Liraglutide 3mg (Saxenda) on Weight, Body Composition, Hormonal and Metabolic Parameters in Obese Women With PCOS

Polycystic Ovary Syndrome Clinical Trial

— SAXAPCOS  

Official title:

A Randomized Placebo-controlled Double Blind Trial of Liraglutide 3 mg [Saxenda] on Weight, Body Composition, Hormonal and Metabolic Parameters in Obese Women With Polycystic Ovary Syndrome (PCOS)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03480022
• Other study ID #: U1111-1198-4126
• Status: Completed
• Phase: Phase 3
• Start date: September 26, 2018
• Est. completion date: May 19, 2021

Study information

• Verified date: June 2021
• Source: Woman's
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

There is a growing need to develop pharmacologic interventions to improve metabolic function in women with polycystic ovary syndrome (PCOS). Given that PCOS is a frequent condition and weight loss is essential but difficult to achieve, it is important to study if the effect on body weight reported in other studies can be confirmed in a selected population of hyperandrogenic patients, especially with medications currently approved for weight reduction. High dose liraglutide alone results in significant weight reduction in obese women without PCOS. There is limited data on weight loss with high dose liraglutide in non-diabetic females with PCOS treated with this agent . Studies on the effect of anti-obesity medication combined with lifestyle changes on body weight and composition and androgen excess in obese women diagnosed with PCOS are lacking. The investigators aim to elucidate the most efficacious weight reduction regime in obese PCOS women. The investigators further hope to determine which treatment(s) addressing the multifaceted disturbances of this disorder in patients with PCOS and obesity emerges as the preferable therapy.

Description:

The drug, liraglutide 3.0 mg was approved for chronic weight management in management in obese adults with an initial BMI of 30 kg/m2 or greater or in overweight adults BMI of 27 kg/m2 or greater with at least one weight-related co-morbid condition as an adjunct to a reduced-calorie diet and increased physical activity. Liraglutide is an acylated human glucagon-like peptide -1 (GLP-1) analog that binds to and activates the GLP-1 receptor. It lowers body weight through decreased caloric intake while stimulating insulin secretion and reducing glucagon via a glucose-dependent mechanism. For obesity management, patients may lose weight with GLP-1 receptor agonists due to other unique actions. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) can slow gastric emptying and increase satiety. While predictors of weight loss success for the general population are available (protein intake, weight loss medications), predictors of weight loss success may differ between normal and hyperandrogenic women. Glucagon-like peptide 1 agonists are linked with dose dependent weight lowering potential in different obesity related populations. The weight loss effects of GLP-1RAs previously demonstrated in diabetic and obese non-diabetic patients, offer a unique opportunity to expand the medical options available to patients with PCOS.

Given this lack of information, the aim of the present study was to investigate the effects of liraglutide 3mg vs. placebo on body composition as well as hormonal and metabolic features in non-diabetic obese women with PCOS.The non-diabetic obese female with PCOS offers a unique model to study the relationship between insulin resistance and adiposity. The investigators propose a double-blind, placebo-controlled 30-week trial designed to directly examine the therapeutic effects of liraglutide 3 mg (LIRA 3 mg) compared to placebo on body weight, hormonal and cardiometabolic parameters in obese non-diabetic women with PCOS. All patients will receive diet and lifestyle counseling, including advice on exercise commencing during the lead-in period and continuing throughout the study. In this study, the investigators will examine the efficacy of LIRA 3mg on body weight and body composition, reproductive function metabolic parameters and cardiovascular risk factors in a well-defined group of pre-menopausal obese non-diabetic women with hyperandrogenism, focusing on the relationship to obesity and insulin resistance.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 88
• Est. completion date: May 19, 2021
• Est. primary completion date: February 22, 2021
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 45 Years

Eligibility

Inclusion Criteria:

• Female gender

• 18-45 years of age

• BMI =30 kg/m2 or BMI =27 kg/m2 with one or more obesity-associated co-morbid conditions (e.g. hypertension, and dyslipidemia)

• PCOS- NIH criteria hyperandrogenism and irregular menstrual cyclicity

• Non-diabetic as determined by a 75 gram oral glucose tolerance test (OGTT) and hemoglobin A1C. Non-diabetic is inclusive of women with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both (IFG/IGT). Participants with diabetes will be excluded

• Willing to use effective contraception consistently during therapy which is defined as:

• an intrauterine device, tubal sterilization, or male partner vasectomy, or

• combination of two barrier methods with one being male condom.

• Written consent for participation in the study

Exclusion Criteria:

• Presence of significant systemic disease, cerebrovascular disease, clinically significant cardiac abnormalities or heart problems including congestive heart failure, unstable angina or acute myocardial infarction, current infectious liver disease, acute stroke or transient ischemic attacks, history of pancreatitis, or diabetes mellitus (Type 1 or 2)

• Any hepatic diseases in the past (infectious liver disease, viral hepatitis, toxic hepatic damage, jaundice of unknown etiology) or severe hepatic insufficiency and/or significant abnormal liver function tests defined as aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) >3x ULN

• Renal impairment (e.g., serum creatinine levels =1.4 mg/dL for women, or eGFR <60 mL/min/1.73 m2) or history of unstable or rapidly progressing renal disease or end stage renal disease.

• Uncontrolled thyroid disease (documented normal TSH), Cushing's syndrome, congenital adrenal hyperplasia or clinically significant elevations in prolactin levels. The clinical significance of prolactin levels will be determined by the treating physician

• Significantly elevated triglyceride levels (fasting triglyceride > 400 mg %)

• Untreated or poorly controlled hypertension (sitting blood pressure > 160/95 mm Hg)

• Use of hormonal medications, the use of medications that cause clinically significant weight gain or loss (prescription or OTC) and medications known to exacerbate glucose tolerance (such as isotretinoin, hormonal contraceptives, GnRH analogues, glucocorticoids, anabolic steroids, C-19 progestins) including herbal medicines for at least 8 weeks. Use of anti-androgens that act peripherally to reduce hirsutism such as 5-alpha reductase inhibitors (finasteride, spironolactone, flutamide) for at least 4 weeks

• Prior history of a malignant disease requiring chemotherapy

• Family or personal history of familial medullary thyroid carcinoma or multiple endocrine neoplasia type 2

• Known hypersensitivity or contraindications to use GLP1 receptor agonists

• Use of metformin, thiazolidinediones, GLP-1 receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium/glucose co-transporter 2 (SGLT2) inhibitors or weight loss medications (prescription or OTC) stopped for at least 4 weeks

• Prior use of medication to treat diabetes except gestational diabetes

• Eating disorders (anorexia, bulimia) or gastrointestinal disorders

• Suspected pregnancy (documented negative serum pregnancy test), desiring pregnancy in next 15 months, breastfeeding, or known pregnancy in last three months

• Active or prior history of substance abuse (smoke or tobacco use within past 6 months) or significant intake of alcohol

• Previous bariatric surgery or device intervention for obesity

• Patient not willing to use barrier contraception during study period (unless sterilized or have an IUD)

• History of major depressive or other severe psychiatric disorders

• Inability or refusal to comply with protocol

• Currently participating or having participated in an experimental drug study in previous three months

Related Conditions & MeSH terms

• Body Weight
• Obesity Android
• Polycystic Ovary Syndrome
• Pre Diabetes
• Prediabetic State
• Syndrome

Intervention

Drug:
• Liraglutide Pen Injector [Saxenda]
daily sc injection of liraglutide with final dose of 3mg daily
• Placebo Liraglutide Pen Injector
daily sc injection of placebo liraglutide with final dose of 3mg daily of placebo

Locations

Country	Name	City	State
United States	Woman's Hospital	Baton Rouge	Louisiana

Sponsors (2)

Lead Sponsor	Collaborator
Woman's	Novo Nordisk A/S

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Absolute Body Weight (BW)	Treatment impact on change in body weight after 32 weeks of treatment.	32 weeks of treatment
Primary	Free Androgen Index (FAI)	Drug treatment effect on free androgen levels as calculated as FAI= total testosterone (T) concentrations divided by sex hormone binding globulin (SHBG) levels. A higher score indicates a worse outcome (more androgenic).	32 weeks of treatment
Secondary	Body Mass Index (BMI)	Treatment effect in reducing body mass	32 weeks of treatment
Secondary	Change in Percent Body Weight	Treatment effect on reducing body weight expressed as percent body weight loss from baseline	Change from baseline (time 0) to study end (32 weeks)
Secondary	5% Weight Loss From Baseline	Frequency of patients achieving 5% weight loss from baseline with treatment	32 weeks of treatment
Secondary	10% Body Weight Loss From Baseline	Frequency of patients with at least 10% reduction in body weight from baseline	32 weeks of treatment
Secondary	Abdominal Adiposity (Waist Circumference [WC]	Treatment effect on loss of WC (abdominal adiposity) with drug treatment	32 weeks of treatment
Secondary	Waist-to-Hip Ratio	Change in central adiposity with treatment as measured by WHR. A reduction in ratio indicates a decrease in truncal fat.	32 weeks of treatment
Secondary	Waist-to Height Ratio [WHtR])	Treatment effect on loss of central adiposity as determined by WHt ratio. The lower the ratio indicates less abdominal adiposity.	32 weeks of treatment
Secondary	Total Fat Mass Evaluated by DEXA	Treatment effect on reduction of fat mass (kg)	32 weeks of treatment
Secondary	Total Body Fat (%) by DXA	Treatment effect on reduction of percent body fat by DXA	32 weeks of treatment
Secondary	Android-Gynoid Ratio (AGR) by DXA	Treatment impact on AGR, measure of central adiposity, as determined by DXA. A lower AGR indicates a reduction in central adiposity.	32 weeks of treatment
Secondary	Trunk/Leg Fat Ratio (TLR) by DXA	Treatment impact on TLR after 32 weeks. A reduction in TLR indicates a loss of central fat.	32 weeks of treatment
Secondary	Menstrual Cycle Frequency	Drug treatment impact on normalization of cycle frequency (cycle every 28-30 days). All cycle data is expressed as number of menses annualized to one year.	32 weeks of treatment
Secondary	Total Testosterone Concentrations (T)	Drug treatment effect on total testosterone concentrations	32 weeks of treatment
Secondary	Adrenal Dehydroepiandrosterone Sulfate (DHEAS)	Treatment efficacy in reducing adrenal hyperandrogenism	32 weeks of treatment
Secondary	Fasting Blood Glucose (FG)	Treatment effect on fasting glucose prior to an oral glucose tolerance test (OGTT)	32 weeks of treatment
Secondary	OGTT Mean Blood Glucose (MBG)	Treatment effect on MBG measured during the oral glucose tolerance test. A decrease in MBG shows improvement in glycemia.	32 weeks of treatment
Secondary	Fasting Insulin Sensitivity (HOMA-IR)	Treatment effect on the HOMA-IR which is an insulin resistance measured derived from fasting blood glucose and insulin . The higher the number the more insulin resistant.	32 weeks of treatment
Secondary	Matsuda Insulin Sensitivity Index Derived From the OGTT (SI OGTT)	The SI OGTT is a measure of peripheral insulin sensitivity derived from the insulin and glucoses measured during an OGTT. A increase in SI OGTTindicates greater insulin sensitivity	32 weeks of treatment
Secondary	Corrected First Phase Insulin Secretion (IGI/HOMA-IR)	Treatment effect on insulin secretion from 0 to 30 minutes after glucose load corrected for by fasting insulin sensitivity. A higher score shows improved first phase insulin secretion in response to glucose.	32 weeks of treatment
Secondary	Insulin Secretion- Insulin Sensitivity Index (Oral Disposition Index-IS-SI)	Treatment effect on an estimation of Beta cell compensatory function, the IS-SI is derived by applying the concept of the disposition index to measurements obtained during the 2 hour OGTT and calculated as the index of insulin secretion factored by insulin sensitivity. A higher score shows improved pancreatic beta cell function relative to insulin sensitivity.	32 weeks of treatment
Secondary	Total Cholesterol Levels	Treatment impact on improving total cholesterol levels	32 weeks of treatment
Secondary	High Density Lipoprotein Cholesterol (HDL-C)	Impact of treatment on HDL levels after 32 weeks of treatment	32 weeks of treatment
Secondary	Triglyceride Levels (TRG)	Drug effect of TRG levels after treatment	32 weeks of treatment
Secondary	Triglyceride to HDL-Cholesterol Ratio (TRG/HDL-C)	Treatment impact on TRG/HDL-C ratio which is a simple measure to estimate insulin action. A decrease in ratio indicates improvement in insulin sensitivity.	32 weeks of treatment
Secondary	Triglyceride and Glucose Index (TyG)	Treatment impact on the TyG index which estimates insulin resistance. A reduction in TyG indicates an improvement in insulin action.	32 weeks of treatment
Secondary	Systolic Blood Pressure	Treatment impact on systolic blood pressure	32 weeks of treatment
Secondary	Diastolic Blood Pressure (BP)	Treatment impact on reducing diastolic blood pressure	32 weeks of treatment