Asherman Syndrome, Intrauterine Adhesion
Conditions
Keywords
Asherman Syndrome, Intrauterine adhesion, Hysteroscopy, Adhesiolysis, Adhesion prevention, Infertility
Brief summary
PREG2 is a randomized controlled trial that aims to evaluate efficacy in preventing intrauterine adhesion recurrence after hysteroscopic adhesiolysis of a novel intrauterine barrier film named Womed Leaf
Detailed description
PREG2 is a prospective, multi-center, randomized, controlled, two arm clinical study. The objective is to evaluate the efficacy of Womed Leaf in preventing intrauterine adhesion recurrence after adhesiolysis compared to adhesiolysis alone. The study will be performed on women with moderate or severe adhesions (AFS score \>=5) scheduled for adhesiolysis. Indeed, the risk of intrauterine adhesion is very high (up to 60%) in this population of patients. A follow-up diagnostic hysteroscopy will be performed 6-8 weeks after the adhesiolysis procedure to determine the presence and severity of IUAs according to the American Fertility Society and European Society of Gynecologic Endoscopy classification systems of adhesions. Fertility-related outcome will include live pregnancy at 1 year, 2 years and 3 years and will be reported as secondary endpoints. 154 women are planned to be included in the PREG2 study.
Interventions
DEVICEWomed Leaf
Womed Leaf™ device is composed of a uterine anti-adhesion film pre-loaded inside a flexible inserter. Womed Leaf™ is inserted in the uterine cavity by the 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. It is degraded and discharged naturally through the cervix and vagina.
Sponsors
Womed
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Women with moderate or severe intrauterine adhesions according to the AFS classification, i.e AFS score \>=5, confirmed by hysteroscopy right before adhesiolysis * Scheduled for hysteroscopic adhesiolysis * Age above or equal to 18 * Subjects who are willing to provide a written informed consent. * Subjects who can comply with the study follow-up (second look hysteroscopy) and other study requirements * Subjects who agree to refrain from intercourse or use a reliable form of barrier contraception to prevent unintended pregnancy until the follow-up hysteroscopy. * Subjects who agree to avoid all intrauterine devices (IUDs) until the follow-up hysteroscopy.
Exclusion criteria
Pre-operative criteria * Post menopause * Pregnant (confirmed by a positive pregnancy test) or lactating * Abnormal uterine cavity according to ESHRE classification I to V such as unicornis, bicornis, septate, duplex * Known or suspected endometrial hyperplasia * History of cervical or endometrial cancer * Active pelvic infection or history of pelvic peritonitis * History of endometrial ablation * Known contraindication or hypersensitivity to Womed Leaf component * Current participation in another clinical investigation that has not yet received the primary endpoint. * Any other condition that makes participation in the study contrary to the patient's best interests. Intra-operative criteria, post adhesiolysis: * Perforation during adhesiolysis * Uterine depth \< 5cm or \> 10cm
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy - IUA Severity | At second look hysteroscopy between 4 and 8 weeks | Change of AFS score between pre-adhesiolysis and second-look hysteroscopy (AFS) score The scale used to assess the severity of intrauterine adhesions is the American Fertility Society score. It is a 12 points composite score that adds-up 3 subcomponents: - Extend of adhesions (1 = less than 1/3 of the uterine cavity involved with adhesions to 4 = more than 2/3 of the uterine cavity involved with adhesions), * Type of adhesions (1 = Filmy adhesions to 4 = dense adhesions) * Menstrual pattern (0= normal to 4 = amenorrhea). The final score allows the following prognostic classification: 1-4 = mild disease, 5-8 = moderate disease 9-12 = severe disease |
| Safety - Adverse Events | At second look hysteroscopy between 4 and 8 weeks | Adverse events up to second look hysteroscopy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Extent of Cavity Involved Component Between Post-adhesiolysis and Second Look Hysteroscopy | At second look hysteroscopy between 4 and 8 weeks | Average of AFS score component extent of cavity involved |
| AFS Score | At second look hysteroscopy between 4 and 8 weeks | Average of AFS score |
| Change of Extent of IUA AFS Score Component | At second look hysteroscopy between 4 and 8 weeks | Average of the change of the AFS score component Extent of IUA |
| Change of Type of IUA AFS Score Component | At second look hysteroscopy between 4 and 8 weeks | Average of the change of the AFS score component type of IUA |
| Menstrual Pattern AFS Score Component | At second look hysteroscopy between 4 and 8 weeks | Average of the change of the AFS score component Menstrual Pattern |
| Percentage of Patients Who Have Mild Adhesions or no Adhesion | At second look hysteroscopy between 4 and 8 weeks | Percentage of patients who have AFS \< 5 |
| Freedom From IUA | At second look hysteroscopy between 4 and 8 weeks | Rate of patients who don't have adhesion |
| ESGE Stage | At second look hysteroscopy between 4 and 8 weeks | Rate of ECGE stage |
| Level of Post-operative Pain | At second look hysteroscopy between 4 and 8 weeks | Level of post-operative pain on a numeric rating scale, with 0 = no pain and 10 = the worst pain. |
| Level of Discomfort Related to Vaginal Discharge | At second look hysteroscopy between 4 and 8 weeks | Level of discomfort related to vaginal discharge on a numeric rating scale, with 0 = no discomfort and 10 = extremely disturbing |
| Timing of Vaginal Discharge | At second look hysteroscopy between 4 and 8 weeks | Timing of vaginal discharge as recalled by the patient |
| High-responder Rate | At second look hysteroscopy between 4 and 8 weeks | Percentage of patients who have improved from severe to mild adhesions or from severe to no adhesions or from moderate to no adhesions |
| Qualitative Description of the Vaginal Discharge | At second look hysteroscopy between 4 and 8 weeks | Qualitative description of the vaginal discharge as recalled by the patient |
| Change of Menstrual Pattern | At second look hysteroscopy between 4 and 8 weeks, 1 year, 2 years | Change of menstrual pattern |
| Reintervention Rate | At second look hysteroscopy or scheduled later up to one year | Reintervention rate, during second look hysteroscopy or scheduled later up to one year |
| Number of Adhesiolysis Procedures | After second look to one year | Number of adhesiolysis procedures after second look to one year |
| Pregnancy Rate | 1 year, 2 years, 3 years | Pregnancy rate defined as presence of foetal sac or heartbeat by ultrasound at 1 year and 2 years, whether spontaneous or IVF |
| Live Birth Rate | 1 year 2 years, 3 years | Live birth rate at 1 year and 2 years |
| Pregnancy Complication Rate | 3 years | Pregnancy complication rate |
| Time to Pregnancy | 3 years | Time to pregnancy (i.e. time between the second look hysteroscopy and pregnancy start) |
| IUA Severity According to Chinese Scoring System | At second look hysteroscopy between 4 and 8 weeks | IUA severity according to Chinese scoring system (for patients enrolled in China only) |
| Responder Rate | At second look hysteroscopy between 4 and 8 weeks | Percentage of patients with an improvement of one clinical category i.e from Severe to Moderate or from Moderate to Mild |
| Duration of the Vaginal Discharge | At second look hysteroscopy between 4 and 8 weeks | Duration of the vaginal discharge as recalled by the patient |
| Change of Extent of Cavity Involved Component | At second look hysteroscopy between 4 and 8 weeks | Average of AFS score component extent of cavity involved |
Countries
Belgium, China, Czechia, France, Italy, Spain, Switzerland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Womed Leaf IUA prevention: The novel intrauterine barrier film (Womed Leaf) is inserted immediately after completion of the hysteroscopic adhesiolysis
Womed Leaf: Womed Leaf™ device is composed of a uterine anti-adhesion film pre-loaded inside a flexible inserter.
Womed Leaf™ is inserted in the uterine cavity by the 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. | 75 |
| Control No IUA barrier - No placebo | 85 |
| Total | 160 |
Baseline characteristics
| Characteristic | Womed Leaf | Total | Control |
|---|---|---|---|
| Age, Continuous | 35.0 years STANDARD_DEVIATION 5.2 | 35.5 years STANDARD_DEVIATION 5.3 | 35.9 years STANDARD_DEVIATION 5.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 9 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 71 Participants | 151 Participants | 80 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 13 Participants | 28 Participants | 15 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 33 Participants | 18 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 47 Participants | 99 Participants | 52 Participants |
| Region of Enrollment Belgium | 5 participants | 11 participants | 6 participants |
| Region of Enrollment China | 11 participants | 24 participants | 13 participants |
| Region of Enrollment Czechia | 13 participants | 26 participants | 13 participants |
| Region of Enrollment France | 37 participants | 79 participants | 42 participants |
| Region of Enrollment Italy | 4 participants | 5 participants | 1 participants |
| Region of Enrollment Spain | 4 participants | 12 participants | 8 participants |
| Region of Enrollment Switzerland | 1 participants | 3 participants | 2 participants |
| Sex: Female, Male Female | 75 Participants | 160 Participants | 85 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 77 | 0 / 86 |
| other Total, other adverse events | 6 / 77 | 3 / 86 |
| serious Total, serious adverse events | 0 / 77 | 0 / 86 |
Outcome results
Primary
Efficacy - IUA Severity
Change of AFS score between pre-adhesiolysis and second-look hysteroscopy (AFS) score The scale used to assess the severity of intrauterine adhesions is the American Fertility Society score. It is a 12 points composite score that adds-up 3 subcomponents: - Extend of adhesions (1 = less than 1/3 of the uterine cavity involved with adhesions to 4 = more than 2/3 of the uterine cavity involved with adhesions), * Type of adhesions (1 = Filmy adhesions to 4 = dense adhesions) * Menstrual pattern (0= normal to 4 = amenorrhea). The final score allows the following prognostic classification: 1-4 = mild disease, 5-8 = moderate disease 9-12 = severe disease
Time frame: At second look hysteroscopy between 4 and 8 weeks
Population: The modified ITT (mITT) included all randomized patients, apart from 3, who were incorrectly randomized prior to, rather than after, their baseline hysteroscopy and were then excluded for not fulfilling the preset operative criteria without contributing any effectiveness data to the study.~There were 163 patients randomized in total. The mITT population includes 163-3= 160 patients; 75 in the Womed Leaf group and 85 in the Control group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Womed Leaf | Efficacy - IUA Severity | 5.2 score on a scale | Standard Deviation 2.8 |
| Control | Efficacy - IUA Severity | 4.2 score on a scale | Standard Deviation 3.2 |
Primary
Safety - Adverse Events
Adverse events up to second look hysteroscopy.
Time frame: At second look hysteroscopy between 4 and 8 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Womed Leaf | Safety - Adverse Events | 6 Participants |
| Control | Safety - Adverse Events | 3 Participants |
Secondary
AFS Score
Average of AFS score
Time frame: At second look hysteroscopy between 4 and 8 weeks
Secondary
Change in Extent of Cavity Involved Component Between Post-adhesiolysis and Second Look Hysteroscopy
Average of AFS score component extent of cavity involved
Time frame: At second look hysteroscopy between 4 and 8 weeks
Secondary
Change of Extent of Cavity Involved Component
Average of AFS score component extent of cavity involved
Time frame: At second look hysteroscopy between 4 and 8 weeks
Secondary
Change of Extent of IUA AFS Score Component
Average of the change of the AFS score component Extent of IUA
Time frame: At second look hysteroscopy between 4 and 8 weeks
Secondary
Change of Menstrual Pattern
Change of menstrual pattern
Time frame: At second look hysteroscopy between 4 and 8 weeks, 1 year, 2 years
Secondary
Change of Type of IUA AFS Score Component
Average of the change of the AFS score component type of IUA
Time frame: At second look hysteroscopy between 4 and 8 weeks
Secondary
Duration of the Vaginal Discharge
Duration of the vaginal discharge as recalled by the patient
Time frame: At second look hysteroscopy between 4 and 8 weeks
Secondary
ESGE Stage
Rate of ECGE stage
Time frame: At second look hysteroscopy between 4 and 8 weeks
Secondary
Freedom From IUA
Rate of patients who don't have adhesion
Time frame: At second look hysteroscopy between 4 and 8 weeks
Secondary
High-responder Rate
Percentage of patients who have improved from severe to mild adhesions or from severe to no adhesions or from moderate to no adhesions
Time frame: At second look hysteroscopy between 4 and 8 weeks
Secondary
IUA Severity According to Chinese Scoring System
IUA severity according to Chinese scoring system (for patients enrolled in China only)
Time frame: At second look hysteroscopy between 4 and 8 weeks
Secondary
Level of Discomfort Related to Vaginal Discharge
Level of discomfort related to vaginal discharge on a numeric rating scale, with 0 = no discomfort and 10 = extremely disturbing
Time frame: At second look hysteroscopy between 4 and 8 weeks
Secondary
Level of Post-operative Pain
Level of post-operative pain on a numeric rating scale, with 0 = no pain and 10 = the worst pain.
Time frame: At second look hysteroscopy between 4 and 8 weeks
Secondary
Live Birth Rate
Live birth rate at 1 year and 2 years
Time frame: 1 year 2 years, 3 years
Secondary
Menstrual Pattern AFS Score Component
Average of the change of the AFS score component Menstrual Pattern
Time frame: At second look hysteroscopy between 4 and 8 weeks
Secondary
Number of Adhesiolysis Procedures
Number of adhesiolysis procedures after second look to one year
Time frame: After second look to one year
Secondary
Percentage of Patients Who Have Mild Adhesions or no Adhesion
Percentage of patients who have AFS \< 5
Time frame: At second look hysteroscopy between 4 and 8 weeks
Secondary
Pregnancy Complication Rate
Pregnancy complication rate
Time frame: 3 years
Secondary
Pregnancy Rate
Pregnancy rate defined as presence of foetal sac or heartbeat by ultrasound at 1 year and 2 years, whether spontaneous or IVF
Time frame: 1 year, 2 years, 3 years
Secondary
Qualitative Description of the Vaginal Discharge
Qualitative description of the vaginal discharge as recalled by the patient
Time frame: At second look hysteroscopy between 4 and 8 weeks
Secondary
Reintervention Rate
Reintervention rate, during second look hysteroscopy or scheduled later up to one year
Time frame: At second look hysteroscopy or scheduled later up to one year
Secondary
Responder Rate
Percentage of patients with an improvement of one clinical category i.e from Severe to Moderate or from Moderate to Mild
Time frame: At second look hysteroscopy between 4 and 8 weeks
Secondary
Time to Pregnancy
Time to pregnancy (i.e. time between the second look hysteroscopy and pregnancy start)
Time frame: 3 years
Secondary
Timing of Vaginal Discharge
Timing of vaginal discharge as recalled by the patient
Time frame: At second look hysteroscopy between 4 and 8 weeks