PREvention of Intrauterine Adhesion After Adhesiolysis With Novel Tri-block deGradable Polymer Film.
Phase: NA
Conditions: Asherman Syndrome, Intrauterine Adhesion
Sponsor: Womed

PREG2 protocol synopsis
Name
PREG2
Title
PREvention of intrauterine adhesion after adhesiolysis with novel
tri-block deGradable polymer film.
NCT04963179.
Protocol version date
December 16th 2022
Rationale for study
Intrauterine adhesions (IUA) are defined as “fibrous strings at opposing
walls of the uterus and/or cervix leading to partial or complete
obliteration of the cavity” . IUA can lead to recurrent pregnancy loss,
1
infertility, abnormal placentation, menstrual abnormalities, and pain.1,2
Treatment by hysteroscopic lysis is recommended if the patient has
clinical symptoms. However, one of the greatest challenge is the
recurrence of adhesive disease1, : the recurrence rate after intrauterine
3
synechiae lysis is 20% to 32% and 42% to 60% in the case of severe
synechiae , , , . The high rate of recurrences makes reproductive
4 5 6 7
outcomes unsatisfactory, even after hysteroscopic treatment . It is
8
acknowledged that the use of an intrauterine barrier potentially
reduces
postoperative
adhesion
reformation.
However,
existing
barriers have suboptimal efficacy due to their limited residence time in
the uterus (HA gel) or need of manual removal (IUD, balloon, amnion
graft). As a result, a golden standard to prevent adhesive disease does
not exist.
Therefore, there is an unmet medical need for an evidence based
effective secondary prevention method. Hence the evaluation of the
efficacy of the anti adhesion effects of Womed Leaf after adhesiolysis.
Study device
Name: Womed Leaf
Device group: Anti-adhesion barrier
Device status: CE marked
8 March CM. Intrauterine adhesions. Obstet Gynecol Clin North Am 1995;22:491–505.
7 Yu et al., Factors affecting reproductive outcome of hysteroscopic adhesiolysis for Asherman’s syndrome.
Fertility and Sterility 2008;89(3):715-722.
6 Accunzo et al., Effectiveness of auto-cross linked hyaluronic acid gel in the prevention of intrauterine
adhesions after hysteroscopic adhesiolysis: a prospective, randomized, controlled study. Human Reproduction
2003;18(9):1918–21
5 Valle 1988 Valle and Sciarra Intrauterine ·adhesions: Hysteroscopic diagnosis, classification, treatment, and
reproductive outcome Am J Obstet Gynecol 1988;158(6):1459-70
4 Pabuccu 1999
3 Warembourg S et al. Prevention and treatment of intrauterine synechiae : Review of literature. J Gynecol
Obstet Biol Reprod. 2015 Apr ; 44 :366-79.
2 Tuuli MG et al. Uterine synechiae and pregnancy complications. Obstet Gynecol 2012 ; 119 :810-4
1 Hooker et al., Prevalence of intrauterine adhesions after the application of hyaluronic acid gel after dilatation
and curettage in women with at least one previous curettage: short-term outcomes of a multicenter,
prospective randomized controlled trial. Fertility and Sterility. 2017;107(5):0015-0282.
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Description:
Womed Leaf™device is composed of a uterine anti-adhesion film
pre-loaded inside a flexible inserter.
Womed Leaf™is a sterile, degradable film of poly(D,L-lactide) (PLA)
and poly(ethylene oxide) (PEO). PEO is a biocompatible polymer with
anti-adhesion and swelling properties. Polymerized with hydrophobic
PLA, it forms a degradable film that swells and expands in contact with
fluid to form a degradable mechanical barrier.
Womed Leaf™is inserted in the uterine cavity by a gynecologist
surgeon as a film folded into a 5 mm diameter flexible inserter. Once
released, the film will unfold and swell into the uterine cavity to keep
uterus walls separated during approximately 5 days. It is degraded and
discharged naturally through the cervix and vagina in less than 30 days.
Objective
Evaluate the effectiveness of Womed Leaf in preventing intrauterine
adhesions recurrence after hysteroscopic
adhesiolysis (secondary
prevention) by comparing it to adhesiolysis without IUA prevention.
Design
Prospective, multi-center, stratified, randomized, controlled, two-arm
superiority clinical trial
Subjects will be followed up for 6 weeks as per AAGL/ESGE guidelines9
for the primary endpoint and up to 2 years for the secondary fertility
endpoints.
Study group
IUA prevention: Womed Leaf is inserted immediately after completion
of the hysteroscopic adhesiolysis
Control group
No IUA prevention - no placebo after adhesiolysis
Estimated
number
of
subjects
154 subjects
Sites
At least 7 specialized centers
Population
Women with moderate or severe intrauterine adhesions (AFS score
>=5)
confirmed
by
hysteroscopy,
scheduled
for
hysteroscopic
adhesiolysis
Randomization
Computer generated randomization in 1:1 ratio
Randomization will be stratified by IUA severity (moderate/severe)
determined at the beginning of adhesiolysis.
Primary
effectiveness
endpoint
Primary safety endpoint
The primary effectiveness endpoint is: Change of AFS score between
pre-adhesiolysis and second-look hysteroscopy (AFS) score.
The primary safety endpoint is: Adverse events up to second look
hysteroscopy (6 weeks +/- 2 weeks).
9 AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the
European Society of Gynecological Endoscopy (ESGE), 2017
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Key Secondary
Effectiveness Endpoints
Other secondary
endpoints
1.
High-responder
rate i.e: percentage of patients who have
improved from severe to mild adhesions or from severe to no
adhesions or from moderate to no adhesions at second look
2.
Change of “extent of cavity involved”, according to the 10-zone
uterine
diagram,
between pre-adhesiolysis and second-look
hysteroscopy
3.
Change in “extent of cavity involved” component between
post-adhesiolysis and second look hysteroscopy
4.
AFS scores at second look hysteroscopy
5.
Extent of IUA AFS score component
6.
Type of IUA AFS score component
7.
Menstrual pattern AFS score component
8.
Percentage of patients who have Mild adhesions or no adhesion at
second look
1.
Freedom from IUA (rate) at second look hysteroscopy (6 weeks +/-
2 weeks)
2.
ESGE stage at second look hysteroscopy
3.
Level of post-operative pain on a numeric rating scale, with 0 = no
pain and 10 = the worst pain.
4.
Level of discomfort related to vaginal discharge on a numeric
rating scale, with 0 = no discomfort and 10 = extremely disturbing.
5.
Timing of vaginal discharge as recalled by the patient
6.
Duration of the vaginal discharge
7.
Qualitative description of the vaginal discharge
8.
Change of menstrual pattern at second look hysteroscopy, 1 year
and 2 years
9.
Reintervention rate, during second look hysteroscopy or scheduled
later up to one year
10. Number of adhesiolysis procedures after second look up to one
year
11. Pregnancy rate defined as presence of foetal sac or heartbeat by
ultrasound at 1 year and 2 years, whether spontaneous or IVF
12. Live birth rate at 1 year and 2 years
13. Pregnancy complication rate
14. Time
to
pregnancy
(i.e.
time
between
the
second
look
hysteroscopy and pregnancy start)
15. IUA severity according to Chinese scoring system (for patients
enrolled in China only)
16. Responder rate: Percentage of patients with an improvement of
one clinical category i.e from Severe to Moderate or from
Moderate to Mild
Inclusion criteria
1.
Women with moderate or severe intrauterine adhesions according
to the AFS classification, i.e AFS score >=5, confirmed by
hysteroscopy right before adhesiolysis
2.
Scheduled for hysteroscopic adhesiolysis
3.
Age above or equal to 18
4.
Subjects who are willing to provide a written informed consent.
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5.
Subjects who can comply with the study follow-up (second look
hysteroscopy) and other study requirements.
6.
Subjects who agree to refrain from intercourse or use a reliable
form of barrier contraception to prevent unintended pregnancy
until the follow-up hysteroscopy.
7.
Subjects who agree to avoid all intrauterine devices (IUDs) until
the follow-up hysteroscopy.
Exclusion criteria
Pre-operative criteria
1.
Post menopause
2.
Pregnant (confirmed by a positive pregnancy test) or lactating
3.
Abnormal uterine cavity according to ESHRE classification I to V
such as unicornis, bicornis, septate, duplex
4.
Known or suspected endometrial hyperplasia
5.
History of cervical or endometrial cancer
6.
Active pelvic infection or history of pelvic peritonitis
7.
History of endometrial ablation
8.
Known contraindication or hypersensitivity to Womed Leaf
component
9.
Current participation in another clinical investigation that has
not yet received the primary endpoint.
10. Any other condition that makes participation in the study
contrary to the patient’s best interests.
Intra-operative criteria, post adhesiolysis:
11. Perforation during adhesiolysis
12. Uterine depth < 5cm or > 10cm
Intervention technique
Hysteroscopic adhesiolysis using tools according to local practice of the
participating center.
Procedure
and
drug
regimen
According to local practice of the participating site
Data
collection
and
Follow up schedule
●
Assessment of IUA severity at the beginning and at the end of
operative hysteroscopy
●
Assessment of procedure or device related adverse event at 2
weeks and 6 weeks
●
Second-look hysteroscopy at 6 weeks (+/-2 weeks) to assess
recurring IUA.
●
All patients will be contacted at 1 year and 2 years (+/- 1 month)
by email and/or phone call to assess their pregnancy status.
See table below.
Timelines
The first patient will be included in Q4 2021.
Patient inclusion will last 24 months.
Evaluation of the primary outcome will be done by Q1 2024.
Total study duration (including long term follow-up): 4 years
Data gathering and analysis before manuscript submission: 3 months.
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Blinding
Open label to the surgeon
Blinded to the study subjects and the hysteroscopy evaluator.
Sample Size Calculation
●
Two sided test
●
Confidence interval: 95% (5% alpha/type I error)
●
Power: 90% (10% beta/type II error)
●
Hypothesis*:
○
Control group: mean difference of AFS score = 5
○
Study group: mean difference of AFS score = 6
○
Standard deviation: 1,8
⇒Sample size: 138
●
Loss to follow up: 10%
⇒Total population: 154 subjects with a 1:1 randomization
Statistical
Analysis Plan
The Intention To Treat (ITT) population is defined by all randomized
patients.
The safety population is defined by all randomized patients.
Standard descriptive statistics will be used.
Randomization being stratified on IUA severity, statistical analysis will
be adjusted on IUA severity.
For the primary effectiveness endpoint (classification of adhesions): A
covariance analysis (ANCOVA) with the mean change of AFS score
between pre-adhesiolysis and SLH as dependent parameter, with IUA
severity stratum as covariate will be conducted to compare the 2
groups. The two-sided 95% CI of the mean change of AFS score
between pre-adhesiolysis and SLH will be estimated independently in
each randomization group using standard error (SE). If H0 is rejected
and ΔWOMED > ΔC then, superiority of Womed Leaf over no IUA
prevention method will be concluded.
If the normality of the change of AFS score cannot be assumed, the
tertiles of the parameter will be used as a dependent parameter and an
ordinal logistic regression model will be used.
For the primary safety endpoint, all AE will be presented.
For key secondary efficacy endpoints: The list of key secondary
endpoints has been hierarchically ordered. For each endpoint, the
hypotheses will be tested using a fixed-sequence method following the
order defined, using 2-sided statistical tests, all at the same significance
level alpha (α = 0.05), moving to a second endpoint only after a success
on the previous endpoint.
Applicable Norms
ISO 14155:2020, Good Clinical Practice, 21 CFR Parts 11, 50, 54, 56, and
812, Medical Device Regulation (EU) 2017/745 (MDR) and MDCG
2020-10/1 guidance, Good Clinical Practice for Medical Devices Clinical
trials (Decree No. 28, 2022) promulgated by NMPA in 2022.
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D-7 days
(±7days)
D0
2 weeks
(+/-1 week)
6 weeks
(+/-2
weeks)
1 year
(+/-1
month)
2 years
(+/-1
month)
Data / imaging
collection
Enrollment Pre-operativ
e visit
Before
adhesiolysis
After
adhesiolysis
Phone call
Second look
HSC
Phone call
and/or
email
Phone call
and/or
email
Patient information
X
Inclusion criteria
validation
X
X
X
Informed consent*
X
Pregnancy test
X
Medical History
X
Baseline
characteristics
X
Uterine depth
X
AFS score
X
X
X
Presence and
location of IUA
(diagram)
X
X
Hysteroscopy
recordings (not
mandatory)
X
X
X
Intervention report
X
X
Device performance
related event
X
Adverse events (AE)
X
X
X
Medication
X
X
X
X
X
X
Menstrual pattern
X
X
X
X
Patient reported
outcomes
X
X
X
Pregnancy status
(and date)
X
X
X
Live birth
X
X
Pregnancy
complications
X
X
Data collection and follow-up table
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