Clinical trial NCT02500147
Conditions: Polycystic Ovary Syndrome Non-Alcoholic Fatty Liver Disease Metabolic Syndrome
Keywords: Polycystic Ovary Syndrome Non-Alcoholic Fatty Liver Disease Adolescents Young Women MRI MRS DXA PNPLA3 Metformin Randomized Clinical Trial Placebo Hirsutism Acne Amenorrhea Metabolic Syndrome Dyslipidemia Percentage liver fat
Sponsor: Columbia University
Start date: 2011-09-08; Completion date: 2021-03-03
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This project, "A double-blind placebo-controlled randomized clinical trial assessing the efficacy of metformin for hepatic fat in adolescents and young adults with polycystic ovary syndrome", proposes exploring the use of novel and noninvasive methodologies in an at-risk adolescent and young adult population with polycystic ovary syndrome (PCOS) who may gain long-term health benefits from early detection and treatment of non-alcoholic fatty liver disease (NAFLD). PCOS is a common condition that frequently presents in adolescence and young adulthood and is defined by elevated androgens (male hormones) in the blood leading to 1. hirsutism and acne and 2. menstrual abnormalities or amenorrhea. Affected individuals are at increased risk of developing insulin resistance (a precursor of diabetes), NAFLD and lipid (cholesterol) abnormalities.These features are all associated with the metabolic syndrome, a rising major public health concern. Recently, an association between PCOS and NAFLD has been noted but has only been superficially studied in the adolescent and young adult population. The susceptibility of certain PCOS patients to developing NAFLD is theorized to be due to having underlying insulin resistance, elevated androgen levels, and a genetic predisposition. Metformin is an insulin sensitizing medication widely used to treat type 2 diabetes mellitus that may have beneficial effects on insulin resistance-related conditions including PCOS and NAFLD. Although widely used in PCOS, its effect on NAFLD in this group has not been previously studied.

The primary aims of this proposal are: 1) To determine whether PCOS with liver fat \>/=4.8% treated with metformin for six months will have a decline in percentage liver fat compared to a placebo group. 2) To measure the association of the PNPLA3 I148M allele with NAFLD in PCOS at baseline (n=40). 2b) To measure the association of percentage liver fat with biomarkers of NAFLD, dyslipidemia, insulin resistance and body composition at baseline (n=40) and after a placebo-controlled intervention with metformin in PCOS with liver fat \>4.8% (n=20).

The goal of this research proposal is to explore the use of novel and noninvasive technologies in a young and at risk population. Dr. Sopher hopes to use the results of this research to lay the groundwork for the prevention and treatment of NAFLD and other metabolic disorders in adolescents and young adults with PCOS and to prevent lifelong morbidity associated with PCOS.

Detailed description:
PCOS subjects will be screened by questionnaire for eligibility with the goal of recruiting 40 subjects who are 14 to 25 years, BMI between the 10th and 95th percentile for age (\<20 years) and 18.5 - 29.9 kg/m2 (20 years or older), and at least two years post-menarche. Oligomenorrheic subjects will complete the protocol during the early follicular phase of the menstrual cycle (days one through seven) and amenorrheic subjects will complete the protocol on any day. The protocol will comprise: a) History and physical exam: Height, weight, body mass index (BMI) (percentile and z-score for \<20 years), blood pressure, physical exam, Ferriman-Gallwey hirsutism scoring, smoking, alcohol and family history; b) Laboratory evaluation will be between 0800 and 0900 after an overnight fast via a 21 gauge intravenous catheter for: 1) General endocrine panel: Thyroid function, prolactin, 17-hydroxyprogesterone; 2) PCOS panel: luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol, sex hormone binding globulin, testosterone, free testosterone, androstenedione, dehydroepiandrosterone; 3) Liver panel: Liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl-transpeptidase (GGT)), apoptosis markers (Fas, cytokeratin-18 fragments, M30), pancreatic polypeptide; 4) Cardiovascular risk panel: Cholesterol, triglycerides, HDL, LDL, free fatty acids, c-reactive protein; 5) IR evaluation: hemoglobin A1C, glucose, insulin, c-peptide and two-hour oral glucose tolerance test (OGTT) after a 75 gram glucose challenge with measurement of glucose and insulin at 30, 60, 90 and 120 minutes. IR will be determined by age- and BMI- specific homeostatic measure of insulin resistance (HOMA-IR) cutoffs based on a National Health and Nutrition Examination Survey (NHANES) study of 1,164 nonobese adolescents 12 to 19 years old. Other IR indices that will be evaluated are whole body insulin sensitivity (WBIS) and insulin area under the curve; 6) Genetic evaluation: A blood sample for the PNPLA3 I148M allele (baseline only). c) Magnetic resonance spectroscopy (MRS) of the liver for intrahepatic lipid content acquired using standard point resolved spectroscopy sequence (PRESS). Percentage liver fat will be calculated. d) Total body magnetic resonance imaging (MRI) with 10 mm slices and 40 mm interslice gaps for total body adipose tissue and VAT. e) Dual-energy x-ray absorptiometry (DXA): Total body DXA will be performed for total body lean and fat mass and percentage body fat. f) Randomization: Subjects whose liver fat is 4.8% or greater (n≈20) will be randomized to placebo or extended-release metformin 1000 mg (2 tablets) daily. Randomization will be double-blind and will be performed by randomly selected permuted size 2 and size 4 blocks determined by the Columbia University Medical Center (CUMC) Research Pharmacy with the guidance of a statistician. g) Intervention: All subjects will receive identically appearing pill bottles labeled "Study Medication" containing their first three-month supply of either metformin or placebo. Subjects will be instructed to take pills with dinner and to take one pill once a day for one week and subsequently two pills once a day for the remainder of the first three months. Subjects will be asked to call with any side effects that they may experience. They will receive weekly calls from a research coordinator and will be asked to bring their empty pill bottles to their follow-up studies do to ensure compliance. h) Brief interim evaluation: After three months of the intervention phase, subjects will be seen for a general health assessment, which includes weight, blood pressure and a physical examination, and will receive their second three-month supply of their assigned intervention. i) Follow-up exam: At the end of six months, subjects will undergo laboratory and body composition testing identical to those performed in the baseline testing.

Arms: arm 1: Adolescents and young adults with PCOS and liver fat greater than or equal to 4.8% will be randomized to metformin or placebo. Metformin ER (extended release) will be administered as two pills of 500 mg each. For the first week subjects will take one pill orally on a daily basis and thereafter will take two pills orally on a daily basis. The intervention will last six months. arm 2: Adolescents and young adults with PCOS and liver fat greater than or equal to 4.8% will be randomized to metformin or placebo. Subjects randomized to placebo will be instructed to take one pill daily by mouth for one week and then to take one pill daily by mouth for the remainder of six months.
Interventions: intervention 1: Metformin intervention 2: Placebo
Intervention descriptions: intervention 1: Metformin ER 500 mg once a day for one week and 1000 mg once a day for the remainder of the six months intervention 2: One placebo pill per day for one week and then two placebo pills per day for the remainder of the six months

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
Metformin for Ectopic Fat Deposition 
and Metabolic Markers in Polycystic 
Ovary Syndrome (PCOS) 
 
 
 
NCT02500147 
 
April 23, 2018 
 
 


23-Apr-2018 
 
 
Title: Body composition and metabolic manifestations of insulin resistance in adolescents with 
polycystic ovary syndrome. Ectopic fat deposition and metabolic markers: Intervention and 
follow-up portion 
Principal Investigator: Aviva Sopher, MD, MS 
Study Purpose and Rationale: 
Polycystic ovary syndrome (PCOS) affects about 7% of females of reproductive age worldwide and is 
associated with development of lifelong morbidities including type 2 diabetes mellitus and cardiovascular 
disease. It commonly first presents in adolescence and young adulthood, which places a significant 
proportion of this young population at risk for long-term morbidity. Although the underlying etiology of 
PCOS has not been fully elucidated, insulin resistance (IR) is suggested to be an important underlying 
causal factor. The association between PCOS and IR further links it to other IR-related disorders including 
obesity, the metabolic syndrome (MeS) and non-alcoholic fatty liver disease (NAFLD). This constellation 
of disorders is associated with dyslipidemia, cardiovascular disease and type 2 diabetes mellitus. Recently, 
NAFLD has been reported to be more prevalent in young individuals with PCOS compared to the general 
population. Additionally, the progression of hepatic steatosis to non-alcoholic steatohepatitis (NASH) is 
described to be substantially more rapid in PCOS than in unaffected individuals. Metformin is an insulin 
sensitizing medication typically used to treat type 2 diabetes mellitus, but also has beneficial effects on IR 
related conditions such as PCOS and NAFLD; however, its effects on NAFLD in PCOS in the adolescent and 
young adult populations have not been adequately studied. If, in fact, metformin reduces liver fat in 
adolescents and young adults with PCOS, their long-term risk of metabolic and cardiovascular disease 
could be diminished. Additionally, this finding would have both personal and far-reaching beneficial public 
health benefits. There are limited data that suggest that metformin may also have beneficial effects on 
bone. If our pilot study demonstrates changes in bone formation markers that corroborate recent 
proposed mechanisms of action, they could provide proof of concept to support further investigation of 
the skeletal effects of metformin in a larger randomized clinical trial.  
This study proposes to explore the efficacy of metformin to reduce liver fat using novel and minimally 
invasive imaging and biomarkers in a pilot randomized double-blind placebo-controlled trial. 
Study Design: 
Eligibility Criteria: PCOS subjects who participated in a previous baseline study and have liver fat greater 
than or equal to 4.8% by MRS or evidence of insulin resistance (on an oral glucose tolerance test) will be 
invited to participate in this study with the goal of recruiting 44 subjects who are 13 to 25 years at least 
two years post-menarche. Oligomenorrheic subjects will complete the protocol during the early follicular 
phase of the menstrual cycle (days one through seven) and amenorrheic subjects will complete the 
protocol on any day. Exclusion criteria: 1. Presence or history of a medical disorder (e.g. non-classical CAH) 
or medication known to affect body composition, insulin secretion and sensitivity, or the GH-IGF1 axis (i.e. 
use of glucocorticoids or thyroid hormone), excessive alcohol use, liver disease (other than NAFLD) 
indwelling hardware, current or past pregnancy and use of metformin or hormonal contraception within 
3 months of enrolling in the previous study. 


23-Apr-2018 
 
 
 
 
The protocol will comprise: 
a) Randomization: Subjects whose liver fat is 4.8% or greater or have evidence of insulin resistance on an 
oral glucose tolerance test (n=22) will be randomized to placebo or extended-release metformin (XR) (500 
mg (1 tablet) once a day for one week and then 1000 mg (2 tablets) daily for six months). Randomization 
will be double-blind and will be performed by randomly selected permuted size 2 and size 4 blocks 
determined by the CUMC Research Pharmacy with the guidance of a statistician and will be stratified 
based on presence or absence of insulin resistance.  
b) Intervention: All subjects will receive identically appearing pill bottles labeled “Study Medication” 
containing their first three-month supply of either metformin XR or placebo. Subjects will be instructed 
to take pills after dinner and to take one pill once a day for one week and subsequently two pills once a 
day for the remainder of the first three months. Subjects will be asked to call with any side effects that 
they may experience. They will be given a pill diary so that they can keep track of their compliance. They 
will be instructed to call our office if they experience any adverse effects and will be asked to bring their 
empty pill bottles to their interim visit to further ensure compliance. 
c) Brief interim evaluation: After three months of the intervention phase, subjects will be seen for a 
general health assessment, which includes weight, blood pressure and a physical examination, and will 
receive their second three-month supply of their assigned intervention along with a second pill diary. They 
will again be instructed to call our office if they experience any adverse effects and will be asked to bring 
their empty pill bottles to their follow-up study visit to further ensure compliance. 
d) Follow-up exam: At the end of six months, subjects will undergo laboratory and body composition 
testing similar to those performed in the baseline testing. Studies that are not repeated in this protocol 
are transabdominal pelvic ultrasound, MRI of the ovaries and DXA of the hip, spine and wrist 
 1) History and physical exam: Height, weight, BMI (percentile and z-score for <20 years), blood 
pressure, physical exam, Ferriman-Gallwey hirsutism scoring, smoking, alcohol and family 
history;  
2) Laboratory evaluation will be between 0800 and 1000 after an overnight fast via an intravenous 
catheter for:  
a) General endocrine panel: Thyroid function, prolactin, 17-hydroxyprogesterone;  
b) PCOS panel: LH, FSH, estradiol, sex hormone binding globulin, testosterone, free 
testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS);  
c) Liver panel: Liver enzymes (ALT, AST, GGT), apoptosis markers (Fas, cytokeratin-18 
fragments, M30), pancreatic polypeptide, irisin 


23-Apr-2018 
 
 
d) Cardiovascular risk panel: Cholesterol, triglycerides, HDL, LDL, free fatty acids, c-
reactive protein;  
e) IR evaluation: hemoglobin A1C, glucose, insulin, c-peptide and two-hour oral glucose 
tolerance test (OGTT) after a 75 g glucose challenge with measurement of glucose and 
insulin at 30, 60, 90 and 120 minutes. IR will be determined by age- and BMI- specific 
HOMA-IR cutoffs based on a National Health and Nutrition Examination Survey 
(NHANES) study of 1,164 nonobese adolescents 12 to 19 years old. Other IR indices that 
will be evaluated are whole body insulin sensitivity index (WBISI) and insulin area under 
the curve (iAUC);  
f) Bone evaluation: 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, osteocalcin, c-
telopeptide, PTH, P1NP  
3) MRS of the liver for intrahepatic lipid content (IHL) and of the right soleus muscle for 
intramyocellular lipid (IMCL) acquired using standard point resolved spectroscopy sequence 
(PRESS). Percentage liver fat will be calculated. 
4) Total body MRI with 10 mm slices and 40 mm interslice gaps for total body adipose tissue , 
subcutaneous adipose tissue (SAT) and visceral adipose tissue(VAT);  
5) MRI for percentage liver fat.  
e) Dual-energy x-ray absorptiometry (DXA): Total body DXA will be performed for total body lean and fat 
mass, percentage body fat and bone mineral density (BMD).  
Statistical Procedures: 
Statistical Analysis:  
1. Change in liver fat is defined as percentage liver fat at six months minus percentage liver fat at 
baseline. The difference in mean change between metformin XR and placebo groups as well as its 
95% confidence intervals will be calculated. The two-sample t-test will be used to compare 
groups. Sample Size and Power Calculations: Over a 1.5 year recruitment period, 44 subjects is a 
feasible recruitable sample size. We generally see at least 100 PCOS patients within our division 
per year. We also work closely with physicians in the Division of Adolescent Medicine and the 
Department of Obstetrics and Gynecology who will also serve as sources of study subjects for us. 
Forty-four subjects randomized 1:1 to metformin versus placebo provided greater than 80% 
power to detect a 1.4 standard deviation difference in the group average change from baseline 
to endpoint assuming a 5% type I error rate and an independent T-test. Preliminary data showing 
subjects with PCOS have an average of 4.8% liver fat, and assuming the average within subject 
change is less than 0.5+0.5% in the placebo group, the power calculations indicate the minimum 
detectable difference attributable to metformin treatment to be a 0.7% absolute, or a 15% 
relative decline in percentage liver fat. After the intent-to-treat analysis we will analyze the 
influence of partial compliance by adding cumulative dose exposure in to a multiple regression 


23-Apr-2018 
 
 
model assessment of the group difference. Subjects will be stratified based on presence or 
absence of insulin resistance. 
2. The association of percent liver fat with IR, dyslipidemia, VAT, total body adipose tissue, and 
markers of NAFLD and NASH will be estimated with correlation/regression and change in IR, 
dyslipidemia, and markers of NAFLD and NASH with change in percent liver fat following 
metformin with multiple regression. Sample Size and Power Calculations: 44 subjects provide 80% 
power and 5% alpha to detect a baseline association of liver fat with continuous measures of liver 
fat markers with r-values > + 0.46 when tested against Ho of r = + 0.10. 20 subjects in the 
longitudinal study provides 80% power and 5% alpha to detect an incremental increase of 0.60 in 
model R2 when percentage liver fat is added to treatment assignment to predict change in 
markers. 
3.  The current state of conflicting or absent data on BMD and bone turnover markers in adolescents 
with PCOS and IR means that the data collected here are vital to providing preliminary estimates 
of between group differences and rates of change for design of future studies. A recent study 
showed changes in bone markers within 14 weeks of treatment of rosiglitazone. We thus predict 
that we will see changes in bone markers within SIX months of treatment with metformin (13 
weeks). (Glintborg D, Andersen M, Hagen C, Heickendorff L, Hermann AP. 2008). Association of 
pioglitazone treatment with decreased bone mineral density in obese premenopausal patients 
with polycystic ovary syndrome: a randomized, placebo-controlled trial. J Clin Endocrinol Metab 
93:1696-1701). 
Potential Risks: 
Protection Against Risk: 
 MRI and MRS: These magnetic resonance and nuclear magnetic resonance studies are without known 
associated risks except claustrophobia while in the magnet or injury from a metal object or indwelling 
metal from prior surgery. All subjects will be fully acquainted with the magnet and will be certified as 
“MRI-safe” before entering.  
Dual Energy X-Ray Absorptiometry (DXA): There is no discomfort associated with DXA. There is minimal 
radiation exposure, but it is well within the limits allowed for this type of research. Over 1500 children 
have had whole body DXA for research purposes in the Body Composition Unit.  
Two-hour Oral Glucose Tolerance Test (OGTT): There may be some bruising at the site of needle insertion, 
but this will resolve spontaneously. 
Metformin: Metformin is rarely associated with development of lactic acidosis in patients with preexisting 
liver disease, kidney disease, heart failure and alcohol abuse. Subjects will have screening for these 
disorders by checking medical history and liver and kidney function by blood tests The liver and kidney 
function blood tests will also be checked the 6 month “follow up visit”, which will occur after six months 
of the study intervention. Study subjects are instructed to call with any new symptoms while they are 
taking the IP. 


23-Apr-2018 
 
 
 
Pregnancy: Study subjects may begin ovulating or menstruating during the study as a response to 
metformin or naturally. Even if the study subject is not getting her period regularly or at all she will be 
instructed to always use a birth control method if she is sexually active. She cannot take a birth control 
pill if she is participating in this study so she should use a barrier method of birth control if she is sexually 
active. It is important to note that metformin is a category B drug in pregnancy, which means that its 
effects on a fetus are not fully known. Study subjects are instructed to call the study team as soon as 
possible if they think they may have become pregnant during the study. 
 
Adverse events:  
A serious adverse event associated with metformin use is lactic acidosis; however, this most commonly 
occurs in patients with congestive heart failure, renal failure and liver failure. We will be screening patients 
by questionnaire and with laboratory data in order to exclude those with underlying medical conditions. 
We will instruct patients to call immediately if they develop unexplained hyperventilation, myalgia. 
Malaise, unusual somnolence or other nonspecific symptoms. 
We will be tracking the follow adverse event data at the 3 month and 6 month visits based on known 
common adverse events associated with metformin use:  diarrhea, abdominal pain, nausea/vomiting, 
gas/bloating and any other side effect the subject may experience. 
Potential Benefits: 
Families and subjects will be provided with detailed analysis of body composition, OGTT and 
cardiovascular risk factor results and will be counseled about the implications for future metabolic 
complications, as well as on how to improve health through diet and exercise. All results will be provided 
to each subject’s primary care physician and/or pediatric endocrinologist if directed by the subject’s 
parents at time of study or later date.