Induced Vaginal DeliveryPhase 3NCT05424445
MISOBEST - Orally Misoprostol Solution (Cytotec®) Versus Orally Misoprostol as a Tablet (Angusta®) for Induction of Labor
A Phase 3 study testing Misoprostol in people with Induced Vaginal Delivery, run by Karolinska Institutet at 1 site in Sweden.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 18 to 45 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Induced Vaginal Delivery
- What is being tested?
- Misoprostol
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 884 participants
- Where
- 1 siteSweden
- Study dates
- 21 Jan 2022to 21 May 2023
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 45 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 9Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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.
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.
Read the detailed description
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.
- Conditions
- Induced Vaginal Delivery
- Being tested
- Misoprostol
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MisoprostolDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Cytotec® | Experimental | 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. Receives: Drug: Misoprostol |
| Angusta® | Active comparator | 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. Receives: Drug: Misoprostol |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Time point for extraction of data: immediately after the intervention/procedure/surgery
Secondary outcomes (7)
Proportion of vaginal deliveries (VD) in total.
VD (dichotomous, electronic patient records).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: Time point for extraction of data: immediately after the intervention/procedure/surgery.
Postpartum bleeding (PPH) >1000 ml.
PPH >1000 ml (electronic patient records.
Measured: 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.
Measured: 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.
Measured: Time point for extraction of data: immediately after the intervention/procedure/surgery.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Jun 2022
- Study start21 Jan 2022
- Primary completion31 Dec 2022
- Study completion21 May 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Induced Vaginal DeliveryStudies of the same condition, open and under way.
- More trials run by Karolinska InstitutetThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 884 participants (actual)
Sponsor and investigators
- Lead sponsor
- Karolinska Institutet
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Tove Wallström, Karolinska Institutet
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05424445
- Sponsor's protocol ID
- EudraCT 2020-000663-23
- Status last verified
- Aug 2023
- First submitted
- 21 Jan 2022
- Last updated
- 18 Aug 2023
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Stephansson O, Petersson K, Bjork C, Conner P, Wikstrom AK. The Swedish Pregnancy Register - for quality of care improvement and research. Acta Obstet Gynecol Scand. 2018 Apr;97(4):466-476. doi: 10.1111/aogs.13266. Epub 2017 Dec 14.
PubMed 29172245Wennerholm UB, Saltvedt S, Wessberg A, Alkmark M, Bergh C, Wendel SB, Fadl H, Jonsson M, Ladfors L, Sengpiel V, Wesstrom J, Wennergren G, Wikstrom AK, Elden H, Stephansson O, Hagberg H. Induction of labour at 41 weeks versus expectant management and induction of labour at 42 weeks (SWEdish Post-term Induction Study, SWEPIS): multicentre, open label, randomised, superiority trial. BMJ. 2019 Nov 20;367:l6131. doi: 10.1136/bmj.l6131.
PubMed 31748223Tang J, Kapp N, Dragoman M, de Souza JP. WHO recommendations for misoprostol use for obstetric and gynecologic indications. Int J Gynaecol Obstet. 2013 May;121(2):186-9. doi: 10.1016/j.ijgo.2012.12.009. Epub 2013 Feb 19.
PubMed 23433680Amini M, Reis M, Wide-Swensson D. A Relative Bioavailability Study of Two Misoprostol Formulations Following a Single Oral or Sublingual Administration. Front Pharmacol. 2020 Feb 12;11:50. doi: 10.3389/fphar.2020.00050. eCollection 2020.
PubMed 32116725Svensk E, Bessfelt E, Brismar Wendel S, Kopp Kallner H, Wallstrom T. Misoprostol as Oral Solution or Oral Tablet for Induction of Labour (MISOBEST): A Randomised Controlled Non-Inferiority Trial. BJOG. 2025 Feb;132(3):288-296. doi: 10.1111/1471-0528.17986. Epub 2024 Oct 23.
PubMed 39440409
Study at a glance
From the registry record, last updated by the sponsor on 18 Aug 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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.
- ClinicalTrials.gov ID
- NCT05424445
- Acronym / sponsor ID
- EudraCT 2020-000663-23
- Conditions
- Induced Vaginal Delivery
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 884 participants (actual)
- Lead sponsor
- Karolinska InstitutetUniversity, hospital or other
- Study start
- 21 Jan 2022 (actual)
- Primary completion
- 31 Dec 2022 (actual)
- Study completion
- 21 May 2023 (actual)
- First posted
- 21 Jun 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Cytotec® | Experimental | Drug: MisoprostolIOL 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. |
| Angusta® | Active comparator | Drug: MisoprostolIOL 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. |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (9 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MisoprostolWomen 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. | Drug | Angusta®, Cytotec® |
Primary outcome
Vaginal delivery within 24 hours (VD 24) rate as difference in proportions in each group according to intention-to-treat (ITT), and per protocol.
Time frame: Time point for extraction of data: immediately after the intervention/procedure/surgery
VD24 - (yes/no) is a dichotomous variable extracted from medical records.
7 secondary outcomes
Proportion of vaginal deliveries (VD) in total.
Time frame: Time point for extraction of data: immediately after the intervention/procedure/surgery.
The induction-to-vaginal delivery time.
Time frame: Time point for extraction of data:immediately after the intervention/procedure/surgery.
The mean number of doses of each preparation.
Time frame: Time point for extraction of data: immediately after the intervention/procedure/surgery.
The proportion of neonates with Apgar <7 at 5 minutes.
Time frame: Time point for extraction of data: immediately after the intervention/procedure/surgery.
Postpartum bleeding (PPH) >1000 ml.
Time frame: 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.
Time frame: Time point for extraction of data: immediately after the intervention/procedure/surgery.
Cost-effectiveness.
Time frame: Time point for extraction of data: immediately after the intervention/procedure/surgery.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Aug 2023.
- Background: PubMed 29172245Stephansson O, Petersson K, Bjork C, Conner P, Wikstrom AK. The Swedish Pregnancy Register - for quality of care improvement and research. Acta Obstet Gynecol Scand. 2018 Apr;97(4):466-476. doi: 10.1111/aogs.13266. Epub 2017 Dec 14.
- Background: PubMed 31748223Wennerholm UB, Saltvedt S, Wessberg A, Alkmark M, Bergh C, Wendel SB, Fadl H, Jonsson M, Ladfors L, Sengpiel V, Wesstrom J, Wennergren G, Wikstrom AK, Elden H, Stephansson O, Hagberg H. Induction of labour at 41 weeks versus expectant management and induction of labour at 42 weeks (SWEdish Post-term Induction Study, SWEPIS): multicentre, open label, randomised, superiority trial. BMJ. 2019 Nov 20;367:l6131. doi: 10.1136/bmj.l6131.
- Background: PubMed 23433680Tang J, Kapp N, Dragoman M, de Souza JP. WHO recommendations for misoprostol use for obstetric and gynecologic indications. Int J Gynaecol Obstet. 2013 May;121(2):186-9. doi: 10.1016/j.ijgo.2012.12.009. Epub 2013 Feb 19.
- Background: PubMed 32116725Amini M, Reis M, Wide-Swensson D. A Relative Bioavailability Study of Two Misoprostol Formulations Following a Single Oral or Sublingual Administration. Front Pharmacol. 2020 Feb 12;11:50. doi: 10.3389/fphar.2020.00050. eCollection 2020.
- Derived from this study: PubMed 39440409Svensk E, Bessfelt E, Brismar Wendel S, Kopp Kallner H, Wallstrom T. Misoprostol as Oral Solution or Oral Tablet for Induction of Labour (MISOBEST): A Randomised Controlled Non-Inferiority Trial. BJOG. 2025 Feb;132(3):288-296. doi: 10.1111/1471-0528.17986. Epub 2024 Oct 23.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Misoprostol in people with Induced Vaginal Delivery, run by Karolinska Institutet at 1 site in Sweden.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Aug 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Sweden. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Vaginal delivery within 24 hours (VD 24) rate as difference in proportions in each group according to intention-to-treat (ITT), and per protocol. (time frame: Time point for extraction of data: immediately after the intervention/procedure/surgery). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05424445, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Aug 2023.