MISO200: Misoprostol 400 µg Versus 200 µg for Cervical Ripening in 1st Trimester Miscarriage

• Sponsor: Hospital de Clinicas de Porto Alegre (Other)
• Overall Status: Completed
• CT.gov ID: NCT02957305
• Collaborator: (none)
• Enrollment: 211
• Location: 1
• Arms: 2
• Actual Duration (Months): 42.3
• Patients Per Site Per Month: 5

Study Details

Study Description

Brief Summary

Local current protocol for cervical ripening in 1st trimester miscarriage recommends 400 µg of misoprostol intravaginally 3 hours before uterine evacuation. This regime has been recommended by some international guidelines . So far, there are no recent studies comparing cervical dilatation between 400 µg of misoprostol and a reduced dose (e.g., 200 µg) for 6 hours. If cervical ripening is similar between these two regimens(i.e., 200µg regimen is not inferior to 400µg regimen), costs reductions and lower side effects may be issued without losing quality of cervix dilatation.

Condition or Disease	Intervention/Treatment	Phase
Miscarriage in First Trimester	Drug: Misoprostol 400mcg Tab; Drug: Misoprostol 200mcg Tab	Phase 4

Detailed Description

Miscarriage is defined by the World Health Organization as the interruption of the pregnancy up to 20-23 weeks, or the products of pregnancy weighing less than 500 grams (1). Nearly 15% of known pregnancies end in miscarriage, especially in the first 12 weeks. Estimates indicate that 68000 women die worldwide each year, as a result of unsafe abortions. Abortions are the major cause of maternal death, particularly in Latin America and the Caribbean. In cases of retained and incomplete abortions, uterine emptying is recommended. In the first trimester of pregnancy, either pharmacological or surgical procedure is accepted according to international guidelines.

Pharmacological treatment for uterine evacuation includes the administration of mifepristone and misoprostol or misoprostol alone. Nevertheless, surgical methods have been shown a greater acceptability and patient satisfaction due to a reduced incidence of adverse effects. Currently, Manual Vacuum Aspiration (MVA) is the technique recommended by the Brazilian Ministry of Health and the Brazilian Federation of Gynecology and Obstetrics.

MVA should be performed after cervical ripening. This pre-surgical procedure makes the procedure safer and more effective. In Brazil, misoprostol is the most suitable drug to be used in these cases because of its efficacy, ease of use, low cost, stability at room temperature, and availability. Misoprostol is a synthetic prostaglandin E1 analog and can be administered by oral, sublingual, buccal, rectal, and vaginal routes.

Study Design

• Study Type: Interventional
• Actual Enrollment: 211 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: Patients, operators and statistical analysis were performed blindly.
• Primary Purpose: Treatment
• Official Title: Comparison Between 400 µg or 200 µg of Misoprostol for Cervical Dilatation in 1st Trimester Miscarriage - A Clinical Trial
• Actual Study Start Date: Dec 21, 2016
• Actual Primary Completion Date: Oct 19, 2019
• Actual Study Completion Date: Jun 30, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Misoprostol 400 µg Participants received misoprostol 400 µg: 2 tablets of misoprostol (200µg each) introduced into the vagina, at least 6 hours before the Manual Vacuum Aspiration (MVA) procedure.	Drug: Misoprostol 400mcg Tab; 400µg of misoprostol (2 tablets); Other Names: Misoprostol control
Experimental: Misoprostol 200 µg Participants received misoprostol 200 µg: 1 tablet of misoprostol introduced into the vagina, at least 6 hours before the Manual Vacuum Aspiration procedure.	Drug: Misoprostol 200mcg Tab; 200µg of misoprostol (1 tablet); Other Names: Misoprostol comparator

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Required Cervix Dilation at Initiation of the Manual Vacuum Aspiration [baseline at initiation of the Manual Vacuum Aspiration]

   this outcome identifies patients that had to have a mechanical dilator for opening the cervix to perform appropriate Manual Vacuum Aspiration

Secondary Outcome Measures

1. Number of Participants With a Presence of a Uterine Cervical Canal With ≥8 mm of Dilation [Baseline before Manual Vacuum Aspiration procedure]

   This outcome measures how many mm of dilation the cervical canal has before the procedure. Cervical permeability (≥8 mm of dilation, used as a cut-off) was measured using Karman cannulas, from higher to low diameter.

Other Outcome Measures

1. Pain Score (VAS) [before Manual Vacuum Aspiration]

   Pain scores were assessed using a verbal analog scale (VAS), ranging from zero (no pain) to 10 (worst possible pain)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• All patients admitted at the Gynecological emergency Unit at Hospital de Clínicas de Porto Alegre scheduled for uterine evacuation with <12 weeks of gestation.

Exclusion Criteria:

• patients who do not wish to participate in the project;

• patients with ectopic pregnancy;

• patients with comorbidities (heart failure congestive, chronic obstructive pulmonary disease);

• patients with hypovolemic shock;

• patients with cervical incompetence;

• patients with infected miscarriage/abortion (presence of fever, pus from the cervix, leukocytosis [> 14000]);

• patients with twin pregnancy;

• patients with Marfan syndrome;

• patients allergic to misoprostol;

• patients with coagulopathy;

• patients with opening of cervical internal os (4 mm of dilatation at the time of consultation);

• patients with previous surgery of the cervix (conization);

• patients with concomitant use of IUDs.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	HCPA	Porto Alegre	RS	Brazil	90035-903

Sponsors and Collaborators

• Hospital de Clinicas de Porto Alegre

Investigators

• Principal Investigator: Ricardo F Ricardo, MD, PhD, HCPA

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form: English version 2020 NCT02957305 - Jun 28, 2020

More Information

Publications

• ACOG Committee Opinion. American College of Obstetrician and Gynecologist. ACOG Committee Opinion. Number 283, May 2003. New U.S. Food and Drug Administration labeling on Cytotec (misoprostol) use and pregnancy. Obstet Gynecol. 2003 May;101(5 Pt 1):1049-50.
• Blanchard K, Clark S, Winikoff B, Gaines G, Kabani G, Shannon C. Misoprostol for women's health: a review. Obstet Gynecol. 2002 Feb;99(2):316-32. Review.
• Kapp N, Lohr PA, Ngo TD, Hayes JL. Cervical preparation for first trimester surgical abortion. Cochrane Database Syst Rev. 2010 Feb 17;(2):CD007207. doi: 10.1002/14651858.CD007207.pub2. Review.
• Marret H, Simon E, Beucher G, Dreyfus M, Gaudineau A, Vayssière C, Lesavre M, Pluchon M, Winer N, Fernandez H, Aubert J, Bejan-Angoulvant T, Jonville-Bera AP, Clouqueur E, Houfflin-Debarge V, Garrigue A, Pierre F; Collège national des gynécologues obstétriciens français. Overview and expert assessment of off-label use of misoprostol in obstetrics and gynaecology: review and report by the Collège national des gynécologues obstétriciens français. Eur J Obstet Gynecol Reprod Biol. 2015 Apr;187:80-4. doi: 10.1016/j.ejogrb.2015.01.018. Epub 2015 Jan 31. Review.
• National Collaborating Centre for Women's and Children's Health (UK). Ectopic Pregnancy and Miscarriage: Diagnosis and Initial Management in Early Pregnancy of Ectopic Pregnancy and Miscarriage. London: RCOG Press; 2012 Dec.
• Tang 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.

• Responsible Party: Ricardo Francalacci Savaris, Head of the Gynecologic Emergency Unit, Hospital de Clinicas de Porto Alegre
• ClinicalTrials.gov Identifier: NCT02957305
• Other Study ID Numbers: 160309
• First Posted: Nov 6, 2016
• Last Update Posted: Apr 30, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Ricardo Francalacci Savaris, Head of the Gynecologic Emergency Unit, Hospital de Clinicas de Porto Alegre: misoprostol; miscarriage
• Additional relevant MeSH terms: Abortion, Spontaneous; Misoprostol

Study Results

Participant Flow

Recruitment Details	Participants with diagnosis of miscarriage and scheduled for Manual Vacuum Aspiration at the Gynecologic Emergency Unit of Hospital de Clínicas de Porto Alegre, a tertiary teaching hospital, were recruited. The first participant was enrolled on December 21, 2016.
Pre-assignment Detail	A total of 269 were screened. From these, 211 were enrolled and randomized to treatment. After randomization, 2 cases, one case of infected abortion and one case with previous cervical conization were identified and they were treated as for intention to treat.

Arm/Group Title	Misoprostol 400µg	Misoprostol 200µg
Arm/Group Description	Participants received misoprostol 400 µg: 2 tablets of misoprostol (200µg each) were introduced into the vagina, at least 6 hours before the Manual Vacuum Aspiration procedure. Misoprostol: 400µg	Participants received misoprostol 200 µg: 1 tablet was introduced into the vagina, at least 6 hours before the Manual Vacuum Aspiration procedure. Misoprostol: 200µg
Period Title: Overall Study
STARTED	106	105
COMPLETED	106	105
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Misoprostol 400 µg	Misoprostol 200	Total
Arm/Group Description	Misoprostol 400 µg 6 hours before Manual Vacuum Aspiration	Misoprostol 200 µg 6 hours before Manual Vacuum Aspiration	Total of all reporting groups
Overall Participants	106	105	211
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	30	31	30
Sex: Female, Male (Count of Participants)
Female	106 100%	105 100%	211 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
Black	29 27.4%	26 24.8%	55 26.1%
Brazilian indian	0 0%	1 1%	1 0.5%
White	76 71.7%	77 73.3%	153 72.5%
Asian	1 0.9%	1 1%	2 0.9%
Region of Enrollment (participants) [Number]
Brazil	106 100%	105 100%	211 100%
Obstetric history (cases) [Median (Full Range) ]
Gesta	2	2	2
Para	1	1	1
Miscarriages	1	1	1
Time from misoprostol to procedure (hours) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [hours]	6.38 (1.47)	6.37 (1.28)	6.37 (1.39)
Gestational age (weeks) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [weeks]	7 (1.4)	7.1 (1.5)	7.1 (1.5)

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Required Cervix Dilation at Initiation of the Manual Vacuum Aspiration
Description	this outcome identifies patients that had to have a mechanical dilator for opening the cervix to perform appropriate Manual Vacuum Aspiration
Time Frame	baseline at initiation of the Manual Vacuum Aspiration

Outcome Measure Data

Analysis Population Description

Intention to Treat Population (all participants assigned to misoprostol 400µg or 200µg)

Arm/Group Title	Misoprostol 400 µg	Misoprostol 200 µg
Arm/Group Description	Misoprostol 400 µg 6 hours before intrauterine suction Misoprostol 400 µg: evaluate the required cervix dilation in the moment of the intrauterine suction	Misoprostol 200 µg 6 hours before intrauterine suction Misoprostol 200 µg: evaluate the required cervix dilation in the moment of the intrauterine suction
Measure Participants	106	105
It was necessary (inadequate cervix dilation)	4 3.8%	16 15.2%
It was not necessary (adequate cervix dilation)	102 96.2%	89 84.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Misoprostol 400 µg, Misoprostol 200 µg
	Comments	If there is a true difference in favour of the standard treatment of 10% (96% vs 86%), then 184 patients are required to be 95% sure that the upper limit of a one-sided 97.5% confidence interval (or equivalently a 95% two-sided confidence interval) will exclude a difference in favour of the standard group of more than 25%
	Type of Statistical Test	Non-Inferiority
	Comments	400µg of misoprostol yields a 96% cervical dilation > 8 mm. We considered 86% of the 200 µg misoprostol group as the minimal acceptable percentage. The non-inferiority margin was determined by 24.46.
Statistical Test of Hypothesis	p-Value	0.025
	Comments	The null hypothesis: percentage of dilation with 400µg ≥ percentage of dilation with 200µg + 25% Alternative hypothesis: percentage of dilation with 400µg - 25% < percentage of dilation with 200µg
	Method	difference between proportions
	Comments	difference between percentages and 95% confidence interval
Method of Estimation	Estimation Parameter	treatment difference
	Estimated Value	25
	Confidence Interval	(1-Sided) 95%; to 97.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Misoprostol 400 µg, Misoprostol 200 µg
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	The non-inferiority margin was determined by ⅓ of the difference between the 400µg effect (96.7%), compared to the 200 µg dose (23.3%), i.e. 73.4 / 3 = 24.46%
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference between proportions
	Estimated Value	0.1146
	Confidence Interval	(2-Sided) 95%; 0.037 to 0.192
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference between both groups was 11.5% (95%CI = 3.7% to 19.2%)

2. Secondary Outcome

Title	Number of Participants With a Presence of a Uterine Cervical Canal With ≥8 mm of Dilation
Description	This outcome measures how many mm of dilation the cervical canal has before the procedure. Cervical permeability (≥8 mm of dilation, used as a cut-off) was measured using Karman cannulas, from higher to low diameter.
Time Frame	Baseline before Manual Vacuum Aspiration procedure

Outcome Measure Data

Analysis Population Description

Intention to Treat (all patients assigned to 400mg or 200µg of misoprostol)

Arm/Group Title	Misoprostol 400 µg	Misoprostol 200 µg
Arm/Group Description	Misoprostol 400 µg 6 hours before intrauterine suction Misoprostol 400 µg: evaluate the required cervix dilation in the moment of the intrauterine suction	Misoprostol 200 µg 6 hours before intrauterine suction Misoprostol 200 µg: evaluate the required cervix dilation in the moment of the intrauterine suction
Measure Participants	106	105
Inadequate (<8 mm)	30 28.3%	50 47.6%
Adequate (≥8 mm)	76 71.7%	55 52.4%

3. Other Pre-specified Outcome

Title	Pain Score (VAS)
Description	Pain scores were assessed using a verbal analog scale (VAS), ranging from zero (no pain) to 10 (worst possible pain)
Time Frame	before Manual Vacuum Aspiration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Misoprostol 400 µg	Misoprostol 200 µg
Arm/Group Description	Misoprostol 400 µg 6 hours before intrauterine suction Misoprostol 400 µg: evaluate the required cervix dilation in the moment of the intrauterine suction	Misoprostol 200 µg 6 hours before intrauterine suction Misoprostol 200 µg: evaluate the required cervix dilation in the moment of the intrauterine suction
Measure Participants	106	105
Median (Full Range) [units on a scale - Verbal Analog Scale]	0	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Misoprostol 400 µg, Misoprostol 200 µg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0
	Confidence Interval	(2-Sided) 95%; 0 to 0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	From the MVA procedure until 6 hours after the procedure
Arm/Group Title	Misoprostol 400 µg		Misoprostol 200 µg
Arm/Group Description	Misoprostol 400 µg 6 hours before MVA		Misoprostol 200 µg 6 hours before MVA
All Cause Mortality
	Misoprostol 400 µg		Misoprostol 200 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/106 (0%)		0/105 (0%)
Serious Adverse Events
	Misoprostol 400 µg		Misoprostol 200 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/106 (0%)		0/105 (0%)
Other (Not Including Serious) Adverse Events
	Misoprostol 400 µg		Misoprostol 200 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/106 (0.9%)		3/105 (2.9%)
Reproductive system and breast disorders
uterine hemorrhage	1/106 (0.9%)	1	1/105 (1%)	1
cervical laceration	0/106 (0%)	0	2/105 (1.9%)	2

Limitations/Caveats

Technical problems with measurement leading to unreliable. Pregnancies with less than 8 weeks had their procedures completely done with small diameter Karman cannulas

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.