Effect of Tafoxiparin on Cervical Ripening and Induction of Labor in Term Pregnant Women With an Unripe Cervix

Study Overview
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Brief Summary
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The study is designed as a randomized, Double-Blind, Placebo-Controlled, Parallel-Group Proof of Concept Study (section A) with a conditional dose finding follow up (Section B) to Evaluate the Efficacy on Cervical ripening, Safety, Tolerability and dose response of Subcutaneously Administered Tafoxiparin in Term Pregnant, Nulliparous Women with an unripe cervix undergoing Labor Induction. If the efficacy and safety profiles of Section A are conclusive in favor of tafoxiparin, the study will continue by adding two additional tafoxiparin dose groups in Section B.

Detailed Description
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Primary objective: To assess the efficacy of tafoxiparin on cervical ripening. Secondary objective: To assess the maternal and neonatal safety, tolerability and dose response of tafoxiparin as a supplement therapy in term pregnant, nulliparous women with an unripe cervix undergoing labor induction Methodology: Term pregnant, nulliparous women with unripe cervix and planned for labor induction are potential study patients unless enrolled in another study. Subjects may be preinformed about the stuyd through the use of advertisement or information at the physician/midwife visits during pregnancy and at the hospital admission. The whole study includes the following steps: Screening and Baseline including informed consent and randomization Study treatment and Induction of Labor Labor Discharge

Official Title
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Randomized, Placebo-Controlled, Proof of Concept Study to Evaluate the Efficacy on Cervical Ripening, Safety, Tolerability and Dose Response of SC Administered Tafoxiparin in Term Pregnant, Nulliparous Women With an Unripe Cervix Undergoing Labor Induction

Conditions
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Labor Onset and Length Abnormalities

Intervention / Treatment
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* Drug: DF01
* Drug: PL1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pregnant women of ≥18 and ≤ 64 years of age Nulliparous Unripe cervix with ≤ 4points according to Bishop/Westin score (0-10 points scale) Planned for labor induction after 4-7 days of IMP treatment Examples of diagnosis as a basis for induction: Post term pregnancy (40-41 weeks of gestation) Gestational diabetes Diabetes type 1 - well controlled Pre-eclampsia (BP diastolic <100, systolic <140) Hypertension - well controlled Hepatosis (without clinically significantly elevated serum bile acids) Maternal age ≥ 40 years Humanitarian-psycho social reasons Oligohydramnios Gestational age > 37 weeks confirmed by ultrasound before 21 weeks of gestation Singleton pregnancy Subject is, as per the discretion of the Investigator, able to comply with the requirements of the protocol including an ability to be present at all required controls Subject can understand and sign an informed form Provision of written informed consent Exclusion Criteria: Subjects who are unable to understand the written and verbal instructions in local language Breech presentation and other abnormal fetal presentations Previous uterine scar Spontaneous rupture of membranes at inclusion Pathologic CTG at inclusion Fetal estimated weight > 2SD of normal fetal estimated weight earlier diagnosed by ultrasound and documented in patient record Mother's BMI > 35 at early pregnancy Known IUGR defined as ≤ 2SD of normal Presence of eclampsia Severe Pre-eclampsia HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) Clinically significant vaginal bleeding in need of hospitalization in the third trimester Placenta previa Previously known coagulation disorders (Leiden, heterozygote - OK) Current use of any drugs that interfere with hemostasis (including heparin /LMWH, direct oral anti-coagulant medication, non-steroidal anti-inflammatory drugs (NSAID) compounds and vitamin K antagonists.) Current use of acetylsalicylic acid (ASA) compounds or use within the week preceding inclusion Diagnosed with HIV or Acute hepatitis Known history of allergy to standard heparin and/or LMWH heparin History of heparin-induced thrombocytopenia Current drug or alcohol abuse which in the opinion of the Investigator should preclude participation in the study. Current participation in other interventional medicinal treatment studies Subject has a fear of needles which is believed by the Investigator to affect study medication compliance

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental DF01 high dose<br>The subject receives sc injections once daily for up to 7 days until labor induction or spontaneous onset of labor. | Drug: DF01<br>* The subject receives sc injections of tafoxiparin solution once daily for up to 7 days until labor induction or spontaneous onset of labor. Induction is done according to clinical practice; 1st balloon, 2nd PGE1<br>* Other names: tafoxiparin;|
| Experimental: Experimental: DF01 medium dose<br>The subject receives sc injections once daily for up to 7 days until labor induction or spontaneous onset of labor. | Drug: DF01<br>* The subject receives sc injections of tafoxiparin solution once daily for up to 7 days until labor induction or spontaneous onset of labor. Induction is done according to clinical practice; 1st balloon, 2nd PGE1<br>* Other names: tafoxiparin;|
| Experimental: Experimental: DF01 low dose<br>The subject receives sc injections once daily for up to 7 days until labor induction or spontaneous onset of labor. | Drug: DF01<br>* The subject receives sc injections of tafoxiparin solution once daily for up to 7 days until labor induction or spontaneous onset of labor. Induction is done according to clinical practice; 1st balloon, 2nd PGE1<br>* Other names: tafoxiparin;|
| Placebo Comparator: Placebo comparator: PL1<br>The subject receives sc injections once daily for up to 7 days until labor induction or spontaneous onset of labor. | Drug: PL1<br>* The subject receives sc injections once daily of placebo solution for up to 7 days until labor induction or spontaneous onset of labor. Induction is done according to clinical practice; 1st balloon, 2nd PGE1<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of cervical ripening | Cervical ripening rate during up to the first seven days of treatment, measured by Bishop Score | From start of study drug administration to cervical ripening (up to 7 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to start of treatment in relation to cervical ripening ≥ 2 points | Time from start of treatment to increase in Bishop score of ≥ 2 points or spontaneous onset of labor, whichever comes first | From start of study drug administration to cervical ripening (up to 7 days) | 
| Time to start of treatment in relation to cervical ripening ≥ 3 points | Time from start of treatment to increase in Bishop score of ≥ 3 points or spontaneous onset of labor, whichever comes first | From start of study drug administration to cervical ripening (up to 7 days) | 
| Time to start of treatment in relation to cervical ripening ≥ 4 points | Time from start of treatment to increase in Bishop score of ≥ 4 points or spontaneous onset of labor, whichever comes first | From start of study drug administration to cervical ripening (up to 7 days) | 
| Time to partus from labor onset | Time from onset of labor to partus. Onset of labor is defined as last record of 4 cm cervical dilatation visualized in the partogram and progress of labor or last record of 4 cm of cervical dilatation in combination with amniotomy and intravenous administration oxytocin | Interval from 4 cm of cervical dilatation until delivery (hours up to 36 hours) | 
| Time of labor ≤ 6 hours | Proportion of women with established labor ≤ 6 hours | Interval from 4 cm of cervical dilatation until delivery (hours up to 36 hours) | 
| Time of labor ≥ 12 hours | Proportion of women with established labor ≥ 12 hours | Interval from 4 cm of cervical dilatation until delivery (hours up to 36 hours) | 
| Dosages of study drug | Total dosages of study drug (IMP) | From start of study drug administration to cervical ripening (up to 7 days) | 
| Secondary Safety and tolerability endpoint - adverse event and serious adverse event | Safety and tolerability will be evaluated through rate and frequency of adverse events and serious adverse events. The AE and SAE will be coded using MedDRA version 19.1. | Through study completion (up to 3 days after delivery) | 
| Secondary Safety and tolerability endpoint- caesarean sections | Proportion of patients undergoing caesarean sections (CS) | From start of study drug administration until delivery (up to 7 days) | 
| Secondary Safety and tolerability endpoint- indications for caesarean sections | Indications for CS | From start of study drug administration until delivery (up to 7 days) | 
| Secondary Safety and tolerability endpoint -instrumental deliveries | Proportion of patients undergoing instrumental deliveries (vacuum extraction (VE)/forceps delivery) | From start of study drug administration until delivery (up to 7 days) | 
| Secondary Safety and tolerability endpoint- VE and forceps deliveries | Indications for VE and forceps deliveries | From start of study drug administration until delivery (up to 7 days) | 
| Secondary Safety and tolerability endpoint- fetal outcome- Birth weight | Fetal outcome measured as Birth weight (kg) | From start of study drug administration until delivery ( up to 7 days) | 
| Secondary Safety and tolerability endpoint- fetal outcome -Apgar score | Fetal outcome measured as Apgar score (1-10 points). A score > 7 is good health. | From start of study drug administration until delivery ( up to 7 days) | 
| Secondary Safety and tolerability endpoint- fetal outcome - Acidosis and/or Base excess | Fetal outcome measured as number of neonatal with Acidosis (pH<7.10) and/or Base Excess < -12 mmol/L arterial or venous in umbilical cord blood | From start of study drug administration until delivery ( up to 7 days) | 
| Secondary Safety and tolerability endpoint - NICU | Indication for referral to neonatal intensive care unit (NICU) | From start of study drug administration until delivery (days) | 
| Secondary Safety and tolerability endpoint - NICU | Proportion of infants staying in the NICU for > 48 hours | From start of study drug administration until delivery (up to 7 days) | 
| Secondary Safety and tolerability endpoint - tocolytica | Uterine hyper stimulation in demand of tocolytic treatment | From start of study drug administration until delivery (up to 7 days) | 
| Secondary Safety and tolerability endpoint - PPH | Proportion of patients with Postpartum Hemorrhage (PPH) > 2000 ml | From start of study drug administration until delivery (up to 7 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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labor induction, cervical ripening