40 (9.07)  
                 40 (9.07)  
                 12 (2.66)  
                 12 (2.66)  
               
               
                 95% CI 1   
                  (6.56%, 12.15%) 
                  (6.56%, 12.15%) 
                 (1.38%, 4.60%) 
                 (1.38%, 4.60%) 
               
               
                 p-value 2   
                    &lt;0.001 
                    &lt;0.001 
               
               
                 Number of subjects with 
                 285 
                 286 
                 275 
                 278 
               
               
                 vaginal delivery 
               
               
                 Delivered within 12 
                 40 (14.04) 
                 40 (13.99) 
                 12 (4.36)  
                 12 (4.32)  
               
               
                 hours, n (%) 3   
               
               
                 Parous 
                 185 
                 237 
                 134 
                 229 
               
               
                 Within 12 hours, n (%) 
                 94 (39.66) 
                 94 (39.66) 
                 45 (19.65) 
                 45 (19.65) 
               
               
                 95% CI 1   
                 (33.39%, 46.20%) 
                 (33.39%, 46.20%) 
                 (14.71%, 25.40%) 
                 (14.71%, 25.40%) 
               
               
                 p-value 2   
                    &lt;0.001 
                    &lt;0.001 
               
               
                 Number of subjects with 
                 212 
                 213 
                 212 
                 213 
               
               
                 vaginal delivery 
               
               
                 Delivered within 12 
                 94 (44.34) 
                 94 (44.13) 
                 45 (21.23) 
                 45 (21.23) 
               
               
                 hours, n (%) 3   
               
               
                   
               
               
                   1 95% exact binomial CI. 
               
               
                   2 Two-sided p-values were obtained from Fisher&#39;s exact tests. 
               
               
                   3 Percentage based on subjects with vaginal delivery. 
               
               
                 *denotes data from a revised analysis of raw data used to obtain the preliminary data a . 
               
             
          
         
       
     
       Incidence of Any Delivery Within 24 Hours of Study Drug Administration 
       [0103]    A higher percentage of subjects in the MVI 200 treatment group had any delivery within 24 hours of study drug administration than in the DVI treatment group (67.70% vs. 40.74%, p&lt;0.001; Table 8). The treatment group difference was also statistically significant among nulliparous subjects (p&lt;0.001) and parous subjects (p&lt;0.001). 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 8 
               
             
             
               
                   
               
               
                 Incidence of Any Delivery Within 24 Hours of Study Drug Administration (ITT/Safety Population) 
               
             
          
           
               
                   
                 MVI 200 
                 MVI 200 
                 DVI 
                 DVI 
               
               
                   
                 (N = 678) a   
                 (N = 678)* 
                 (N = 680) a   
                 (N = 680)* 
               
               
                   
                   
               
             
          
           
               
                 Any parity 
                 459 
                 678 
                 277 
                 680 
               
               
                 Within 24 hours, n (%) 
                 459 (67.70) 
                 459 (67.70) 
                 277 (40.74) 
                 277 (40.74) 
               
               
                 95% CI 1   
                 (64.03%, 71.21%) 
                 (64.03%, 71.21%) 
                 (37.02%, 44.54%) 
                 (37.02%, 44.54%) 
               
               
                 p-value 2   
                 &lt;0.001 
                 &lt;0.001 
               
               
                 Nulliparous 
                 259 
                 441 
                 137 
                 451 
               
               
                 Within 24 hours, n (%) 
                 259 (58.73) 
                 259 (58.73) 
                 137 (30.38) 
                 137 (30.38) 
               
               
                 95% CI 1   
                 (53.98%, 63.37%) 
                 (53.98%, 63.37%) 
                 (26.16%, 34.85%) 
                 (26.16%, 34.85%) 
               
               
                 p-value 2   
                 &lt;0.001 
                 &lt;0.001 
               
               
                 Parous 
                 200 
                 237 
                 140 
                 229 
               
               
                 Within 24 hours, n (%) 
                 200 (84.39) 
                 200 (84.39) 
                 140 (61.14) 
                 140 (61.14) 
               
               
                 95% CI 1   
                 (79.13%, 88.76%) 
                 (79.13%, 88.76%) 
                 (54.49%, 67.49%) 
                 (54.49%, 67.49%) 
               
               
                 p-value 2   
                 &lt;0.001 
                 &lt;0.001 
               
               
                   
               
               
                   1 95% exact binomial CI. 
               
               
                   2 Two-sided p-values were obtained from Fisher&#39;s exact tests. 
               
               
                 *denotes data from a revised analysis of raw data used to obtain the preliminary data a . 
               
             
          
         
       
     
       Incidence of Any Delivery Within 12 Hours of Study Drug Administration 
       [0104]    A higher percentage of subjects in the MVI 200 treatment group had any delivery within 12 hours of study drug administration than in the DVI treatment group (23.16% vs. 9.26%, p&lt;0.001; Table 9). The treatment group difference was also statistically significant among nulliparous subjects (p&lt;0.001) and parous subjects (p&lt;0.001). 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 9 
               
             
             
               
                   
               
               
                 Incidence of Any Delivery Within 12 Hours of Study Drug Administration (ITT/Safety Population) 
               
             
          
           
               
                   
                 MVI 200 
                 MVI 200 
                 DVI 
                 DVI 
               
               
                   
                 (N = 678) a   
                 (N = 678)* 
                 (N = 680) a   
                 (N = 680)* 
               
               
                   
                   
               
             
          
           
               
                 Any parity 
                 459 
                 678 
                 277 
                 680 
               
               
                 Within 12 hours, n (%) 
                 157 (23.16) 
                 157 (23.16) 
                 63 (9.26) 
                 63 (9.26) 
               
               
                 95% CI 1   
                 (20.03%, 26.52%) 
                 (20.03%, 26.52%) 
                  (7.19%, 11.70%) 
                  (7.19%, 11.70%) 
               
               
                 p-value 2   
                 &lt;0.001 
                 &lt;0.001 
               
               
                 Nulliparous 
                 259 
                 441 
                 137 
                 451 
               
               
                 Within 12 hours, n (%) 
                  57 (12.93) 
                  57 (12.93) 
                 16 (3.55) 
                 16 (3.55) 
               
               
                 95% CI 1   
                  (9.94%, 16.42%) 
                  (9.94%, 16.42%) 
                      2.04%, 5.70%) 
                      2.04%, 5.70%) 
               
               
                 p-value 2   
                 &lt;0.001 
                 &lt;0.001 
               
               
                 Parous 
                 200 
                 237 
                 140 
                 229 
               
               
                 Within 12 hours, n (%) 
                 100 (42.19) 
                 100 (42.19) 
                  47 (20.52) 
                  47 (20.52) 
               
               
                 95% CI 1   
                 (35.83%, 48.76%) 
                 (35.83%, 48.76%) 
                 (15.49%, 26.34%) 
                 (15.49%, 26.34%) 
               
               
                 p-value 2   
                 &lt;0.001 
                 &lt;0.001 
               
               
                   
               
               
                   1 95% exact binomial CI. 
               
               
                   2 Two-sided p-values were obtained from Fisher&#39;s exact tests. 
               
               
                 *denotes data from a revised analysis of raw data used to obtain the preliminary data a . 
               
             
          
         
       
     
       Incidence of Vaginal Delivery Within 24 Hours of Study Drug Administration 
       [0105]    A higher percentage of subjects in the MVI 200 treatment group had vaginal delivery within 24 hours of study drug administration than in the DVI treatment group (54.57% vs. 33.97%, p&lt;0.001; Table 10). The treatment group difference was also statistically significant among nulliparous subjects (p&lt;0.001) and parous subjects (p&lt;0.001). 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 10 
               
             
             
               
                   
               
               
                 Incidence of Vaginal Delivery Within 24 Hours of Study Drug Administration (ITT/Safety Population) 
               
             
          
           
               
                   
                 MVI 200 
                 MVI 200 
                 DVI 
                 DVI 
               
               
                   
                 (N = 678) a   
                 (N = 678)* 
                 (N = 680) a   
                 (N = 680)* 
               
               
                   
                   
               
             
          
           
               
                 Any parity 
                 370 
                 678 
                 231 
                 680 
               
               
                 Within 24 hours, n (%) 
                 370 (54.57) 
                 370 (54.57) 
                 231 (33.97) 
                 231 (33.97) 
               
               
                 95% CI 1   
                 (50.74%, 58.37%) 
                 (50.74%, 58.37%) 
                 (30.41%, 37.67%) 
                 (30.41%, 37.67%) 
               
               
                 p-value 2   
                    &lt;0.001 
                    &lt;0.001 
               
               
                 Number of subjects with 
                 497 
                 499 
                 487 
                 491 
               
               
                 vaginal delivery 
               
               
                 Delivered within 24 
                 370 (74.45) 
                 370 (74.45) 
                 231 (47.43) 
                 231 (47.05) 
               
               
                 hours, n (%) 3   
               
               
                 Nulliparous 
                 185 
                 441 
                  97 
                 451 
               
               
                 Within 24 hours, n (%) 
                 185 (41.95) 
                 185 (41.95) 
                  97 (21.51) 
                  97 (21.51) 
               
               
                 95% CI 1   
                 (37.30%, 46.71%) 
                 (37.30%, 46.71%) 
                 (17.80%, 25.59%) 
                 (17.80%, 25.59%) 
               
               
                 p-value 2   
                    &lt;0.001 
                    &lt;0.001 
               
               
                 Number of subjects with 
                 285 
                 286 
                 275 
                 278 
               
               
                 vaginal delivery 
               
               
                 Delivered within 24 
                 185 (64.91) 
                 185 (64.69) 
                  97 (35.27) 
                  97 (34.89) 
               
               
                 hours, n (%) 3   
               
               
                 Parous 
                 185 
                 237 
                 134 
                 229 
               
               
                 Within 24 hours, n (%) 
                  94 (39.66) 
                 185 (78.06) 
                  45 (19.65) 
                 134 (58.52) 
               
               
                 95% CI 1   
                 (72.24%, 83.16%) 
                 (72.24%, 83.16%) 
                 (51.84%, 64.97%) 
                 (51.84%, 64.97%) 
               
               
                 p-value 2   
                    &lt;0.001 
                    &lt;0.001 
               
               
                 Number of subjects with 
                 212 
                 213 
                 212 
                 213 
               
               
                 vaginal delivery 
               
               
                 Delivered within 24 
                 185 (87.26) 
                 185 (86.85) 
                 134 (63.21) 
                 134 (62.91) 
               
               
                 hours, n (%) 3   
               
               
                   
               
               
                   1 95% exact binomial CI. 
               
               
                   2 Two-sided p-values were obtained from Fisher&#39;s exact tests. 
               
               
                   3 Percentage based on subjects with vaginal delivery. 
               
               
                 *denotes data from a revised analysis of raw data used to obtain the preliminary data a . 
               
             
          
         
       
     
       Overall Incidence of Vaginal Delivery 
       [0106]    No statistically significant difference between treatment groups was observed for the incidence of vaginal delivery during first hospitalisation overall or by parity (Table 11). 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 11 
               
             
             
               
                   
               
               
                 Incidence of Vaginal Delivery During First 
               
               
                 Hospitalisation (ITT/Safety Population) 
               
             
          
           
               
                   
                 MVI 200 
                 DVI 
               
               
                   
                 (N = 678) 
                 (N = 680) 
               
               
                   
                   
               
             
          
           
               
                   
                 Any parity 
                   
                   
               
               
                   
                 N 
                 678 
                 680 
               
               
                   
                 n (%) 
                 497 (73.30) 
                 487 (71.62) 
               
               
                   
                 95% CI 1   
                 (69.80%, 76.60%) 
                 (68.07%, 74.98%) 
               
               
                   
                 p-value 2   
                 0.504 
               
               
                   
                 Nulliparous 
               
               
                   
                 N 
                 441 
                 451 
               
               
                   
                 n (%) 
                 285 (64.63) 
                 275 (60.98) 
               
               
                   
                 95% CI 1   
                 (59.96%, 69.09%) 
                 (56.30%, 65.50%) 
               
               
                   
                 p-value 2   
                 0.268 
               
               
                   
                 Parous 
               
               
                   
                 N 
                 237 
                 229 
               
               
                   
                 n (%) 
                 212 (89.45) 
                 212 (92.58) 
               
               
                   
                 95% CI 1   
                 (84.82%, 93.06%) 
                 (88.38%, 95.62%) 
               
               
                   
                 p-value 2   
                 0.261 
               
               
                   
                   
               
               
                   
                   1 95% exact binomial CI. 
               
               
                   
                   2 Two-sided p-values were obtained from Fisher&#39;s exact tests. 
               
             
          
         
       
     
         [0107]    Tables 12-21 (below) present data comparing the occurrence of a series of outcomes/adverse events in female subjects administered MVI 200 or DVI. The tables show that induction of labour using MVI 200 confers benefits not observed when labour is induced using DVI. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 12 
               
             
             
               
                   
               
               
                 Reduced category II FHR pattern &amp; 
               
               
                 reduced risk of intrapartum resuscitation 
               
               
                 Subjects Induced for Cholestatis 
               
             
          
           
               
                   
                 MVI 200 
                 DVI 
                 Total 
               
               
                   
                 (N = 13) 
                 (N = 4) 
                 (N = 17) 
               
               
                   
                   
               
             
          
           
               
                 Category II FHR Pattern 
                 2 (15.4%) 
                 1 (25.0%) 
                 3 (17.6%) 
               
               
                 Intrapartum Resuscitation 
                 1 (7.7%)  
                 1 (25.0%) 
                 2 (11.8%) 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 13 
               
             
             
               
                   
               
               
                 Outcomes and Adverse Events of Special Interest 
               
               
                 Subjects Induced for Preeclampsia 
               
             
          
           
               
                   
                 MVI 200 
                 DVI 
                 Total 
               
               
                   
                 (N = 71) 
                 (N = 59) 
                 (N = 130) 
               
               
                   
                   
               
             
          
           
               
                 Category II FHR Pattern 
                 10 (14.1%) 
                 18 (30.5%) 
                 28 (21.5%) 
               
               
                 Intrapartum Resuscitation 
                 6 (8.5%) 
                  7 (11.9%) 
                 13 (10.0%) 
               
               
                 Tocolysis Use 
                 2 (2.8%) 
                 3 (5.1%) 
                 5 (3.8%) 
               
               
                 Meconium in Amniotic Fluid 
                 3 (4.2%) 
                 5 (8.5%) 
                 8 (6.2%) 
               
               
                 Caesarean Delivery During 
                 17 (23.9%) 
                 17 (28.8%) 
                 34 (26.2%) 
               
               
                 First Hospitalisation 
               
               
                 Instrumented Vaginal 
                 4 (5.6%) 
                  7 (11.9%) 
                 11 (8.5%)  
               
               
                 Delivery During First 
               
               
                 Hospitalisation 
               
               
                 Postpartum Hemorrhage 
                 4 (5.6%) 
                  7 (11.9%) 
                 11 (8.5%)  
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 14 
               
             
             
               
                   
               
               
                 Reduced Chorioamnionitis 
               
               
                 Subjects Induced for Post-Term 
               
             
          
           
               
                   
                 MVI 200 
                 DVI 
                 Total 
               
               
                   
                 (N = 210) 
                 (N = 227) 
                 (N = 437) 
               
               
                   
                   
               
             
          
           
               
                   
                 Chorioamnionitis 
                 17 (8.1%) 
                 32 (14.1%) 
                 49 (11.2%) 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 15 
               
             
             
               
                   
               
               
                 Reduced neonatal ICU admission 
               
               
                 Subjects Induced for Post-Term (40 to &lt;41 weeks) 
               
             
          
           
               
                   
                 MVI 200 
                 DVI 
                 Total 
               
               
                   
                 (N = 91) 
                 (N = 115) 
                 (N = 206) 
               
               
                   
                   
               
             
          
           
               
                 Neonatal ICU Admission 
                 7 (7.7%) 
                 13 (11.3%) 
                 20 (9.7%) 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 16 
               
             
             
               
                   
               
               
                 Reduced allocation of low minute 1 APGAR 
               
               
                 score &amp; reduced neonatal ICU admission 
               
               
                 Subjects Induced for Post-Term (&gt;=41 weeks) 
               
             
          
           
               
                   
                 MVI 200 
                 DVI 
                 Total 
               
               
                   
                 (N = 119) 
                 (N = 112) 
                 (N = 231) 
               
               
                   
                   
               
             
          
           
               
                 Minute 1 Apgar Score Low 
                 12 (10.1%) 
                 15 (13.4%) 
                 27 (11.7%) 
               
               
                 (&lt;7) 
               
               
                 Neonatal ICU Admission 
                 10 (8.4%)  
                 13 (11.6%) 
                 23 (10.0%) 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 17 
               
             
             
               
                   
               
               
                 Reduced instrumented vaginal delivery &amp; reduced neonatal ICU admission 
               
               
                 Subjects Induced for Intrauterine Growth Restriction 
               
             
          
           
               
                   
                 MVI 200 
                 DVI 
                 Total 
               
               
                   
                 (N = 35) 
                 (N = 35) 
                 (N = 70) 
               
               
                   
                   
               
             
          
           
               
                 Instrumented Vaginal 
                 1 (2.9%) 
                 2 (5.7%)  
                 3 (4.3%)  
               
               
                 Delivery During First 
               
               
                 Hospitalisation 
               
               
                 Neonatal ICU Admission 
                 2 (5.7%) 
                 6 (17.1%) 
                 8 (11.4%) 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 18 
               
             
             
               
                   
               
               
                 Outcomes and Adverse Events of Special Interest 
               
               
                 Subjects Induced for Premature Rupture of Membranes 
               
             
          
           
               
                   
                 MVI 200 
                 DVI 
                 Total 
               
               
                   
                 (N = 22) 
                 (N = 25) 
                 (N = 47) 
               
               
                   
                   
               
             
          
           
               
                 Category II FHR Pattern 
                  5 (22.7%) 
                 10 (40.0%)  
                 15 (31.9%)  
               
               
                 Intrapartum Resuscitation 
                 2 (9.1%) 
                 6 (24.0%) 
                 8 (17.0%) 
               
               
                 Tocolysis Use 
                 2 (9.1%) 
                 3 (12.0%) 
                 5 (10.6%) 
               
               
                 Neonatal ICU Admission 
                 2 (9.1%) 
                 6 (24.0%) 
                 8 (17.0%) 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 19 
               
             
             
               
                   
               
               
                 Reduced category II FHR pattern 
               
               
                 Subjects Induced for Suspected Foetal Macrosomia 
               
             
          
           
               
                   
                 MVI 200 
                 DVI 
                 Total 
               
               
                   
                 (N = 1) 
                 (N = 3) 
                 (N = 4) 
               
               
                   
                   
               
             
          
           
               
                 Category II FHR Pattern 
                 0 (0.0%) 
                 3 (100.0%) 
                 3 (75.0%) 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 20 
               
             
             
               
                   
               
               
                 Reduced allocation of low minute 1 APGAR 
               
               
                 score &amp; reduced risk of postpartum hemorrhage 
               
               
                 Subjects with Tocolysis Use 
               
             
          
           
               
                   
                 MVI 200 
                 DVI 
                 Total 
               
               
                   
                 (N = 83) 
                 (N = 28) 
                 (N = 111) 
               
               
                   
                   
               
             
          
           
               
                 Category II FHR Pattern AE 
                 41 (49.4%) 
                 20 (71.4%) 
                 61 (55.0%) 
               
               
                 Minute 1 Apgar Score Low 
                 15 (18.1%) 
                 10 (35.7%) 
                 25 (22.5%) 
               
               
                 (&lt;7) 
               
               
                 Postpartum Hemorrhage 
                 7 (8.4%) 
                  4 (14.3%) 
                 11 (9.9%)  
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 21 
               
             
             
               
                   
               
               
                 Reduced Category II FHR pattern 
               
               
                 Subjects with Intrapartum Resuscitation 
               
             
          
           
               
                   
                 MVI 200 
                 DVI 
                 Total 
               
               
                   
                 (N = 85) 
                 (N = 66) 
                 (N = 151) 
               
               
                   
                   
               
             
          
           
               
                 Category II FHR Pattern AE 
                 73 (85.9%) 
                 64 (97.0%) 
                 137 (90.7%) 
               
               
                   
               
             
          
         
       
     
       Conclusions 
       [0000]    
       
         
           
             MVI 200 reduced time to vaginal delivery, time to any delivery, and time to onset of active labour compared with DVI. 
             MVI 200 reduced pre-delivery oxytocin use compared with DVI. 
             MVI 200 had a greater percentage of subjects with vaginal delivery within 12 and 24 hours, any delivery within 12 and 24 hours, and cervical ripening success at 12 hours compared with DVI. 
             Results of pharmacoeconomic endpoints demonstrated decreases in duration in L&amp;D, percentage of subjects requiring pre-delivery oxytocin, and duration of maternal hospitalisation with MVI 200 compared with DVI.