Clinical trial NCT03151005
Conditions: Polycystic Ovary Syndrome (PCOS) Overweight Obesity
Keywords: Polycystic Ovary Syndrome (PCOS) Overweight Obesity GLP-1 Agonist Oral contraceptives (OCs) Metformin Reproductive Disorders Cardiovascular risk factor Lipid Metabolism
Sponsor: Xinqiao Hospital of Chongqing
Start date: 2017-07-01; Completion date: 2021-04-23
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Polycystic ovary syndrome (PCOS) is a health problem that affects one in 10 women of childbearing age, which is usually characterized by hormonal imbalance and metabolism problems such as hyperandrogenism and obesity. Diane 35 pills are classified as oral contraceptives, which effectively reduces circulating androgens and are treatment for hyperandrogenism caused androgenic skin symptoms and irregular menstrual cycles. GLP-1 Receptor Agonist(e.g. exenatide, liraglutide) have the effects of lowering blood sugar and weight control by inhibiting of gastric emptying and reducing food intake. This study aims to evaluate the effect of metformin-GLP-1 Receptor agonist combination versus metformin-Diane-35 combination treatment on lipid metabolism and cardiovascular risks in overweight polycystic ovarian syndrome (PCOS) patients.

Detailed description:
Groups:

Experimental treatment: Metformin-GLP-1 Receptor Agonist Therapy.

Regular treatment: Metformin-Oral Contraceptive(OC) Therapy.

Time Point:

Initial treatment;

Post-treatment (4w);

Post-treatment (8w);

Post-treatment (12w);

Assess reproductive functions and cardiovascular risk factors.

Arms: arm 1: Metformin-GLP-1 Receptor Agonist Therapy: metformin 0.5 g/time by mouth, 3 times per day, with 5 ug exenatide subcutaneous injection twice per day, for 4 weeks, then change to 10ug exenatide subcutaneous injection twice per day for 8 weeks; or metformin 0.5 g/time by mouth, 3 times per day, with 0.6mg liraglutide subcutaneous injection once per day, for 1 weeks, then change to 1.2-1.8 mg liraglutide subcutaneous injection according to patient's blood glucose condition, twice per day for 8 weeks. arm 2: Metformin-Oral Contraceptive(OC) Therapy: metformin 0.5 g/ time by mouth, 3 times per day, with Diane 35(OC) 1 piece per day by mouth, for 12 weeks.
Interventions: intervention 1: Metformin-GLP-1 Receptor Agonist intervention 2: Metformin-Oral Contraceptive(OC)
Intervention descriptions: intervention 1: metformin oral with exenatide/liraglutide subcutaneous injection. intervention 2: metformin with Diane 35 oral intake.

Protocol documents:
Prot_000.pdf: 
Abstract: Polycystic ovarian syndrome (PCOS) is one of the common endocrine diseases that lead to female
reproductive dysfunction. Up to 75% of PCOS patients have endocrine and metabolic abnormalities such as obesity,
hyperinsulinemia and hyperandrogenemia. As a classic PCOS drug, CPA/EE is mainly used to adjust estrogen and
progesterone levels and menstrual cycle. Recent studies have found that this drug may worsen blood lipids and
reduce insulin sensitivity. On the other hand, studies have found that reproductive disorders secondary to metabolic
disorders can be improved by correcting metabolic disorders. glucagon-like peptide1 receptor agonist (GLP-1 RA)
is a new type of glucagon-like glucagon-like peptide1 receptor agonist, which has a significant effect on the
improvement of metabolic disorders in obese patients. This topic aims to study.To observe the effects of metformin
combined with CPA/EE or GLP-1RA on blood glucose, blood lipids, sex hormone levels and menstrual cycle in
overweight PCOS patients.
Sponsor/Contact Person/Phone
Number
Xinqiao Hospital Endocrinology Department/ Min Long /13640599383
Research department/project
leader
Endocrinology Department / Min Long
Research category
Clinical research, source: self raised
Title of the study
The Effect of GLP-1 Agonists Versus OCs on Reproductive Disorders and
Cardiovascular Risks in Overweight PCOS
NTC Number
NCT03151005
Research duration
3 years
Number of research and design
cases in this center
60 cases
Study design
All subjects underwent height, weight, waist and hip, hip circumference, blood
pressure, hairy score, blood biochemistry (blood routine, liver and kidney
function, electrolyte, thyroid funct ion, fasting blood glucose, glycated
hemoglobin, insulin release test, inflammatory markers, sex hormones, eight
items), gynecologic color Doppler ultrasound and glucose clamp examination
before admission. After informed consent was obtained, 1ml of the remaining
plasma was collected and frozen in the refrigerator at -80℃. Patients with
BMI≥24kg/m² or waist circumference ≥85cm were randomly assigned to GLP-
1RA+ metformin or Diane-35 + metformin. After 1 month, all subjects were
examined: height, weight, BMI, waist circumference, hip circumference, waist-to-
hip ratio, menstrual history, hirsutism score, diet, exercise frequency and
intensity, blood pressure and blood biochemistry. After 3 months, the general
condition of all subjects and general biochemical tests such as blood lipid, liver
and kidney function, fasting blood glucose, glycated hemoglobin, insulin release
test, inflammation markers and gynecological color ultrasound were tested again,
and 1ml of plasma was collected and frozen in the refrigerator at -80℃.
Trial objective
1. Provide new treatments for overweight or obese patients with PCOS.
2. Improve PCOS and establish regular menstrual cycles by reducing weight and
correcting metabolic disorders.
Name and specifications of the
required drugs or equipment
Grid, manufacturer, and quantity
Metformin enteric coated tablets: Hebei Tiancheng Pharmaceutical Co., Ltd., trade
name: Junshida, dosage: 0.5g orally 3/day; Liraglutide injection: Novo Nordisk,
Denmark, trade name: Novo Nordisk, dosage: 0.6mg subcutaneous injection once a
d a y , i n c r e a s e d t o 1 . 2 m g a f t e r 1 w e e k , m a x i m u m d o s e i s 1 . 8 m g / d ;
Acetylenylestradiol cycloproterenone tablets: Bayer AG, Germany, trade name:
Diane-35, dosage: 1 tablet taken orally starting from the first day of the menstrual
cycle,Take 1 tablet daily for 21 consecutive days, discontinue for 7 days。
Inclusion and exclusion criteria
Inclusion criteria : a) clinical diagnosis of PCOS according to the Rotterdam criteria based on the
presence of two of three criteria (3) , oligomenorrhoea, clinical or biochemical hyperandrogenism, and
polycystic ovaries on ultrasound after exclusion of other endocrine causes of hyperandrogenism; b)
participants had no concurrent illness and were not on any prescription or over-the-counter medication
that was likely to affect insulin sensitivity or lipids for the preceding 12 weeks; c) participants were
advised not to change physical activity or dietary habits during the study period; d) given that all
subjects were of Asian ethnicity, overweight was defined as BMI ≥24 kg/m2. e.) all subjects had
n o r m a l
t h y r o i d - s t i m u l a t i n g
h o r m o n e
a n d
p r o l a c t i n
l e v e l s .
exclusion criteria : a) age below 18 years or over 50 years; b) uncontrolled hypertension (blood
pressure ≥160/100 mmHg); c) signs of liver or renal failure or active liver disease (alanine
transaminase (ALT) > 2.5× the upper limit of normal values); d) patients who were postmenopausal
or pregnant; e) alcohol intake greater than 20 g/day; f) patients who could not complete the
intervention or had other conditions that made them ineligible for participation. For example, patients
taking glucocorticoid steroids or under treatment for a malignant tumor were excluded.


Subject benefits and possible risks
and compensate
This study is an intervention clinical observation trial. Due to the needs of the
treatment of their own diseases, the subjects need to collect venous blood for blood
sugar, insulin and other tests. After informed consent, the researchers will collect
1ml of the remaining serum, 1m of plasma and 1ml of urine after testing in the
laboratory, so as to avoid repeated blood extraction of the subjects and protect the
interests of the subjects to the greatest extent. The drugs used in the study were all
conventional treatment drugs for newly diagnosed polycystic ovary syndrome. For
the survey subjects, through baseline examination and follow-up, the drug response
of patients and the therapeutic effect of improving metabolic and reproductive
disorders can be clarified, providing a basis for the postoperative treatment of
patients and the selection of drugs for the prevention and treatment of complications.
In addition, survey subjects can also pass after 3 months.Follow-up examination to
understand the efficacy and safety of its treatment.
Document Date
July 28, 2017

SAP_001.pdf: 
Statistical analysis
Title of the study
The Effect of GLP-1 Agonists Versus OCs on Reproductive Disorders and
Cardiovascular Risks in Overweight PCOS
NTC Number
NCT03151005
Statistical method
Statistical analyses were performed using SPSS 23.0 and GraphPad Prism 8. For
normally distributed con tinuous variables of clinical parameters, variables are
described as the mean ± standard deviation (SD),a paired t-test was used to
compare pretreatment and posttreatment values of continuous variables in eac h
of the treatment groups, and between-group differences were compared by an
independent sample t-te st. For nonnormally distributed continuous variables,
the nonparametric Wilcoxon signed-rank test for rel ated samples was used to
compare pretreatment and posttreatment values in each of the treatment grou ps.
The chi-square test was used for counting data. To compare the changes in
clinical parameters betwe en different treatment groups, the nonparametric
Mann-Whitney test was used. Proteomic data analysis was described by
proteomic data acquisition and analysis. Protein levels are described as the
mean±sta ndard error of the mean (SEM), and a paired ttest was used to
compare plasma protein levels measured by ELISA. Pvalues <0.05 were
considered statistically significant.
Document Date
July 28, 2017


Table 1-Baseline and posttreatment characteristics of cliniccal parameters after 12-week of treatment.
CPA/EE+Met(n=30)
GLP-1 RA+Met(n=30)
Characteristics
Baseline
Posttreatment
Pvalue
Baseline
Posttreatment
Pvalue
Biometric features
Weight(kg)
BMI (kg/m²)
Waist(cm)
WHR
SBP(mm/Hg)
DBP(mm/Hg
Reproductive function
Dominant follicle,n(%)
Regular menstruation, n(%)
Amenorrhoea, n(%)*
Oligomenorrhoea,n(%)+
Polycystic ovaries according t
o Rotterdam criteria, n(%)
T(nmol/L)
LH(mlU/ml)
FSH(mlU/ml)
LH/FSH
DHEA-S(ug/dL)
SHBG (nmol/L)
FAI
E2(pg/ml)
P(ng/ml)
PRL(ng/ml)
Biochemical profile of glucose metabolism
HbA1c(%)
HbA1c(mmol/mol)
FBG(mmol/L)
AUCI
FINS(uU/ml)
HOMA-IR
Biochemical profile of lipid metabolism
TG(mmol/L)
TC(mmol/L)
Data are mean±SD orn(%). BMI, body mass index; WHR, waist-to-hip ratio; SBP, systolic blood pressure; DBP, diastolic blood press
ure; T, testerone; LH, luteinizing hormone; FSH, follicle- stimulating hormone; DHEA-S, dehydroepiandrosterone; SHBG, sex hormone-
binding globulin; FAl, free androgen index; E2, estradiol; P, progesterone; PRL, prolactin. HbA1c, hemoglobin A1c; FBG, fasting blood gl
ucose; FINS, fasting insulin; AUCl, area under curve of insulin; HOMA- IR, homoeostasis model assessment of insulin resistance; T
G, triglycerides; TC, total cholesterol


Table 2-Characteristics change after treatment in this study.
Characteristics
CPA/EE +Met
(n=30)
GLP-1 RA +Met
(n=30)
t/z
Pvalue
Biometric features
△Weight(kg)
△BMI(kg/m²)
△Waist(cm)
△WHR
△SBP(mm/Hg)
△DBP(mm/Hg)
Sex hormones and related indicators
△T(nmol/L)
△LH(mlU/ml)
AFSH
(mlU/ml)
ALH/FSH
△DHEA-S(ug/dL)
△SHBG
(nmol/L)
△FAI
△E2(pg/ml)
△P(ng/ml)
△PRL(ng/ml)
Biochemical profile of lipid metabolism
△TG(mmol/L)
△TC(mmol/L)