Labor Onset and Length Abnormalities
Conditions
Keywords
Priming of labor, Unripe cervix, Home treatment, Cervical ripening, Labor induction
Brief summary
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
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 study 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
Interventions
DRUGDF01
DF01: The subject receives sc injections of tafoxiparin solution once daily for up to 7 days until spontaneous onset of labor or ripe cervix (Amniotomy/oxytocin without restriction).If not enough ripening cervical ripening according to clinical practice with intracervical ballon/prostaglandins
DRUGPL1
DF01: The subject receives sc injections of placebo solution once daily for up to 7 days until spontaneous onset of labor or ripe cervix (Amniotomy/oxytocin without restriction).If not enough ripening cervical ripening according to clinical practice with intracervical ballon/prostaglandins
Sponsors
Dilafor AB
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 64 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cervical Ripening Rate, Measured by Bishop Score - Slope | Daily measures of Bishop Score from start of study drug administration until delivery (up to 7 days). | Cervical ripening rate during up to the first seven days of treatment, measured by Bishop Score - Slope. Bishop score is an Assessment of the cervical stage by its: dilatation, position, effacement and consistency. The score was calculated as the sum of the following 5 categories where each category is scored between 0-2: * Fetal station (0-2) * Cervical diameter at inner meatus (0-2) * Cervical effacement (0-2) * Consistency at inner meatus (0-2) * Cervical position (0-2) Graded from 0-10, Bishop score of ≤ 4 is unripe and ≥ 6 is ripe. Bishop score was measured daily from start of treatment up until 7 days. The cervical ripening rate was calculated from the slope of the curve (score/day) when plotting Bishop score against days of treatment. |
Countries
Finland, Sweden
Participant flow
Pre-assignment details
Number of subjects screened/enrolled: 365 Number of subjects started: 348 Reason: 17 subjects did not pass inclusion/exclusion
Participants by arm
| Arm | Count |
|---|---|
| Experimental DF01 High Dose The subject receives sc injections once daily for up to 7 days until labor induction or spontaneous onset of labor.
DF01: The subject receives sc injections of tafoxiparin solution once daily for up to 7 days until spontaneous onset of labor or ripe cervix (Amniotomy/oxytocin without restriction).If not enough ripening cervical ripening according to clinical practice with intracervical ballon/prostaglandins. | 91 |
| Experimental: DF01 Medium Dose The subject receives sc injections once daily for up to 7 days until labor induction or spontaneous onset of labor.
DF01: The subject receives sc injections of tafoxiparin solution once daily for up to 7 days until spontaneous onset of labor or ripe cervix (Amniotomy/oxytocin without restriction).If not enough ripening cervical ripening according to clinical practice with intracervical ballon/prostaglandins. | 85 |
| Experimental: DF01 Low Dose The subject receives sc injections once daily for up to 7 days until labor induction or spontaneous onset of labor.
DF01: The subject receives sc injections of tafoxiparin solution once daily for up to 7 days until spontaneous onset of labor or ripe cervix (Amniotomy/oxytocin without restriction).If not enough ripening cervical ripening according to clinical practice with intracervical ballon/prostaglandins. | 83 |
| Placebo Comparator: PL1 The subject receives sc injections once daily for up to 7 days until labor induction or spontaneous onset of labor.
PL1: The subject receives sc injections of placebo solution once daily for up to 7 days until spontaneous onset of labor or ripe cervix (Amniotomy/oxytocin without restriction).If not enough ripening cervical ripening according to clinical practice with intracervical ballon/prostaglandins | 89 |
| Total | 348 |
Baseline characteristics
| Characteristic | Experimental DF01 High Dose | Experimental: DF01 Medium Dose | Experimental: DF01 Low Dose | Placebo Comparator: PL1 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 91 Participants | 85 Participants | 83 Participants | 89 Participants | 348 Participants |
| Age, Continuous | 31.2 years STANDARD_DEVIATION 4.34 | 31.4 years STANDARD_DEVIATION 4.22 | 31.6 years STANDARD_DEVIATION 5.28 | 31.3 years STANDARD_DEVIATION 5.04 | 31.4 years STANDARD_DEVIATION 4.73 |
| Race and Ethnicity Not Collected | — | — | — | — | 0 Participants |
| Region of Enrollment Finland | 64 participants | 55 participants | 57 participants | 61 participants | 237 participants |
| Region of Enrollment Sweden | 27 participants | 30 participants | 26 participants | 28 participants | 111 participants |
| Sex: Female, Male Female | 91 Participants | 85 Participants | 83 Participants | 89 Participants | 348 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 91 | 0 / 85 | 0 / 83 | 0 / 88 |
| other Total, other adverse events | 52 / 91 | 54 / 85 | 54 / 83 | 47 / 88 |
| serious Total, serious adverse events | 6 / 91 | 7 / 85 | 2 / 83 | 2 / 88 |
Outcome results
Primary
Cervical Ripening Rate, Measured by Bishop Score - Slope
Cervical ripening rate during up to the first seven days of treatment, measured by Bishop Score - Slope. Bishop score is an Assessment of the cervical stage by its: dilatation, position, effacement and consistency. The score was calculated as the sum of the following 5 categories where each category is scored between 0-2: * Fetal station (0-2) * Cervical diameter at inner meatus (0-2) * Cervical effacement (0-2) * Consistency at inner meatus (0-2) * Cervical position (0-2) Graded from 0-10, Bishop score of ≤ 4 is unripe and ≥ 6 is ripe. Bishop score was measured daily from start of treatment up until 7 days. The cervical ripening rate was calculated from the slope of the curve (score/day) when plotting Bishop score against days of treatment.
Time frame: Daily measures of Bishop Score from start of study drug administration until delivery (up to 7 days).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental DF01 High Dose | Cervical Ripening Rate, Measured by Bishop Score - Slope | 0.86 Slope (Bishop Score/day) | Standard Deviation 0.062 |
| Experimental: DF01 Medium Dose | Cervical Ripening Rate, Measured by Bishop Score - Slope | 0.81 Slope (Bishop Score/day) | Standard Deviation 0.062 |
| Experimental: DF01 Low Dose | Cervical Ripening Rate, Measured by Bishop Score - Slope | 0.78 Slope (Bishop Score/day) | Standard Deviation 0.061 |
| Placebo Comparator: PL1 | Cervical Ripening Rate, Measured by Bishop Score - Slope | 0.62 Slope (Bishop Score/day) | Standard Deviation 0.06 |