Conditions: Pre Diabetes Polycystic Ovary Syndrome Obesity Android
Keywords: prediabetes PCOS GLP-1 agonist weight loss
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 88
Healthy volunteers: no

Brief 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.

Detailed 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.

Arms:
arm 1: Start injection liraglutide 0.6 mg subcutaneously (SC) 1week daily (QD), step up to 1.2 mg SC QD for 1week, to 1.8 mg SC QD for 1 week, 2.4 mg SC QD for 1week, to a final dose of 3.0 mg liraglutide SQ daily arm 2: Start injection of placebo liraglutide 0.6 mg subcutaneously (SC) 1week daily (QD), step up to 1.2 mg SC QD for 1week, to 1.8 mg SC QD for 1 week, 2.4 mg SC QD for 1week, to a final dose of 3.0 mg placebo liraglutide SQ daily

Interventions: intervention 1: Liraglutide Pen Injector [Saxenda] intervention 2: Placebo Liraglutide Pen Injector
Intervention descriptions: intervention 1: daily sc injection of liraglutide with final dose of 3mg daily intervention 2: daily sc injection of placebo liraglutide with final dose of 3mg daily of placebo

Protocol document:
Prot_SAP_001.pdf: 
 
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A randomized placebo-controlled double blind trial of liraglutide 3 mg 
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[Saxenda] on weight, body composition, hormonal and metabolic 
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parameters in obese women with polycystic ovary syndrome (PCOS) 
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INVESTIGATOR-SPONSORED STUDY PROPOSAL 
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Universal Trial Number (UTN) is U1111-1198-4126 
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Woman’s Health Research Department 
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Woman’s Hospital 
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100 Woman’s Way 
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Baton Rouge, Louisiana 
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Correspondence to:  
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Karen Elkind-Hirsch, PhD 
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Director of Research 
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Woman’s Hospital -Support Services Building 
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100 Woman’s Way 
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Baton Rouge, Louisiana 
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phone-(225) 231-5278 
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fax-(225) 231-5290 
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karen.elkind-hirsch@womans.org 
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ClinicalTrials.gov ID: NCT03480022 
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Background and Significance: 
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Polycystic ovary syndrome (PCOS), a common, heterogeneous, heritable condition, is 
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characterized by disordered reproductive and metabolic function that accounts for the myriad of 
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clinical features including androgen excess, chronic anovulation, hyperinsulinemia, adiposity, 
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and dyslipidemia.  Hyperandrogenism, ovarian dysfunction and metabolic abnormalities - the 
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main determinants of PCOS – all appear to be involved in a synergistic way in the 
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pathophysiology of PCOS.  Women with PCOS are more likely to be obese although PCOS can 
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also manifest in lean women.  Obesity, particularly abdominal obesity, plays a central role in the 
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development of PCOS, and exacerbates the reproductive and metabolic dysfunction.  Rather 
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than absolute body weight, it is the distribution of fat that is important with central adiposity 
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being a risk factor.  Compared with weight-matched healthy women, those with PCOS have a 
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similar amount of total and trunk fat, but a higher quantity of central (visceral) abdominal fat.  
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Visceral adipose tissue is more metabolically active than subcutaneous fat and the amount of 
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visceral fat correlates with insulin resistance and hyperinsulinemia.  Weight gain is also often an 
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important pathogenic factor, with the PCOS condition becoming clinically manifest in women 
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with a presumable genetic predisposition for PCOS who subsequently gain weight.  Therefore, 
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environmental (particularly dietary) factors are important.  However, body mass is also 
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influenced by genetic factors such as fat mass and obesity-associated protein, and obesity itself 
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is a highly heritable condition.  Therefore, the weight gain responsible for the manifestation of 
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PCOS in many women with this condition is itself influenced by genetic factors.  Ethnicity, 
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genetic background, personal and family history, degree of obesity must all be taken into 
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account because they might aggravate or even trigger metabolic disturbances women with 
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PCOS.  Moreover, the incidence of glucose intolerance, dyslipidemia, gestational diabetes, and 
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type 2 diabetes (T2D) is increased in women with PCOS at all weight levels and at a young age.  
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Several studies have demonstrated that T2D occurs with increased frequency in women with 
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PCOS so that recently the American Diabetes Association and the International Diabetes 
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Federation have identified PCOS as a significant non-modifiable risk factor associated with type 2 
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diabetes.  PCOS may be a more important risk factor than ethnicity or race for glucose 
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intolerance in young women.  The exact factors responsible for this excess risk in women with 
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PCOS have not been identified; family history of T2D, obesity, insulin resistance, beta cell (ß-cell) 
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secretory dysfunction, and hyperandrogenism are possible candidates.  With better 
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understanding of its pathophysiology, the metabolic consequences of the syndrome are now 
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evident.   
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Obesity is considered one of the most important features of PCOS and it exacerbates 
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insulin resistance and impaired glucose tolerance (IGT) in women with PCOS.  Its mean 
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prevalence in diseased women varies between 61 and 76%.  The prevalence of obesity reaches 
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80% in the United States and 50% outside which indicates that this figure depends on local 
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environmental factors, ethnic backgrounds, and lifestyle, and not on the mere presence of PCOS 
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itself.  The increased prevalence of obesity in PCOS is associated with an increased frequency of 
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metabolic syndrome and T2D.  Obesity has been associated with a number of diseases and 
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metabolic abnormalities that have high morbidity and mortality.  Obesity appears to exert an 
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additive, synergistic effect on manifestations of PCOS and PCOS is more prevalent in obese than 
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in lean women.  Moreover, obesity itself is a common pathogenic factor in insulin resistance, 
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lipid dysfunction and metabolic syndrome and is usually accompanied by hypertension.  The 
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degree of obesity is positively associated with an increase in the incidence and degree of insulin 
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resistance.  Obesity may play a pathogenic role in the development of PCOS in susceptible 
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individuals and weight loss has been found to improve many clinical features of PCOS.  Even a 
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modest weight loss (5% of initial body weight) in overweight or obese women with PCOS 
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improves ovulation frequency and conception, reduces miscarriage, hyperlipidemia, 
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hypertension, hyperglycemia and insulin resistance.  The loss of intra-abdominal fat is 
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specifically associated with resumption of ovulation.  Weight loss has beneficial effects on 
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cardiovascular risk factors such as dyslipidemia and blood pressure.  Features of PCOS (e.g., 
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hirsutism, testosterone levels, insulin resistance, menstrual cyclicity and ovulation) showed 
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marked improvements, and PCOS frequently resolved after substantial weight loss induced by 
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bariatric surgery.  Furthermore, studies show that women with PCOS who achieve reductions in 
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weight and waist circumference after a diagnosis of prediabetes are twice more likely to regress 
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to normal glycemia than those who maintained baseline weight or gained weight. 
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While PCOS is the most common endocrine disorder among women in their reproductive 
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years, many aspects of the condition are not fully understood.  The fundamental 
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pathophysiological defect in PCOS is unknown, but women with PCOS often demonstrate insulin 
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resistance with compensatory hyperinsulinemia.  Insulin resistance occurs in around 50% to 80% 
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of women with PCOs, primarily in the more severe NIH diagnosed PCOS and in those who are 
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overweight.  Hyperinsulinemia may be directly responsible for the development of androgen 
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excess, through its effects in reducing sex hormone-binding globulin (SHBG) synthesis and 
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circulating concentrations, and in stimulating ovarian androgen production rates.  Androgen 
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excess, in turn, represents one of the major factors leading to altered ovarian physiology and 
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associated ovulatory disturbances.  In addition to the association of hyperinsulinemia and insulin 
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resistance with the reproductive disorders that characterize PCOS, a number of metabolic 
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abnormalities have also been associated with insulin resistance.  The insulin resistance 
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syndrome has been characterized by glucose intolerance, hypertension and dyslipidemia. 
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Hyperandrogenism (HA) comprises the biochemical hallmark of PCOS with elevated free 
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testosterone levels accounting for the majority of the abnormal laboratory findings in women 
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with oligomenorrhea.  Hyperandrogenism has also been linked with several components of 
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metabolic syndrome.  Metabolic syndrome (MetS) is characterized by a cluster of risk factors 
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including hypertension, elevated triglycerides, low high-density lipoprotein cholesterol, glucose 
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intolerance, and obesity, which also identifies those at risk for cardiovascular disease.  Insulin 
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resistance with subsequent hyperinsulinemia plays a major role in the development of MetS. 
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The association of carbohydrate metabolism abnormalities with androgen excess disorders, 
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particularly PCOS, is a well-defined entity.  In particular, androgen excess in PCOS may 
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contribute to increased visceral fat, decreased lipolysis in subcutaneous fat, reduced insulin 
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sensitivity in adipose tissue and skeletal muscle, decreased high-density cholesterol (HDL-C) 
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levels, and increased low-density lipoprotein cholesterol (LDL-C) levels.  Some studies have 
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indicated a positive association between MetS and HA in women with PCOS.  Metabolic 
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syndrome and its individual components are common in PCOS, particularly among women with 
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the highest insulin levels and body mass index (BMI).  In women with PCOS, there is an insulin 
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post-binding defect in receptor signaling due to increased insulin receptor substrate-1 serine 
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phosphorylation that selectively affects metabolic, but not mitogenic pathways in classic insulin 
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target tissues and in the ovary.  Hyperandrogenism per se may have a role in the higher 
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prevalence of glucose intolerance in these patients.  In the United States, 33–47% of women 
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with PCOS have MetS, a rate two to three times higher than that of age-matched healthy 
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women without PCOS.  An estimated 30–40% of PCOS patients have IGT and 7.5–10% have T2D.  
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Studies suggest that the annual progression rate from normal glucose tolerance to IGT and from 
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IGT to T2D in women is substantially enhanced among women with PCOS, with the highest risk 
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in women who are also obese and have a family history of type 2 diabetes.   
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Excess body weight is associated with hyperandrogenism.  Sex hormone binding globulin, 
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synthesized in the liver, not only provides transport for steroids in the blood, but also regulates 
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hormone access to target tissues through varied degrees of binding affinity.  Furthermore, the 
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hyperinsulinemia in obese women may directly increase free testosterone levels by lowering the 
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SHBG synthesis in the liver.  On the other hand, rodent models have shown that 
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hyperandrogenism promotes insulin resistance, reduces energy expenditure, and accordingly, 
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increases the risk of abdominal obesity and metabolic risk factors.  In a multiethnic sample of 
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more than 2500 U.S. women between 42 and 52 years of age, oligomenorrhea was associated 
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with the MetS only when coincident with HA.  Conversely, women with HA had a significantly 
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increased risk of the MetS independent of the menstrual frequency status.  Animal (rodent) 
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studies indicate that androgens may produce IR by direct effects on skeletal muscle and adipose 
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tissue, mediated by alterations in the insulin receptor–glycogen synthesis, by altering adipokine 
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secretion, and by increasing visceral adiposity.  Moreover, a small study of 13 obese and 30 non-
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obese women showed that anti-androgen treatment partly reversed the peripheral insulin 
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resistance (IR) in non-obese women only, whereas central obesity may have a direct role in 
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androgen hypersecretion.  Also, a recent study of young, overweight women suggested that the 
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association between body fat and HA was predominantly mediated by insulin resistance.  The 
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interrelationships between body fat, IR and HA contribute to the complex pattern making it a 
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difficult task to specify the role of each component.  
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There is considerable heterogeneity in clinical studies among women with 
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hyperandrogenism and there could be multiple clinical phenotypes, even in a single patient at 
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different ages.  Obesity significantly affects the circulating concentrations of total testosterone 
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and SHBG.  Body fat excess, particularly visceral fat accumulation, is another common finding in 
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these women regardless of weight and even at a young age.  Literature data consistently confirm 
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that up to 80% of PCOS subjects are overweight or obese, with a typical central distribution of 
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adipose tissue.  It has been hypothesized that body fat could have a direct role in determining 
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insulin resistance and possibly androgen hypersecretion in these women, by mechanisms such 
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as increased lipolysis, abnormal adipokine secretion, and altered steroid hormone metabolism.  
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Body weight status was the major factor determining the risk of IGT and MetS in women with 
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PCOS.  However, the intricate interrelationships between body fat excess, insulin resistance, and 
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hyperandrogenism make it difficult to assess the specific role of each of them.  Obesity-related 
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insulin resistance and resulting hyperinsulinemia may cause a decreased SHBG and an increased 
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ovarian androgen production, both of which contribute to the hyperandrogenism.  However, this 
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may form a vicious circle as hyperandrogenism may also contribute to the insulin resistance by 
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increasing free fatty acid flux to the liver and muscle through visceral lipolysis and, in addition, 
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by altering muscle structure toward less insulin-sensitive muscle fibers.  Indeed, obese women 
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with PCOS have more profound IR or T2D, gestational diabetes, dyslipidemia and risk of 
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cardiovascular disease and greater level of androgens due to low levels of SHBG.  Ethnicity, 
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genetic background, personal and family history, degree of obesity must all be taken into 
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account because they might aggravate or even trigger metabolic disturbances women with 
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PCOS.  
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Women suffering from PCOS are subjected to a range of symptoms associated with 
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menstrual dysfunction, excess of androgen, which significantly influence the quality of life.  The 
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sweet spot for intervention in PCOS occurs early in patients who don’t yet desire pregnancy and 
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who are experiencing the classic PCOS progressive weight gain.  This occurs at an early age, 
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before or around the time of puberty.  Aggressive treatment at this stage will reduce the risk of a 
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host of potential health problems later.  In addition to infertility issues, these include increased 
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long-term risks of diabetes, hypertension, dyslipidemia, metabolic syndrome, endometrial 
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cancer, obstructive sleep apnea, and nonalcoholic fatty liver disease.  Weight reduction is the 
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most important treatment target when PCOS is linked to obesity.  Obese women referred for 
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assistance with weight loss had a prevalence of PCOS of 28.3%.  Obesity is a great problem in 
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women with PCOS and we do not have a conventional satisfactory treatment for it.  Weight 
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management by lifestyle intervention often remains unsatisfactory in obese women with PCOS.  
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Lifestyle interventions remain essential to the management of women with PCOS; however, the 
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majority of non-diabetic obese patients with PCOS do not reach their therapeutic goals with 
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these interventions alone and require pharmacologic therapies. 
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A great deal of attention has been given to the metabolic disturbances that accompany 
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PCOS as well as these disturbances later in life.  The growing body of evidence linking PCOS to an 
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inherited resistance to insulin action, aggravated by lifestyle problems such as obesity, poor diet 
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and physical inactivity has led to trials of drug therapies in patients with PCOS.  Over the last 
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years, considering the importance given to insulin resistance in the pathogenesis of the 
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syndrome, clinical studies have focused on insulin sensitizing drugs for the treatment of women 
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with PCOS, with metformin being the drug most extensively studied in this syndrome.  Although 
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no antidiabetic agents have US Food and Drug Administration approval for the treatment of 
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PCOS, metformin was preferred due to the fact that it had the safest risk-benefit ratio, and could 
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cause weight loss, while thiazolidinediones increased weight as a result of fluid retention.  
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Metformin acts by decreasing hepatic gluconeogenesis and free fatty acid oxidation while 
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increasing peripheral glucose uptake.  Early studies in PCOS suggested that metformin indirectly 
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reduces insulin levels, dyslipidemia and systemic inflammation; however, recent placebo-
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controlled trials failed to demonstrate significant metabolic benefit.  Considerable variability in 
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the metabolic responses to metformin has been observed in women with PCOS, attributable to 
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several potential factors such as different doses of the drug and genetic background.  While 
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metformin is not a weight loss drug it is possible that the weight loss that often accompanies 
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protracted metformin therapy may account for some of the beneficial effects observed in many 
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studies.  Weight loss has been claimed to be a beneficial secondary effect of extended release 
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metformin but the effect is not very consistent.  Metformin has inconsistently demonstrated 
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weight reduction.  In addition, metformin has been shown to have no clinically significant effect 
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in reducing abdominal adiposity.  Interestingly, most studies have not found any beneficial 
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effects of metformin treatment in obese patients with PCOS.  Irrespective of treatment group 
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(after adjustment for baseline BMI and age), only weight loss, but not the use of metformin, was 
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associated with a significant improvement in metabolic and reproductive function in obese 
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women with PCOS.  Furthermore, a number of studies have substantiated the view that obesity 
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may reduce the benefit of metformin treatment. 
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Novelty of Study 
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Polycystic ovary syndrome is now recognized as one of the most common endocrine 
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system disorders among women of reproductive age.  Earlier studies using National Institute of 
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Health criteria estimated PCOS affects between 5% and 10% of the female population ages 18 to 
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44.  The diagnostic criteria used to define PCOS are frequently being modified with the projected 
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figure of affected women using the newer diagnostic criteria to be about one in every 10 to 15 
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women.  .Most women are diagnosed during their twenties or thirties, but recent studies warn 
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that PCOS may affect even prior to age of teens and as young as 11 years of age, much ahead of 
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their puberty.  The economic burden of PCOS is significantly huge.  Around 4 billion dollars are 
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spent annually in the United States to screen for the disease and treat its various morbidities, 
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including hirsutism, infertility, obesity, and diabetes mellitus.   
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The realization that hyperinsulinemia is a key component in the pathogenesis of PCOS 
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provided a basis for advances in treatment strategies for women with the disorder. Lifestyle 
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modification, including diet and exercise, is considered a cornerstone of the management of 
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women with PCOS presenting with obesity, particularly the abdominal phenotype.  PCOS is 
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characterized by a vicious cycle whereby androgen excess favors abdominal fat deposition, 
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which in turn aggravates insulin resistance and compensatory hyperinsulinism, further 
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enhancing ovarian androgen secretion.  Hence, therapeutic strategies ameliorating abdominal 
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adiposity and weight excess may inhibit this vicious cycle, improving not only the metabolic co-
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morbidities of PCOS but also androgen excess and reproductive aberrations for overweight, 
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anovulatory women with PCOS.  Modest weight loss (5-10% of total body weight) can improve 
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ovulation, decrease serum androgen levels and in some cases improve hirsutism.  While weight 
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loss is the key in the treatments of obese patients with PCOS, current non-pharmacologic 
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management of body weight is hard to achieve.  Thus, in the majority of patients with PCOS 
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pharmaceutical intervention is an additional essential therapeutic aid to lifestyle changes.   
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The genetic disruption of insulin signaling in the brain has indicated that this pathway is 
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important for the ovulation and body weight regulation.  These insights have been directly 
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translated into a novel pharmacotherapy aiming to achieve weight loss for obese PCOS patients 
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with insulin-sensitizing drugs such as metformin and use of antidiabetes medications.  The most 
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widely used drug is metformin for women with PCOS and metabolic disturbances, but the weight 
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loss effects of metformin are disputed.  Several studies have shown an increase in insulin 
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sensitivity and pregnancy rate accompanied by decreased insulin and androgen levels in PCOS 
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patients taking metformin but it has limited efficacy in obese women.  Other studies with orlistat 
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and metformin showed a significant reduction in body weight, androgen levels and metabolic 
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cardiovascular risk factors in obese PCOS women.  Recently a number of antidiabetes drugs have 
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been approved which facilitate weight loss and improve the underlying insulin resistance.  
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Incretin mimetics evolved as therapeutic options for the treatment of T2D primarily because of 
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their effects on insulin and glucagon secretion, with weight loss as an additional benefit.  Early 
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studies of human glucagon-like peptide-1 (GLP-1) showed that continuous peripheral infusion 
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was associated with decreased appetite and increased satiety.  Continuous infusion of GLP-1 
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also was shown to improve insulin sensitivity, glycemic control, and pancreatic beta cell function 
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in individuals with T2D.  Weight loss ranging from 2 to 6 kg has been a consistent finding in 
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studies designed to investigate the glycemic benefits of GLP-1 agonists in individuals with T2D.  
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Additionally, this therapy has produced progressive weight loss in obese people without 
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diabetes.  A recent meta-analysis concluded that GLP-1 receptor agonists not only had a 
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significant effect on weight loss in overweight T2D patients but also in non-diabetic overweight 
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persons, reducing subcutaneous fat areas in particular.  The mechanisms of weight loss with 
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GLP-1 agonists are not fully understood but may include changes in energy expenditure, changes 
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in leptin sensitivity, or nausea resulting in decreased food intake.  Available clinical trials of GLP-
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1 receptor agonist therapy in the treatment of excess body weight in women with PCOS 
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demonstrate that exenatide and liraglutide are effective in weight reduction either as 
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monotherapy or in combination with metformin (Elkind-Hirsch et al.2008; Jensterle et al, 2016).  
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One small study has investigated the effect of liraglutide in a subset of obese patients with PCOS 
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and higher metabolic risk profile reporting a significantly greater weight loss with liraglutide in 
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combination with metformin than metformin alone (Jensterle et al, 2015).  Another preliminary 
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report confirmed that liraglutide had an add-on effect on weight loss in obese women with PCOS 
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who had lost <5% body weight during a 6-month pre-treatment with metformin (Jensterle et al, 
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2014a).  Similar to native GLP-1, liraglutide causes glucose-dependent insulin secretion, 
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promotes weight loss and may subsequently improve insulin resistance.  Short-term liraglutide 
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treatment was associated with weight loss and significantly improved eating behavior in obese 
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women with PCOS (Jensterle et al, 2014b).  These studies in women with PCOS also showed that 
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androgens may be modestly decreased and menstrual frequency may be increased (Nylander et 
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al, 2017).  Glucose parameters were generally improved.  We reported that treatment with 
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exenatide for 24 weeks was superior to single agent metformin treatment in improving insulin 
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action and reducing body weight and hyperandrogenism in obese women with PCOS (Elkind-
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Hirsch et al.2008).  We further found exenatide treatment in women with PCOS significantly 
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improved first-phase insulin responses to oral glucose administration.  Since aberrant first-phase 
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insulin secretion and impaired suppression of endogenous glucose production are major 
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contributors to postprandial hyperglycemia and development of T2D, the effects of the GLP-1 
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agonist, liraglutide, to target these defects, and normalize  glucose excursions are likely to be 
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clinically significant in obese patients with PCOS.   
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The drug, liraglutide 3.0 mg was approved for chronic weight management in 
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management in obese adults with an initial BMI of 30 kg/m2 or greater or in overweight adults 
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BMI of 27 kg/m2 or greater with at least one weight-related co-morbid condition as an adjunct to 
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a reduced-calorie diet and increased physical activity.   Liraglutide is an acylated human GLP-1 
287 
analog that binds to and activates the GLP-1 receptor.  It lowers body weight through decreased 
288 
caloric intake while stimulating insulin secretion and reducing glucagon via a glucose-dependent 
289 
mechanism.  For obesity management, patients may lose weight with GLP-1 receptor agonists 
290 
due to other unique actions.  Glucagon-like peptide-1 receptor agonists (GLP-1RAs) can slow 
291 
gastric emptying and increase satiety.  While predictors of weight loss success for the general 
292 
population are available (protein intake, weight loss medications), predictors of weight loss 
293 
success may differ between normal and hyperandrogenic women.  Glucagon-like peptide 1 
294 
agonists are linked with dose dependent weight lowering potential in different obesity related 
295 
populations.  The weight loss effects of GLP-1RAs previously demonstrated in diabetic and obese 
296 
non-diabetic patients, offer a unique opportunity to expand the medical options available to 
297 
patients with PCOS.  Given this lack of information, the aim of the present study was to 
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investigate the effects of liraglutide 3mg vs. placebo on body composition as well as hormonal 
299 
and metabolic features in non-diabetic obese women with PCOS. 
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Study Rationale 
302 
The non-diabetic obese female with PCOS offers a unique model to study the relationship 
303 
between insulin resistance and adiposity.  We propose a double-blind, placebo-controlled 30-
304 
week trial designed to directly examine the therapeutic effects of liraglutide 3 mg (LIRA 3 mg) 
305 
compared to placebo on body weight, hormonal and cardiometabolic parameters in obese non-
306 
diabetic women with PCOS.  All patients will receive diet and lifestyle counseling, including 
307 
advice on exercise commencing during the lead-in period and continuing throughout the study.  
308 
In this study, we will examine the efficacy of LIRA 3mg on body weight and body composition, 
309 
reproductive function metabolic parameters and cardiovascular risk factors in a well-defined 
310 
group of pre-menopausal obese non-diabetic women with hyperandrogenism, focusing on the 
311 
relationship to obesity and insulin resistance.  Women with PCOS demonstrate abnormal body 
312 
composition characterized by a greater percent body fat, body fat mass, and increased ratio of 
313 
fat to lean mass (F/L ratio).  Studies using DEXA methodology report a higher degree of 
314 
metabolic dysfunction in patients with PCOS which appears be directly associated with their 
315 
higher F/L ratio.  The use of DEXA technology that is simple, operator independent, safe, 
316 
accurate and cost-effective will be used to assess fat quantity and distribution. 
317 
There is a growing need to develop pharmacologic interventions to improve metabolic 
318 
function in women with PCOS.  Given that PCOS is a frequent condition and weight loss is 
319 
essential but difficult to achieve, it is important to study if the effect on body weight reported in 
320 
other studies can be confirmed in a selected population of hyperandrogenic patients, especially 
321 
with medications currently approved for weight reduction.  High dose liraglutide alone results 
322 
in significant weight reduction in obese women without PCOS.  There is limited data on weight 
323 
loss with high dose liraglutide in non-diabetic females with PCOS treated with this agent 
324 
(Jensterle et al, 2016).  Studies on the effect of anti-obesity medication combined with lifestyle 
325 
changes on body weight and composition and androgen excess in obese women diagnosed with 
326 
PCOS are lacking.  The investigators aim to elucidate the most efficacious weight reduction 
327 
regime in obese PCOS women.  We hope to determine which treatment(s) addressing the 
328 
multifaceted disturbances of this disorder in patients with PCOS and obesity emerges as the 
329 
preferable therapy. 
330 
Benefit/Risk and Ethical Assessment 
331 
Glucagon-like peptide-1 receptor agonists (GLP-1RA) are peptides that mimic native GLP-
332 
1, binding to its receptors to elicit the same effects, but at much higher pharmacological levels 
333 
than the physiological profiles.  The most common treatment-related adverse effects of GLP-
334 
1RAs are gastrointestinal in nature and include nausea, vomiting, and diarrhea, which are usually 
335 


 
10 
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mild and tend to subside over time.  The GLP-1RAs are usually well-tolerated, with nausea being 
336 
the most significant adverse side effect.  Other documented but infrequent concerns with GLP-1 
337 
receptor agonists include mild injection site reactions.  When looking at the benefit–risk 
338 
assessment, the GLP-1 receptor agonists demonstrate clinical advantages such as reduced risk 
339 
for drug-related hypoglycemia and often favorable effects on body weight. 
340 
Women with PCOS are more likely to be overweight or obese.  Research has increased 
341 
the understanding of the persistent alterations in physiological and behavioral processes that 
342 
contribute to weight gain and hamper weight loss.  Evidence suggests that pharmacotherapy for 
343 
the management of obesity may modify these processes and thereby help individuals adhere to 
344 
diet and exercise regimens, to lose more weight and to maintain weight loss.  Although no 
345 
pharmacological agent is without some risk, LIRA 3mg therapy appears to have wide margins of 
346 
safety when used appropriately.  The robust clinical benefits observed with this pharmacologic 
347 
agent may confer a significant advantage to improve outcomes in patients at high risk of 
348 
developing T2D and cardiovascular disease.  
349 
 
350 
Study Hypothesis 
351 
Randomized, Parallel, Placebo-Controlled, Double-Blind Prospective Study Trial 
352 
This is a prospective double-blind randomized outpatient drug efficacy study comparing 
353 
the use of liraglutide (3 mg) to placebo in nondiabetic obese women with polycystic ovary 
354 
syndrome.  Seventy-two women will be allocated to treatment, in a 2:1-subject distribution 
355 
ratio, with a daily regimen liraglutide 3.0 mg or placebo (see Figure 1-Flow of Patients through 
356 
Trial) for 28-30 weeks of intervention.  We hypothesize that the use of the GLP-1 agonist 
357 
liraglutide 3.0 mg (LIRA 3mg) compared with placebo in obese women with PCOS will lead to a 
358 
beneficial reduction in biochemical hyperandrogenism due to greater reduction in body weight.   
359 
The resulting weight loss will assist in decreasing insulin resistance leading to improved 
360 
hormonal and cardiometabolic parameters in this patient population., To investigate this, we 
361 
will perform a randomized double-blind clinical trial (RCT) treating obese women with PCOS with 
362 
either liraglutide or placebo for 28-30 weeks. 
363 
STUDY OBJECTIVES 
364 
 
365 
Primary objective 
366 
The primary objectives of this study are to compare the therapeutic impact of liraglutide 
367 
3 mg versus placebo on reduction of body weight and biochemical hyperandrogenism (as 
368 
determined by the free androgen index) in obese non-diabetic women with PCOS. We will 1) 
369 
determine the percentage of participants achieving ≥5% reduction in baseline body weight with 
370 
each treatment and 2) assess the inhibition of biochemical hyperandrogenism (ovarian androgen 
371 
production and sex hormone binding capacity) in response to each treatment. 
372 


 
11 
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Secondary study objectives  
373 
The secondary study objectives are to determine the effect of treatment with anti-
374 
obesity medication versus placebo on anthropometric, clinical, hormonal and metabolic 
375 
parameters in non-diabetic obese women with hyperandrogenism.  
376 
 
377 
EFFICACY VARIABLES/MEASURES 
378 
Primary endpoints 
379 
The co-primary end points are to compare obese women with PCOS receiving liraglutide 3mg 
380 
(LIRA 3 mg) with those receiving placebo on body weight and bioavailable ovarian androgen 
381 
concentrations as determined by: 
382 
1a. 
percent change in body weight from baseline to week 30 and  
383 
1b 
percentage of participants achieving ≥5% reduction in body weight from baseline 
384 
to week 30  
385 
2 
reduction of free androgen index [FAI=testosterone (T)/sex hormone binding 
386 
globulin (SHBG) levels] from baseline to 30 weeks 
387 
Secondary endpoints 
388 
We will further examine the impact of the administration of these pharmacotherapies in obese 
389 
non-diabetic PCOS women on: 
390 
Anthropometric and Clinical Indices 
391 
1. Change from baseline of body mass index [BMI], absolute body weight, waist 
392 
circumference (WC), waist: hip ratio (WHR) , waist-height ratio (WHtR), and whole-body 
393 
dual-energy X-ray absorptiometry [DXA]) measures of body composition (trunk fat mass 
394 
and truck fat/extremities fat ratio ) to determine the relative contribution of changes in 
395 
fat mass (FM) vs. lean mass (LM) to overall weight loss at week 30 
396 
2. Compare women with hyperandrogenism for frequency of patients achieving a body 
397 
weight reduction of at least 10% [Time Frame from baseline to 30 weeks] 
398 
3. Change in menstruation frequency (normalized to the number of menstruations per 
399 
year) from before and after 30 weeks of treatment 
400 
Metabolic Parameters 
401 
1. Change in glycemic values from baseline to 30weeks 
402 
2. Fasting and 2 hour glucose levels after an OGTT 
403 
3. Surrogate measures of insulin action derived from 75 gram OGTT [insulin sensitivity index 
404 
(HOMA-IR, Matsuda index), corrected early insulin secretory response (insulinogenic 
405 
index/HOMA-IR), area under the curve (AUC) for insulin and glucose, and oral disposition 
406 
index (product of Matsuda index and insulinogenic index; SIOGTT x Δinsulin 30–0 min to 
407 
glucose 30–0 min)] 
408 


 
12 
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Cardiovascular Risk Factors (change from baseline to 30 weeks) 
409 
1. Plasma lipid fractions 
410 
2. Blood pressure 
411 
Other endocrine levels (change from baseline to 30 weeks) 
412 
1. Adrenal androgen concentration- dehydroepiandrosterone sulfate (DHEAS) levels 
413 
The following will be documented for each patient: 
414 
1. Presence of polycystic ovary syndrome (PCOS) will be recorded using modified National 
415 
Institutes of Health (NIH) criteria which are inclusive of presence of oligo-/amenorrhea 
416 
(cycle >35 days or <8 cycles year), and clinical and/or biochemical hyperandrogenism, 
417 
after exclusion of related disorders.  Other causes to bleeding irregularities and androgen 
418 
excess will be excluded. 
419 
2. Metabolic syndrome (MetS) will also be documented and defined (2005 National 
420 
Cholesterol Education Program, Adult Treatment Panel III) as the presence of at least 
421 
three of the following criteria: abdominal obesity (waist circumference >80 cm in 
422 
women); serum triglycerides ≥1.7 mmol/L; serum HDL <1.3 mmol/L; systolic blood 
423 
pressure ≥130 mmHg and/or diastolic blood pressure ≥85 mmHg; and fasting plasma 
424 
glucose ≥7.0 mmol/L 
425 
 
426 
Safety variables/Measures 
427 
Safety and tolerability will be assessed by collating data on treatment-emergent adverse 
428 
events (AE), laboratory tests, physical examinations, and vital signs.  Prevention of pregnancy 
429 
will be monitored monthly by both laboratory and home pregnancy testing.  All patients will be 
430 
educated about not becoming pregnant and perform monthly urine home pregnancy tests 
431 
during the months that they do not have laboratory evaluations.  Patients will be educated 
432 
about the side effects and use of liraglutide 3.0 mg and the injection delivery system.  Liraglutide 
433 
3.0 mg is a well-tolerated long-term weight loss agent.  The most common expected AEs 
434 
(prevalence >5%) are nausea, diarrhea, constipation, vomiting, dyspepsia, fatigue, dizziness, and 
435 
abdominal pain (see reference 77 - prescribing information).  Patients will be asked about the 
436 
most common adverse events related to liraglutide such as nausea, headache, diarrhea, 
437 
constipation and vomiting if not volunteered.  This protocol and the associated Informed 
438 
Consent as well as any addenda or amendments, must be reviewed and approved by the 
439 
Woman’s Hospital Institutional Review Board (WHIRB) review committee prior to the start of the 
440 
study.  All revisions to this Protocol are considered “protocol amendments; these must be 
441 
approved in advance, in writing, by the WHIRB.  Every patient will have given her written 
442 
informed consent prior to participating in the study.  Prior to participation in this trial, each 
443 
subject will have an opportunity to ask questions and will sign (and date) a written Informed 
444 
Consent, which must be witnessed.  The signed consent forms will be filed with the 
445 


 
13 
Version 6, 5/15/18 
investigator's study charts for each subject.  Any subject may voluntarily withdraw from the 
446 
study at any time without prejudicing treatment. 
447 
 
448 
STUDY PLANS AND PROCEDURES 
449 
Subjects 
450 
Up to 92 non-diabetic women with PCOS, aged 18 years to 45 years of age, meeting BMI 
451 
criteria, will be invited to participate.  We will define hyperandrogenism using biochemical 
452 
evidence (elevated testosterone and/or free androgen index with exclusion of androgen 
453 
secreting tumors).  Subjects will be recruited using flyers distributed in the metabolic clinic, 
454 
gynecology clinics and pathology laboratory associated with Woman’s Hospital.  All participants 
455 
will be provided a written informed consent and be asked to sign a copy before being enrolled in 
456 
the study.  The Woman’s Hospital Institutional Review Board (WHIRB) will have approved both 
457 
the protocol and consent.  All subjects will undergo a verbal screen, and if they are eligible and 
458 
sign a medical release form, their medical records will be obtained to confirm their medical 
459 
history. All subjects will provide a medical and gynecological history including assessment of 
460 
regularity and length of the menstrual cycle, with recording of menses in the 12-month period 
461 
before the study.  Patients will be specifically asked about the number of menses in previous 12 
462 
months (menstrual frequency).  To be eligible for the study, subjects will be required to have 
463 
irregular periods (cycle length outside 24–35 days or <8 cycles per year).  All enrolled patients 
464 
will then undergo baseline clinical and laboratory evaluations to exclude diabetes, thyroid 
465 
disorder, 
significant 
hyperprolactinemia, 
elevated 
liver 
enzymes 
and/or 
severe 
466 
hypertriglycidemia.  A negative serum pregnancy test is a prerequisite for commencing 
467 
treatment.  Subjects will be instructed to use an IUD or double barrier methods of contraception 
468 
(unless sterilized) during the study since hormonal methods are not permitted. Glycemic status 
469 
will be measured at the beginning and end of each treatment period by a standard 75 g oral 
470 
glucose tolerance test (OGTT).  Obese women who meet study eligibility criteria (see inclusion 
471 
and exclusion criteria) will be eligible to be randomized to treatment.  We anticipate that 72 
472 
women will be randomized to treatment (this allows for 20 women to fail screening).  Exclusion 
473 
criteria include any condition, which in the opinion of the investigator would place the subject at 
474 
increased risk or otherwise make the subject unsuitable for participation in the study.  
475 
Key Inclusion Criteria 
476 
 Female gender 
477 
  18-45 years of age 
478 
  BMI ≥30 kg/m2 or BMI ≥27 kg/m2 with one or more obesity-associated co-morbid 
479 
conditions (e.g. hypertension, and dyslipidemia)  
480 


 
14 
Version 6, 5/15/18 
 PCOS- NIH criteria hyperandrogenism and irregular menstrual cyclicity 
481 
 Non-diabetic as determined by a 75 gram oral glucose tolerance test (OGTT) and 
482 
hemoglobin A1C.  Non-diabetic is inclusive of women with impaired fasting glucose (IFG), 
483 
impaired glucose tolerance (IGT), or both (IFG/IGT).  Participants with diabetes will be 
484 
excluded 
485 
 Willing to use effective contraception consistently during therapy which is defined as: 
486 
o an intrauterine device, tubal sterilization, or male partner vasectomy, or 
487 
o combination of two barrier methods with one being male condom. 
488 
 Written consent for participation in the study 
489 
Key Exclusion Criteria 
490 
 Presence of significant systemic disease, cerebrovascular disease, clinically significant 
491 
cardiac abnormalities or heart problems including congestive heart failure, unstable 
492 
angina or acute myocardial infarction, current infectious liver disease, acute stroke or 
493 
transient ischemic attacks,  history of pancreatitis, or diabetes mellitus (Type 1 or 2) 
494 
 Any hepatic diseases in the past (infectious liver disease, viral hepatitis, toxic hepatic 
495 
damage, jaundice of unknown etiology) or severe hepatic insufficiency and/or significant 
496 
abnormal liver function tests defined as aspartate aminotransferase (AST) >3x upper limit 
497 
of normal (ULN) and/or alanine aminotransferase (ALT) >3x ULN 
498 
 Renal impairment (e.g., serum creatinine levels ≥1.4 mg/dL for women, or eGFR <60 
499 
mL/min/1.73 m2) or history of unstable or rapidly progressing renal disease or end stage 
500 
renal disease.  
501 
 Uncontrolled thyroid disease (documented normal TSH), Cushing’s syndrome, congenital 
502 
adrenal hyperplasia or clinically significant elevations in prolactin levels. The clinical 
503 
significance of prolactin levels will be determined by the treating physician 
504 
 Significantly elevated triglyceride levels (fasting triglyceride > 400 mg %)  
505 
 Untreated or poorly controlled hypertension (sitting blood pressure > 160/95 mm Hg) 
506 
 Use of hormonal medications, the use of medications that cause clinically significant 
507 
weight gain or loss (prescription or OTC) and medications known to exacerbate glucose 
508 
tolerance 
(such 
as 
isotretinoin, 
hormonal 
contraceptives, 
GnRH 
analogues, 
509 


 
15 
Version 6, 5/15/18 
glucocorticoids, anabolic steroids, C-19 progestins) including herbal medicines for at least 
510 
8 weeks. Use of anti-androgens that act peripherally to reduce hirsutism such as 5-alpha 
511 
reductase inhibitors (finesteride, spironolactone, flutamide) for at least 4 weeks 
512 
 Prior history of a malignant disease requiring chemotherapy 
513 
 Family or personal history of familial medullary thyroid carcinoma or multiple endocrine 
514 
neoplasia type 2 
515 
 Known hypersensitivity or contraindications to use GLP1 receptor agonists  
516 
 Use of metformin, thiazolidinediones, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT2 
517 
inhibitors or weight loss medications (prescription or OTC) stopped for at least 4 weeks 
518 
 Prior use of medication to treat diabetes except gestational diabetes  
519 
 Eating disorders (anorexia, bulimia) or gastrointestinal disorders 
520 
 Suspected pregnancy (documented negative serum ßhCG test), desiring pregnancy in 
521 
next 15 months, breastfeeding, or known pregnancy in last three months 
522 
 Active or prior history of substance abuse (smoke or tobacco use within past 6 months) 
523 
or significant intake of alcohol 
524 
 Previous bariatric surgery or device intervention for obesity 
525 
 Patient not willing to use barrier contraception during study period (unless sterilized or 
526 
have an IUD) 
527 
 History of major depressive or other severe psychiatric disorders 
528 
 Inability or refusal to comply with protocol 
529 
 Currently participating or having participated in an experimental drug study in previous 
530 
three months 
531 
 
532 
STUDY PLANS AND PROCEDURES 
533 
Treatment Regimen 
534 
Obese non-diabetic women with PCOS will be treated for 28-30 weeks with either 
535 
liraglutide 3 mg (LIRA 3mg) or placebo (see Figure 1-Flow of Patients through Trial).   
536 
 
537 


 
16 
Version 6, 5/15/18 
 
538 
Study Assessments 
539 
Following written consent, all participants will undergo the following clinical, metabolic 
540 
and laboratory evaluations before, during and after 30 weeks of treatment.  To ensure that 
541 


 
17 
Version 6, 5/15/18 
patients remain unidentified, all study subjects will be assigned an individual study identifier 
542 
which includes the study acronym, patient initials, and unique number. All blood samples will be 
543 
obtained and results identified and reported using this unique study identifier. 
544 
A. Baseline (Pretreatment) assessment- A full physical examination will be performed and 
545 
vital signs (blood pressure, respiration and temperature) determined.  Trained personnel using 
546 
standardized protocols at the baseline and follow-up examination will obtain anthropometric 
547 
measurements and blood specimens.  Absolute body weight, height, waist and hip 
548 
circumference, body fat distribution (waist/hip {WHR}) and waist/height ratio ({WHtR}) and 
549 
blood pressure (BP) will be determined.  Body weight will be measured to the nearest 0.1 kg 
550 
using a calibrated digital scale with participants in light clothing and no shoes.  Height will be 
551 
measured to the nearest centimeter.  The total body adiposity (total fatness), defined as the 
552 
accumulation of body fat without regard to regional distribution, will be expressed as BMI and 
553 
calculated as weight (kg)/ height (m) 2.  The circumference measurements will be taken in the 
554 
upright position using a 15-mm width flexible metric tape held close to the body but not tight 
555 
enough to indent the skin.  Waist circumference (WC) will be measured at the narrowest level 
556 
midway between the lowest ribs and the iliac crest and hip circumference measured at the 
557 
widest level over the buttocks while the subjects are standing and breathing normally.  The WHR 
558 
and WHtR will be calculated for measure of body fat distribution. 
559 
Oral glucose tolerance tests (OGTTs) with glucose (G) and insulin (I) measured at 0, 30, 60, 
560 
and 120 after glucose load to assess diabetes, fasting (FBG) and mean blood glucose (MBG) 
561 
concentrations, insulin resistance and pancreatic beta-cell function will be determined prior to 
562 
randomization and at 30-32 weeks after full doses of study medications are reached.  Mean 
563 
blood glucose (MBG) concentrations will be calculated by summing glucose values obtained at 
564 
0,30,60 and 120 minutes during the OGTT and dividing by 4.  At the initial lab evaluation, a 
565 
complete metabolic profile (Chem 12) and calculated eGFR, TSH, prolactin, hemoglobin A1C, and 
566 
beta-hCG levels will be determined for study inclusion.  A baseline blood sample will also be 
567 
used to measure an androgen profile (total testosterone [T], dehydroepiandrosterone sulfate 
568 
[DHEAS], sex hormone-binding globulin [SHBG]), and a lipid panel (total cholesterol, high-density 
569 
lipoprotein [HDL-C], low-density lipoprotein [LDL-C], and triglycerides [TRG]. 
570 
Body composition analyses will be performed using dual-energy x-ray absorptiometry 
571 
(DXA) (Hologic Discovery A model, software version 12.5; Hologic, Inc., Waltham, MA) at the 
572 
start and completion of the study trial.  For the scan, the participants will be asked to change 
573 
into a hospital gown and asked to lie supine on on the table with hands by the side palms facing 
574 
down away from the thighs and look at the ceiling to maintain head position.  DXA can estimate 
575 
3 body compartments consisting of fat mass, lean body mass, and bone mass.  The relative 
576 
attenuation of two different x-ray energies by body tissues produces a three-component model 
577 
comprising total fat mass (FM), total lean mass (LM including fluid and muscle), and total body 
578 
bone mineral content (BMC) and density.  DXA also has the ability to determine body 
579 


 
18 
Version 6, 5/15/18 
composition in defined regions such as the arms, legs, and trunk.  DXA measurements are based 
580 
in part on the assumption that the hydration of fat-free mass remains constant at 73%.  Total 
581 
body fat mass [FM]) and fat content of head, trunk and extremities (arms+ legs) is provided by 
582 
the software.  Default software readings provide lines positioned to divide the body into six 
583 
compartments, i.e. head, trunk, arms and legs.  The trunk is defined by a horizontal line below 
584 
the chin, vertical lines between trunk and arms and oblique lines passing through the colli 
585 
femuri.  The region below this lower border of the trunk, including both legs and the hip region 
586 
is called lower body region.  For each region of the whole body, fat and lean body mass and BMC 
587 
are determined.  Standard software options are used to calculate the total fat-free mass (FFM), 
588 
fat mass (FM) vs. lean mass (LM).   
589 
For a better description of the sex specific fat distribution the fat distribution index (FDI) 
590 
will be calculated as:  
591 
FDI = Upper body fat mass in kg/Lower body fat mass in kg 
592 
A fat distribution index below 0.9 indicates a gynoid fat distribution, i.e. the fat mass of the 
593 
lower body surpassed the fat mass of the upper body.  A fat distribution index >1.1 defines an 
594 
android fat distribution. In this case the amount of fat tissue of the abdominal region surpassed 
595 
the fat mass of the lower body.  An FDI between 0.9 and 1.1 is classified as an intermediate 
596 
stage of fat distribution. We will use the FDI for further quantification of the fat distribution 
597 
compared to the widely used waist to hip ratio.  The WHR describes body shape and silhouette 
598 
while the FDI provides the quantitative amount of fat distribution.  Nevertheless we have to be 
599 
aware that the FDI describes not the ratio of abdominal fat to gluteal-femoral fat, but the ratio 
600 
between upper body fat, including abdominal fat and breast fat mass, and lower body fat. 
601 
Following baseline screening, eligible patients will be randomly assigned, in a 2:1 ratio, to 
602 
receive once-daily subcutaneous injections of liraglutide, starting at a dose of 0.6 mg with 
603 
weekly 0.6-mg increments to 3.0 mg, or placebo; both groups will also receive counseling on 
604 
lifestyle modification.  All subjects will be allocated to one of these 2 groups based on computer-
605 
generated random numbers using a block randomization method.  The randomization list will be 
606 
generated at the study site by the unblinded research assistant.  Liraglutide and placebo will be 
607 
provided in pre-filled pens (Novo Nordisk).  The study drug (liraglutide and placebo) will 
608 
delivered in identical prefilled pens, labeled with serial numbers and accompanied by a 
609 
dispensing unit list.  Printed directions for use of the medication will be handed out to subjects 
610 
before administration of trial drug.  All patients will receive the same instructions on how to 
611 
take the medicine.  As investigators and participants are blinded to drug assignment, an 
612 
independent unblinded research assistant will instruct the investigators as to which serial 
613 
numbers to supply each woman with.  The participants will be randomized in a 2:1 ratio 
614 
(liraglutide: placebo), as we believe that this will facilitate the recruitment to the study. 
615 
B. Treatment- all patients will be dispensed 5 months (18 weeks) of liraglutide 3 mg (LIRA 3 
616 
mg) treatment or placebo and 4 home pregnancy test kits. 
617 


 
19 
Version 6, 5/15/18 
Patients on LIRA -Start injection 0.6 mg SC QD 1week, step up to 1.2 mg SC QD 1 week, to 
618 
1.8 mg SC QD 1 week, 2.4 mg SC QD 1week, to a max dose of 3.0 mg SQ daily.  
619 
Patients on PL -Start injection 0.6 mg SC QD 1week, step up to 1.2 mg SC QD 1 week, to 
620 
1.8 mg SC QD 1 week, 2.4 mg SC QD 1week, to a max dose of 3.0 mg SQ daily. 
621 
All patients will be called monthly to document the results of their home pregnancy tests 
622 
and to assess compliance with the medication.  Patients will receive the same counseling 
623 
concerning the benefits of lifestyle modification through diet and exercise.  The patients will be 
624 
also encouraged to increase daily exercise (such as walking, using stairs) although this will not be 
625 
formally assessed.  The participants will receive further encouragement to adhere to the regime 
626 
by frequent contact using follow-up phone calls.  Side effects of the treatment and reason for 
627 
any withdrawals from the study will be recorded.  
628 
C. Week 16-18 assessment- Patients will return to clinic for an 18-week re-evaluation of 
629 
clinical and anthropometric variables (height, weight, body mass index [BMI], waist and hip 
630 
circumference and blood pressure) and a safety assessment.  A serum pregnancy test and 
631 
complete metabolic profile (Chem 12) and calculated eGFR will also be performed.  Side effects 
632 
of the treatment and reason for any withdraws from the study will be recorded.  Another 18 
633 
weeks of medication will be dispensed and 4 home pregnancy test kits following a negative 
634 
serum pregnancy test. 
635 
D. Final (week 30-32) assessment- After 28 weeks of treatment, patients will be 
636 
scheduled for final evaluation.  They will be instructed to stop medications 1 week prior to their 
637 
laboratory assessment visit.  All laboratory tests (except prolactin, TSH and hemoglobin A1C) will 
638 
be repeated.  All anthropometric parameters and physical including vital signs and DXA will again 
639 
be performed and calculations will be repeated for post-treatment effects.   
640 
 
641 
During the study period, cycle control will be assessed daily by the subjects using a 
642 
menstrual diary.  Vaginal bleeding will be classified by the subject as either spotting (requiring at 
643 
least one pad/tampon per day) or bleeding (two or more pads/ tampons per day).  The effects of 
644 
treatment intervention on menstrual abnormalities will be evaluated by assessing post-
645 
treatment changes in menstruation frequency over 30 weeks from the patient’s menstrual cycle 
646 
diary and normalized to the number of menstruations per year (52 weeks). 
647 
All side-effects will also be recorded and summarized for the 30 week-treatment period.  
648 
During the whole study period, compliance to the treatment will be documented.  Compliance 
649 
with treatment will be checked by questioning about the side-effects and a subjective evaluation 
650 
of the tolerability of the administered drug; the patients will also asked about incidental missed 
651 
administrations and whether they had correctly followed the scheduled treatment.  Questioning 
652 
regarding the occurrence of adverse events and use of concomitant medication will take place 
653 
throughout the trial.  
654 
 
655 


 
20 
Version 6, 5/15/18 
Study Medication 
656 
Study Drug Storage- All investigational products (study drugs) will be stored under 
657 
appropriate storage conditions in a secure area according to local regulations. The investigator is 
658 
responsible for ensuring that it is dispensed only to study subjects and only from official study 
659 
sites by authorized personnel, as dictated by local regulations. The investigator is responsible for 
660 
ensuring that the investigational product is stored under the appropriate environmental 
661 
conditions (temperature, light, and humidity), as noted in the product labeling.  Novo Nordisk 
662 
will supply all investigational products.  The distribution of all supplied medications is the 
663 
investigators’ responsibility.   
664 
Study Drug Records- It is the responsibility of the investigator to ensure that the 
665 
unblinded study coordinator maintains a current disposition record of investigational product. 
666 
Records or logs must comply with applicable regulations and guidelines and should include: 
667 
 amount received and placed in storage area; amount currently in storage area 
668 
 label ID number or batch number  
669 
 amount dispensed to and returned by each subject, including unique subject 
670 
identifiers 
671 
 non-study disposition (e.g., lost, wasted)  
672 
 amount destroyed at study site 
673 
 dates and initials of person responsible for Investigational Product dispensing/ 
674 
accountability. 
675 
Destruction of Investigational Product- If the study drugs are to be destroyed on site, it is 
676 
the investigator’s responsibility to ensure that arrangements have been made for disposal, and 
677 
that procedures for proper disposal have been established according to applicable regulations, 
678 
guidelines, and institutional procedures.  Appropriate records of the disposal will be maintained. 
679 
 
680 
Biological Sampling Procedures 
681 
Laboratory Measures  
682 
Hormonal and metabolic parameters will be measured at baseline and 30 weeks of 
683 
treatment.  All participants will undergo a standard 2-h oral glucose tolerance test (OGTT) after 
684 
an overnight fast (10–12 h).  Blood samples for the determination of glucose and insulin levels 
685 
will be obtained in the fasting state (time 0) and collected at 1/2, 1, and 2 h after a standardized 
686 
75 g oral glucose load (OGTT with INS).  Blood samples will be centrifuged, divided into aliquots, 
687 
and assayed.  Plasma glucose levels will be determined with a glucose analyzer using the glucose 
688 
oxidase method (Glucose Reagent Kit, Bayer Newbury, UK).  Serum insulin will be determined in 
689 
all samples in duplicate by microparticle enzyme immunoassay (Abbott AxSYM System, Abbott 
690 
Laboratories, Abbott Park, IL).  Levels of total cholesterol, high-density lipoprotein cholesterol 
691 
(HDL-C) and triglycerides will be determined in the initial basal sample using standard enzymatic 
692 
colorimetric assays on an automated clinical chemistry analyzer whereas low-density lipoprotein 
693 


 
21 
Version 6, 5/15/18 
cholesterol (LDL-C) will be calculated according to the Friedewald equation.  Electrolytes, serum 
694 
creatinine, and liver enzymes will be measured using standard automated kinetic enzymatic 
695 
assay.  Circulating levels of TSH, prolactin, ß human chorionic gonadotropin (ßhCG), testosterone, 
696 
sex-hormone binding globulin (SHBG) and DHEAS will be measured using a two-site sandwich 
697 
immunoassay with direct chemiluminometric technology (Diagnostic Products, Los Angeles, CA).  
698 
The intra- and interassay coefficients of variation are less than 7 and 11%, respectively, over the 
699 
sample concentration range.   
700 
Assessment of Insulin Sensitivity and Secretion 
701 
Indices of insulin sensitivity and secretion using the serum glucose and insulin 
702 
concentrations obtained in the fasting state and during the 2hr OGTT will be computed by 
703 
several previously validated measures.  Fasting and glucose-stimulated insulin sensitivity will be 
704 
estimated by homeostasis model assessment of insulin sensitivity (HOMA-IR) and by Matsuda's 
705 
insulin sensitivity index (SIOGTT).  Early pancreatic beta (β)-cell response will be estimated as the 
706 
insulinogenic index (IGI) derived from the ratio of the increment of insulin to that of glucose 30 
707 
minutes after a glucose load (insulin 30 min − insulin 0 min/glucose 30 min − glucose 0 min) 
708 
corrected for by the relative level of insulin resistance (IGI/HOMA-IR).  The area under the curve 
709 
(AUC) for glucose and insulin will be calculated using the mathematical model developed by Tai 
710 
using measures obtained during the OGTT.  An estimation of β-cell compensatory function, the 
711 
insulin secretion-sensitivity index (IS-SI) will be derived by applying the concept of the 
712 
disposition index to measurements obtained during the 2-h OGTT.  The composite IS-SI is 
713 
defined as the product of 1) insulin secretion as measured by insulinogenic index (IGI) and 2) 
714 
insulin sensitivity as measured by the Matsuda index (ΔINS/ΔGLU 30 x Matsuda SIOGTT).  The IS-SI 
715 
is a validated OGTT-derived measure of β-cell function analogous to the disposition index 
716 
obtained from the intravenous glucose tolerance test.  Improving β-cell compensatory function 
717 
(increasing insulin sensitivity and enhancing insulin release after an oral glucose load) is 
718 
reflective of improvement and/or delays in declining glucose tolerance. 
719 
The most frequent biochemical parameters of androgen excess include elevated total 
720 
testosterone or free androgen index (FAI). Baseline blood samples will be collected for 
721 
measurement of total testosterone (T) and sex hormone-binding globulin (SHBG) 
722 
concentrations. The free androgen index (FAI) is calculated from the total T concentration 
723 
(nmol/l)/ concentration of SHBG (nM/L) x100.  While clinical markers of hyperandrogenism in 
724 
females include cutaneous manifestations such as the presence of acne, hirsutism and/or male 
725 
pattern alopecia, many of these will not be altered with 30 weeks of therapy.     
726 
 
727 
Collateral Research 
728 
Several other endpoints will be assessed at each study visit.  Baseline blood samples will 
729 
also be collected for measurement of lipid profiles (cholesterol, HDL and LDL cholesterol, and 
730 


 
22 
Version 6, 5/15/18 
triglycerides), adrenal androgens (DHEAS), and liver enzymes (AST/ALT).  Dyslipidemia is defined 
731 
as the presence of at least one of the mentioned lipid parameters abnormalities. 
732 
Safety assessments 
733 
The safety and tolerability assessments will include incidence and intensity of adverse 
734 
events, withdrawals because of adverse events, physical exams, vital sign measurements and 
735 
clinical laboratory parameters.  Patients will be seen at 16-18 weeks and 30-32 weeks for 
736 
laboratory evaluation for a complete chemistry profile and to confirm they are not pregnant. 
737 
Patients will also be required to perform monthly home pregnancy tests. 
738 
STATISTICAL/ANALYTICAL PLAN 
739 
Statistical Methods  
740 
Statistical analysis will be performed using SPSS version 15.1 for Windows (SPSS, Inc.; 
741 
Chicago, IL).  Continuous variables will be tested for normality of distribution using the 
742 
Kolmogorov-Smirov test.  When necessary, non-normally distributed data will be subjected to 
743 
logarithmic or square-root transformation to obtain a normal distribution where necessary for 
744 
subsequent analyses.  The primary endpoints are comparison of percent change in body weight 
745 
and therapeutic impact on biochemical hyperandrogenism (as determined by FAI) from baseline 
746 
to week 30 of treatment.  The secondary endpoints include changes in surrogate measures of 
747 
insulin action (HOMA-IR, SIOGTT, IGI/HOMA-IR and IS-SI) and glycemic parameters (fasting blood 
748 
glucose [FBG] and 2 hour post OGTT glucose), glucose and insulin AUC, and mean blood glucose 
749 
(MBG), anthropometric parameters (BMI, absolute weight, WC and fat distribution by DXA), 
750 
blood pressure, lipid profiles, and adrenal androgen levels (DHEAS).  Direct and indirect 
751 
estimates of insulin sensitivity and secretion (HOMA, SIOGTT, IGI/HOMA, β-cell compensatory 
752 
function, glycemic parameters (FBG, MBG, 2 hour post OGTT glucose level, AUC) anthropometric 
753 
measurements (body weight, BMI), fat distribution (WC, WHR and WHtR), BP, androgen and 
754 
lipid profiles will be considered as dependent variables.   
755 
For all analyses, in which the measures are continuous, data from evaluable subjects will 
756 
be submitted to a repeated-measures general linear model (SS/ Drug treatments x repeated 
757 
measures ANOVA) including the arm of drug treatment (liraglutide 3mg vs. placebo) as the 
758 
between-subjects effect, and the visit (baseline and 30 wks) as the within-subjects effect.  To 
759 
evaluate the differences in the response to each treatment over visits, the interaction effect will 
760 
be calculated.  Baseline comparisons between groups will be made by one-way ANOVAs. 
761 
Frequency of patients achieving a body weight reduction of at least 5% and 10% before 
762 
and after treatment will be compared with the McNemar test (complex chi square [χ2] for 
763 
paired data), which formally tests for a change between the observed proportions of k related 
764 
samples.  Dysglycemia occurrence before and after different treatment will also be compared 
765 


 
23 
Version 6, 5/15/18 
with the McNemar test.  The difference in frequency of menstruation before and after 
766 
treatment will also be compared using the McNemar test.  
767 
Data will be analyzed on completed treatment parameters where relevant (evaluable 
768 
population).  The evaluable population is defined as all randomized subjects who complete 
769 
treatment through week 30-32 week.  Results will be reported as mean +/- S.E.M for normally 
770 
distributed data and as median (interquartile range) if the distribution is not normal. Categorical 
771 
data will be presented as percentage.  P < 0.05 is considered statistically significant. 
772 
 
773 
Sample Size and Justification 
774 
A priori sample size analysis was performed using the online calculator provided by the 
775 
Massachusetts 
General 
Hospital 
Mallinckrodt 
General 
Clinical 
Research 
Center 
776 
(http://hedwig.mgh.harvard.edu/sample_size/size.html).  To calculate sample size, we used the 
777 
standard formula suggested for clinical trials by considering a type one error (α) of 0·05 and type 
778 
two error (β) of 0·20 (power = 80%).  Sample size calculation revealed that 57 participants 
779 
randomized in a 2:1 ratio (liraglutide: placebo) were needed.  Using a 30% drop-out rate, the 
780 
study is designed to recruit 92 patients, enroll 48 liraglutide and 24 placebo to ensure that the 
781 
number of subjects completing the study (38 LIRA/19 PL) as derived by the sample size 
782 
calculation is met. 
783 
 
784 
Ethical and Regulatory Requirements 
785 
This protocol and the associated Informed consent as well as any addenda or 
786 
amendments, must be reviewed and approved by the Woman’s Hospital Foundation 
787 
Institutional Review Board (WHIRB) review committee prior to the start of the study.  
788 
Recruitment materials and advertising must be reviewed and approved by the WHIRB prior to 
789 
use.  All revisions to this Protocol are considered “protocol amendments” these must be 
790 
approved in advance, in writing, by the WHIRB.  Every patient will have given her written 
791 
informed consent prior to participating in the study.  Prior to participation in this trial, each 
792 
subject will have an opportunity to ask questions and will sign (and date) a written Informed 
793 
Consent, which must be witnessed.  The signed consent forms will be filed with the 
794 
investigator's study charts for each subject.  A copy of the informed consent will be provided to 
795 
the subject.  Any subject may voluntarily withdraw from the study at any time without 
796 
prejudicing treatment. 
797 
Good Clinical Practice - This study will be conducted in accordance with Good Clinical 
798 
Practice (GCP), as defined by the International Conference on Harmonization (ICH) and in 
799 
accordance with the ethical principles underlying the United States Code of Federal Regulations, 
800 
Title 21, Part 50 (21CFR50).  The study will be conducted in compliance with the protocol.  All 
801 
potential serious breaches must be reported to Novo Nordisk (NOVO) immediately.  A serious 
802 
breach is a breach of the conditions and principles of GCP in connection with the study or the 
803 


 
24 
Version 6, 5/15/18 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental 
804 
integrity of the subjects of the study or the scientific value of the study. Study personnel 
805 
involved in conducting this study will be qualified by education, training, and experience to 
806 
perform their respective tasks.  This study will not use the services of study personnel where 
807 
sanctions have been invoked or where there has been scientific misconduct or fraud (e.g., loss of 
808 
medical licensure; debarment).  
809 
The United States Food and Drug Administration (FDA) have assigned pregnancy category 
810 
X to Saxenda (3 mg liraglutide).  Studies in animals or humans have demonstrated there is 
811 
positive evidence of human fetal risk based on adverse reaction data from investigational or 
812 
marketing experience, and the risks involved in use of the drug in pregnant women clearly 
813 
outweigh potential benefits.  Safer alternatives exist.  If patients become pregnant during the 
814 
study, all medications will be stopped and the patient will discontinue from the study. 
815 
For safety, all subjects who enter the study are evaluable.  Subjects will be monitored for 
816 
safety by assessment of adverse events, physical exams, vital signs and laboratory values.  
817 
Continued patient safety assessment will be carried out and all adverse events documented and 
818 
reported to the WHIRB.  On each visit, compliance with treatment will be checked with 
819 
questions about the side-effects and a subjective evaluation of the tolerability of the 
820 
administered drug; the patients will also asked about incidental missed administrations. 
821 
Adverse events will be evaluated on a continuous basis while the patient is on study and 
822 
until 30 days after the last dose of study drug.  Patients should be followed until all treatment-
823 
related adverse events have recovered to baseline or are deemed irreversible by the principal 
824 
investigator. 
825 
 
826 
Adverse Event Procedures    
827 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening 
828 
of a preexisting medical condition in a clinical investigation subject administered an 
829 
investigational (medicinal) product and that does not necessarily have a causal relationship with 
830 
this treatment. An AE can therefore be any unfavorable and unintended sign (such as an 
831 
abnormal laboratory finding), symptom, or disease temporally associated with the use of 
832 
investigational product, whether or not considered related to the investigational product. 
833 
An Adverse Reaction (AR) is defined as any untoward and unintended responses to an 
834 
investigational medicinal product related to any dose administered Thus, for an AR, a causal 
835 
relationship must be at least suspected by the medical practitioner. Unexpected Adverse 
836 
Reaction (UAR) is an adverse reaction, the nature or severity of which is not consistent with the 
837 
applicable product information (e.g. investigator’s brochure for an investigational product or 
838 
summary of product characteristics for an authorized product). 
839 


 
25 
Version 6, 5/15/18 
The causal relationship to study drug is determined by a physician and should be used to 
840 
assess all adverse events (AE). The casual relationship can be one of the following: 
841 
Related: There is a reasonable causal relationship between study drug administration and 
842 
the AE. 
843 
Not related: There is not a reasonable causal relationship between study drug 
844 
administration and the AE.  
845 
The term "reasonable causal relationship" means there is evidence to suggest a causal 
846 
relationship.  
847 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
848 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not 
849 
be questioned regarding the specific occurrence of one or more AEs.) 
850 
Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) or Suspected Unexpected 
851 
Serious Adverse Reaction (SUSAR)  
852 
A serious adverse event (experience) or adverse reaction is any untoward medical 
853 
occurrence that at any dose:  
854 
 results in death 
855 
 is life-threatening (defined as an event in which the subject was at risk of death at the time 
856 
of the event; it does not refer to an event which hypothetically might have caused death if it 
857 
were more severe) 
858 
 requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
859 
NOTE below) 
860 
 results in persistent or significant disability/incapacity 
861 
 is a congenital anomaly/birth defect  
862 
 is an important medical event (defined as a medical event(s) that may not be immediately 
863 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
864 
and scientific judgment, may jeopardize the subject or may require intervention [e.g., 
865 
medical, surgical] to prevent one of the other serious outcomes listed in the definition 
866 
above.) Examples of such events include, but are not limited to, intensive treatment in an 
867 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that 
868 
do not result in hospitalization.) Potential drug induced liver injury (DILI) is also considered 
869 
an important medical event.  
870 
Serious adverse reaction (SAR): an adverse event fulfilling both the criteria for a Serious Adverse 
871 
event (SAE) and the criteria for an Adverse Reaction (ADR). 
872 
A Suspected Unexpected Serious Adverse Reaction is known as a SUSAR.  Sometimes during a 
873 
clinical trial, there may be serious adverse reactions in subjects given the drug, which may or 
874 


 
26 
Version 6, 5/15/18 
may not be dose related, but are unexpected, as they are not consistent with current 
875 
information and regarded as possibly or probably related to the trial/study product by the 
876 
investigator. 
877 
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study 
878 
drug is an SAE.  
879 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
880 
always serious by regulatory definition, these events must be handled as SAEs.  
881 
NOTE:   
882 
The following hospitalizations are not considered SAEs:  
883 
 a visit to the emergency room or other hospital department < 24 hours, that does not 
884 
result in admission (unless considered an important medical or life-threatening event) 
885 
 elective surgery, planned prior to signing consent 
886 
 admissions as per protocol for a planned medical/surgical procedure 
887 
 routine health assessment requiring admission for baseline/trending of health status 
888 
(e.g., routine colonoscopy) 
889 
 medical/surgical admission other than to remedy ill health and planned prior to entry 
890 
into the study. Appropriate documentation is required in these cases 
891 
 admission encountered for another life circumstance that carries no bearing on health 
892 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
893 
inadequacy, caregiver respite, family circumstances, administrative reason). 
894 
1A. Serious Adverse Event Collection and Reporting 
895 
Following the subject’s written consent to participate in the study, all SAEs, whether 
896 
related or not related to study drug, must be collected, including those thought to be associated 
897 
with protocol-specified procedures.  All SAEs must be collected that occur during the screening 
898 
period and within 30 days of discontinuation of dosing.  The investigator should report any SAE 
899 
that occurs after these time periods and that is believed to be related to study drug or protocol-
900 
specified procedure.  All SAEs, whether they are related or not related to study drug, and 
901 
pregnancies must be reported to Novo Nordisk (or designee) within 24 hours.  They will also be 
902 
reported immediately to the Woman’s Hospital Foundation Institutional Review Board at (225) 
903 
231-5296 and Woman’s Health Research Department at (225) 231-5275.  SAEs must be recorded 
904 
on an SAE Report Form or similar form (e.g. CIOMS, MedWatch); pregnancies on a Novo Nordisk 
905 
approved Pregnancy Surveillance Form.  Reports are to be transmitted via email or confirmed 
906 
facsimile (fax) transmission. 
907 
Investigators and other site personnel must inform the FDA, via a MedWatch/AdEERs 
908 
form, of any serious or unexpected adverse events that occur in accordance with the reporting 
909 
obligations of 21 CFR 312.32, and will concurrently forward all such reports to Novo Nordisk.  A 
910 
copy of the MedWatch/AdEERs report must be be transmitted via email or confirmed facsimile 
911 


 
27 
Version 6, 5/15/18 
(fax) transmission to Novo Nordisk at the time the event is reported to the FDA.  It is the 
912 
responsibility of the investigator to compile all necessary information and ensure that the FDA 
913 
receives a report according to the FDA reporting requirement timelines and to ensure that these 
914 
reports are also submitted to Novo Nordisk at the same time. 
915 
When 
reporting 
to 
Novo 
Nordisk, 
a 
cover 
page 
should 
accompany the 
916 
MedWatch/AdEERs form indicating the following: 
917 
 
Investigator Sponsored Study (ISS) 
918 
 
The investigator IND number assigned by the FDA (if applicable) 
919 
 
The investigator’s name and address 
920 
 
The trial name/title and Novo Nordisk ISS reference number 
921 
 
 
922 
Investigative site must also indicate, either in the SAE report or the cover page, the 
923 
causality of events in relation to all study medications and if the SAE is related to disease 
924 
progression, as determined by the principal investigator.  An SAE report should be completed for 
925 
any event where doubt exists regarding its seriousness.  If the investigator believes that an SAE 
926 
is not related to study drug, but is potentially related to the conditions of the study (such as 
927 
withdrawal of previous therapy or a complication of a study procedure), the relationship should 
928 
be specified in the narrative section of the SAE Report Form.  All SAE reports and accompanying 
929 
cover page will be transmitted to Novo Nordisk via email or confirmed facsimile (fax) 
930 
transmission. 
931 
Serious adverse events that do not require expedited reporting to the FDA need to be 
932 
reported to Novo Nordisk preferably using the MedDRA coding language for serious adverse 
933 
events.  In the case of blinded trials, the investigator will provide a copy of the randomization 
934 
list or unblind those SAEs which require expedited reporting. 
935 
All SAEs will be reported to Novo Nordisk, whether or not considered causally related to 
936 
the investigational product.  All SAEs will be documented.  The investigator is responsible for 
937 
informing the IRB and/or the Regulatory Authority of the SAE as per local requirements.  If an 
938 
ongoing SAE changes in its intensity or relationship to study drug or if new information becomes 
939 
available, a follow-up SAE report should be sent within 24 hours to Novo Nordisk (or designee) 
940 
using the same procedure used for transmitting the initial SAE report.  
941 
In cases where the investigator learns of the SAE after its occurrence and resolution, the 
942 
time and circumstances of the event will be recorded.  The reporting requirements will still be 
943 
followed.  All SAEs should be followed to resolution or stabilization. 
944 
Nonserious Adverse Events 
945 
A nonserious adverse event is an AE not classified as serious. 
946 
2A. Nonserious Adverse Event Collection and Reporting 
947 


 
28 
Version 6, 5/15/18 
The collection of nonserious AE information should begin at initiation of study drug. 
948 
Nonserious AE information should also be collected from the start of a placebo lead-in period or 
949 
other observational period intended to establish a baseline status for the subjects.  
950 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if 
951 
they become serious.  Follow-up is also required for nonserious AEs that cause interruption or 
952 
discontinuation of study drug and for those present at the end of study treatment as 
953 
appropriate. All identified nonserious AEs must be recorded and described on the nonserious AE 
954 
page of the study record.  
955 
Completion of supplemental study records may be requested for AEs and/or laboratory 
956 
abnormalities that are reported/identified during the course of the study. 
957 
Laboratory Test Result Abnormalities 
958 
The following laboratory test result abnormalities should be captured on the nonserious AE 
959 
study record page or SAE Report Form as appropriate: 
960 
 Any laboratory test result that is clinically significant or meets the definition of an SAE  
961 
 Any laboratory test result abnormality that required the subject to have study drug 
962 
discontinued or interrupted 
963 
 Any laboratory test result abnormality that required the subject to receive specific corrective 
964 
therapy. 
965 
 
966 
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
967 
the reporting investigator (e.g., anemia versus low hemoglobin value). 
968 
 
969 
Pregnancy 
970 
If, following initiation of the investigational product, it is subsequently discovered that a 
971 
study subject is pregnant or may have been pregnant at the time of investigational product 
972 
exposure, including during at least 6 half-lives after product administration, the investigational 
973 
product will be permanently discontinued. 
974 
Protocol-required procedures for study discontinuation and follow-up must be performed on 
975 
the subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate 
976 
pregnancy follow-up procedures should be considered if indicated. 
977 
The investigator must immediately notify Novo Nordisk (or designee) Medical Monitor of this 
978 
event and complete and forward a Pregnancy Surveillance Form to Novo Nordisk (or designee) 
979 
within 24 hours and in accordance with SAE reporting procedures described in Section 1A.   
980 
Follow-up information regarding the course of the pregnancy, including perinatal and 
981 
neonatal outcome and, where applicable, offspring information must be reported on the 
982 
Pregnancy Surveillance Form. 
983 


 
29 
Version 6, 5/15/18 
Overdose 
984 
An overdose is defined as the accidental or intentional administration of any dose of a 
985 
product that is considered both excessive and medically important. All occurrences of overdose 
986 
must be reported as an SAE (see Section 1A for reporting details.). 
987 
1. Potential Drug Induced Liver Injury (DILI) 
988 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities 
989 
should occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
990 
meeting the defined criteria, must be reported as SAEs (see Section 1A for reporting details). 
991 
Potential drug induced liver injury is defined as:  
992 
AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
993 
AND  
994 
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
995 
alkaline phosphatase), 
996 
AND  
997 
No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
998 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or 
999 
the administration of other drug(s) known to be hepatotoxic.  
1000 
 
1001 
2. Adverse Events of Special Interest 
1002 
Certain serious adverse events are informative as single cases because they are uncommon 
1003 
and are known to be strongly associated with drug exposure (in accordance with the reporting 
1004 
obligations of 21 CFR 312.32).  The occurrence of even one case of such adverse events would 
1005 
meet the definition of suspected adverse reaction (i.e., there is a reasonable possibility that the 
1006 
drug caused them).  
1007 
In this study, the following adverse events are to be reported to Novo Nordisk, regardless of 
1008 
whether these reports are classified as serious or unexpected: 
1009 
1. 
liver test abnormalities accompanied by jaundice or hyperbilirubinemia 
1010 
2. 
opportunistic infections  
1011 
3. 
pancreatitis 
1012 
4.  
anaphylaxis 
1013 
5. 
angioedema 
1014 
6.  
Steven-Johnson’s Syndrome 
1015 
 
1016 
When one of these events meets the criteria for a serious adverse event, report the event using 
1017 
SAE reporting procedures. When one of these events does not meet the criteria for a serious 
1018 
adverse event, report the event within 24 hours as a non-serious event. 
1019 


 
30 
Version 6, 5/15/18 
3. Other Safety Considerations 
1020 
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
1021 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
1022 
by protocol should also be recorded as a nonserious or serious AE, as appropriate. 
1023 
 
1024 
Discontinuations 
1025 
The reason for a subject discontinuing from the study will be recorded in the patient chart.  
1026 
A discontinuation occurs when an enrolled subject ceases participation in the study, regardless 
1027 
of the circumstances, prior to completion of the protocol.  The investigator must determine the 
1028 
primary reason for discontinuation.  Withdrawal due to adverse event will be distinguished from 
1029 
withdrawal due to insufficient response according to the definition of adverse event noted 
1030 
earlier.  The final evaluation required by the protocol will be performed at the time of study 
1031 
discontinuation.  The investigator will record the reason for study discontinuation, provide or 
1032 
arrange for appropriate follow-up (if required) for such subjects, and document the course of 
1033 
the subject’s condition.  They will also to be reported to Woman’s Hospital Foundation 
1034 
Institutional Review Board at (225) 231-5296 and Woman’s Health Research Department at 
1035 
(225) 231-5275.  
1036 
Subjects MUST discontinue investigational product for any of the following reasons: 
1037 
 Withdrawal of informed consent (subject’s decision to withdraw for any reason). 
1038 
 Any clinical adverse event, laboratory abnormality, or intercurrent illness, which, in 
1039 
the opinion of the investigator, indicates that continued participation in the study is 
1040 
not in the best interest of the subject. 
1041 
 Pregnancy 
1042 
o Instruct subjects to contact the investigator or study staff immediately if they 
1043 
suspect they might be pregnant (e.g., missed or late menstrual period) at any 
1044 
time during study participation. Institutional policy and local regulations should 
1045 
determine the frequency of study pregnancy tests for subjects enrolled in the 
1046 
study. 
1047 
o The investigator must immediately notify Novo Nordisk if a study subject 
1048 
becomes pregnant. 
1049 
 Loss of ability to freely provide consent through imprisonment or involuntary 
1050 
incarceration for treatment of either a psychiatric or physical (e.g., infectious disease) 
1051 
illness. 
1052 
All subjects who discontinue should comply with protocol-specified follow-up procedure. 
1053 
The only exception to this requirement is when a subject withdraws consent for all study 
1054 
procedures or loses the ability to consent freely (i.e., is imprisoned or involuntarily incarcerated 
1055 
for the treatment of either a psychiatric or physical illness).  
1056 
 
 
1057 


 
31 
Version 6, 5/15/18 
References cited in alphabetical order: 
1058 
1. Andreoli A, Scalzo G, Masala S, Tarantino U, Guglielmi G.  Body composition assessment 
1059 
by dual-energy x-ray absorptiometry (DXA). Radiol Med 2009; 114:286–300. 
1060 
2. Apridonidze T, Essah PA, Iuorno MJ, Nestler JE. Prevalence and characteristics of the 
1061 
metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 
1062 
2005; 90:1929–1935. 
1063 
3. Astrup A, Carraro R, Finer N, et al. Safety, tolerability and sustained weight loss over 2 
1064 
years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond) 2012; 
1065 
36(6):843–854.  
1066 
4. Astrup A, Rossner S, Van Gaal L et al.  Effects of liraglutide in the treatment of obesity: a 
1067 
randomized double-blind, placebo-controlled study. Lancet 2009; 374: 1606-1616. 
1068 
5. Asunción M, Calvo RM, San Millán JL, Sancho J, Avila S, Escobar-Morreale HF. A 
1069 
prospective study of the prevalence of the polycystic ovary syndrome in unselected 
1070 
Caucasian women from Spain. J Clin Endocrinol Metab. 2000; 85:2434–2438 
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