The Efficacy of A New Crosslinked Hyaluronan Gel in the Prevention of Postoperative Intrauterine Adhesion After Dilatation and Curettage in Women With Delayed Miscarriage: A Prospective, Randomized, Controlled Trial
Phase: NA
Conditions: Intrauterine Adhesion
Sponsor: BioRegen Biomedical (CHangzhou) Co., Ltd

Study protocol and statistical analysis plan 
 
 
 
The Efficacy of A New Crosslinked Hyaluronan Gel in the Prevention of 
Postoperative Intrauterine Adhesion After Dilatation and Curettage in Women 
With Delayed Miscarriage: A Prospective, Randomized, Controlled Trial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2016.05.09 
 
 
 
 

Introduction 
Intrauterine adhesions (IUAs) are defined as fibrous strings opposing walls of the 
uterus and/or cervix leading to partial or complete obliteration of the cavity. IUAs are 
frequently encountered in one out of five women after miscarriage. Trauma to a 
gravid uterine cavity is known to be the main cause of IUAs. Such trauma could be 
induced by uterine curettage in the postpartum period, after spontaneous miscarriage 
or during termination of pregnancy, or by cesarean section. After pregnancy, the 
uterus could be in a vulnerable state that making the basal layer of endometrium more 
easily damaged by any trauma, especially dilatation and curettage (D&C).  
Study Objective 
To evaluate the efficacy of a new crosslinked hyaluronan gel (Materegen®) in 
reducing intrauterine adhesions formation after D&C. 
Study Design 
Randomized controlled trial.  
Study Site:  
Six hospitals for maternal and child health care in China.  
 Department of Obstetrics, Hunan Province Meternal and Child Health Care 
Hospital, Changsha, Hunan, China 
 The Women’s Health Center, Changsha Hospital for Maternal & Child Health 
Care, Changsha, Hunan, China 
 Department of Obstetrics, The Maternal and Child Health Care Hospital of 
Hengyang City, Hengyang, Hunan, China 
 Department of Obstetrics, The Maternal and Child Health Care Hospital of 
Changde City, Changde, Hunan, China 
 Department of Obstetrics, Huaihua City Meternal And Child Health Care 
Hospital, Huaihua, Hunan, China 
 Department of Obstetrics, Yueyang Maternal and Child Health-Care Hospital, 
Yueyang, Hunan, China 
Statistical Analysis Site: 
School of Medicine, The Third Xiangya Hospital of Central South University, 

Changsha, Hunan, China. 
Study Device: 
A new crosslinked hyaluronan gel (MateRegen®), manufactured and supplied by 
BioRegen Biomedical (Changzhou, China), is a sterile, transparent, viscoelastic and 
non-pyrogenic gel composed of highly purified crosslinked hyaluronan molecules. 
Participants: 
Women undergoing dilatation and curettage for delayed miscarriage without previous 
dilatation and curettage. All participants were required to give their written, signed 
informed consent before participating. 
The inclusion criteria: 
 
Patients to be female, aged 18-45 years 
 
Without previous dilatation and curettage 
 
Undergoing dilatation and curettage for the current delayed miscarriage 
 
All participants should be with normal liver/rental function and without 
systemic disease 
 
Agree to use adequate forms of contraception throughout the study 
 
Be in good compliance with the follow-up examination according to the study 
protocol 
The exclusion criteria: 
 
Known/suspected intolerance or hypersensitivity to hyaluronan or its 
derivatives 
 
Genital tract malformation 
 
Inflammation of genital tract or pelvic cavity, clinical evidence of cancer in 
genital tract 
 
Suspected genital tuberculosis 
 
Abnormal blood coagulation 
 
Medical histories of peripheral vascular disease, alcohol/drug abuse, and 
mental illness 
 
Acute or severe infection 
 
Autoimmune diseases. 

Trial Process Flow 
Trail processes 
Recruitment and Treatment 
Follow-up 
Time points 
Two weeks before 
surgery 
Surgery 
Three months after 
surgery（±7 day） 
Window period 
X 
 
 
Informed consent form 
X 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
Dropout criteria 
 
 
X 
General data 
X 
 
 
Physical exam on vital 
signs 
X 
 
 
Medical history 
X 
 
 
Surgical history 
X 
 
 
Diagnosis 
X 
 
 
Surgery evaluation 
 
X 
 
Medication 
 
X 
 
AFS adhesion evaluation 
X 
 
X 
Clinical symptoms and 
vital signs 
X 
X 
X 
AE 
 
X 
X 
Randomization 
 
X 
 
Device application 
 
X 
 
Randomization and Interventions:  
The participants were randomly assigned into group of either D&C alone (control 
group) or D&C plus intrauterine MateRegen
® gel application (treatment group) in a 
1:1 ratio; and the random sequences were generated by SAS® 9.13 (center stratified 
blocked randomization, block=10) (SAS Institute, Cary NC). 
Surgical Procedure and Gel Application 
All D&C procedures were performed by suction curettage under general anesthesia in 
accordance with procedural standards. At the end of the D&C procedure a syringe of 
MateRegen® gel (3ml) was applied to the uterine cavity for patients assigned to the 
treatment group through a 15-cm sterile delivery cannula, whereas nothing was 
applied to the uterine cavity for patients in the control group. 
Follow-up and Measurement: 

A follow-up hysteroscopic examination was scheduled 3 months (±7 days) after the 
D&C procedure at about one week after the clean of menstrual bleeding. A pregnancy 
test was performed and before hysteroscopic examination. For patients with positive 
pregnancy test, the hysteroscopic examination was canceled.  
Findings at follow-up hysteroscopy were evaluated and recorded according to the 
American Fertility Society (AFS) classification.  
 
Table. The American Fertility Society (AFS) classification of intrauterine adhesion 
(1988)
Extent of cavity involved 
<1/3 
1/3-2/3 
>2/3 
Score 
1 
2 
4 
Type of adhesions 
Filmy 
Filmy & dense 
Dense 
Score 
1 
2 
4 
Menstrual pattern 
Normal 
Hypomenorrhea 
Amenorrhea 
Score 
0 
2 
4 
Prognostic classification 
 
 
 
Disease severity 
Cumulative score
 
 
Stage I (mild) 
1-4 
 
 
Stage II (moderate) 
5-8 
 
 
Stage III (severe) 
9-12 
 
 

Endpoints: 
The primary endpoint was the number of women with formation of IUAs. The 
secondary endpoints included the adhesion scores of extent of uterine cavity involved, 
type of adhesion and menstrual pattern, the cumulative adhesion score and the 
severity of IUAs graded according to AFS classification. The safety was monitored 
based on the complications and adverse events recorded that was possibly related to 
the MateRegen® gel application. 
Participant number 

The primary hypothesis of this trial was to demonstrate the superiority of D&C plus 
MateRegen® gel over the D&C alone, with respect to the incidence of IUAs. The 
primary assumption was that the estimated incidence was 30% in control group and 
would be reduced to 15% by application of MateRegen® gel. With a 2-tailed 0.05 
significance level and 20% loss rate during follow-up, 300 patients with 1:1 allocation 
would yield 80% power to detect the superiority. 
Statistical analysis Plan 
All randomized women who started treatment were included in analysis according to 
the intent-to-treat (ITT) principle. Continuous variables were expressed as mean ± 
standard deviation (SD) or median ± quartile range (QR). Categorical variables were 
described by counts and percentages. The student’s t-test/Wilcoxon rank-sum 
non-parametric test and chi-square test/Fisher’s exact test were used to check the 
homogeneity of baseline characteristics. The Wilcoxon rank-sum non-parametric test 
was used if variables do not follow the normal distribution and the results were 
expressed as median (Quartile Range) (QR). The Cochran-Mantel-Haenszel (CMH) 
Chi-Square test with center effect adjustment was performed to estimate the incidence 
difference between groups. The analysis of covariance with center effect adjustment 
was performed to estimate the difference of intrauterine adhesion scores between 
groups. All analyses were performed by using SAS® 9.13 (SAS Institute, Cary NC), 
and a p≤0.05 (two-tailed, α=0.05) was considered to be statistically significant.