Misoprostol Composition

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 g misoprostol for intravaginal use. The use encompasses methods of therapy as well as compositions for use in such methods.

Claims

1-8. (canceled)

9. A method of achieving one or more of: (i) a reduction in the incidence of category II foetal heart rate pattern; (ii) a reduction in incidences of intrapartum resuscitation; (iii) reduced use of tocolytics; (iv) a reduced incidence of meconium in amniotic fluid; (v) a reduced requirement for a caesarean delivery during first hospitalisation; (vi) a reduced requirement for instrumented vaginal delivery during first hospitalisation; and (vii) a reduced incidence of postpartum haemorrhage. in a female induced for labour due to pre-eclampsia, 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 g misoprostol; (i), (ii), (iii), (iv), (v), (vi), and (vii) being reduced in comparison to the administration of said insert containing 10 mg dinoprostone.

10-38. (canceled)

39. The method of claim 9, wherein the insert is a sustained or controlled delivery device.

40. The method of claim 9, wherein the insert comprises retrieval means for withdrawal of the insert.

41. The method of claim 9, wherein the method reduces at least the incidence of category II foetal heart rate pattern.

42. The method of claim 9, wherein the method reduces at least incidences of intrapartum resuscitation.

43. The method of claim 9, wherein the method reduces at least use of tocolytics.

44. The method of claim 9, wherein the method reduces at least incidence of meconium in amniotic fluid.

45. The method of claim 9, wherein the method reduces at least requirement for a caesarean delivery during first hospitalisation.

46. The method of claim 9, wherein the method reduces at least requirement for instrumented vaginal delivery during first hospitalisation.

47. The method of claim 9, wherein the method reduces at least incidence of postpartum haemorrhage.

48. A method of achieving: (i) a reduction in the incidence of category II foetal heart rate pattern; (ii) a reduction in incidences of intrapartum resuscitation; (iii) reduced use of tocolytics; (iv) a reduced incidence of meconium in amniotic fluid; (v) a reduced requirement for a caesarean delivery during first hospitalisation; (vi) a reduced requirement for instrumented vaginal delivery during first hospitalisation; and (vii) a reduced incidence of postpartum haemorrhage. in a female induced for labour due to pre-eclampsia, 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 g misoprostol; (i), (ii), (iii), (iv), (v), (vi), and (vii) being reduced in comparison to the administration of said insert containing 10 mg dinoprostone.

Description

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: [0063] a hydrogel polymer base measuring approximately 30100.8 mm [0064] 200 mcg reservoir of misoprostol released at a controlled rate [0065] a retrieval tape consisting of inert woven polyester into which the polymer base was placed

[0066] The DVI had three components: [0067] a hydrogel polymer base measuring approximately 30100.8 mm [0068] 10 mg reservoir of dinoprostone released at approximately 0.3 mg/hour [0069] a retrieval tape consisting of inert woven polyester into which the polymer base was placed.
Batch number information is provided in Table 1.

TABLE-US-00001 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: [0083] Mode of delivery (spontaneous vaginal, instrumented vaginal, or caesarean) [0084] If caesarean delivery, the reason for the caesarean delivery was recorded. [0085] 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&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'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<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<0.001) and parous subjects (p<0.001). Kaplan Meier estimates of time to vaginal delivery are presented in Table 2.

TABLE-US-00002 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.sup.1 (1200.00, 1402.00) (1812.00, 2093.00) (20 hours, 23.4 (30.2 hours, 34.9 hours) hours) p-value.sup.1 <0.001 Number (%) of censored 181 (26.7) 193 (28.4) subjects.sup.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.sup.1 (1524.00, 1963.00) (2272.00, 2926.00) (25.4 hours, 32.7 (37.9 hours, 48.8 hours) hours) p-value.sup.1 <0.001 Number (%) of censored 156 (35.4) 176 (39.0) subjects.sup.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.sup.1 (748.00, 885.00) (1065.00, 1368.00) (12.5 hours, 14.75 (17.75 hours, 22.8 hours) hours) p-value.sup.1 <0.001 Number (%) of censored 25 (10.5) 17 (7.4) subjects.sup.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) .sup.1Two-sided p-values and CIs were obtained from a Log-Rank Test .sup.2Subjects 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&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<0.001). Time to caesarean delivery was also significantly shorter in MVI 200 subjects compared with DVI subjects among both nulliparous subjects (p<0.001) and parous subjects (p<0.001). The summary of time to caesarean delivery is presented in Table 3.

TABLE-US-00003 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.sup.1 <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.sup.1 <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.sup.1 0.163 .sup.1P-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<0.001). Time to any delivery was also significantly shorter in MVI 200 subjects compared with DVI subjects among both nulliparous subjects (p<0.001) and parous subjects (p<0.001). Kaplan Meier estimates of time to any delivery are presented Table 4.

TABLE-US-00004 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.sup.1 (1031.00, 1170.00) (1573.00, 1731.00) (17.1 hours, 19.5 (26.2 hours, 28.9 hours) hours) p-value.sup.1 <0.001 Number (%) of censored 5 (0.7) 9 (1.3) subjects.sup.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.sup.1 (1203.00, 1376.00) (1764.00, 2016.00) (20.1 hours, 23 (29.4 hours, 33.6 hours) hours) p-value.sup.1 <0.001 Number (%) of censored 4 (0.9) 8 (1.8) subjects.sup.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.sup.1 (732.00, 823.00) (1040.00, 1321.00) (12.2 hours, 13.7 (17.3 hours, 22 hours) hours) p-value.sup.1 <0.001 Number (%) of censored 1 (0.4) 1 (0.4) subjects.sup.2 Discharged prior to delivery 1 (0.4) 1 (0.4) (imputed value: 1642 minutes) .sup.1Two-sided p-values and CIs were obtained from a Log-Rank Test. .sup.2Subjects who did not deliver during their first hospitalisation were censored using the longest time interval from study drug administration to L&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<0.001). Time to active labour was also significantly shorter in MVI 200 subjects compared with DVI subjects among both nulliparous subjects (p<0.001) and parous subjects (p<0.001). Kaplan-Meier estimates of time to active labour are presented in Table 5.

TABLE-US-00005 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.sup.1 (719.00, 773.00) (1083.00, 1352.00) (12 hours, 12.9 (18.1 hours, 22.5 hours) hours) p-value.sup.1 <0.001 Number (%) of censored 47 (6.9) 54 (7.9) subjects.sup.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.sup.1 (810.00, 948.00) (1352.00, 1558.00) (13.5 hours, 15.8 (22.5 hours, 26 hours) hours) p-value.sup.1 <0.001 Number (%) of censored 41 (9.3) 50 (11.1) subjects.sup.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.sup.1 (535.00, 616.00) (715.00, 913.00) (8.92 hours, 10.3 (11.9 hours, 15.2 hours) hours) p-value.sup.1 <0.001 Number (%) of censored 6 (2.5) 4 (1.7) subjects.sup.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) .sup.1Two-sided p-values and CIs were obtained from a Log-Rank Test. .sup.2Subjects 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&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<0.001 ; Table 6).

[0100] The statistically significant treatment differences (p0.001) 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<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<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<0.001), and lower maximum dose/minute (mean 10.6 vs. 14.1 mU; p<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).

TABLE-US-00006 TABLE 6 Pre-Delivery Oxytocin Use During First Hospitalisation (ITT/Safety Population) MVI 200 MVI 200 DVI DVI (N = 678).sup.a (N = 678)* (N = 680).sup.a (N = 680).sup.a Subjects who delivered during first 673 673 671 671 hospitalisation Subjects requiring pre-delivery oxytocin.sup.1 n (%) 319 (47.4) 324 (48.1) 496 (73.9) 497 (74.1) 95% CI.sup.2 (43.57%, 51.25%) (44.24%, 51.92%) (70.42%, 77.20%) 70.58%, 77.35%).sup. p-value.sup.3 <0.001 <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.sup.4 <0.001 <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.sup.4 <0.001 <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.sup.4 <0.001 <0.001 .sup.1Percentage based on subjects who delivered or received oxytocin during first hospitalisation. .sup.295% exact binomial CI. .sup.3Two-sided p-values were obtained from Fisher's exact tests. .sup.4Two-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.sup.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<0.001; Table 7). The treatment group difference was also statistically significant among nulliparous subjects (p<0.001) and parous subjects (p<0.001).

TABLE-US-00007 TABLE 7 Incidence of Vaginal Delivery Within 12 Hours of Study Drug Administration (ITT/Safety Population) MVI 200 MVI 200 DVI DVI (N = 678).sup.a (N = 678)* (N = 680).sup.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.sup.1 (16.83%, 22.96%) (16.83%, 22.96%) (6.41%, 10.72%) (6.41%, 10.72%) p-value.sup.2 <0.001 <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 (%).sup.3 Nulliparous 185 441 97 451 Within 12 hours, n (%) 40 (9.07) 40 (9.07) 12 (2.66) 12 (2.66) 95% CI.sup.1 (6.56%, 12.15%) (6.56%, 12.15%) (1.38%, 4.60%) (1.38%, 4.60%) p-value.sup.2 <0.001 <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 (%).sup.3 Parous 185 237 134 229 Within 12 hours, n (%) 94 (39.66) 94 (39.66) 45 (19.65) 45 (19.65) 95% CI.sup.1 (33.39%, 46.20%) (33.39%, 46.20%) (14.71%, 25.40%) (14.71%, 25.40%) p-value.sup.2 <0.001 <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 (%).sup.3 .sup.195% exact binomial CI. .sup.2Two-sided p-values were obtained from Fisher's exact tests. .sup.3Percentage based on subjects with vaginal delivery. *denotes data from a revised analysis of raw data used to obtain the preliminary data.sup.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<0.001; Table 8). The treatment group difference was also statistically significant among nulliparous subjects (p<0.001) and parous subjects (p<0.001).

TABLE-US-00008 TABLE 8 Incidence of Any Delivery Within 24 Hours of Study Drug Administration (ITT/Safety Population) MVI 200 MVI 200 DVI DVI (N = 678).sup.a (N = 678)* (N = 680).sup.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.sup.1 (64.03%, 71.21%) (64.03%, 71.21%) (37.02%, 44.54%) (37.02%, 44.54%) p-value.sup.2 <0.001 <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.sup.1 (53.98%, 63.37%) (53.98%, 63.37%) (26.16%, 34.85%) (26.16%, 34.85%) p-value.sup.2 <0.001 <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.sup.1 (79.13%, 88.76%) (79.13%, 88.76%) (54.49%, 67.49%) (54.49%, 67.49%) p-value.sup.2 <0.001 <0.001 .sup.195% exact binomial CI. .sup.2Two-sided p-values were obtained from Fisher's exact tests. *denotes data from a revised analysis of raw data used to obtain the preliminary data.sup.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<0.001; Table 9). The treatment group difference was also statistically significant among nulliparous subjects (p<0.001) and parous subjects (p<0.001).

TABLE-US-00009 TABLE 9 Incidence of Any Delivery Within 12 Hours of Study Drug Administration (ITT/Safety Population) MVI 200 MVI 200 DVI DVI (N = 678).sup.a (N = 678)* (N = 680).sup.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.sup.1 (20.03%, 26.52%) (20.03%, 26.52%) (7.19%, 11.70%) (7.19%, 11.70%) p-value.sup.2 <0.001 <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.sup.1 (9.94%, 16.42%) (9.94%, 16.42%) .sup.2.04%, 5.70%) .sup.2.04%, 5.70%) p-value.sup.2 <0.001 <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.sup.1 (35.83%, 48.76%) (35.83%, 48.76%) (15.49%, 26.34%) (15.49%, 26.34%) p-value.sup.2 <0.001 <0.001 .sup.195% exact binomial CI. .sup.2Two-sided p-values were obtained from Fisher's exact tests. *denotes data from a revised analysis of raw data used to obtain the preliminary data.sup.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<0.001; Table 10). The treatment group difference was also statistically significant among nulliparous subjects (p<0.001) and parous subjects (p<0.001).

TABLE-US-00010 TABLE 10 Incidence of Vaginal Delivery Within 24 Hours of Study Drug Administration (ITT/Safety Population) MVI 200 MVI 200 DVI DVI (N = 678).sup.a (N = 678)* (N = 680).sup.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.sup.1 (50.74%, 58.37%) (50.74%, 58.37%) (30.41%, 37.67%) (30.41%, 37.67%) p-value.sup.2 <0.001 <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 (%).sup.3 Nulliparous 185 441 97 451 Within 24 hours, n (%) 185 (41.95) 185 (41.95) 97 (21.51) 97 (21.51) 95% CI.sup.1 (37.30%, 46.71%) (37.30%, 46.71%) (17.80%, 25.59%) (17.80%, 25.59%) p-value.sup.2 <0.001 <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 (%).sup.3 Parous 185 237 134 229 Within 24 hours, n (%) 94 (39.66) 185 (78.06) 45 (19.65) 134 (58.52) 95% CI.sup.1 (72.24%, 83.16%) (72.24%, 83.16%) (51.84%, 64.97%) (51.84%, 64.97%) p-value.sup.2 <0.001 <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 (%).sup.3 .sup.195% exact binomial CI. .sup.2Two-sided p-values were obtained from Fisher's exact tests. .sup.3Percentage based on subjects with vaginal delivery. *denotes data from a revised analysis of raw data used to obtain the preliminary data.sup.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).

TABLE-US-00011 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.sup.1 (69.80%, 76.60%) (68.07%, 74.98%) p-value.sup.2 0.504 Nulliparous N 441 451 n (%) 285 (64.63) 275 (60.98) 95% CI.sup.1 (59.96%, 69.09%) (56.30%, 65.50%) p-value.sup.2 0.268 Parous N 237 229 n (%) 212 (89.45) 212 (92.58) 95% CI.sup.1 (84.82%, 93.06%) (88.38%, 95.62%) p-value.sup.2 0.261 .sup.195% exact binomial CI. .sup.2Two-sided p-values were obtained from Fisher'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.

TABLE-US-00012 TABLE 12 Reduced category II FHR pattern & 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%)

TABLE-US-00013 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%)

TABLE-US-00014 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%)

TABLE-US-00015 TABLE 15 Reduced neonatal ICU admission Subjects Induced for Post-Term (40 to <41 weeks) MVI 200 DVI Total (N = 91) (N = 115) (N = 206) Neonatal ICU Admission 7 (7.7%) 13 (11.3%) 20 (9.7%)

TABLE-US-00016 TABLE 16 Reduced allocation of low minute 1 APGAR score & reduced neonatal ICU admission Subjects Induced for Post-Term (>=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%) (<7) Neonatal ICU Admission 10 (8.4%) 13 (11.6%) 23 (10.0%)

TABLE-US-00017 TABLE 17 Reduced instrumented vaginal delivery & 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%)

TABLE-US-00018 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%)

TABLE-US-00019 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%)

TABLE-US-00020 TABLE 20 Reduced allocation of low minute 1 APGAR score & 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%) (<7) Postpartum Hemorrhage 7 (8.4%) 4 (14.3%) 11 (9.9%)

TABLE-US-00021 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

[0108] MVI 200 reduced time to vaginal delivery, time to any delivery, and time to onset of active labour compared with DVI. [0109] MVI 200 reduced pre-delivery oxytocin use compared with DVI. [0110] 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. [0111] Results of pharmacoeconomic endpoints demonstrated decreases in duration in L&D, percentage of subjects requiring pre-delivery oxytocin, and duration of maternal hospitalisation with MVI 200 compared with DVI.