A Proof of Concept Study Assessing the Effect of Four Different Single Bolus Intravenous Doses of FE200440 and Placebo on Stopping Preterm Labor

• Primary endpoint
• • Percentage of women who did not deliver within 48h post-dosing

• Secondary Endpoints
• • Percentage of women who did not deliver within 12h and 24h post-dosing
• • Time to delivery
• • Percentage change from baseline in number of uterine contractions at each hour during the initial 12h post-dosing and at each assessment time point during the 12h to 48h post-dosing period
• • AUC for percentage change from baseline in number of uterine contractions within the initial 12h post-dosing and during the overall 48h post-dosing period
• • Time to ≥ 25%, ≥ 50%, ≥ 75% and to maximum reduction in number of uterine contractions during the overall 48h post-dosing period
• • Percentage of women with ≥ 25%, ≥ 50%, ≥ 75% reduction of number of uterine contractions as well as with no contractions at each hour during the initial 12h post-dosing and at each assessment time point during the 12h to 48h post-dosing period
• • Percentage of women with no progression of labour at 24h and 48h post-dosing
• • Pharmacokinetic parameters of FE200440: AUCt, AUC∞, Cmax, z, t½, CL, Vz and Vss
• • Incidence and severity of maternal adverse events, fetal adverse events and infant adverse events
• • Time from delivery to expulsion of the placenta
• • Incidence and severity of postpartum haemorrhage
• • Change in haemoglobin level from screening to 24-48h after delivery
• • Time from delivery to established lactation
• • Percentage of mothers lactating 5 days after delivery

• To determine the effects of four different single bolus doses of FE200440 administered intravenously on stopping preterm labour compared to placebo in pregnant women with advanced gestational age

• To determine the effects of four different single bolus doses of FE200440 administered intravenously on stopping preterm labour compared to placebo in pregnant women with advanced gestational age
• To establish the effects of four different single bolus doses of FE200440 administered intravenously on uterine contractions compared to placebo
• To evaluate the effects of four different single bolus doses of FE200440 administered intravenously on labour progression compared to placebo
• To establish the dose-response curve of single bolus doses of FE200440 administered intravenously in terms of time to delivery, uterine contractions and labour progression
• To determine the duration of action of four different single bolus doses of FE200440 administered intravenously in terms of time to delivery, uterine contractions and labour progression
• To establish the pharmacokinetic parameters of FE200440 after single bolus intravenous administration
• To determine the relation between plasma concentrations of FE200440 and uterine contractions and labour progression
• To compare the maternal, fetal and infant safety profile after intravenous administration of four different single bolus doses of FE200440 and placebo
• To evaluate the impact of four different single bolus doses of FE200440 administered intravenously on delivery outcome, postpartum events and lactation

• Labor, Premature
• Premature Birth

Inclusion Criteria:

1. Signed Informed Consent Form, prior to screening evaluations
2. Mother and fetus in good general health
3. Pregnant women age ≥ 18 years
4. Gestational age (verified by early ultrasound or if an ultrasound is not available by Last Menstrual Period) between 34 weeks + 0 days and 35 weeks + 6 days (both days inclusive)
5. At randomisation, there must be 6 or more uterine contractions of at least 30 seconds duration during a 30 minutes interval
6. At randomisation, the cervical length must be ≤ 15 mm (by transvaginal ultrasound)
7. At randomisation, the cervical dilatation must be >1 cm and <4 cm (by vaginal examination

Exclusion Criteria:

1. Contraindications for the mother or the fetus to stop labour, including

   • clinical suspicion of abruptio placenta
   • known or suspected infection (e.g. urinary tract infection, chorioamnionitis)
2. Controlled or uncontrolled diabetes mellitus (pre-gestational or gestational)
3. Eclampsia or severe preeclampsia in the current pregnancy
4. Previous major uterine surgery (e.g. myomectomy for leiomyomas), congenital uterine abnormalities, large leiomyomas, or retained intrauterine device
5. Rupture of membrane in the current pregnancy
6. Placenta praevia in the current pregnancy
7. a)
8. Oligohydramnios or polyhydramnios in the current pregnancy defined as amniotic fluid index (AFI) below 7.2 cm or above 27.8 cm
9. Fetal weight (based on ultrasound) outside the ± 2SD limits provided in Appendix B
10. Use of cervical cerclage in the current pregnancy
11. Current multiple pregnancy
12. Fetal death in utero in previous or current pregnancy
13. Fetus with known or suspected abnormal karyotype or major malformations in the current pregnancy
14. Abnormal fetal heart rate which the Investigator judges to reflect fetal distress
15. Treatment with nifedipine, non-steroidal anti-inflammatory agents (NSAIDs) or intravenously administered magnesium sulphate for contractions during the current pregnancy or treatment with beta-mimetics, atosiban or progesterone within the last 7 days prior to randomisation
16. Treatment with anticoagulation or fibrinolytic therapies prior to screening, or known or suspected or past history of thromboembolic disorders
17. Known, suspected or past history of hypocoagulability or coagulation deficiency conditions
18. Known or suspected hemoglobinopathies
19. Use of any investigational drug during the current pregnancy
20. Known, suspected or past history (last 12 months) of alcohol or drug abuse
21. Known hypersensitivity to the active ingredient or to any of its excipients