PREvention of Intrauterine Adhesion After Hysteroscopic Surgery With Novel deGradable Film
Phase: NA
Conditions: Intrauterine Adhesion
Sponsor: Womed

PREG1 
Protocol  synopsis 
 
Name 
PREG1 
Title 
PRE vention  of  intrauterine  adhesion  after  hysteroscopic 
surgery  with  novel  tri-block  de G radable  polymer  film 
Protocol  version  number 
06  (April  27th  2020) 
Study  rationale 
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” .  IUAs  are  the  major 
 
 
 
 
 
 
 
 
 
 
1
long-term  complication  of  operative  hysteroscopy.  Their 
 
 
 
 
 
 
prevalence  following  myomectomy  is  high  and  varies 
 
 
 
 
 
 
 
significantly  across  the  literature  (7.5%-45.5%) , , .  hey  are 
 
 
 
 
 
 
 
2 3 4
frequently  associated  with  pelvic  pain.  The  prevention  tools 
 
 
 
 
 
 
 
 
available  today  do  not  sufficiently  meet  the  specifications 
 
 
 
 
 
 
 
 
required  for  the  prevention  of  IUAs  which  are:  1)  ergonomic 
 
 
 
 
 
 
 
 
 
 
device,  specifically  designed  for  intrauterine  use  and  adapted 
 
 
 
 
 
 
 
 
to  the  cervical  passage  and  2)  anti-adhesion  barrier  that  keep 
 
 
 
 
 
 
 
 
 
 
the  wound  tissue  apart  during  the  repair  phase  for  optimal 
 
 
 
 
 
 
 
 
 
 
efficiency.  
Study  device 
Name :  Womed  Leaf 
Device  group :  Anti-adhesion  barrier 
Device  status :  CE  marked  
Classification  (according  to  MDD  93/42/EEC  as  amended  per 
 
 
 
 
 
 
 
 
2007/47/EC):  IIa  according  to  rule  5 
 
Intended  purpose:  
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 
 
 
 
 
 
 
 
 
 
water  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 
 
 
  
 
 
   
 
 
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;107:1223-31 
2  Taskin  et  al.  Role  of  endometrial  suppression  on  the  frequency  of  intrauterine  adhesions  after  resectoscopic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
surgery.  The  Journal  of  the  American  Association  of  Gynecologic  Laparoscopists  2000;7(3):351–4 
3  Guida  et  al.  Effectiveness  of  auto-crosslinked  hyaluronic  acid  gel  in  the  prevention  of  intrauterine  adhesions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
after 
 hysteroscopic 
 surgery: 
 a 
 prospective,  randomized,  controlled  study.  Human  Reproduction 
 
 
 
 
 
 
 
 
 
 
2004;19(6):1461-64 
4  Touboul  et  al.  Uterine  synechiae  after  bipolar  hysteroscopic  resection  of  submucosal  myomas  in  patients  with 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
infertility.  Fertility  and  Sterility  2009;92(5):1690-93 
1 / 4 

PREG1 
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.  
Intended  use 
Womed  Leaf™  is  intended  to  be  used  for  the  prevention  or 
 
  
 
 
 
 
 
 
 
 
reduction  of  new  or  recurrent  intrauterine  adhesion 
 
 
 
 
 
 
 
formation  subsequent  to  a  transcervical  procedure  by 
 
 
 
 
 
 
 
creating  a  mechanical  barrier. 
Design 
Prospective,  multi-center,  single  arm  clinical  study.  
Subjects  will  be  followed  up  for  4  to  8  weeks. 
Objective 
Evaluate  the  safety  of  Womed  Leaf  after  hysteroscopic 
 
 
 
 
 
 
 
 
myomectomy  and  its  potential  efficacy  in  preventing  IUA  at 
 
 
 
 
 
 
 
 
 
second  look  hysteroscopy.  
Number  of  subjects 
20  subjects 
Sites 
●
Kremlin  Bicêtre  (APHP),  Paris,  France,  
●
CHU  Nîmes,  France,  
●
AMC,  Amsterdam,  The  Netherlands 
●
Zaans,  The  Netherlands 
●
Isala,  Zwolle,  The  Netherlands 
●
Gent,  Belgium 
●
CHR  La  Citadelle,  Liège,  Belgium 
Population 
Women  with  one  or  more  myoma(s),  one  myoma  being 
 
 
 
 
 
 
 
 
 
larger 
 than 
 10mm, 
 who 
 qualify 
 for 
 hysteroscopic 
 
 
 
 
 
 
 
myomectomy  
Co-primary  endpoints 
●
Safety  endpoint:  number  and  type  of  device-related 
 
 
 
 
 
 
 
adverse  events  (AE)  up  to  30  days: 
○
Per-operative  AEs  during  device  use  (cervical 
 
 
 
 
 
 
trauma,  uterine  perforation…) 
○
Polymer  film  tolerance  defined  as  fever,  pain  or 
 
 
 
 
 
 
 
 
bleeding  between  48  hours  post  procedure  and  30 
 
 
 
 
 
 
 
 
days 
An  Interim  Analysis  of  the  safety  endpoint  will  be  conducted 
 
 
 
 
 
 
 
 
 
 
on  the  first  10  subjects  at  30  day  follow-up. 
●
Efficacy  endpoint:  freedom  from  intrauterine  adhesion  at 
 
 
 
 
 
 
 
second  look  hysteroscopy  between  4  and  8  weeks,  and 
 
 
 
  
  
 
 
evaluation  of  severity  according  to  American  Fertility 
 
 
 
 
 
 
 
Society  (AFS)  and  European  Society  of  Gynecological 
 
 
 
 
 
 
 
Endoscopy  classifications  systems  of  adhesions.  
Secondary  endpoints 
1. Number,  type  and  severity  of  adverse  events  (AE)  at  30 
 
 
 
 
 
 
 
 
 
 
days 
2. Performance:  device  technical  success,  defined  as 
 
 
 
 
 
 
success  of  the  following  2  steps  : 
2 / 4 

PREG1 
a. Insertion  of  the  inserter  into  the  cervix  with  loaded 
 
 
 
 
 
 
 
 
 
film 
b. Release  of  the  film  in  the  uterus  defined  as  empty 
 
 
 
 
 
 
 
 
 
 
inserter  after  withdrawal 
3. Menstrual  bleeding  according  to  Higham  score 
4. Presence  of  Womed  Leaf  residuals  in  the  uterus  at 
 
 
 
 
 
 
 
 
 
hysteroscopic  control 
5. Uterine  film  discharge  experience  as  recalled  by  subject 
 
 
 
 
 
 
 
 
at  second  look  hysteroscopy  visit  :  
a. Subject  estimation  of  film  discharge  timing  and 
 
 
 
 
 
 
 
duration.  
b. Vulvar  pruritus  or  other  discomfort 
c.
Qualitative  impression 
6. Device 
 manipulation  duration,  from  insertion  to 
 
 
 
 
 
 
withdrawal 
Inclusion  criteria 
1. Women  ≥  40  years  AND  no  childbearing  wish,  OR  history 
  
 
 
 
 
 
 
 
 
of  permanent  sterilization 
2. Subject  scheduled  for  myomectomy  for  one  or  more 
 
 
 
 
 
 
 
 
myoma(s)  where  one  myoma  is  at  least  10mm  in  size 
 
 
 
 
 
 
 
 
 
 
(≥10mm)  as  estimated  by  pre-operative  ultrasound 
 
 
 
 
 
 
measurement  of  the  largest  diameter 
3. Hysterometry  ≥6  cm  and  ≤9  cm  as  measured  prior  to 
 
 
 
 
 
 
 
 
 
 
device  insertion 
4. Subjects  who  are  willing  to  provide  a  written  informed 
 
 
 
 
 
  
 
 
consent  as  approved  by  the  applicable  Ethics  Committee 
 
 
 
 
 
 
 
 
prior  to  participating  in  this  clinical  investigation. 
5. Subjects  who  can  comply  with  the  study  follow-up  or 
 
 
 
 
 
 
 
 
 
other  study  requirements 
Exclusion  criteria 
1. Current  pregnancy 
2. Abnormal  uterine  cavity  according  to  ESHRE  classification 
 
 
 
 
 
 
 
I  to  VI,  such  as  unicornis,  bicornis,  septate,  duplex 
3. Known  or  suspected  endometrial  hyperplasia 
4. Medical  history  of  cervical  or  endometrial  cancer 
5. Active  pelvic  infection  or  medical  history  of  pelvic 
 
 
 
 
 
 
 
 
peritonitis 
6. Intrauterine  device  in  situ 
7. Known  contraindication  or  hypersensitivity  to  Womed 
 
 
 
 
 
 
Leaf  components  and  to  medications  such  as  aspirin;  
8. Concurrent  medical  condition  with  a  life  expectancy  of 
 
 
 
  
 
 
 
less  than  12  months; 
9. Full  endometrial  ablation 
3 / 4 

PREG1 
Per-operative  exclusion  criteria: 
10. Adenomyosis 
11. Inflammation  (endometritis) 
12. Abnormal  uterine  cavity,  including  IUA 
13. Hysterometry  <  6cm  or  >9cm 
14. Any  complication  during  the  intervention  that  is  deemed 
 
 
 
 
 
  
 
to  potentially  interfere  with  the  objective  of  the  study  by 
 
 
 
 
 
 
 
 
 
 
the  investigator 
Intervention  technique 
●
No  monopolar  energy 
●
Resection  is  limited  to  myoma  and  excludes  full 
endometrial  ablation 
Drug  regimen 
According  to  local  practice  of  the  participating  site 
Assessment  /  Data  and 
image  collection  /  Follow 
up  schedule 
●
Intervention:  recording  of  hysteroscopy  procedures  and 
 
 
 
 
 
 
2D  or  3D  US  imaging 
●
2  hours  after  the  procedure  (i.e.before  discharge):  2D  or 
 
 
 
 
 
 
 
 
 
3D  ultrasound  in  order  to  visualize  the  polymer  position 
 
 
 
 
 
 
 
 
 
and  swelling  in  the  uterine  cavity.  
●
All  subjects  will  be  contacted  at  30  days  post  procedure 
 
 
 
 
 
 
 
 
 
 
to  assess  their  clinical  status  and  adverse  events. 
●
All  subjects  will  undergo  “second  look”  hysteroscopic 
 
 
 
 
 
 
 
procedure  between  4  to  8  weeks.  Recording  of 
 
 
 
 
 
 
 
 
hysteroscopy  images. 
Timelines 
First  subject  will  be  included  in  S2  2019.  Enrollment  of  the  20 
 
 
 
 
  
 
 
 
 
 
 
subjects  will  last  12  months.  Study  is  expected  to  be  closed 
 
 
 
 
 
  
 
 
 
 
by  Q4  2020. 
Statistical  
Analysis  Plan 
Descriptive  statistics  will  be  provided  for  all  variables 
 
 
 
 
 
 
 
 
considered  in  the  analysis.  For  categorical  variables,  the  data 
 
 
 
 
 
 
 
 
 
will  be  presented  as  counts  and  incidence  rates.  For 
 
 
 
 
 
 
 
 
 
continuous  variables,  the  data  will  be  presented  as  mean, 
 
 
 
 
 
 
 
 
 
standard  deviation,  median,  minimum,  maximum  and 
 
 
 
 
 
 
number  of  observations. 
Applicable  Norms 
ISO  14155 
 
4 / 4