Download Evaluation of efficacy and safety of Hyaluronic acid

Evaluation of efficacy and safety of Hyaluronic
acid vaginal gel (Hyalofemme) for improvement
of vaginal dryness
A multicenter, randomized, open, positive and
parallel controlled clinical trial
Clinical Study Final Report
Study centers: □ Peking University First Hospital
□ Peking University Third Hospital
□ Beijing Chao-Yang Hospital Attached to
Capital Medical University
□ Beijing Shijitan Hospital
Sponsor: Zhaoke Pharmaceutical (Hefei) Co., Ltd
Report completion: July 20, 2010
Hyaluronic acid vaginal gel (Hyalofemme)
Clinical Study Final Report
Study device: Hyaluronic acid vaginal gel (Hyalofemme)
Study objective:
to evaluate the efficacy and safety of Hyaluronic acid
vaginal gel (Hyalofemme) for improvement of vaginal
dryness
Study type: clinical verification of medical device type III
Study design:
a multicenter, randomized, open, positive and parallel
controlled clinical trial
Product standard: standard for registration
Inspection report:
SFDA, Jinan Quality Supervision and Inspection
Center for Medical Devices, Report no.: Y2008022105
Sponsor: Zhaoke Pharmaceutical (Hefei) Co., Ltd
Study centers and investigators:
Peking University First Hospital
Peking University Third Hospital
Beijing Chao-Yang Hospital Attached
to Capital Medical University
Beijing Shijintan Hospital
Professor
Professor
Liao Qinping
Geng Li
Professor
Professor
Song Xuehong
Li Hongxia
Statistic Department:
Institute of Basic Medical Sciences Chinese Academy of Medical Sciences
Professor
Han Shaomei
Study principal investigator: Professor
Study period: May, 2009-May, 2010
Liao Qinping
TABLE OF CONTENTS
ABBREVIATIONS.......................................................................................................4
Abstract of Hyaluronic acid vaginal gel (Hyalofemme) .......................................5
Clinical Study Final Report .......................................................................................5
Study General Information ..........................................................................................12
1 Clinical general information.................................................................................13
1.1 Inclusion criteria..........................................................................................15
1.2 Exclusion criteria.........................................................................................15
1.3 Withdrawal criteria.....................................................................................16
1.4 Elimination criteria .....................................................................................16
1.5 Withdrawal procedures .............................................................................16
2 Clinical trial method (including setup of control group if necessary) ...........17
2.1 Randomization ............................................................................................17
2.2 Study control................................................................................................17
2.3 Study products ............................................................................................17
2.4 Packaging of study products.....................................................................18
2.5 Dispensation of study products................................................................18
2.6 Concomitant therapy..................................................................................19
2.7 Study procedures ........................................................................................19
2.8 Safety evaluation.........................................................................................21
2.9 Statistical analysis .......................................................................................22
3 Statistical method and evaluation method.........................................................22
4 Clinical evaluation standards...............................................................................23
4.1 Efficacy evaluation......................................................................................23
4.2 Safety evaluation.........................................................................................24
5 Clinical trial results ................................................................................................24
5.1 Allocation, dropout and elimination of subjects ....................................24
5.2 Baseline information and comparability analysis ..................................26
5.3 Analysis of concomitant medications ......................................................28
5.4 Efficacy analysis ..........................................................................................30
5.5 Safety analysis .............................................................................................35
5.4 Endometrial thickness ................................................................................40
6 Adverse events and side effects and the treatment during the clinical trial .41
7 Analysis of clinical trial results ............................................................................44
8 Conclusion of the clinical trial..............................................................................47
9 Indications, applicable range, contraindication and attentions ......................47
10 References .............................................................................................................48
11 Participants of clinical trial .....................................................................................49
12 Declaration and signatures of investigators.....................................................50
13 Opinions of clinical trial management department of medical institution .51
ABBREVIATIONS
AE
Adverse Event
ADR
Adverse Drug Reacion
BP
Blood Pressure
VSH
Vagina Health Score
CRF
Case Report Form
EC
Ethics Committee
GCP
Good Clinical Practice
ICH
International Conference on Harmonization
SAE
Serious Adverse Event
SFDA
State Food and Drug Administration
SOP
Standard Operating Procedure
FAS
Full Analysis Set
PPS
Per Protocol Set
SAS
Safety Analysis Set
Abstract of Hyaluronic acid vaginal gel (Hyalofemme)
Clinical Study Final Report
Sponsor
Zhaoke Pharmaceutical (Hefei) Co., Ltd
Clinical
Zhaoke Pharmaceutical (Hefei) Co., Ltd
Monitoring
Evaluation of efficacy and safety of Hyaluronic acid vaginal gel
(Hyalofemme) for improvement of vaginal dryness
Study title
A multicenter, randomized, open, positive and parallel controlled clinical
trial
Study product
Hyaluronic acid vaginal gel（Hyalofemme）
Inspection
SFDA, Jinan Quality Supervision and Inspection Center for Medical
certificate
Devices, Report no.: Y2008022105
Clinical
Peking University First Hospital, Obstetrics-Gynecology
study
Liao Qinping, director, professor
responsible
center
and
Principal
investigator
Starting time
May, 2009
Completion
May, 2010
time
Report
July, 2010
completion
time
Study
To evaluate the efficacy and safety of Hyaluronic acid vaginal gel
objective
(Hyalofemme) for improvement of vaginal dryness
Study method
The study is a multicenter, randomized, open, positive and parallel
controlled study, evaluating the efficacy and safety of Hyaluronic acid
vaginal gel (Hyalofemme) for improvement of vaginal dryness. According
to the protocol design, all subjects will be randomized into test group and
control group. Each subject will be treated continuously by the device for
10 times, once every 3 days and the period will last for about one month (30
days). The investigator has responsibility for observation and evaluation of
the efficacy and safety of the study device throughout the course and after
finishing. If any serious adverse event related to test group occurs during
the trial, it should be discontinued and the investigator should discuss the
relationship between the event and test product. If the adverse event is
closely related to the test product, the trial will discontinue, otherwise it
will go on. The investigator will judge the efficacy and safety of Hyaluronic
acid vaginal gel (Hyalofemme) for improvement of vaginal dryness after
that.
Sample size
144 cases, test group:72 cases, control group: 72 cases
Study
The vaginal mucosa tunica consists of a non cornified, stratified squamous
epithelium rich in glycogen and of basal lamina rich in elastic fibers.
The characteristics of the vaginal epithelium change depending on the
variations in the concentration of estrogenic and progestational hormones
in which women undergo during their life span. During the fertile period it
is stratified squamous epithelium and rich in glycogen, moistening and
elastic, while during menopause, due to a decrease in estrogenic hormones,
the epithelium atrophies. The cells residing in the intermediate levels of the
stratified squamous epithelium are mainly involved in this process thus
leading to thinning of the vaginal mucosa. The number of stratification
diminishes and only basal and parabasal cells, which however are
dystrophic and flake easily leaving the chorion unprotected, remain. The
vagina mucosa in these conditions is more susceptible directly to germs
and is more permeable to their toxic metabolic products. As a consequence,
it is not unusual to observe small lacerations that may easily become
infected.
background
The vagina is soft and elastic during the fertile period due to the balance
mechanism of the vaginal epithelium that maintains the appropriate
hydration and lubrication. During some situations, such as post partum,
lactation and menopause, oral contraceptives or stress, the balance may be
disturbed. In all of these situations, signs of vaginal dryness, burning
sensation or itching may be observed. Because of the insufficient vaginal
lubrication, the epithelium is injured thus leading to symptoms of vaginal
dryness, burning sensation, dyspareunia and itching. The physiological
lubricating film that characterizes the fertile period of a woman’s life plays
an important role in maintaining the integrity of the vaginal mucosa. This
film is no longer present during menopause thus leading to fragility of the
vagina mucosa.
The therapeutic resolutions in these situations are represented by topically
applied products that produce a hydrating effect to the vagina mucosa and
help to regain elasticity and softness. Hyaluronic acid vaginal gel
(Hyalofemme) is a colorless gel with high hydrating properties. The gel
contains Hydeal-D®, a derivative of hyaluronic acid, which maintains the
biocompatibility and interactivity of hyaluronic acid, and also adequate
hydration of mucosa. Topical administration of the gel has a good
adhesiveness to the vaginal mucosa and long acting hydration thus
improving the dry state of the vagina. It also improves the spontaneous
recovery of small lesions that caused by friction of vagina.
Hyaluronic acid vaginal gel (Hyalofemme), a colorless gel with high
hydrating properties, is manufactured by Fidia Advanced Biopolymers, srl,
Italy and has been marketed in Italy for years. Hyaluronic acid is a natural
molecule that can maintain a right level of hydration and plays an
important role in tissue repair. The product has no pharmacological effect
for it is not a drug but a type Ⅲ medical device. The gel’s hydrating
properties are attributed to the characteristics of the Hydeal-D® which
releases water molecules to the tissue, thus improving the dry state of the
vagina. Therefore, the gel is applicable to supplementary treatment of
【 】
vaginal dryness symptoms induced by any reason
1
.
The vaginal ecosystem is composed of a complex microflora, constituted of
different microorganisms. The presence of these microorganisms is subject
to qualitative and quantitative modifications some of which can result in
pathological conditions. Thus it is of utmost importance to understand the
influence of Hyalofemme gel in vaginal ecosystem. However, due to the
extreme complexity of the factors which influence this ecosystem, there is
no single theory capable of explaining the mechanisms which govern the
colonization and the homeostasis of this organ.
The hormone dependent dynamic nature of the vaginal physiology has
been demonstrated. The hormonal state of the subject determines directly
or indirectly the qualitative and quantitative variations of the vaginal
microbial components, mainly influencing the lactobacilli.
This microorganism is responsible for the vaginal homeostasis by:
·producing lactic acid which maintains an acidic vaginal ambient,
·competing for bacterial adherence,
·producing hydrogen peroxide,
·producing bacteriocins,
·stimulating the local immune system.
For these reasons the vaginal homeostasis is assessed through vagina PH
and vaginal smears (variations of the vaginal microbial components), so as
to evaluate the influence of Hyalofemme gel on vaginal ecosystem and the
safety.
Major
z
Primary efficacy endpoint: percentage of improvement of vaginal
dryness symptoms
evaluation
criteria
z
Secondary efficacy endpoint: percentage of improvement of itching,
dyspareunia and burning sensation
z
Safety evaluation: vital signs, laboratory examinations of vaginal
microecosystem, vaginal PH value, vaginal B ultrasound and incidence
of adverse event.
Statistical
Institute of Basic Medical Sciences Chinese Academy of Medical Sciences
method
undertook the overall process from statistical analysis and data management
to analysis summary. Statistical analysis report was provided after completion
of data analysis. Interim analysis was not done in the study.
Statistical analysis: use SAS 9.1 statistic analysis software for calculation.
All statistical tests used double-sided tests, and the tested difference was
considered of statistical significance when P-value≤0.05.
Measurement data of each visit in the two groups would apply sample size,
mean, standard deviation, median, maximum and minimum for statistical
description. Comparison of differences before and after within group
would be carried out with paired t-test. Changes of the two groups prior
and post treatment would use t-test and Wilcoxon rank-sum test for
comparison between groups.
Numeration data of each visit in different groups would use frequency
(constituent ratio) for descriptive statistics. Comparison between two
groups would be carried out with χ2 test or Fisher’s exact test.
Main contents of statistical analysis:
·Efficacy analysis:
The rate of disappearance between two groups used χ2 test. Multicenter
effect analysis used Cochran-Mantel-Haenszel χ2 test. The differences of
vagina health score between two groups were compared by Wilcoxon
rank-sum test.
·Safety analysis
Comparison for incidence of adverse events between two groups used χ2 test
and all adverse events occur in the study were described in a table.
Normal/abnormal changes of laboratory examination results before and after
study and relationship to the study products.
Results
and
conclusions
The study was a multicenter, randomized, open, positive and parallel
controlled clinical trial, to evaluate the efficacy and safety of Hyaluronic
acid vaginal gel (Hyalofemme) for improvement of vaginal dryness. The
results showed that applying Hyaluronic acid vaginal gel and Estriol cream
in test group and control group according to the protocol, could
remarkably improve the clinical symptoms of vaginal dryness. The final
(after administration for 10 times) improvement rate were 84.44% and
89.42%, respectively, without significant statistical differences between
them (P＞0.05). Mean of rate difference was -3.33% and 95%CI was [-9.40,
2.74], the lower limit of which did not exceed the boundary value of
non-inferiority evaluation (15%). Thus we could think that the efficacy of
the Hyaluronic acid vaginal gel is not inferior to that of Estriol cream, with
no significant difference between them. At the first visit, the improvement
rate of vaginal dryness in Hyaluronic acid vaginal gel group and Estriol
cream group were 49.17% and 53.53%, and had no statistical significant
differences. That meant the two products had a short onset time and they
could release the clinical symptoms of vaginal dryness after three times of
administration of the products. That the improvement rate on first visit was
lower than that on final visit showed the continuous release effect on the
symptoms as time of medication increased. The final improvement rate of
the secondary efficacy endpoints (itching, dyspareunia and burning
sensation) in Hyaluronic acid vaginal gel group and Estriol cream group
were 86.23% and 81.97%, 56.96% and 62.33%, 85.83% and 87.87%,
respectively. The differences between the two groups had no statistical
significance (P>0.05), and FAS results were in line with PPS. See Table 4.1.1
~ Table 4.2.3.
Totally 13 adverse events occurred throughout the clinical study, seven in
the test group (incidence: 9.7%, 7/72) and six in the control group
(incidence: 8.3%, 6/72). The differences between the two groups had no
statistical significance (P>0.05). No serious adverse event occurred, and the
AE that were related to the test product or suspicious were in mild level.
See Table 5.1 and Table 6.
No changes of vaginal micro-ecological environment appeared after
treatment in 80.6% (54/67) of subjects in Hyaluronic acid vaginal gel group,
while 77.27% (51/66) in Estriol cream group. It indicated that applying
Hyaluronic acid vaginal gel would not alter the internal environment of
vagina and it was able to maintain the homeostasis, with a high safety. See
Table 5.2.
Mean of vaginal PH value in Hyaluronic acid vaginal gel group was 5.63
prior to treatment and 5.30 after treatment, with no statistical difference.
Vaginal PH value after treatment (5.30) in Hyaluronic acid vaginal gel was
higher than that in Estriol cream group and the difference between them
had statistical significance (P＜0.05). It suggested that the hyaluronic acid
vaginal gel was not as good as the estriol cream on reducing vaginal PH
value. It was mainly because the estrin in the estriol cream could help the
growth of lactobacilli in vagina, promoting lactose broken down into lactic
acid, to reduce PH value. While the hyaluronic acid vaginal gel had no
pharmacological effect. Its biological effect was acted through Hydeal-D®,
the derivative of hyaluronic acid, without mechanism to reduce PH value.
See Table 5.3.
The endometrial thickness prior to treatment in test group and control
group were 3.19mm and 3.21mm, respectively. While 3.43mm and 3.52mm
after treatment. The difference between the two group had no statistical
difference (P＞0.05). However, the endometrial thickness of the No. 003
subject (applying estriol cream) in Peking University First Hospital
increased from 3mm to 9mm. On follow-up after drug withdrawal, the
endometrial thickness of the subject reduced gradually and the symptoms
were relieved. It indicated that estriol cream had influence on the
endometrial thickness. The doctors should apply it strictly in accordance
with the indications. Because of its narrow applicability, the doctors should
be cautious when using it. The hyaluronic acid vaginal gel did not have
hormonelike effect, thus it had no influence on endometrium or
hormones-endocrine system and had a high safety. See Table 5.4.
Hyaluronic acid vaginal gel (Hyalofemme), a colorless gel with high
hydrating properties, is manufactured by Fidia Advanced Biopolymers, srl,
Italy and has been marketed in numerous foreign countries for years.
Hyaluronic acid is a natural molecule that can maintain a right level of
hydration and plays an important role in tissue repair. The product has no
pharmacological effect for it is not a drug but a type Ⅲ medical device. The
gel’s hydrating properties are attributed to the characteristics of the
hyaluronic acid based biopolymer which releases water molecules to the
tissue, thus improving the dry state of the vagina without any irritation of
vaginal mucosa. Therefore, the gel is applicable to supplementary
treatment of vaginal dryness symptoms induced by any reason. Compared
with estriol cream, hyaluronic acid vaginal gel has the characteristics of
wider applicable range, no hormonelike effect, higher safety and better
acceptability of patients.
The clinical trial showed that the hyaluronic acid vaginal gel played a part
in repair of vaginal epithelial cells. It could improve the epithelium
condition, making the subjects feel better after application. The mechanism
need further study.
Though the results would be inevitably influenced by the investigator
because of the open-label trial, they still had reference value. The certain
evaluation of the efficacy and safety of hyaluronic acid vaginal gel
depended on further blind trial.
To sum up, the hydration and adhesion of hyaluronic acid vaginal gel can
improve vaginal dryness throughout the spontaneous recovery of small
lesions that caused by friction of vagina. Therefore, the gel is applicable to
supplementary treatment of vaginal dryness symptoms induced by any
reason.
Study General Information
Clinical study responsible center: Peking University First Hospital
Address: No.8, Xishiku Avenue, Xicheng District,
Postcode: 100034
Beijing
Email: [email protected]
Investigator: Professor Liao Qinping
Tel.:010-85299246
Study center: Peking University Third Hospital
Address: No.49, Huayuanbei Road, Haidian District,
Postcode: 100083
Beijing
Email: [email protected]
Investigator: Professor Geng Li
Tel.: 010-62017691
Study center: Beijing Chao-Yang Hospital Attached to Capital Medical
University
Address: No.8, Baijiazhuang, Chaoyang District,
Postcode: 100020
Beijing
Email: [email protected]
Investigator: Professor Song Xuehong
Tel.:010-85231715
Study center: Beijing Shijitan Hospital
Address: No.10, Yangfangdian Tie Hospital Road,
Postcode: 100038
Haidian District, Beijing
Email:[email protected]
Investigator: Professor Li Hongxia
Tel.: 010-63926375
Statistic Department: Institute of Basic Medical Sciences Chinese Academy of
Medical Sciences
Address: No.1, Wangfujing Shuaifuyuan, Dongcheng
Postcode: 100730
District, Beijing
Email: [email protected]
Principal: Professor Han Shaomei
Tel.:010-65296408
Report for serious adverse events
Department: Ethics Committee of Peking University
First Hospital
Contact person: Zhao Xia
Address:No.6,Dahongluochang Street, Xicheng
District, Beijing
Postcode: 200025
Email:
Tel.:010-66119025
Sponsor: Zhaoke Pharmaceutical (Hefei) Co., Ltd.
Address: New and High-tech Industrial Development Zone, No.669,
Changjiangxi Road, Hefei, Anhui Province
Project leader: Jiang Su
010-65262690-801/13901063831
Monitor: Jiang Su, Yu Jinhuan
Email: [email protected]
Tel.: 010-65262690-804/ 13911909335
Fax: 010-65262290
Hyaluronic acid vaginal gel (Hyalofemme)
Clinical Study Final Report
1 Clinical general information
The vaginal mucosa tunica consists of a non cornified, stratified squamous
epithelium rich in glycogen and of basal lamina rich in elastic fibers.
The characteristics of the vaginal epithelium change depending on the
variations in the concentration of estrogenic and progestational hormones in
which women undergo during their life span. During the fertile period it is
stratified squamous epithelium and rich in glycogen, moistening and elastic,
while during menopause, due to a decrease in estrogenic hormones, the
epithelium atrophies. The cells residing in the intermediate levels of the
stratified squamous epithelium are mainly involved in this process thus
leading to thinning of the vaginal mucosa. The number of stratification
diminishes and only basal and parabasal cells, which however are dystrophic
and flake easily leaving the chorion unprotected, remain. The vagina mucosa
in these conditions is more susceptible directly to germs and is more
permeable to their toxic metabolic products. As a consequence, it is not
unusual to observe small lacerations that may easily become infected.
The vagina is soft and elastic during the fertile period due to the balance
mechanism of the vaginal epithelium that maintains the appropriate
hydration and lubrication. During some situations, such as post partum,
lactation and menopause, oral contraceptives or stress, the balance may be
disturbed. In all of these situations, signs of vaginal dryness, burning
sensation or itching may be observed. Because of the insufficient vaginal
lubrication, the epithelium is injured thus leading to symptoms of vaginal
dryness, burning sensation, dyspareunia and itching. The physiological
lubricating film that characterizes the fertile period of a woman’s life plays an
important role in maintaining the integrity of the vaginal mucosa. This film is
no longer present during menopause thus leading to fragility of the vagina
mucosa.
The therapeutic resolutions in these situations are represented by topically
applied products that produce a hydrating effect to the vagina mucosa and
help to regain elasticity and softness. Hyaluronic acid vaginal gel
(Hyalofemme) is a colorless gel with high hydrating properties. The gel
contains Hydeal-D®, a derivative of hyaluronic acid, which maintains the
biocompatibility and interactivity of hyaluronic acid, and also adequate
hydration of mucosa. Topical administration of the gel has a good
adhesiveness to the vaginal mucosa and long acting hydration thus
improving the dry state of the vagina. It also improves the spontaneous
recovery of small lesions that caused by friction of vagina.
Hyaluronic acid vaginal gel (Hyalofemme), a colorless gel with high
hydrating properties, is manufactured by Fidia Advanced Biopolymers, srl,
Italy and has been marketed in Italy for years. Hyaluronic acid is a natural
molecule that can maintain a right level of hydration and plays an important
role in tissue repair. The product has no pharmacological effect for it is not a
drug but a type Ⅲ medical device. The gel’s hydrating properties are
attributed to the characteristics of the Hydeal-D® which releases water
molecules to the tissue, thus improving the dry state of the vagina. Therefore,
the gel is applicable to supplementary treatment of vaginal dryness
symptoms induced by any reason【1】.
The vaginal ecosystem is composed of a complex microflora, constituted of
different microorganisms. The presence of these microorganisms is subject to
qualitative and quantitative modifications some of which can result in
pathological conditions. Thus it is of utmost importance to understand the
influence of Hyalofemme gel in vaginal ecosystem. However, due to the
extreme complexity of the factors which influence this ecosystem, there is no
single theory capable of explaining the mechanisms which govern the
colonization and the homeostasis of this organ【1】.
The hormone dependent dynamic nature of the vaginal physiology has been
demonstrated. The hormonal state of the subject determines directly or
indirectly the qualitative and quantitative variations of the vaginal microbial
components, mainly influencing the lactobacilli.
This microorganism is responsible for the vaginal homeostasis by:
·producing lactic acid which maintains an acidic vaginal ambient,
·competing for bacterial adherence,
·producing hydrogen peroxide,
·producing bacteriocins,
·stimulating the local immune system.
For these reasons the vaginal homeostasis is assessed through vagina PH and
vaginal smears (variations of the vaginal microbial components), so as to
evaluate the influence of Hyalofemme gel on vaginal ecosystem and the
safety.
144 subjects were enrolled in the clinical study to evaluate the efficacy and
safety of Hyaluronic acid vaginal gel (Hyalofemme) for improvement of
vaginal dryness. Peking University First Hospital: 36 subjects, Peking
University Third Hospital: 40 subjects, Beijing Chao-Yang Hospital Attached
to Capital Medical University: 32 subjects and Beijing Shijitan Hospital: 36
subjects.
Selection criteria of subjects:
1.1 Inclusion criteria
⑴ Women under 70 years old, with natural menopause or surgery-induced
menopause for more than 6 months;
⑵ Patients with vaginal dryness symptoms induced by various reasons;
⑶ Patients without contraindications of local application with estrogen;
⑷ Patients with good compliance who are voluntary to written informed
consent.
1.2 Exclusion criteria
⑴ Unmarried women;
⑵ Women during pregnancy and lactation;
⑶ Patients who are allergic to hyaluronic acid gel;
⑷ Patients using other topically applied vaginal products within one week
⑸ Patients with vaginal infections such as trichomonas, candida infection
and bacterial vaginosis;
⑹ Patients with breast cancer, uterine cancer and estrogen hormone
dependent tumors, genital bleeding of unknown origin; and patients with
acute hepatopathy, embolic disorders, severe primary disease of kidney and
hematopoietic system and malignant tumor recently;
⑺ Patients using estrogens within one month;
⑻ Patients who are attending or have attended other clinical trials within 2
weeks;
⑼ Patients with mental disorder and no insight, who are unable to express
themselves exactly;
⑽ Patients who do not give informed consent;
⑾ Patients who is not suitable to participate in the clinical trial for it may
aggravate patients’ condition in the investigator’s opinion.
1.3 Withdrawal criteria
⑴ All subjects, meeting inclusion criteria and signing informed consent
forms, who have been randomized and received study products, but do not
complete observation period as the protocol stated;
⑵ Protocol violation;
⑶ Patient who is unwilling to continue the study and requests to drop out
⑷ Patient with poor compliance and unable to adhere to treatment though
he/she does not request to drop out;
⑸ A severe infection or allergic response occurs thus not able to continue
application of the study product;
⑹ A serious adverse event or a serious adverse reaction occurs thus the
investigator believes that drop-out is best for the subject;
Patient, who drops out because of adverse event, should be recorded and the
investigator should inform the monitor;
⑺ Severe complications occurs to the patient during the study, unsuitable
to continue;
⑻ Patient’s condition gets worse and needs emergency treatments.
1.4 Elimination criteria
⑴ Patients do not meet selection of study population, including inclusion
criteria and exclusion criteria.
⑵ Patients using other medications that can promote lesion healing
⑶ Patients, who have been randomized, haven’t received any treatment.
1.5 Withdrawal procedures
Patient can drop out of the study freely at any time, without any influence on
the following treatment and follow-up visit. The investigator should ask the
patient about the drop-out reason and whether any AE occurs. If possible, the
last follow-up visit should be completed. The patient should receive the
laboratory examinations and the investigator should complete AE record and
follow up the adverse event.
2 Clinical trial method (including setup of control group
if necessary)
There were no similar products that treat vaginal dryness in China, thus
according to suggestion of the investigators (choosing the product with
definite efficacy verified to sell in China’s market by SFDA), estriol cream
(Ovestin) was used as control article.
Because the packages, size and dosage of hyaluronic acid vaginal gel and
Ovestin were not identical, blinding method was not suitable and the study
would be a multicenter, randomized, open, positive and parallel controlled
study. Subjects received hyaluronic acid vaginal gel（Hyalofemme）or Ovestin
for evaluation of efficacy and safety of Hyaluronic acid vaginal gel
(Hyalofemme) for improvement of vaginal dryness【2】.
144 patients with symptoms of vaginal dryness were anticipated to be
included in the study. There were four study centers, 36 cases in each center
while the case number could be regulated on the basis of enrolling conditions.
Using hyaluronic acid vaginal gel（Hyalofemme）or Ovestin should be
randomized.
2.1 Randomization: the trial used segmented balance randomization. Subjects
were randomized to test group and control group in a ratio of 1:1. The
random allocation form was produced through SAS program by the staff of
Institute of Basic Medical Sciences Chinese Academy of Medical Sciences and
at the same time the sealed random envelopes of corresponding sequence
【 】
numbers were created 4 .
2.2 Study control: the trial applied positive control, Ovestin as control group.
2.3 Study products: provided by Zhaoke Pharmaceutical (Hefei) Co., Ltd.
2.3.1 Test group: Name: Hyaluronic acid vaginal gel (Hyalofemme)
Size: 30g/aluminum tube
Product standard: registered standard
Manufacture batch no.:017000
Expiry date: to June, 2010
Manufacturer: Italy FIDIA FARMACEUTICI S.P.A.
Instructions
1. Revolve the vaginal applicator into the tube.
2. Squeeze the tube to fill the applicator to half of it (about 5g).
3. Release the applicator from the tube and plug it in patient’s
vagina. The patient should keep crouching or lying position.
4. Impel the applicator until all of the gel is discharged.
5. Clean the applicator after administration. Wash out the
remaining gel with water and disinfectants, then rinsing it
thoroughly. Finally remove the water from the applicator.
6. Put the applicator into the box for use next time.
7. In case of severe dryness, it is suggested that eject a little gel so as
to make enough lubricating before plugging the applicator into
vagina.
Application frequency
Application frequency depends on the dry state of the vaginal mucosa.
Patients in the study applied the gel every 3 days, totally 10 times
continuously except other prescription.
2.3.2 Control group: Name: Estriol cream (Ovestin cream)
Size: 15mg/15g/vial
Product standard: registered standard
Manufacture batch no.:661514
Expiry date: to August, 2011
Manufacturer: provided by Zhaoke Pharmaceutical
(Hefei) Company Limited and manufactured
by Organon (Ireland) Ltd.
Patients in the study applied 0.5g of the cream every 3 days, totally 10 times
continuously except other prescription.
2.4 Packaging of study products
Test products and control products were packaged respectively in large white
boxes. On the boxes should be marked the name of the products, quantity,
usage, site number, storage condition, expiry date, sponsor and ‘For Clinical
Verification’.
2.5 Dispensation of study products
Registration: All products of each site were stored in one place and
managed by a specially-assigned person. The dispensation and reclaiming
should be registered.
Sequence: Random envelope numbers of Peking University First Hospital
were 001-036, Peking University Third Hospital 037-072 and Beijing
Chaoyang Hospital Attached to Capital Medical Hospital 073-108, Beijing
Shijitan Hospital 109-144. 145-192 were reserved random envelope
numbers.
Dispensation: The investigator opened the corresponding random
envelopes from small number to large number according to the sequence of
each patient’s visit, confirming the subject received hyaluronic acid vaginal
gel (Hyalofemme) or Ovestin cream on the basis of the content. The random
envelope number was the unique number of the subject.
The product should be given to each subject according to her sequence and
random envelope content, and should not be chosen. The subject serial
number remained unchanged during the study. The investigator should fill
in the Drug Dispensation Form exactly in time and write down related
records on the envelope (signature and date). If the patient lost the product,
she could get new product from the investigator. The investigator should
check the product to ensure it was the same as that of patient’s random
number. And should record the reason, quantity and date, then sign his
name in the dispensation form.
Storage: The study products were conducted unified preservation,
management and distribution by each center. The products should be
stored in the shade place.
Remaining Products: The products remaining in case of patients not using
them on time, dropping out midway and not using up or the treatment
protocol changing, the products should be reclaimed and recorded in
detail.
2.6 Concomitant therapy
In order to eliminate any affect of other drugs, all subjects were not allowed
to apply other drugs or products that may improve the dry state of vagina,
or Chinese patent medicines and drugs for external use with similar
efficiency.
Subject, who met inclusion criteria but need continued medication for other
diseases during the study or addition of other drugs or therapies, should be
recorded on the CRF (name of the drugs or therapies, dosage, application
frequency and time, etc.)
2.7 Study procedures
144 patients with vaginal dryness were anticipated to be treated in the study.
2.7.1 Screening: patients, who met inclusion criteria but did not accord with
exclusion criteria, become subjects after they gave informed consent. Then
they were randomized into treatment group according to the random
envelope.
2.7.2 Treatment period Day 0: after the selection of qualified patient, the
investigator recorded subject’s demographic information and medical history.
Physical examinations should be done and subject’s evaluation of vaginal
dryness and other symptoms (itching, dyspareunia and burning) by visual
analogue scale (VAS) should be recorded. The vaginal microecosystem
laboratory examinations were evaluated by taking a vaginal smear (the
method is attached below) and measuring the PH (measuring method is
attached below), and the endometrial thickness was measured by vaginal B
ultrasound. The administration of test group and control group were identical.
The investigator dispensed the study products and filled in the dispensation
form.
2.7.3 First visit (visit by phone): the investigator should telephone the
subjects between the 3rd and the 4th administration, and should record the
evaluation of vaginal dryness and other symptoms.
2.7.4 Final visit: the subjects should come to the study centers for the final
visit on the 3±1st day after the 10th administration. The investigator should ask
the subjects to have physical examinations (weight, breath, heart rate, pulse
and blood pressure), vaginal microecosystem laboratory examinations, PH
value and endometrial thickness measured by vaginal B ultrasound. Subjects
should give the evaluation of their symptoms.
Measuring method of vaginal PH value:
The PH was measured using strips of “accurate PH indicators〞(produced by
Merck &Co., Inc., Germany), the range of PH was from 2.0 to 9.0, with
intervals of 0.5 units. It should be used within expiry date and stored in dry
and dark place. The patient took lithotomy position and the investigator got
some secretions from the 1/3 part of vaginal lateral wall after having exposed
the zone with one-off vaginal dilator. The PH value was obtained by
confronting the color of the strip, after the secretions touching it for 5 seconds,
with the given color scale.
The vaginal smear:
The vaginal smear was taken from the posterior fornix of the vagina. The
microscope slide was then fixed with heat and colored using the Gram
method and then observed with an optimal microscope. The following
observations were made: intensity and variety of vaginal bacterial flora and
predominant bacteria.
Throughout the study the investigator should record adverse events and
concomitant therapy.
Study schedule
Items
Periods
Screening
First visit
Final visit
Treatment
（by phone）
（on-site）
Day 0
between the 3rd and
the 3±1st day after the
the
Informed consent
×
Inclusion/Exclusion Criteria
×
4th
administration
10th administration
Demographic information and
×
medical history
Physical examinations
×
*Evaluation of vaginal symptoms
×
Vaginal PH value
×
×
×
×
Endometrial thickness
×
×
Dispensation of study products
×
×
×
×
* Vaginal microecosystem
laboratory examinations
Reclaiming of study products
×
Concomitant therapy
×
×
×
Adverse reaction/event
×
×
×
*The disappearance rate of vaginal symptoms included that of dryness,
itching, dyspareunia and burning.
* Vaginal microecosystem laboratory examinations included intensity and
variety of vaginal bacterial flora and predominant bacteria.
2.8 Safety evaluation
2.8.1 Physical examinations
Routine examinations of weight, temperature, breath, blood pressure and
pulse.
2.8.2 Vaginal microecosystem laboratory examinations
To evaluate whether the vaginal bacterial flora was normal by the results of
intensity and variety of vaginal bacterial flora and predominant bacteria.
Standard of vaginal microecosystem laboratory examinations:
The intensity grading standard of vaginal bacterial flora includes 4 grades,
with oil immersion lens (10×100 amplification). Grade 1 (marked ‘+’): average
bacterial number 1-9 per visual field, about 105～6/ml bacteria in the sample;
grade 2 (++): average bacterial number 10-99 per visual field, about 107～8/ml
bacteria in the sample; grade 3 (+++): average bacterial number, more than
100, the visual field is full of bacteria, about 109~10/ml bacteria in the sample;
grade 4 (++++): the bacteria aggregate or cover the epithelium, more than
1010/ml bacteria in the sample.
The variety of vaginal bacterial flora includes 4 grades: grade 1(marked ‘+’):
1-3 kinds of bacteria are distinguished; grade 2(++): 4-6 kinds of bacteria are
distinguished; grade 3 (+++):7-10 kinds of bacteria are distinguished; grade 4
(++++): more than 11 kinds of bacteria are distinguished.
Definition of normal value of vaginal microecosystem laboratory
examinations: intensity (grade 2-3), variety (grade 2-3) and the predominant
bacteria (Large Gram positive bacillus, G+b(L)).
2.8.3 Vaginal PH value
2.8.4 Examination of endometrial thickness
2.8.5 Incidence of adverse events
2.9 Statistical analysis: The statistical analysis applied SAS 9.1 statistic
analysis software for calculation. All statistical tests used double-sided tests,
and the tested difference was considered of statistical significance when
P-value≤0.05.
3 Statistical method and evaluation method
3.1 Selection of statistical analysis data
3.1.1 Full Analysis Set (FAS)
According to ITT, eliminate the subject with the minimal and reasonable
method. This data set includes all patients except who never used the study
products or who had no efficacy data. The missing data of primary endpoint
should apply last observation carry forward (LOCF).
3.1.2 Per-Protocol Set (PPS)
Composed of all patients who conformed to the protocol and the following
terms:
·patients with compliance of 80%-120%
·patients do not use the forbidden medication during the study
·patients who match all inclusion criteria with none of exclusion criteria
·patients in whom there are serious violations to the protocol.
3.1.3 Safety Analysis Set (SAS)
Composed of all subjects who received the treatment at least once and whose
safety information were collected.
3.2 Statistical analysis plan
The statistical analysis applied SAS 9.1 statistic analysis software for
calculation.
All statistical tests used double-sided tests, and the tested difference was
considered of statistical significance when P-value≤0.05.
Measurement data of each visit in the two groups applied sample size,
mean, standard deviation, median, maximum and minimum for statistical
description. Comparison of differences before and after within group were
carried out with paired t-test. Changes of the two groups prior and post
treatment used t-test and Wilcoxon rank-sum test for comparison between
groups.
Numeration data of each visit in different groups used frequency
(constituent ratio) for descriptive statistics. Comparison between two
groups was carried out with χ2 test or Fisher’s exact test.
4 Clinical evaluation standards
4.1 Efficacy evaluation【5、6】
4.1.1 Primary efficacy variable: percentage of improvement of vaginal
dryness symptoms
Before receiving treatment, after the 3rd and the 10th administration, the
patient should give the evaluation of the vaginal dryness with visual
analogue scale (VAS, 0-10, 0= absent, 10= intolerable). The patient should
report her subjective perception truly and independently.
Scoring method:
0___________________________10
Absent
intolerable
Computing method:
Percentage of improvement of
vaginal dryness symptoms
Mean score after treatment —Mean score before treatment
= ---------------------------------------------------------- ×100%
Mean score before treatment
4.1.2 Secondary efficacy variable: percentage of other vaginal symptoms
Before receiving treatment, after the 3rd and the 10th administration, the
patient should give the evaluation of itching, dyspareunia and burning
sensation with visual analogue scale (VAS, 0-10, 0= absent, 10= intolerable).
The patient should report her subjective perception truly and independently.
4.2 Safety evaluation
4.2.1 Physical examinations: recorded subject’s general conditions including
weight, temperature, breath, blood pressure and pulse.
4.2.2 Laboratory examinations of vaginal microecosystem: did the
examinations before and after treatment. To evaluate whether the vaginal
bacterial flora was normal by the results of intensity and variety of vaginal
bacterial flora and predominant bacteria.
4.2.3 Vaginal PH value: measured before and after treatment.
4.2.4 Examination of endometrial thickness: through vaginal B ultrasound
before and after treatment, the increased endometrial thickness ＜5mm.
4.2.5 Incidence of adverse event: regardless of whether the subjects were
voluntary, the investigator should collect and record all adverse events
observed by physical examinations or other methods. Then the investigator
should assess the relationship between the adverse events and the products.
In case of serious adverse event the investigator should take emergency
measures and report it, recording it in CRF.
5 Clinical trial results
5.1 Allocation, dropout and elimination of subjects
144 subjects were planned to enroll in the clinical trial (36 subjects for each
center). In fact, 144 subjects participated in the study and 4 cases were
transferred from Beijing Chao-Yang Hospital Attached to Capital Medical
University to Peking University Third Hospital. There were 11 subjects
dropping out of the study (dropout rate 7.6%, lower than 20%). Five subjects
in Group A and six subjects in Group B dropped out. Four subjects among
them dropped out because of AE and four subjects for lost of follow-up. Two
subjects required to quit the study and one dropped out because of too long
suspension of administration. On the basis of completion and dropout
distribution analysis, the study data could be considered reliable and the
difference of dropout rate between the two groups had no statistical
significance. Statistical results were the followings (Table 1.1, Table 1.2, Table
1.3)
Group A: Hyaluronic acid vaginal gel (Hyalofemme);
Group B: Estriol cream (Ovestin cream)
Table 1.1 Subject distribution of each center
Group A
Cent
er
Enrolled
FAS
PPS
Group B
SS
Dropout/
Enrolled
FAS
PPS
Total
SS
Elimination
Dropout/
Enrolled
FAS
PPS
SS
Elimination
Dropout/
Elimination
1
18
18
16
18
2
18
18
18
18
0
36
36
34
36
2
2
20
20
20
20
0
20
20
17
20
3
40
40
37
40
3
3
16
16
15
16
1
16
16
15
16
1
32
32
30
32
2
4
18
18
16
18
2
18
18
16
18
2
36
36
32
36
4
Total
72
72
67
72
5
72
72
66
72
6
144
144
133
144
11
* Center 1: Peking University First Hospital
Center 2: Peking University Third Hospital
Center 3: Beijing Chao-Yang Hospital Attached to Capital Medical University
Center 4: Beijing Shijitan Hospital
Table 1.2 Dropout/Elimination analysis
Group
Completion
N
Dropout/Elimination
％
N
％
χ2
P
0.0984
0.7537
Total
Group A
Group B
67
66
93.1
91.7
5
6
6.9
8.3
72
72
Total
133
92.4
11
7.6
144
*χ2 test.
Enrollment
number:
144,
qualified
completion
number:
dropout/elimination number: 11 and dropout/elimination rate: 7.6%.
133,
Table 1.3 List of the subjects unqualified to enter PPS
Center
No.
Name
Group
1
1
2
2
2
3
3
4
16
29
43
55
67
89
104
116
LSJU
LYLI
SDME
ZXLA
ZHYA
LSRO
ZRHU
XXYU
A
A
B
B
B
A
B
A
4
117
YXLI
B
Dropout/discontinuation
reason
Discontinuation
time
Lost to follow-up
First visit
Lost to follow-up
Final visit
Subject asked to quit
Final visit
AE
Final visit
AE
Final visit
Lost to follow-up
Final visit
AE
Final visit
Lost to follow-up
Final visit
The patient gave informed consent on
Jan.22 and discontinued administration for
business trip. Then restarted receiving
administration on Feb.11.
FAS
PPS
SS
√
√
√
√
√
√
√
√
√
×
×
×
×
×
×
×
×
×
√
√
√
√
√
√
√
√
√
4
4
140
144
AIYA
ZPKU
B
A
Subject asked to quit
AE
Final visit
Final visit
√
√
×
×
5.2 Baseline information and comparability analysis
Statistical analysis of baseline data prior to the study showed no statistical
difference on every parameter between the two groups (age, nationality,
weight, systolic pressure, diastolic pressure, body temperature, pulse, breath,
menstrual cycle, menopause time and way, diagnosis and treatment history of
gynecologic disease)(P＞0.05). Based on the statistical analysis of vaginal
microecology laboratory examinations, vaginal PH value, endometrial
thickness prior to treatment, each parameter between the two groups on
baseline had no statistical difference (P＞0.05). There were no statistical
differences of vital signs (weight, body temperature, breath, systolic pressure,
diastolic pressure and heart rate) before and after administration (P＞0.05).
The followings are statistical results (Table 2.1, Table 2.2)
Table 2.1 Demographics of the subjects
---------------------------------------------------------------------------------------------------------------------Indexes
Statistics
Group A
Group B
Statistics p-value
---------------------------------------------------------------------------------------------------------------------Nationality
n (missing)
72 (0)
72 (0)
Fisher 1.0000
The Han People
71 (98.6%)
72 (100.0%)
The minority groups 1 (1.4%)
0 (0.0%)
Age
(years old)
n (missing)
Mean±SD
Median
Q1; Q3
Min; Max
72 (0)
54.05 ±4.27
54.07
51.75 ;55.79
39.39; 65.71
72 (0)
-0.4860
54.41 ±4.60
54.22
52.14 ;56.75
44.49; 67.61
0.6277
Systolic pressure n (missing)
mmHg
Mean±SD
Median
Q1; Q3
Min; Max
72 (0)
72 (0)
-0.0926
118.14 ±12.59 118.35 ±14.36
120.00
120.00
110.00; 120.00 110.00 ;124.00
90.00; 150.00 90.00; 160.00
0.9264
Diastolic pressure n (missing)
mmHg
Mean±SD
Median
Q1; Q3
Min; Max
72 (0)
77.33 ±7.64
80.00
70.00; 80.00
60.00; 98.00
0.3870
72 (0)
0.8678
76.19 ±8.11
79.00
70.00; 80.00
60.00; 100.00
√
√
Heart rate
n (missing)
Times/min Mean±SD
Median
Q1; Q3
Min; Max
72 (0)
75.86 ±7.45
76.00
72.00; 80.00
52.00; 88.00
72 (0)
-0.4160
76.40 ±8.16
79.00
70.00; 82.50
56.00; 90.00
n (missing)
Mean±SD
Median
Q1; Q3
Min; Max
72 (0)
36.34 ±0.17
36.30
36.20; 36.50
35.80; 36.70
72 (0)
0.4331
36.33 ±0.18
36.30
36.20; 36.50
35.80; 36.80
0.6656
Breath
n (missing)
Times/min Mean±SD
Median
Q1; Q3
Min; Max
72 (0)
20.90 ±4.52
20.00
18.00; 26.00
14.00; 28.00
72 (0)
-0.6183
21.36 ±4.38
20.00
18.00; 25.00
14.00; 30.00
0.5374
Weight
Kg
72 (0)
60.99 ±7.34
60.00
55.00; 65.50
47.00; 82.00
72 (0)
60.61 ±8.66
60.00
55.00; 65.50
41.00; 82.50
0.2854
0.7757
72 (0)
29.01 ±3.05
28.00
28.00; 30.00
23.00; 40.00
72 (0)
28.39 ±3.63
28.00
28.00; 30.00
20.00; 45.00
0.8923
0.3722
71 (1)
4.44 ±3.71
3.50
1.50; 6.67
0.50; 19.67
72 (0)
5.58 ±5.45
4.08
2.13; 7.00
0.50; 30.92
-1.0824
0.2791
72 (0)
62 (86.1%)
10 (13.9%)
0.055
0.8133
Body
temperature
℃
n (missing)
Mean±SD
Median
Q1; Q3
Min; Max
Menstrual cycle n (missing)
days
Mean±SD
Median
Q1; Q3
Min; Max
Menopause
time
n (missing)
years
Mean±SD
Median
Q1; Q3
Min; Max
Menopause
Way
n (missing)
72 (0)
Natural menopause 61 (84.7%)
Surgical menopause 11 (15.3%)
0.6781
Diagnosis and
n (missing)
treatment history No
of gynecologic
Yes
disease
72 (0)
46 (63.9%)
26 (36.1%)
72 (0)
52 (72.2%)
20 (27.8%)
1.152
0.2830
Note: 1. Q1: 25% quantile, 2. Q3: 75% quantile, 3. comparison of classification indexes
used χ2 test and χ2 were statistics, 4. Group comparison of quantitative indexes used
t-test and t was statistic, 5. Comparison of menstrual cycle and menopause time used
Wilcoxon rank sum test and statistic was Z.
Table 2.2 Vaginal microecology laboratory examination on baseline
------------------------------------------------------------------------------Indexes
Statistics
Group A
Group B
Statistics p-value
------------------------------------------------------------------------------Vaginal microecology n (missing)
72 (0)
72 (0)
0.747
0.3873
laboratory
Normal flora
29 (40.3%)
24 (33.3%)
examination
Abnormal flora
Vaginal PH value n (missing)
Mean±SD
Median
Q1; Q3
Min; Max
Endometrial
thickness
mm
n (missing)
Mean±SD
Median
Q1; Q3
Min; Max
43 (59.7%)
48 (66.7%)
72 (0)
71 (1)
0.1223
5.63 ±1.04
5.61 ±0.98
5.50
5.45
5.00; 6.50
5.00; 6.50
3.80; 8.00
3.80; 7.50
62 (10)
3.19 ±1.20
3.00
2.40; 4.00
1.00; 8.30
62 (10)
3.21 ±1.80
3.00
2.10; 4.00
1.00; 12.00
-0.0704
0.9028
0.9440
------------------------------------------------------------------------------Note: 1. Q1: 25% quantile, 2. Q3: 75% quantile, 3. comparison of classification indexes
used χ2 test and χ2 were statistics, 4. Group comparison of quantitative indexes used
t-test and t was statistic.
5.3 Analysis of concomitant medications
Several concomitant medications were applied in the test group and control
group during the clinical study. They were mainly antihypertensive drugs.
Concomitant medications were appended to nine subjects, two receiving
nutrition and health-care medicine and seven because of AE. According to
statistical analysis, the difference of concomitant medications between the two
groups had no statistical significance (P＞0.05). See Table 3.1 and Table 3.2.
Table 3.1 Comparison of concomitant medications
------------------------------------------------------------------------------Index
Statistic
Group A
Group B
Statistic p-value
------------------------------------------------------------------------------Concomitant
n (missing)
72 (0)
72 (0)
2.118
0.1455
medications
no
59 (81.9%)
65 (90.3%)
yes
13 (18.1%)
7 (9.7%)
-----------------------------------------------------------------------------Note: comparison of concomitant medication rate used χ2 test and statistic was χ2.
Table 3.2 Concomitant medication list
Center Random
No.
Name
Group Medication
Reason
Starting
Date
1
1
LIBI
B
Lotensin
2001
2
2
2
2
2
2
2
37
39
41
42
50
50
54
ZGFA
DXYI
HZHU
YLHO
LXFE
LXFE
ZHJI
B
A
A
B
A
A
A
2
2
55
55
ZXLA
ZXLA
B
B
2
2
55
55
ZXLA
ZXLA
B
B
2
2
2
2
2
2
58
61
62
62
62
62
WZYU
ZJPI
JSLA
JSLA
JSLA
JSLA
A
A
A
A
A
A
Fosinopril
Captopril
Valsartan
Nifedipine
Fosinopril
Nifedipine
Losartan
potassium
Irbesartan
Levothyroxine
sodium
Levofloxacin
Chinese
decoction
Betaloc
Fosinopril
Aspirin
Metoprolol
Amlodipine
Shuanghuanglian
Oral liquid
High blood
pressure
Hypertension
Hypertension
Hypertension
Hypertension
Hypertension
Hypertension
Hypertension
2
62
JSLA
A
2
62
JSLA
A
Ending
Date
20010430
19990901
20081101
19891001
2005
2005
200601
Hypertension 20060330
Hypokalemia 20060330
Cystitis
Cystitis
Hypokalemia
Hypokalemia
Hypokalemia
Hypokalemia
Hypokalemia
Upper
Respiratory
infection
Soluble granules Upper
For cold
Respiratory
infection
Acetylspiramycin Upper
Respiratory
infection
20100108
201002
20100114
20041201
200711
2007
2007
2007
20100218
20100224
20100218
20100224
20100218
20100224
2
2
2
66
67
67
WYLI
ZHYA
ZHYA
B
B
B
2
3
70
80
WSHU
HXLI
A
A
3
4
93
111
CXME
LFLA
A
B
4
111
LFLA
B
4
4
111
111
LFLA
LFLA
B
B
4
113
WCRO
A
4
131
ZHHO
A
4
4
131
142
ZHHO
DJHE
A
A
Levoamlodipine
Metformin
Metronidazole
Suppositories
Fosinopril
Shenshitong
(traditional
Chinese medicine)
Caltrate-D
Bixie Fenqing Wan
Hypertension 2007
Diabetes
Vaginal
201002
itching
Hypertension
Kidney stone 20100101
Osteoporosis
Urinary
infection
Osteoporosis
Alendronate
Sodium Tablets
Calcitriol
Osteoporosis
Valsartan capsules Hypertensive
disease
Yinhua Miyanling Urinary
tablets
infection
Chinese Dragon’s Appendagitis
Blood
Gongyanping
Appendagitis
Sporanox
Mycotic
vaginitis
201003
20100115
20100210
20091223
20091227
20091218
20100117
20091218
20091218
20100117
20100117
20091228
20100104
20100223
20100223
20100331
20100402
5.4 Efficacy analysis
5.4.1 Primary efficacy endpoint: percentage of improvement of vaginal
dryness symptoms
Non-inferiority test was used for primary efficacy endpoint, thus analysis
would apply PPS and the results of FAS were the same as PPS.
Prior to administration, the average VAS scores of vaginal dryness symptoms
were 5.76 in test group and 5.26 in control group. On the first visit, the scores
were 3.01 and 2.55, respectively. On the final visit, the scores were 0.90 and
0.62, respectively. From all the above, both the test group (applying
Hyaluronic acid vaginal gel) and the control group (applying Estriol cream)
could effectively reduce the scores of vaginal dryness symptoms. And as the
administration time prolonged, the symptoms could be almost entirely
relieved and even disappeared.
The primary efficacy endpoint was percentages of improvement of vaginal
dryness symptoms in the two groups. On the first visit, the mean percentages
of vaginal dryness were 49.17% in test group and 53.53% in control group.
While on the final visit, the percentages were 84.44% and 89.42, respectively.
The differences between the two groups had no statistical significance (P＞
0.05).
On the first visit, the mean difference of the percentages between test group
and control group was -3.26% and 95%CI was [-11.23％，4.72％]. On the final
visit, the mean difference of the percentages between test group and control
group was -3.33% and 95%CI was [-9.40％，2.74％]. Though data showed that
the improvement percentages of Estriol cream group were higher than that of
Hyaluronic acid vaginal gel group on the two visits, the 95%CI lower limit of
mean difference did not exceed the 15% non-inferiority margin specified by
protocol design. It proved that the efficacy of Hyaluronic acid vaginal gel was
not inferior to that of Estriol cream. The difference between them had no
clinical significance.
See Table 4.1.1-4.1.4.
Table 4.1.1 Primary efficacy endpoint- improvement rate of vaginal dryness
(PPS)
--------------------------------------------------------------------------------------------------------------------Indexes
Statistics
Group A
Group B
Statistics p-value
--------------------------------------------------------------------------------------------------------------------Vaginal dryness n (missing)
67 (0)
66 (0)
-1.6182 0.1056
Score
Mean±SD
5.76 ±1.88
5.26 ±1.82
Prior to administration
Vaginal dryness n (missing)
67 (0)
66 (0)
-1.6658 0.0957
Score
Mean±SD
3.01 ±1.74
2.55 ±1.82
First visit
Vaginal dryness n (missing)
Score
Mean±SD
Final visit
Vaginal dryness n (missing)
Improvement
Mean±SD
Rate
First visit
67 (0)
0.90 ±1.18
67 (0)
49.17 ±23.90
66 (0)
0.62 ±1.06
66 (0)
53.53 ±27.67
-1.4993
1.0190
0.1338
0.3082
Vaginal dryness n (missing)
67 (0)
66 (0)
1.5093 0.1312
Improvement
Mean±SD
84.44 ±20.60 89.42 ±17.21
Rate
Final visit
------------------------------------------------------------------------------------------------------------------Note: t-test was used for comparison within groups and statistic was t. Wilcoxon test was
used for group comparison and statistic was Z.
Table 4.1.2 Non-inferiority CI of vaginal dryness improvement rate between
the two groups with center effects (PPS)
------------------------------------------------------------------------------Indexes
Statistics
Test group
Control group
------------------------------------------------------------------------------53.54
Change values (First visit-Baseline) 50.29
Standard error
2.82
2.85
95%CI
[44.70, 55.87]
[47.91, 59.17]
-----------------------------------Group comparison
1－2mean difference (95%CI)
-3.26 [-11.23,
Change values (Final visit-Baseline) 85.63
Standard error
2.15
95%CI
[81.38, 89.88]
4.72]
88.96
2.17
[84.67, 93.24]
-----------------------------------Group comparison
1－2 mean difference (95%CI)
-3.33 [ -9.40, 2.74]
Note: 1 the covariance analysis used multi-center effects analysis to control the center
effects and baseline effects. Mean and the 95% CI were modified.
Table 4.1.3 Primary efficacy endpoint- improvement rate of vaginal dryness
(FAS)
---------------------------------------------------------------------------------------------------------------------Indexes
Statistics
Group A
Group B
Statistics p-value
---------------------------------------------------------------------------------------------------------------------Vaginal dryness n (missing)
72 (0)
72 (0)
1.5014
0.1333
Score
Mean±SD
5.71 ±1.89
5.26 ±1.89
Prior to administration
Vaginal dryness n (missing)
72 (0)
72 (0)
1.4837 0.1379
Score
Mean±SD
3.04 ±1.78
2.64 ±1.88
First visit
Vaginal dryness n (missing)
Score
Mean±SD
Final visit
Vaginal dryness n (missing)
Improvement
Mean±SD
Rate
First visit
72 (0)
1.06 ±1.44
72 (0)
48.19 ±25.00
72 (0)
0.86 ±1.45
72 (0)
51.89 ±27.48
1.0926
0.2746
-0.8746
0.3818
Vaginal dryness n (missing)
72 (0)
72 (0)
-1.0146
0.3103
Improvement
Mean±SD
81.36 ±25.30 85.03 ±22.84
Rate
Final visit
---------------------------------------------------------------------------------------------------------------------Note: t-test was used for comparison within groups and statistic was t. Wilcoxon test was
used for group comparison and statistic was Z.
Table 4.1.4 Non-inferiority CI of vaginal dryness improvement rate between
the two groups with center effects (FAS)
---------------------------------------------------------------------------------------------------------------------Indexes
Statistics
Test group
Control group
---------------------------------------------------------------------------------------------------------------------Change values (First visit-Baseline) 49.40
52.03
Standard error
2.76
2.76
95%CI
[43.95, 54.86]
[46.58, 57.49]
------------------------------------------------Group comparison
1－2mean difference (95%CI)
-2.63 [-10.37, 5.11]
Change values (Final visit-Baseline) 82.25
85.21
Standard error
2.71
2.71
95%CI
[76.90, 87.61]
[79.85, 90.56]
--------------------------------------------------Group comparison
1－2mean difference (95%CI)
-2.95 [-10.55, 4.64]
Note: 1 the covariance analysis used multi-center effects analysis to control the center
effects and baseline effects. Mean and the 95% CI were modified.
5.4.2 Secondary efficacy endpoints
Evaluating the secondary efficacy endpoints: improvement rate of vaginal
itching, dyspareunia and burning sensation. On the first visit, improvement
rate of itching were 63.66% in test group and 67.29% in control group; that of
dyspareunia were 24.33% and 26.64%, respectively; improvement rate of
burning sensation were 53.68% and 65.06%, respectively. On the final visit,
improvement rate of itching were 86.23% in test group and 81.97% in control
group; that of dyspareunia were 56.96% and 62.33%, respectively;
improvement rate of burning sensation were 85.83% and 87.87%, respectively.
The differences between the two groups of each secondary endpoints had no
statistical significance (P＞0.05). And the results of FAS were consistent with
that of PPS.
See Table 4.2.1-Table 4.2.3
Table 4.2.1 Secondary efficacy endpoint-improvement rate of vaginal itching
(PPS)
--------------------------------------------------------------------------------------------------------------------Indexes
Statistics
Group A
Group B
Statistics p-value
---------------------------------------------------------------------------------------------------------------------Prior to
n (missing)
67 (0)
66 (0)
0.9546 0.3398
Administration
First visit
n (missing)
Improvement Mean±SD
Rate (%)
Final visit
Rate (%)
n (missing)
Mean±SD
27 (40)
63.66 ±38.25
27 (40)
86.23 ±26.11
35 (31)
67.29 ±37.79
35 (31)
81.97 ±29.05
-0.3713
0.4381
0.7104
0.6613
Table 4.2.2 Secondary efficacy endpoint- improvement rate of dyspareunia
(PPS)
-------------------------------------------------------------------------------------------------------------------Indexes
Statistics
Group A
Group B
Statistics p-value
-------------------------------------------------------------------------------------------------------------------Prior to
n (missing)
64 (3)
64 (2)
1.1380
0.2551
Administration
First visit
n (missing)
Improvement Mean±SD
Rate (%)
56 (11)
24.33 ±31.78
54 (12)
26.64 ±35.62
0.1502
0.8806
Final visit
n (missing)
56 (11)
54 (12)
1.0542
0.2918
Improvement Mean±SD
56.96 ±41.47 62.33 ±43.80
Rate (%)
--------------------------------------------------------------------------------------------------------------------
Table 4.2.3 Secondary efficacy endpoint- improvement rate of burning
sensation (PPS)
-------------------------------------------------------------------------------------------------------------------Indexes
Statistics
Group A
Group B
Statistics p-value
--------------------------------------------------------------------------------------------------------------------Prior to
n (missing)
67 (0)
65 (1)
-1.8758 0.0607
Administration
First visit
n (missing)
Improvement Mean±SD
Rate
48 (19)
53.68 ±35.28
36 (30)
65.06 ±33.71
1.3826
0.1668
Final visit
n (missing)
Improvement Mean±SD
Rate
48 (19)
85.83 ±24.63
36 (30)
87.87 ±36.66
1.6111
0.1072
5.5 Safety analysis
5.5.1 Adverse event
Thirteen adverse events occurred throughout the clinical trial, seven in test
group (9.7%) and six in control group (8.3%).
The difference between the two groups had no statistical significance. See
Table 5.1.
Table 5.1 Comparison of adverse event incidence of the two groups
---------------------------------------------------------------------------------------------------------------------Indexes
Statistics
Group A
Group B
Statistics p-value
---------------------------------------------------------------------------------------------------------------------Adverse events n (missing)
72 (0)
72 (0)
0.084
0.7711
no
65 ( 90.3%)
66 ( 91.7%)
yes
7 (9.7%)
6 (8.3%)
Note: comparison of adverse events used χ2 test and statistic was χ2
5.5.2 Laboratory examinations of vaginal microecosystem
The vaginal microenvironment is a unique dynamic system. It changes
depending on the variations of physiological conditions and local physical
and chemical factors. Large numbers of microflora exist in vagina and
lactobacilli are predominant bacteria. Patients feel uncomfortable if the
predominant bacteria change. The main causes of the changes can be
endogenous and exogenous. Studies showed that menstruation, vaginal
douche, contraceptive agents, vaginal medication, number of sexual partners,
frequency of intercourse, application of sanitary articles during menstrual
period (sanitary towel or tampons) will influence the constitution of vagina
flora[7]. The laboratory examinations of vaginal microecosystem in this clinical
study are to find out and evaluate whether the application of Hyaluronic acid
vaginal gel causes changes of vagina flora and maintains stability of
endovaginal environment.
5.5.2.1 Overall evaluation of vaginal microecosystem
Clinical evaluation system of vaginal microecosystem is to give an overall
evaluation of vaginal microenvironment by describing the intensity, variety of
vaginal flora and predominant bacteria, inflammatory response and causative
bacteria morphology, and considering the functional parameters (vaginal PH
value, H2O2 and leucocyte esterase. In view of limit of the clinical study
design, this study evaluated the vaginal microenvironment mainly by the
intensity, variety of vaginal flora and predominant bacteria.
In the overall evaluation of vaginal microecosystem on the final visit,
29.85% (20/67) of subjects in test group were normal without changes before
and after administration, 50.75% (34/67) abnormal without changes. 8.96%
(6/67) of subjects became abnormal and 10.45% (7/67) became normal. While
in control group, 33.33% (22/66) of subjects were normal without changes
before and after administration, 43.94% (29/66) abnormal without changes.
1.52% (1/66) of subjects became abnormal and 21.21% (14/66) became normal.
From the above data, 80.6% (54/67) of subjects in Hyaluronic acid vaginal gel
group and 77.27% (51/66) in Estriol cream group had no changes on vaginal
microenvironment before and after application. The subjects who became
abnormal in test group were a little more than that in control group (6 vs 1)
while subjects who became normal in control group were a little more than
that in test group (14 vs 7). It suggested that Estriol cream had therapeutical
effect, promoting the synthesis of epithelium glycogen of vaginal mucosa and
the growth of lactobacilli, helping vaginal microenvironment get better. While
Hyaluronic acid vaginal gel did not have therapeutical effect, not changing
the stability of microenvironment though it was not able to make the
microenvironment better.
5.5.2.2 Analysis of intensity, variety of bacterial flora and predominant
bacteria
On the final visit, 71.6% (48/67), 68.7% (46/67) and 80.6% (54/67) of
subjects in test group had no changes in intensity, variety of bacterial flora
and predominant bacteria, respectively (before-after administration). While
71.6% (48/67), 73.1% (49/67) and 76.1% (51/67) of subjects in control group
had no changes in intensity, variety of bacterial flora and predominant
bacteria, respectively (before-after administration). The difference of
laboratory examination of vaginal microenvironment between the two groups
had no statistical significance. It showed that the products of test group and
control group had no influence on the intensity, variety of bacterial flora and
predominant bacteria. From the above data, we could also find more subjects
became normal in control group. It suggested Estriol cream, as a therapeutic
product, can help vaginal microenvironment get better.
See Table 5.2
Table 5.2 Changes of vaginal microenvironment laboratory examination
indexes on Final visit
----------------------------------------------------------------------------------------------------------------------------------------Indexes
Prior to administration →
Test group
Control group
After administration
---------------------------------------------------------------------------------------------------------------------------------------Overall evaluation
n (missing)
67 (5)
66 (6)
20 (29.85%)
22 (33.33%)
normal→abnormal (%)
6 (8.96%)
1 (1.52%)
abnormal→normal (%)
7 (10.45%)
14 (21.21%)
abnormal→abnormal (%)
34 (50.75%)
29 (43.94%)
67 (5)
67 (5)
normal→normal (%)
34 (50.75%)
44 (65.67%)
normal→abnormal (%)
9 (13.43%)
3 (4.48%)
abnormal→normal (%)
10 (14.93%)
16 (23.88%)
abnormal→abnormal (%)
14 (20.90%)
4 (5.97%)
Of microecosystem normal→normal (%)
Intensity of
n (missing)
bacterial flora
Variety of
n (missing)
67 (5)
67 (5)
normal→normal (%)
39 (58.21%)
49 (73.13%)
normal→abnormal (%)
9 (13.43%)
1 (1.49%)
abnormal→normal (%)
12 (17.91%)
17 (25.37%)
abnormal→abnormal (%)
7 (10.45%)
0 (0.00%)
bacterial flora
Predominant bacteria
n (missing)
G+
bacillus→G+
67 (5)
bacillus (%)
21 (31.34%)
67 (5)
23 (34.33%)
G+ bacillus → others (%)
5 (7.46%)
2 (2.99%)
Others→G+ bacillus (%)
8 (11.94%)
14 (20.90%)
Others→others (%)
33 (49.25%)
28 (41.79%)
----------------------------------------------------------------------------------------------------------------------------------------Note: baseline- final visit
5.5.2.3 Typical pictures in vaginal microecosystem examinations
Test group-- Hyaluronic acid vaginal gel group
012
Prior treatment
Normal flora
017
Prior treatment
Abnormal flora
017
Post-treatment
Normal flora
095
Prior
treatment
Normal flora
095
Post-treatment
Abnormal flora
022
Post-treatment
Abnormal flora
022
Prior
treatment
Abnormal flora
012
Post-treatment
Normal flora
Control group-- Estriol cream group
001
Prior treatment
Normal flora
015
Prior treatment
Abnormal flora
027
Prior treatment
Normal flora
009
Prior treatment
Abnormal flora
001
Post-treatment
Normal flora
015
Post-treatment
Normal flora
027
009
Post-treatment
Abnormal flora
Post-treatment
Abnormal flora
5.5.3 Vaginal PH value
Prior to administration, vaginal PH values were 5.63 in test group and 5.61 in
control group. And the difference between the two groups had no statistical
significance (P＞0.05). Vaginal PH values were 5.30 in test group and 4.87 in
control group after administration. The difference between the two groups
had statistical significance (P＜0.05). It proved that Estriol cream could
efficiently reduce vaginal PH value and improve the vaginal health score.
Though application of Hyaluronic acid vaginal gel was not able to reduce
vaginal PH value, it did not affect the PH value, maintaining the stability of
vaginal PH value.
See Table 5.3.
Table 5.3 Comparison of vaginal PH value
---------------------------------------------------------------------------------------------------------------------Indexes
Statistics
Group A
Group B
Statistics p-value
---------------------------------------------------------------------------------------------------------------------Vaginal PH value n (missing)
72 (0)
71 (1)
0.1223
0.9028
Prior to
Mean± SD
5.63 ±1.04
5.61 ±0.98
Administration Median
5.45
5.50
Q1; Q3
5.00; 6.50
5.00; 6.50
Min; Max
3.80; 8.00
3.80; 7.50
Vaginal PH value n (missing)
67 (5)
68 (4)
3.1691
0.0019
Final visit Mean± SD
5.30 ±0.84
4.87 ±0.71
Median
5.40
5.00
Q1; Q3
5.00; 6.00
4.50; 5.00
Min; Max
3.50; 7.00
3.00; 7.00
-------------------------------------------------------------------------------------------------------------------Note: 1. Q1: 25% quantile, 2. Q3: 75% quantile, 3. Group comparison used t-test and t was
statistic.
5.4 Endometrial thickness
Prior to administration, endometrial thickness in test group and control group
were 3.19mm and 3.21mm, respectively. After administration, were 3.43mm
in test group and 3.52mm in control group. The difference between the two
groups had no statistical significance (P＞0.05).
The endometrial thickness of one subject (No. 003) in Peking University First
Hospital, who received Estriol cream, increased to 9mm from 3mm. On
follow-up after drug withdrawal, her endometrial thickness reduced
gradually and became normal finally. It indicated that a part of Estriol cream
could go into blood to cause some influence on endometrium though the
application was topical. Thus doctors should be cautious when using it,
especially for people hypersensitive to estrogen.
See Table 5.4
Table 5.4 Comparison of endometrial thickness
---------------------------------------------------------------------------------------------------------------------Indexes
Statistics
Group A
Group B
Statistics p-value
---------------------------------------------------------------------------------------------------------------------mm
n (missing)
62 (10)
62 (10)
-0.0704
0.9440
Prior to
Mean± SD
3.19 ±1.20
3.21 ±1.80
Administration
mm
n (missing)
57 (15)
59 (13)
-0.2661 0.7907
Final visit
Mean± SD
3.43 ±1.49
3.52 ±1.93
---------------------------------------------------------------------------------------------------------------------Note: Group comparison used t-test and statistic was t.
6 Adverse events and side effects and the treatment
during the clinical trial
Throughout the clinical study, seven adverse events (9.7%) occurred in test
group. Peking University: No.050 subject, whose laboratory examination
result was VVC, of mild grade with no clinical symptoms, received no
relevant treatment and AE have relieved. No.056 subject, whose laboratory
examination result was BV, of mild grade with no clinical symptoms, received
no relevant treatment and AE have relieved. No. 062 subject had upper
respiratory tract infection and relieved after receiving relevant medication.
No. 070 subject, whose laboratory examination result was VVC, of mild grade
with no clinical symptoms, received no relevant treatment and AE have
relieved. Beijing Chaoyang Hospital: No. 073 subject, who had upper
respiratory tract infection of mild grade, did not receive relevant treatment
and AE relieved. Beijing Shijingtan Hospital: No. 142 subject, who had VVC,
relieved after receiving corresponding medication. No. 144 subject, who had
severe mixed prolapse of intestinal mucosa, dropped out of the trial and the
AE existed till the end.
Six adverse events (8.3%) occurred in control group. Peking University First
Hospital: No. 003 subject’s B-ultrasonic examination showed her endometrial
thickness increased to 9mm from 3mm on final visit. She did not receive
relevant treatment because it was mild grade and she finished study. Her
B-ultrasonic examination on follow-up visit showed the endometrial thickness
reduced, so the AE relieved. Peking University Third Hospital: No. 047
subject’s B-ultrasonic examination on final visit showed cysts of left ovary and
right adnexa and she did not receive relevant treatment because the condition
was mild grade and she finished study. The follow-up B-ultrasonic
examination on follow-up showed that the left ovary cyst still existed while
the cyst of right adnexa was relieved. No. 055 subject had cystitis of moderate
degree and received new concomitant medication. But she asked to quit for
frequent fluctuation of the cystitis. The AE existed at the end of the study. No.
064 subject, whose examination result was BV of mild grade with no clinical
symptoms, received no relevant treatment and AE have relieved. No. 067
subject, who had vaginal itching, received concomitant medication. She asked
to quit the study and her symptoms relieved at the end. Beijing Chaoyang
Hospital: No. 104 subject, who had vulva itching, received no relevant
treatment and AE still existed at the end of the study. See Table 6.
No. 2 study centers reported more adverse events (8 subjects, 9 cases of AE)
than other centers. That was because the investigator’s criteria of AE in this
center was stricter than others and he was more careful when asking about
AE.
Table 6 List of adverse events
Center
No.
Name
Group
Description
Start Date
Degree
Influence on
dosage
Relationship
With the drug
Outcome
Date of
relieving
1
3
DILI
B
Endometrial thickness
increased
2009-12-30
Mild
End of study
Probably related
Relieved
2
47
WEYU
B
Left ovary cyst
2010-01-15
Mild
End of study
Impossibly related
Still existed
Cyst of right adnexa
2010-01-15
Mild
End of study
Impossibly related
Relieved
2010-04-23
2010-02-18
2010-01-07
2
50
LXFE
A
VVC
2010-02-08
Mild
End of study
Suspiciously
Relieved
2
55
ZXLA
B
Cystitis
2010-01-08
Moderate
Permanent withdrawal
Impossibly related
Still existed
2
56
MPYU
A
BV
2010-01-27
Mild
End of study
Suspiciously
Relieved
2
62
JSLA
A
Upper respiratory
tract infection
2010-02-18
Mild
Permanent withdrawal
Impossibly related
Relieved
2
64
GLLA
B
BV
2010-03-09
Mild
End of study
Suspiciously
Relieved
2010-NA
2
67
ZHYA
B
Vaginal itching
2010-02-NA
Moderate
Permanent withdrawal
Suspiciously
Relieved
2010-02-NA
2
70
WSHU
A
VVC
2010-03-29
Mild
End of study
Suspiciously
Relieved
NA
3
73
LIHO
A
Fever
2009-11-25
Moderate
Unchanged dosage
Impossibly related
Relieved
2009-11-30
3
104
ZRHU
B
vulva itching
2010-04-09
Mild
Drug discontinued
temporarily
Probably related
Still existed
4
142
DJHE
A
VVC
2010-03-30
Mild
Unchanged dosage
Suspiciously
Relieved
4
144
ZPKU
A
mixed prolapse of
intestinal mucosa
2010-04-10
Severe
Permanent withdrawal
Impossibly related
Still existed
2010-NA
2010-02-24
2010-04-02
7 Analysis of clinical trial results
The study is a multicenter, randomized, open, positive and parallel controlled
study, evaluating the efficacy and safety of Hyaluronic acid vaginal gel
(Hyalofemme) for improvement of vaginal dryness. The clinical study results
showed that applying Hyaluronic acid vaginal gel and Estriol cream in test
group and control group according to the protocol, could remarkably
improve the clinical symptoms of vaginal dryness. The final (after
administration for 10 times) improvement rate were 84.44% and 89.42%,
respectively, without significant statistical differences between them (P＞0.05).
Mean of rate difference was -3.33% and 95%CI was [-9.40, 2.74], the lower
limit of which did not exceed the boundary value of non-inferiority
evaluation (15%). Thus we could think that the efficacy of the Hyaluronic acid
vaginal gel is not inferior to that of Estriol cream, with no significant
difference between them. At the first visit, the improvement rate of vaginal
dryness in Hyaluronic acid vaginal gel group and Estriol cream group were
49.17% and 53.53%, and had no statistical significant differences. That meant
the two products had a short onset time and they could release the clinical
symptoms of vaginal dryness after three times of administration of the
products. That the improvement rate on first visit was lower than that on final
visit showed the continuous release effect on the symptoms as time of
medication increased. The final improvement rate of the secondary efficacy
endpoints (itching, dyspareunia and burning sensation) in Hyaluronic acid
vaginal gel group and Estriol cream group were 86.23% and 81.97%, 56.96%
and 62.33%, 85.83% and 87.87%, respectively. The differences between the two
groups had no statistical significance (P>0.05), and FAS results were in line
with PPS.
Totally 13 adverse events occurred throughout the clinical study, seven in the
test group (incidence: 9.7%, 7/72) and six in the control group (incidence:
8.3%, 6/72). The differences between the two groups had no statistical
significance (P>0.05). No serious adverse event occurred, and the AEs that
were related to the test product or suspicious were in mild degree, which
could relieve.
The vaginal microecosystem is composed of intravaginal microflora, incretion
regulating function and anatomic structure. Normal microflora in vaginal is
core content of vaginal microecosystem study. Vaginal microecosystem is a
complex and vulnerable system, which may be easily affected by various
endogenous and exogenous factors. And vaginal medication is one of the
important factors. Once the balance of vaginal microecosystem is broken, a
series of clinical symptoms may occur, such as itching, unpleasant odor and
abnormal leucorrhea, etc. The clinical study is to evaluate whether applying
Hyaluronic acid vaginal gel influences the stability of vaginal environment by
investigating the variations of vaginal microecosystem before and after
treatment.
In
the
vaginal
microecosystem
evaluation,
no
changes
of
vaginal
micro-ecological environment appeared after treatment in 80.6% (54/67) of
subjects in Hyaluronic acid vaginal gel group, while 77.27% (51/66) in Estriol
cream group. It indicated that applying Hyaluronic acid vaginal gel would
not alter the internal environment of vagina and it was able to maintain the
homeostasis, with a high safety. Vaginal microecosystem evaluation is a
lightspot of this clinical study. It objectively evaluated that no changes
occurred in intensity, variety and predominant bacteria of vaginal flora after
applying Hyaluronic acid vaginal gel.
Mean of vaginal PH value in Hyaluronic acid vaginal gel group was 5.63 prior
to treatment and 5.30 after treatment, with no statistical difference. Vaginal
PH value after treatment (5.30) in Hyaluronic acid vaginal gel was higher than
that in Estriol cream group and the difference between them had statistical
significance (P＜0.05). It suggested that the hyaluronic acid vaginal gel was
not as good as the estriol cream on reducing vaginal PH value. It was mainly
because the estrin in the estriol cream could help the growth of lactobacilli in
vagina, promoting lactose broken down into lactic acid, to reduce PH value.
While the hyaluronic acid vaginal gel had no pharmacological effect. Its
biological effect was acted through Hydeal-D®, the derivative of hyaluronic
acid, without mechanism to reduce PH value.
The endometrial thickness prior to treatment in test group and control group
were 3.19mm and 3.21mm, respectively. While 3.43mm and 3.52mm after
treatment. The difference between the two group had no statistical difference
(P ＞ 0.05). However, the endometrial thickness of the No. 003 subject
(applying estriol cream) in Peking University First Hospital increased from
3mm to 9mm. On follow-up after drug withdrawal, the endometrial thickness
of the subject reduced gradually and the symptoms were relieved. It indicated
that estriol cream had influence on the endometrial thickness. The doctors
should apply it strictly in accordance with the indications. Because of its
narrow applicability, the doctors should be cautious when using it. The
hyaluronic acid vaginal gel did not have hormonelike effect, thus it had no
influence on endometrium or hormones-endocrine system and had a high
safety.
Hyaluronic acid vaginal gel (Hyalofemme), a colorless gel with high
hydrating properties, is manufactured by Fidia Advanced Biopolymers, srl,
Italy and has been marketed in numerous foreign countries for years.
Hyaluronic acid is a natural molecule that can maintain a right level of
hydration and plays an important role in tissue repair. The product has no
pharmacological effect for it is not a drug but a type Ⅲ medical device. The
gel’s hydrating properties are attributed to the characteristics of the
hyaluronic acid based biopolymer which releases water molecules to the
tissue, thus improving the dry state of the vagina without any irritation of
vaginal mucosa. Therefore, the gel is applicable to supplementary treatment
of vaginal dryness symptoms induced by any reason. Compared with estriol
cream, hyaluronic acid vaginal gel has the characteristics of wider applicable
range, no hormonelike effect, higher safety and better acceptability of
patients.
The clinical trial showed that the hyaluronic acid vaginal gel played a part in
repair of vaginal epithelial cells. It could improve the epithelium condition,
making the subjects feel better after application. The mechanism need further
study.
Though the results would be inevitably influenced by the investigator because
of the open-label trial, they still had reference value. The certain evaluation of
the efficacy and safety of hyaluronic acid vaginal gel depended on further
blind trial.
8 Conclusion of the clinical trial
To sum up, the hydration and adhesion of hyaluronic acid vaginal gel can
improve vaginal dryness throughout the spontaneous recovery of small
lesions that caused by friction of vagina. Therefore, the gel is applicable to
supplementary treatment of vaginal dryness symptoms induced by any
reason.
9 Indications, applicable range, contraindication and
attentions
Indications:
Supplementary treatment of vaginal dryness induced by various reasons and
promoting the spontaneous recovery of small lesions caused by frictions of
vaginal mucosa
Instructions
1. Revolve the vaginal applicator into the tube.
2. Squeeze the tube to fill the applicator to half of it (about 5g).
3. Release the applicator from the tube and plug it in patient’s vagina. The
patient should keep crouching or lying position.
4. Impel the applicator until all of the gel is discharged.
5. Clean the applicator after administration. Wash out the remaining gel with
water and disinfectants, then rinsing it thoroughly. Finally remove the water
from the applicator.
6. Put the applicator into the box for use next time.
7. In case of severe dryness, it is suggested that eject a little gel so as to make
enough lubricating before plugging the applicator into vagina.
Application frequency
Application frequency depends on the dry state of the vaginal mucosa.
Patients in the study applied the gel every 3 days, totally 30 days
continuously except other prescription.
Contraindication
Patients who are allergic to the product.
Attentions:
In case of vaginal infection, patient should consult the doctors before
application of the product.
The product can be used during menstruation and it will not affect the
gynecologic test results.
Do not use if packaging is damaged.
Do not litter the packaging.
Store in a cool and dry place (temperature＜40℃）to prevent property
changes.
Do not use if exceeding valid date.
10 References
⑴ HYALGEL VAGINAL（Hyalofemme）registration materials
⑵ Regulations of medical device clinical trials, SFDA No.5, 2004.1.7
⑶ Bei Zhengping, Lai Peili, Zhang Bin, Diagnositic criteria of gynecological
and obstetrical disease, 2nd version, Science Press, Beijing, 318－319,2006
⑷ Liu Qin, Jin Pihuan, chief editor. Statistical analysis of classification data
and SAS programming. Shanghai: Fudan University Press, 2002.
⑸ Gao Jing, compiled, Hormone replacement therapy and senile
vaginitis——evaluation of vagina health score, Foreign Medicine Obstetrics
and Gynecology volume, 25(2):101-102, 1998
⑹ Hong Xiuqin, Zhou Fengjie, Analysis of conjugated estrogen in treatment
of 68 patients with postmenopausal urogenital atrophy, the Journal of
Practical Medicine, 21(12):1353-1354, 2005.
⑺ Liao Qinping, Female vaginal ecosystem and vaginal microecological
evaluation, Journal of Practical Obstetrics and Gynecology, 2010, 26(2): 81-83.
11 Participants of clinical trial
Peking University First Hospital
Name
Position
Professional Title
Department
Telephone no.
Liao Qinping Head of the Chief physician
Obstetrics and
department
Gynecology
Lin Huaixian
Associate chief physician
Obstetrics and
Gynecology
Chen Junya
Attending physician
Obstetrics and
Gynecology
Zhang Miao
Associate chief physician
Obstetrics and
Gynecology
Peking University Third Hospital
Geng Li
Chief physician
Obstetrics and
Gynecology
Chen
Chief physician
Obstetrics and
Bingfeng
Gynecology
Guo Yanli
Chief physician
Obstetrics and
Gynecology
Yao Yanjun
Senior nurse
Obstetrics and
Gynecology
Beijing Chao-Yang Hospital Attached to Capital Medical University
Song
Chief physician
Obstetrics and
Xuehong
Gynecology
Wang Qiuxi
Associate chief physician
Obstetrics and
Gynecology
Liu Jun
Attending physician
Obstetrics and
Gynecology
Wei Shuang
Nurse-in-charge
Obstetrics and
Gynecology
Beijing Shijitan Hospital
Li Hongxia
Head of the Chief physician
Obstetrics and
department
Gynecology
Yan
Associate chief physician
Obstetrics and
Shuxiang
Gynecology
Huang Bin
Attending physician
Obstetrics and
Gynecology
Xu Zimei
Technologist-in-charge
Obstetrics and
Gynecology
Institute of Basic Medical Sciences Chinese Academy of Medical Sciences
Han Shaomei Director
of Professor
Statistics Office
010-65296408
Statistics
Office
Xu Tao
Statistics Office
010-65296408
12 Declaration and signatures of investigators
I have read this report. According to my understanding, I confirm that the
report has described the process and results of the clinical trial truly and
accurately.
Study responsible center: Peking University First Hospital
Liao Qinping
signature: ________ Date: YY-MM-DD
Study centers: Peking University Third Hospital
Geng Li
signature: ________ Date: YY-MM-DD
Beijing Chao-Yang Hospital Attached to Capital Medical
University
Song Xuehong
signature: ________ Date: YY-MM-DD
Beijing Shijitan Hospital
Li Hongxia
signature: ________ Date: YY-MM-DD
Statistic department: Institute of Basic Medical Sciences Chinese Academy of
Medical Sciences
Han Shaomei
signature: ________ Date: YY-MM-DD
13 Opinions of clinical trial management department of
medical institutions
Management department of Peking University First Hospital
(Stamp)
Date: YY-MM-DD
Management department of Peking University Third Hospital
(Stamp)
Date: YY-MM-DD
Management department of Beijing Chao-Yang Hospital Attached to Capital
Medical University
(Stamp)
Date: YY-MM-DD
Management department of Beijing Shijitan Hospital
(Stamp)
Date: YY-MM-DD