MISOBEST - Orally Misoprostol Solution (Cytotec®) Versus Orally Misoprostol as a Tablet (Angusta®) for Induction of Labor

Study Overview
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Brief Summary
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The aim of the study is to evaluate efficacy of the cervical ripening of misoprostol administration in oral tablet, Angusta® compared with the off-label solution of misoprostol (Cytotec®) for induction of labor (IOL). Since there is a large cost difference between the preparations (Angusta® is 43 times more expensive than Cytotec®) it is, from a socio-economic perspective, of great interest to evaluate if Angusta can be replaced by Cytotec.

Detailed Description
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In Sweden as in most other countries, the rate of induction of labor (IOL) has steadily increased, peaking at 27% of all deliveries in 2020. Due to recently published studies showing decreased perinatal mortality with IOL at 41 instead of 42 gestational weeks, national guidelines have changed to offering all pregnant women reaching 41 weeks IOL, which will increase induction rates and subsequent cost of IOL for medication further. Spontaneous onset of labor is usually preferred, as it generally means lower risk of complications compared to IOL. If delivery needs to be induced in women with an unfavorable cervical status, an oral solution of misoprostol is a safe and inexpensive method that is easy to control and provides a high success rate of vaginal deliveries with a very low risk of hyper stimulation. Since the preparation of misoprostol (Cytotec®) has been used off-label with the solution being prepared locally at every unit, the profession has been looking for alternatives. Angusta® 25 ug tablets is the alternative that has been developed and approved but without being compared to the oral solution of misoprostol, the most commonly used method for IOL in Sweden. In addition, Angusta® is 43 times more expensive (1011 SEK compared to 23.60 SEK for Cytotec® for eight doses) considering a typical induction for primiparous women. Both methods are currently in use in clinical practice in Sweden. A recent study conducted in Sweden 2020 shows that the Area Under the Curve (AUC) for the concentration in the blood of misoprostol after administration of 25 ug Cytotec® po compared to Angusta® 25ug po differs . The AUC is 32.9% higher with Cytotec® compared to Angusta®. The lower AUC for Angusta® may result in lower efficacy and time to delivery. However, this is unknown. The reason for this difference may be that a greater proportion of misoprostol is absorbed buccally and/or sublingually with use of misoprostol as a solution compared to when it is used as a tablet. Misoprostol has significantly different effect on uterine contractility depending on method of administration(1). Thus, using Angusta® may result in negative health economic outcomes due to higher price and in addition, a longer time spent in the delivery unit. No comparison of these two formulations has been performed in clinical practice.

Official Title
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Orally Administered Misoprostol Solution (Cytotec®) Versus Orally Administered Misoprostol as a Tablet (Angusta®) for Induction of Labor in Women With Mixed Parity and an Unfavorable Cervix, a Randomized Controlled Trial.

Conditions
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Induced Vaginal Delivery

Intervention / Treatment
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* Drug: Misoprostol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Singleton gestations Cephalic presentation ≥37-42+0 weeks of gestation Unfavorable cervix score BS <6 in nulliparous women and <5 in parous women All participating women in the studies will receive oral and written information and must give informed consent before participation Exclusion Criteria: Inability to understand the study information written in Swedish or English Previous hysterotomy (scar in the uterine myometrium) Non-reassuring cardiotocography (CTG) on admission (the door-test, first 20 minutes of registration of CTG). Hypersensitivity to the active substance If active labor has started When oxytocin infusion is already used Placenta previa Renal failure (GFR <15 ml/min/1.73 m2). Any condition or circumstance due to which the investigator considers it is not in the best interest of subject to participate in the study or the inclusion of a subject risks negatively impacting the scientific or ethical integrity of the clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cytotec®<br>IOL with misoprostol oral solution (Cytotec®) 25 ug every second hour, up to eight doses, or until painful contractions are obtained. Thereafter IOL will proceed according to clinical practice. | Drug: Misoprostol<br>* Women presenting at the study site with an indication for IOL will receive written and oral information about the study. They will have the opportunity to ask questions. If the woman agrees to participate and is deemed eligible, she will sign informed consent. The Swedish national guidelines regarding the method of IOL will be followed. Women will have an abdominal palpation to exclude malpresentation, a CTG, and a digital cervical exam to establish bishop score (BS) prior to inclusion (as per clinical practice). Randomization will be performed by the attending physician, midwife or study coordinator. Randomization will be by opening numbered opaque sealed envelopes in sequential order containing the randomization code. There are no restrictions for use of other medications. All concomitant medication will be recorded in the CRF.<br>|
| Active Comparator: Angusta®<br>IOL with misoprostol oral tablets (Angusta®) 25 ug every second hour, up to eight doses, or until painful contractions are obtained. Thereafter IOL will proceed according to clinical practice. | Drug: Misoprostol<br>* Women presenting at the study site with an indication for IOL will receive written and oral information about the study. They will have the opportunity to ask questions. If the woman agrees to participate and is deemed eligible, she will sign informed consent. The Swedish national guidelines regarding the method of IOL will be followed. Women will have an abdominal palpation to exclude malpresentation, a CTG, and a digital cervical exam to establish bishop score (BS) prior to inclusion (as per clinical practice). Randomization will be performed by the attending physician, midwife or study coordinator. Randomization will be by opening numbered opaque sealed envelopes in sequential order containing the randomization code. There are no restrictions for use of other medications. All concomitant medication will be recorded in the CRF.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vaginal delivery within 24 hours (VD 24) rate as difference in proportions in each group according to intention-to-treat (ITT), and per protocol. | VD24 - (yes/no) is a dichotomous variable extracted from medical records. | Time point for extraction of data: immediately after the intervention/procedure/surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of vaginal deliveries (VD) in total. | VD (dichotomous, electronic patient records). | Time point for extraction of data: immediately after the intervention/procedure/surgery. | 
| The induction-to-vaginal delivery time. | Induction-to-delivery interval (continuous, electronic patient records). | Time point for extraction of data:immediately after the intervention/procedure/surgery. | 
| The mean number of doses of each preparation. | Number of doses of each preparation (electronic patient records). | Time point for extraction of data: immediately after the intervention/procedure/surgery. | 
| The proportion of neonates with Apgar <7 at 5 minutes. | Children with Apgar <7 at 5 minutes (electronic patient records). | Time point for extraction of data: immediately after the intervention/procedure/surgery. | 
| Postpartum bleeding (PPH) >1000 ml. | PPH >1000 ml (electronic patient records. | Time point for extraction of data: immediately after the intervention/procedure/surgery. | 
| The proportion of women with hyper stimulation defined as painful contractions. exceeding 5 in 10 minutes with CTG abnormalities. | Cardiotocography electronic patient records. | Time point for extraction of data: immediately after the intervention/procedure/surgery. | 
| Cost-effectiveness. | Cost effectiveness calculated as ICER (incremental cost effectiveness ratio). The ICER considers changes in effectiveness as well as cost of treatment and was established using the formula: [Cost of Intervention-Cost of Standard treatment]/ [Effectiveness Intervention-Effectiveness of Standard treatment]. The intervention is Cytotec® and the control is Angusta®. The parameters included in the calculation are: Normal birth (no complications), normal birth( with complications), assisted delivery, Cesarean section ( no complications), Cesarean section (with complications, misoprostol as a tablet ((Angusta®) and as a solution (Cytotec®),oxytocin infusion, Midwife - hospital appointment (unit cost/minute), Consultant (unit cost/minute), Cost of perinatal death, Hospital admission for induction (hospital hotel costs), Cost of admission to neonatal nursery (per day) according to a study (8), in the book chapter in NICE guidelines, induction of labor. | Time point for extraction of data: immediately after the intervention/procedure/surgery. |