Optimizing Metformin Use in Polycystic Ovary Syndrome - A Randomized Controlled Trial
Phase: PHASE3
Conditions: Polycystic Ovary Syndrome (PCOS)
Sponsor: Helsinki University Central Hospital

EUCT: 2023-509259-15-01, Melin et al. 
 
1 
 
STUDY TITLE 
Optimizing metformin use in polycystic ovary syndrome –  
A randomized controlled trial  
 
REFERENCE NUMBERS 
EU trial number: 2023-509259-15-01 
 
Date and version number: 15th January 2025, 5. version 
STUDY SPONSOR 
HUS-yhtymä 
COMPLIANCE STATEMENT  
This trial is to be conducted in compliance with this protocol, with the Regulation 536/2014 of 
the European Parliament and of the Council and with the principles of Good Clinical Practice. 
CONFIDENTIALITY STATEMENT 
This document contains confidential information that must not be disclosed to anyone other 
than the sponsor, the study team, regulatory authorities, and members of the Ethics Committee. 

EUCT: 2023-509259-15-01, Melin et al. 
 
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CONTACT DETAILS 
Contact details 
Chief investigator/ Co-ordinating investigator 
Name/title: Johanna Melin 
Contact details: Johanna.Melin@hus.fi 
Principal Investigators  
Name(s)/ titles: Johanna Melin, MD 
Contact details: Johanna.Melin@hus.fi 
 
Name(s)/ titles: Hanna Savolainen-Peltonen, adjunct professor 
Contact details: Hanna.Savolainen-Peltonen@hus.fi 
 
Name(s)/ titles: Hanna-Mari Hautamäki 
Contact details: Hanna-Mari.Hautamaki@helsinki.fi 
 
Name(s)/ titles: Kristiina Rönö, adjunct professor 
Contact details: Kristiina.Rono@hus.fi 
 
 
Sponsor  
Name: Helsinki University Hospital (HUS) 
Contact details: Johanna.Melin@hus.fi 
Funder(s): 
Name: Valtion Tutkimusrahoitus, Finska Läkaresällskapet 
Signatures 
Johanna Melin, MD, chief investigator and principal investigator 
Hanna Savolainen-Peltonen, adjunct professor, chief physician at the Reproductive Medicine 
Unit and part of the research team 
Hanna-Mari Hautamäki, PhD student, part of the research team 
Kristiina Rönö, adjunct professor, part of the research team 
 
 
 
 

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TABLE OF CONTENTS  
 
 
1 
SYNOPSIS 
4 
2 
ABBREVIATIONS AND DEFINITION OF TERMS 
6 
3 
INTRODUCTION 
7 
4 
STUDY OBJECTIVE 
8 
5 
TRIAL DESIGN 
10 
6 
TREATMENT OF TRIAL SUBJECTS 
22 
7 
SAFETY REPORTING 
24 
8 
STATISTICS 
28 
9 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
32 
10 
DATA HANDLING AND RECORD KEEPING 
32 
11 
RETENTION OF ESSENTIAL DOCUMENTS 
33 
12 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
33 
13 
AUDITS AND INSPECTIONS 
33 
14 
ETHICAL CONSIDERATIONS 
33 
15 
FINANCING AND INSURANCE 
34 
16 
CLINICAL STUDY REPORT AND PUBLICATION POLICY 
34 
17 
REFERENCES 
35 
 
 
 
 

EUCT: 2023-509259-15-01, Melin et al. 
 
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1 
SYNOPSIS 
 
Title of study 
Optimizing metformin use in polycystic ovary syndrome – A randomized 
controlled trial  
Name of 
sponsor/company 
Helsinki University Hospital 
Aim 
To evaluate if a metformin dose of 1500 mg per day is inferior to 2250 mg per day 
in improving biochemical and clinical outcomes, as well as side-effects, mental 
health and quality of life in individuals 18-37 years of age with PCOS and a BMI ≥ 
25 and <40 kg/m2 
Trial design 
A double blinded randomized controlled trial 
Key inclusion criteria 
Individuals with PCOS (diagnosed according to the International evidence-based 
Guideline for PCOS 2023) 
Age: 18-37 years 
BMI: ≥ 25 and <40 kg/m2 
Key exclusion criteria 
-Individuals not meeting the criteria according to the International evidence-based 
Guideline for PCOS 2023) 
-Individuals with hormonal contraceptive during the last 3 months 
-Individuals that are pregnant or breastfeeding 
-Individuals with an untreated diabetes, hypothyroidism or hyperprolactinemia 
-Use of medications for diabetes, high cholesterol, obesity and cortisone (per oral) 
-Individuals with contraindication for use of metformin (hypersensitivity to 
metformin, acute metabolic acidosis, renal impairment, hepatic insufficiency, 
heart- or respiratory failure) 
-Serious mental illness. 
-Alcoholism 
- Investigator site staff directly involved in the conduct of the study and their 
family members 
Test product, dose 
and mode of 
administration 
Metformin 500 mg x3 /day orally 
Metformin 750 mg x3/day orally 
Duration of 
treatment 
26 weeks (first two weeks with reduced dose) 
Statistical methods 
We will summarise the outcomes by number of patients, mean, standard deviation, 
median, minimum, and maximum values and report mean differences. We will 
follow the intention-to-treat principle and adjust/perform sub-analyses according 
to age, BMI and PCOS phenotype.  
Primary analysis: For normally distributed variables, independent-sample t-tests 
will be used to compare values between and within the two treatment groups at 

EUCT: 2023-509259-15-01, Melin et al. 
 
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each time point (baseline, 14 and 26 weeks). Mann-Whitney will be performed for 
variables with skewed distribution.  
Supplementary analysis: Repeated measures ANOVA will be performed to estimate 
the within-group modifications. We will also use linear mixed-effects models when 
comparing the two metformin doses regarding change from baseline 
measurement and when comparing the two groups to each other.  
Sample size 
184 individuals (92 in each group) 
 
 

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2 
ABBREVIATIONS AND DEFINITION OF TERMS 
BMI 
Body Mass Index 
PCOS 
Polycystic Ovary Syndrome 
WHR 
 
waist-hip ratio 
WC 
 
Waist circumference 
BAI 
 
Body adiposity index 
BP 
 
blood pressure 
FAI 
 
free androgen index 
SHBG 
 
sex hormone binding globulin 
DHEAS  
dehydroepiandrosterone sulfate 
HOMA-IR 
Homeostatic model assessment for insulin resistance 
CRP 
 
C-reactive protein 
FLI 
 
Fatty Liver Index 
ALAT 
 
Alanine aminotransferase 
GGT 
 
Gamma-glutamyltransferase 
QoL 
 
Quality of life 
GI AE 
 
Gastrointestinal adverse effects 
AMH 
 
anti-mullerian hormone 
FNPO   
Follicle number per ovary 
TSH 
 
Thyroid stimulating hormone 
PRL 
 
Prolactin 
17-OHP 
17-hydroxyprogesterone 
GFR 
 
Glomerular filtration rate 
OD 
 
Ovulatory dysfunction 
HA 
 
Hyperandrogenism 
PCOM  
Polycystic ovary morphology 
TyG 
 
Triglyceride glucose 
RSI 
 
Reference safety information 
CTIS  
 
Clinical Trials Information System 
CRF 
Case report form 
SAE 
Serious adverse event 
SUSAR 
Suspected unexpected serious adverse reaction 
GCP 
 Good Clinical Practice 
 

EUCT: 2023-509259-15-01, Melin et al. 
 
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3 
INTRODUCTION 
Polycystic ovary syndrome (PCOS) remains a key public health burden as it is one of the most 
common endocrine and metabolic disorders affecting up to 13% of women globally (1). The 
Rotterdam diagnostic criteria were updated and internationally endorsed in the 2023 
International PCOS guideline and include a) ovulatory and menstrual dysfunction, b) 
biochemical and/or clinical hyperandrogenism and c) polycystic ovary morphology (PCOM) at 
ultra-sound. For a diagnosis in adults two of three criteria are required, with PCOM remaining 
nonspecific for PCOS in adolescents (2, 3). 
 
3.1 Background information 
Women with PCOS present with diverse features; metabolic (weight gain, obesity, insulin 
resistance and diabetes) reproductive (infertility and pregnancy complications), endocrine 
(hyperandrogenism, hirsutism and acne) and psychosocial (depression, anxiety and poor quality 
of life) (3, 4).   
 
 
Figure of the most common features of PCOS 
 
While lifestyle management is strongly recommended for weight management (2, 5), for those 
with higher BMI, sustainable efficacy for weight loss can be limited and additional 
pharmacological treatment may be needed. The 2023 Updated International PCOS Guideline 
recommends that metformin, in addition to lifestyle, should be considered in adults with PCOS 
and BMI ≥ 25 kg/m2 for prevention of weight gain and management of weight and metabolic 
disorders. Metformin may be considered in adults with BMI < 25 kg/m2 and adolescents with 
PCOS, acknowledging more limited evidence (6).  
 
3.2 Rationale for the study 
MD Johanna Melin has been working on the 2023 update of the International Evidence-based 
PCOS Guideline as the team leader of the clinical question “is metformin alone or in 

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combination, effective for management of hormonal and clinical PCOS features and weight in 
adolescents and adult with PCOS”. During her work with the PCOS guideline she has identified 
the following key knowledge gaps:  
a) the optimal metformin dose for adults with PCOS is unclear regarding metabolic 
outcomes, hyperandrogenism, cycle regularity and side-effects. 
b) we lack information on mental health and quality of life in women with PCOS and if they 
can be improved by medical treatment with metformin 
c) we lack information on whether anti-mullerian hormone (AMH) levels will change after 
use of metformin. 
 
4 
STUDY OBJECTIVE 
The aim of this randomized controlled trial (RCT) is to evaluate whether a metformin dose of 
1500 is inferior compared to a dose of 2250 mg per day in improving biochemical and clinical 
outcomes, as well as side-effects, mental health and quality of life in females 18-37 years of age 
with PCOS. 
During the rigorous systematic review comparing the effect of metformin to other medical 
treatments in the updated 2023 PCOS guidelines, only one small study compared different 
metformin doses. This is a highly relevant question, as side-effects are a common reason for 
discontinuing the metformin treatment and they will increase with higher metformin doses.  
Our hypothesis is that individuals using the lower metformin dose might improve their 
biochemical (hyperandrogenism, insulin resistance, lipids etc) and clinical outcomes (hirsutism 
and weight) to the same extent than those using a higher metformin dose. 
 
4.1 Primary objective 
Altogether six publications with six primary objectives are planned from this RCT:  
1. to evaluate whether a metformin dose of 1500 mg per day is inferior to a dose of 2250 
mg per day in improving anthropometric outcomes in women with PCOS 
2. to evaluate whether a metformin dose of 1500 mg per day is inferior to a dose of 2250 
mg per day in improving metabolic outcomes in women with PCOS 
3. to evaluate whether a metformin dose of 1500 mg per day is inferior to a dose of 2250 
mg per day in improving hyperandrogenism in women with PCOS 
4. to evaluate whether metformin at a dose of 1500 mg per day is inferior to a dose of 
2250 mg per day regarding gastrointestinal side-effects in women with PCOS 
5. to evaluate whether a metformin dose of 1500 mg per day is inferior to a dose of 2250 
mg per day in improving quality of life/mental health and weight stigma in women 
with PCOS 
6. to evaluate whether a metformin dose of 1500 mg per day is inferior to a dose of 2250 
mg per day in improving polycystic ovary morphology and menstrual cyclicity in 
women with PCOS. 

EUCT: 2023-509259-15-01, Melin et al. 
 
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4.2 Primary and secondary/exploratory endpoints/outcome measures 
Primary outcomes below are bolded, whereas all not bolded are secondary endpoints. 
Anthropometric:  
- 
Weight. Primary outcome. Change in weight (kg) from baseline to 14 and 26 weeks.  
- 
BMI (Body Mass Index). Change in BMI (kg/m2) from baseline to 14 and 26 weeks 
- 
WC (waist circumference. Change in WC from baseline to 14 and 26 weeks 
- 
WHR (Waist-hip-ratio). Change in WHR from baseline to 14 and 26 weeks 
- 
BAI (Body adiposity Index). Change in BAI from baseline to 14 and 26 weeks 
- 
Body composition measurement. Change in body composition from baseline to 14 and 
26 weeks 
- 
BP (bloodpressure) (systolic and diastolic) and pulse. Change in BP (mmHg) from 
baseline to 14 and 26 weeks 
 
Metabolic:  
For all the below mentioned laboratory tests we measure change from baseline to 14 and 26 
weeks 
- 
HOMA-IR (Homeostatic model assessment for insulin resistance). Primary outcome 
- 
fasting glucose 
- 
fasting insulin 
- 
HbA1C 
- 
Lipids (cholesterol and its subclasses, triglycerides) 
- 
CRP (C-reactive protein) 
- 
2 hour OGTT (oral glucose tolerance test) 
- 
ALAT (alanine aminotransferase) 
- 
G-GT (gamma-glutamyltransferase).  
From these tests, following indexes can be calculated: 
FLI (fatty liver index (FLI)  
Matsuda Index (indicator for insulin resistance)  
Triglyceride glucose (TyG) index (indicator for insulin resistance)  
 
Androgenicity:  
Clinical: 
- 
Hirsutism. Primary outcome. Here we measure change in modified Ferriman-Gallwey 
score from baseline to 14 and 26 weeks 
- 
Acne 
- 
Alopecia 
 
Biochemical: 
For all the below mentioned laboratory tests we measure change from baseline to 14 and 26 
weeks 
- 
Testosterone. Primary outcome. 
- 
FAI (free androgen index) 

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- 
SHBG (sex hormone binding globulin) 
- 
DHEAS (dehydroepiandrosterone sulfate) 
- 
Androstenedione 
- 
free testosterone 
 
Menstrual Cyclicity: 
- 
Questionnaire, where asking if the menstrual cycle is regular (defined as 21 days or 
more but under 36 days) and measuring change from baseline to 14 and 26 weeks. 
- 
Questionnaire, where asking how long the two previous cycles were (days) and 
measuring change from baseline to 14 and 26 weeks 
 
Gastrointestinal side-effects: 
- 
Questionnaire, where asking about the appearance and severeness of the 
following symptoms: abdominal pain, reflux, nausea, diarrhoea, loss of appetite 
and measuring change from baseline to 14 and 26 weeks. Primary outcome will 
be severeness of gastrointestinal adverse effects (GI AE). A severe adverse effect 
is defined as a score of 4 or more in one of the questions in the questionnaire 
(indicating a daily experience of abdominal pain, reflux, nausea, diarrhoea or 
loss of appetite during the last two weeks). Secondary outcomes will be 
appearance of GI AE (never/everything else but never), appearance of different 
AE (abdominal pain, reflux, nausea, diarrhoea, loss of appetite) and 
discontinuation of metformin due to GI AE. 
 
Quality of life and weight stigma: 
- 
The PCOS-Q- a questionnaire that was specifically designed to measure quality of life in 
women with PCOS.  
 
Polycystic ovary morphology:  
- 
AMH (anti-Mullerian hormone). Here we measure change from baseline to 14 and 26 
weeks. Primary outcome. 
- 
Vaginal ultrasound where we measure follicle number per ovary and ovarian volume 
and change from baseline to 14 and 26 weeks. 
 
 
5 
TRIAL DESIGN 
5.1 General considerations 
The present study is a double-blind, randomized controlled trial, including adults (age 18-37 
years) with PCOS and a BMI ≥ 25 and <40 kg/m2. Potential participants for the study will be 
recruited from individuals referred to the Reproductive Medicine Unit at Helsinki University 
Hospital in Finland and by advertising via the Finnish patient organization for those with PCOS 

EUCT: 2023-509259-15-01, Melin et al. 
 
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(Korento). Medicine use included and excluded in this study are listed in Table 1. The PICO 
(Population, Intervention, Comparison and Outcome) frameworks for this RCT have been 
established a priori and will be used for study selection (Table 2).  
 
5.1.1 
Overall description of trial subjects 
The 2023 updated international evidence-based guideline for the assessment and management 
of PCOS recommends using the Rotterdam criteria for the diagnosis of PCOS (3). For a PCOS 
diagnosis in adults, two out of three following criteria are required: ovulatory dysfunction (OD); 
clinical or biochemical hyperandrogenism (HA); and/or polycystic ovary morphology (PCOM). In 
addition, other causes, for example hypothyroidism and hyperprolactinemia, should be 
excluded.  
Adolescents have other diagnostic criteria for PCOS than adults, as menstrual irregularities and 
PCOM are much more common in this age category, which is why we have excluded them from 
this study.  
 
Ovarian dysfunction (OD) 
The OD criterium indicates oligo-or anovulation, with irregular menstrual cycles as the most 
common symptom. In the updated 2023 PCOS guideline, criteria for OD are defined as a 
menstrual cycle < 21 or > 35 days, three years after menarche until perimenopause. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Figure 1: Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Selection of study population 
Individuals, aged 18-37 years and a BMI≥ 25 and <40 kg/m2, with suspected 
hyperandrogensim, menstrual irregularities and/or polycystic ovaries will be sent 
an electronic link to express interest in participating in the study 
N=220 
Screening call (0-2 wks from express of 
interest) 
– interview 
- information 
- if eligible for the study, written information and 
letter for informed consent is sent home 
Baseline visit (within 2 wks from screening visit) 
-delivery of medication by the pharmacy (metformin, 
contraceptive if needed) 
-clinical examination (hirsutism, weight, height, whr, BP) 
- Vaginal ultrasound (FNPO, ovarian volume)  
- Collection of filled questionnaires 
Screening visit (2-3 wks from screening call) 
- sign informed consent 
- Referral to lab* 
- Questionnaires to the participant 
14 weeks visit (12 weeks use of full metformin dose) 
-lab** 
-clinical examination (hirsutism, weight, whr, BP) 
- Vaginal ultrasound (FNPO, ovarian volume)  
- Collection of filled questionnaires 
26 weeks visit (24 weeks use of full metformin dose) 
-lab** 
-clinical examination (hirsutism, weight, whr, BAI, body 
composition, BP) 
- Vaginal ultrasound (FNPO, ovarian volume)  
- Collection of filled questionnaires 
-Discussion on future treatment and follow-up 
Exclusion: 
-BMI and/or age criteria not fulfilled 
-No PCOS according to the 2023 
International PCOS guideline 
-Use hormonal contraceptive during the 
last 3 months 
-Individuals that are pregnant or 
breastfeeding 
-Individuals with untreated diabetes, 
hypothyroidism or hyperprolactinemia 
-Use of medications listed in Table 2 
-Individuals with contraindication for use 
of metformin (hypersensitivity to 
metformin, acute metabolic acidosis, renal 
impairment, hepatic insufficiency, heart- or 
respiratory failure) 
-Serious mental illness. 
-Alcoholism 
-A planned surgical intervention during 
the next 26 weeks  
 
-Investigator site staff directly involved in 
the conduct of the study and their family 
members 
N=92 
Metformin 500mgx3/day 
N=92 
Metformin 750mgx3/day 
- 
*lab: FAI, SHBG, DHEAS, testosterone, 
androstenedione, HOMA-IR, fasting 
glucose, fasting insulin, HbA1C, lipids, 
CRP, ALAT, GGT, AMH, OGTT, s-hcg, 
TSH, PRL, 17-OHP, GFR. 
- 
**lab: FAI, SHBG, DHEAS, 
testosterone, androstenedione, 
HOMA-IR, fasting glucose, fasting 
insulin, HbA1C, lipids, CRP, AMH, 
ALAT, GGT, OGTT, s-hcg, GFR 

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Hyperandrogenism (HA) 
HA can be assessed either clinically or biochemically. Regarding clinical HA, hirsutism is highly 
correlated with biochemical HA whereas acne and alopecia are less specific. For objective 
assessment of hirsutism, the use of the modified Ferriman-Gallwey (mFG) score is 
recommended, recognizing that self-treatment is frequently employed. For hirsutism, a mFG 
score of 4 or more is required in Caucasian women. If clinical HA is not present, biochemical 
hyperandrogenism can be determined. Biochemical HA is best assessed using total testosterone 
or free androgen index (FAI) analysed with highly accurate tandem mass spectrometry (LC-
MS/MS) assays. A testosterone of 2,0 nmol/l or higher or a FAI of 6 or higher is regarded as 
biochemical hyperandrogenism. 
 
Polycystic ovary morphology (PCOM) 
PCOM can only be assessed when over 8 years has passed from the menarche. The assessment 
of PCOM has until recently been done by ultrasonography but in the 2023 international PCOS 
guideline, measurement of serum anti-Müllerian hormone (AMH) has been added as an 
alternative.  Ultrasound is at present still the primary method for assessing PCOM in most 
clinical settings, however, it is expensive, and the availability is often limited or even absent. 
According to the diagnostic criteria as defined in the evidence-based guideline, the cut-off for 
PCOM is ≥ 20 follicles with a diameter of 2-9 mm in at least one ovary on transvaginal 
ultrasonography. As AMH strongly correlates with antral follicle count (AFC) on ultrasound, the 
2023 guideline has now incorporated this as an alternative method to estimate PCOM. An AMH 
above the reference interval is regarded as PCOM. 
 
 
5.1.2 
Inclusion criteria 
To be eligible for inclusion, each participant must meet each of the following criteria at Baseline 
(Visit 1): 
- 
Signed informed consent and willingness to comply with the trial procedures 
- 
Sufficient skills in the Finnish or Swedish language 
- 
Participants with PCOS (diagnosed by the updated 2023 PCOS guideline) 
- 
Participants 18-37 years of age at screening 
- 
Participants with a BMI ≥ 25 kg/m2 and < 40 kg/m2 
5.1.3 
Exclusion criteria 
Participants are excluded from the study if any of the following criteria is met at screening or at 
Baseline: 
- Inability to provide written informed consent  
- Participants not meeting the criteria by the updated PCOS guideline  
- Participants with hormonal contraceptive during the last 3 months 
- Participants that are pregnant or breastfeeding 
- Participants with an untreated diabetes, hypothyroidism or hyperprolactinemia 
- Use of medications for diabetes, high cholesterol, obesity and cortisone (per oral). Please 
see detailed list in Table 1. 

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- Participants with contraindication for use of metformin (hypersensitivity to metformin, 
acute metabolic acidosis, renal impairment, hepatic insufficiency, heart- or respiratory 
failure) 
- Serious mental illness. 
- Alcoholism 
- Investigator site staff directly involved in the conduct of the study and their family 
members 
 
5.1.4 
Withdrawal of subjects from treatment 
Participants who become pregnant during the study period or commence medication listed in 
Table 1, will be instructed to withdraw from the interventional component of a study, but we will 
still include them in the study and analyse blood samples and results from clinical examination 
and questionnaires, already performed. 
 
Table 1 Instructions on inclusion and exclusion regarding medicine use in potential participants 
Include 
Exclude 
Medication for hypothyroidism 
Medication for hyperprolactinemia 
Medication for mental illness (depression, 
anxiety) 
Local cortisone (lotion) 
Metformin during the last 3 months 
Inositol  
Medication for diabetes 
Medication for hypercholesterolemia 
Medication for obesity 
Cortisone (per oral or iv) 
Hormonal contraceptive use during the last 3 
months (including progesterone only substances) 
Medicines used for ovulation induction or IVF 
 
Table 2 Selection criteria for inclusion and exclusion of studies in the RCT 
 
Include 
Exclude 
Population 
Signed informed consent and 
willingness to comply with the trial 
procedures  
Participants with PCOS (by the updated 
2023 PCOS guideline) 
Age: 18-37 years 
BMI: ≥ 25 kg/m2 and < 40 kg/m2 
Subgroups: age, BMI, PCOS phenotype 
-Participants not meeting the criteria of 
PCOS in the updated 2023 PCOS guideline 
(including a 17-OHP, TSH and PRL above 
reference)  
-Participants with hormonal contraceptive 
during the last 3 months 
-Participants that are pregnant or 
breastfeeding 
-Participants with an untreated diabetes, 
hypothyroidism or hyperprolactinemia 

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-Use of medications for diabetes, high 
cholesterol, obesity and cortisone (per 
oral) 
-Participants with contraindication for use 
of metformin (hypersensitivity to 
metformin, acute metabolic acidosis, renal 
impairment, hepatic insufficiency, heart- 
or respiratory failure) 
-Serious mental illness. 
-Alcoholism 
-A planned surgical intervention during 
the next 26 weeks 
- Investigator site staff directly involved in 
the conduct of the study and their family 
members 
Intervention 
Metformin 1500mg/day for 26 weeks 
NA 
Comparison 
Metformin 2250mg/day for 26 weeks 
NA 
Outcomes 
Anthropometric: weight, height, BMI, 
WHR, BAI, body composition, BP, pulse, 
gastrointestinal effects, irregular cycles 
Androgenicity: Hirsutism, FAI, SHBG, 
DHEAS, testosterone, androstenedione, 
free testosterone 
Metabolic: HOMA-IR, fasting glucose, 
fasting insulin, HbA1C, lipids, ALAT, GGT, 
CRP, OGTT, FLI, Matsuda Index, TyG 
 
Psychological: Qol, depression, anxiety, 
weight stigma  
Polycystic ovary morphology: AMH, 
ultrasound (follicle number per ovary, 
ovarian volume) 
 
NA 
 
 

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5.2 Randomisation and blinding  
5.2.1 
Randomisation 
A double-blind, randomized controlled trial, including adults (age 18-37 years) with PCOS and a 
BMI ≥ 25 and <40 kg/m2 will be carried out.  The randomization will be computer-generated 
and performed by the hospital pharmacy with 1:1 allocation in random blocks. We intend to do 
blinded analyses as well; hence the hospital pharmacy will provide the randomisation codes 
when the analyses have been performed. 
 
5.2.2 
Blinding  
After the baseline visit has been performed, the participant will receive the medication, delivered 
by the University pharmacy to the Reproductive Medicine Unit (where all the visits will take 
place). The study will be conducted in a double-blind fashion. Thus, study treatment assignment 
will be blinded for both the investigators and the subject. The maintenance of clinical trial 
treatment randomisation codes will be done by the University pharmacy. The blinding can only 
be broken if a participant experiences serious adverse events (acute metabolic acidosis,  renal 
impairment, hepatic insufficiency, heart- or respiratory failure). Any intentional or unintentional 
breaking of the blind will be recorded and reported to the sponsor as soon as possible. 
 
5.3 Study assessments and procedures 
Informed consent will be obtained prior to any study-related procedures being undertaken. The 
study is anticipated to last between 28 to 32 weeks after informed consent has been received. 
The schedule of assessments in the trial is summarised in Table 3. 
 
Table 3. Schedule of events  
Procedures 
 
Call 
 
Screen 
Visit 1 
Baseline 
Visit 2 
14 weeks 
Visit 3 
26 weeks 
Day 
D1 
-2-4 weeks 
D1 
-0-2 weeks 
D1 
D1+14 weeks 
±14 days 
D1+26 weeks 
±14 days 
Eligibility Criteria 
x 
x 
 
 
 
Informed consent 
 
x 
 
 
 
Medical history 
x 
 
x 
x 
x 
Physical examination  
 
 
xa 
xa 
xa 
Vaginal ultrasound 
 
 
x 
x 
x 
Laboratory 
 
x 
 
x 
x 
Pregnancy test 
 
x 
 
x 
x 
Randomisation 
 
 
x 
 
 
Dispensing of study medications  
 
 
x 
x 
 
Questionnaires (own and PCOSQ) 
 
x 
 
x 
x 
Adverse events  
 
 
 
x 
x 
Medication compliance  
 
 
 
x 
x 
Instructions on how to contact the research 
team if adverse events or questions 
x 
x 
x 
x 
 
Discussion on future treatment 
 
 
 
 
x 
aper investigator’s discretion  
 

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5.3.1 
Description of Study Assessments 
Demographics: Age, BMI and ethnicity will be recorded.  
Physical Examination: The physical examination will include height, weight, wc and WHR, BP, 
pulse, as well as hirsutism (mFG score) 
Vaginal ultrasound: will include follicle number per ovary and ovarian volume 
Laboratory tests: Please see Table 2 and Figure 1 
Questionnaires: Two separate questionnaires are included in this study. The first one includes 
questions on medical history and adverse events, whereas the second one (PCOSQ) is a 
validated questionnaire developed specifically to measure quality of life for individuals with 
PCOS. 
 
5.3.2 
Endpoints assessments 
Efficacy Assessment 
Anthropometric:  
 
- Weight and height: will be measured with participants allowed to wear light clothing 
after an overnight fasting. Weight will be measured by a standard scale to an accuracy of 
+/- 0,1kg. Height will be measured to an accuracy of +/- 0,1cm  
- BMI (Body Mass Index): will be measured as kg/m2 
- 
WHR (Waist-hip-ratio). Will be calculated as waist measurement divided by hip 
measurement (W⁄H). Hip circumference is determined as the maximum value over the 
glottal region, measured to the nearest centimetre. 
- WC (Waist circumference). Measured halfway between the participant’s lowest rib and 
the top of the participant’s hipbone 
- BAI (Body adiposity index). Will be measured using the following equation: hip 
circumference (cm)/height (m) – 18 
- BP (blood pressure) (systolic and diastolic) and pulse. Will be measured twice with at 
least 3 minutes apart after at least 10 min rest from non-dominant upper extremity in a 
subject in supine position  
 
Metabolic:  
All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting. 
- 
HOMA-IR (Homeostatic model assessment for insulin resistance). Calculated with the 
formula: fasting plasma glucose (mmol/L) × fasting serum insulin (mU/L) divided by 22.5 
(9) 
- 
fasting glucose mmol/l (photometric hexokinase method) 
- 
fasting insulin mU/l (immunochemiluminometric assay) 
- 
HbA1C mmol/mol (photometric enzymatic method) 
- 
Lipids (total cholesterol, mmol/l and triglycerides mmol/l with an enzymatic photometric 
method, LDL and HDL mmol/l with a direct enzymatic photometric method)  
- 
CRP (C-reactive protein) mg/l (photometric immunochemical method) 
- 
GGT U/l (photometric method according to IFCC recommendation) 

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- 
ALAT U/l (photometric method according to IFCC recommendation) 
- 
2-hour OGTT mmol/l 
- 
 
- 
From these tests, following indexes can be calculated: FLI, Matsuda Index, TyG index  
 
Androgenicity:  
Clinical: 
- 
Hirsutism. Modified Ferriman Gallwey score (mFG) will be measured and a score of 4 or 
more will be regarded as hirsutism in Caucasian women, whereas a score of 6 or more 
will be regarded hirsutism for other ethnicities. 
 
Biochemical: 
All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting. 
- 
Testosterone nmol/l (liquid chromatography with tandem mass spectrometry (LC-
MS/MS)) 
- 
FAI (free androgen index) (FAI = 100 X ((Total Testosterone (nmol/L)/SHBG (nmol/L)) 
- 
SHBG (sex hormone binding globulin) nmol/l (immunochemiluminometric assay) 
- 
DHEAS (dehydroepiandrosterone sulfate) nmol/l (immunochemiluminometric assay) 
- 
Androstenedione nmol/l (liquid chromatography with tandem mass spectrometry (LC-
MS/MS)) 
- 
free calculated testosterone pmol/l (by Anderson Formula) (8). 
 
Menstrual Cyclicity: 
- 
Questionnaire, where asking if the menstrual cycle is regular (defined as 21 days or 
more but under 36 days) 
- 
Questionnaire, where asking how long the two previous cycles were (days) 
 
Side-effects: 
- 
Questionnaire, where asking about the appearance and severeness of the following 
symptoms: abdominal pain, reflux, nausea, diarrhoea, loss of appetite. 
 
 
Quality of life and weight stigma: 
- 
The PCOS-Q- a validated questionnaire that was specifically designed to measure 
quality of life in women with PCOS.  
 
Polycystic ovary morphology:  
- 
AMH (anti-Mullerian hormone) (ug/l) will be taken in the morning, between 7-10 am, 
after 12 hours fasting (with other laboratory measurements).  
- 
Vaginal ultrasound where we measure follicle number per ovary and ovarian volume will 
be measured at any stage of the cycle.  

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The primary timepoint for this study is 26 weeks, whereas the 14 weeks timepoint will be 
secondary.  
 
Safety Assessment 
Safety evaluations will be performed as adverse event monitoring during the 14 week and 26 
week visits. In case of acute symptoms of acute metabolic acidosis, renal impairment, hepatic 
insufficiency, heart- or respiratory failure, patients will be asked to call the emergency 
department. Participants will be instructed to do a home pregnancy test during week 4, 8, 12, 18 
and 22 of the trial. If the participant becomes pregnant, we will instruct them to withdraw from 
the interventional component of the study (discontinue the metformin-medication), but we will 
still include them in the study and analyse blood samples and results from clinical examination 
and questionnaires, already performed. 
For further information on safety assessments, please see the summary of product 
characteristics. 
 
5.4 Study visit structure 
5.4.1 
Screening procedure  
Screening call: 
1. Potential participants for the study will be recruited from individuals referred to the 
Reproductive Medicine Unit at Helsinki University Hospital in Finland and by advertising 
via the Finnish patient organization for those with PCOS (Korento). Potential participants 
will be sent an electronic link to express interest in participating in the study 
2. Check the age (18-37 years) and BMI (BMI≥ 25 kg/m2 and <40 kg/m2) of the 
individuals that have expressed interest in participating in the study 
3. Ask the individual on signs of PCOS (menstrual irregularities, biochemical and clinical 
hyperandrogenism, PCOM)  
4. Ask if the individual is pregnant or breastfeeding, illnesses and medication use 
5. Exclude the participants that don’t meet the inclusion criteria 
6. Describe the study in detail 
7. If the participant is eligible and willing to participate in the study, send written 
information and letter for informed consent to home address 
8. Book a screening visit within 2 weeks 
 
Screening visit: 
1. Collect the signed informed consent 
2. Check the age (18-37 years) and BMI (BM I≥ 25 and <40 kg/m2) of the woman. Weight 
and height measurement if needed! 
3. Check the inclusion and exclusion criteria 
4. Answer possible questions that the participant might have 
5. Refer the participant to laboratory and give her the questionnaires 
6. Book a baseline visit within 2 weeks from the screening visit 

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Individuals who are incapable of giving informed consent will be excluded from the study and 
informed consent will be obtained prior to any study related procedures being undertaken.  
The maximum duration allowed between screening call and randomisation is 28 days and 14 
days between screening visit and randomisation. 
Date of screening, age of the individual and reason for ineligibility (if the individual is not 
eligible) will be recorded. The results of the screening evaluation must meet the 
inclusion/exclusion criteria for the individual to continue in the study. 
 
Laboratory check: 
1. Check the laboratory results and make sure the participant is eligible for the study 
 
 
5.4.2 
Baseline assessments (+0-14 days, Visit 1) 
1. Clinical examination (hirsutism – mFG score, weight, height whr, BP) 
2. Vaginal ultrasound (FNPO, ovarian volume)  
3. Collection of filled questionnaires (own and PCOSQ) 
4. Inform the participants how metformin is taken (1 tabl per day for the first week, 2 tabl per 
day for the second week, 3 tabl per day starting third week and always together with a 
meal). 
5. Ask if the participants wish to receive condoms as contraception and provide if needed 
6. Give the participant metformin for the next 14 weeks (delivery of medication will be made 
by the university pharmacy) 
7. Instruct the participant to do home pregnancy test on week 4,8 and 12 and contact us for 
exclusion from the study and termination of the medication if pregnant 
8. Ask the participant to bring with her the Metformin medication not used 
9. Refer for laboratory tests and give the link to questionnaires to be filled out for next 
appointment 
10. Book the next appointment 
 
5.4.3 
Visit 2 (+14 weeks +/-14 days) 
1. Check the laboratory results and make sure the participant can continue the study (not 
pregnant, no serious, adverse events) 
2. Check and document how much metformin is unused 
3. Clinical examination (hirsutism – mFG score, weight, whr, BP) 
4. Vaginal ultrasound (FNPO, ovarian volume)  
5. Collection of filled questionnaires (own and PCOSQ) 
6. Ask if the participants wish to receive condoms as contraception and provide if needed 
7. Give the participant metformin for the next 12 weeks (delivery of medication will be 
made by the university pharmacy) 
8. Instruct the participant to do home pregnancy test on week 18 and 22 and contact us 
for exclusion from the study and termination of the medication if pregnant 
9. Ask the participant to bring with her the metformin medication not used 
10. Refer for laboratory tests and give the link to questionnaires to be filled out for next 
appointment 

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11. Provide a card with sponsor contact details in case emergency unblinding becomes 
necessary. 
12. Book the next appointment 
 
5.4.4 
End-of-Treatment visit (+12 weeks +/- 14 days, Visit 3) 
1. Check the laboratory results  
2. Check and document how much metformin is unused 
3. Clinical examination (hirsutism – mFG score, weight, whr, BP) 
4. Vaginal ultrasound (FNPO, ovarian volume)  
5. Collection of filled questionnaires (own and PCOSQ) 
6. Discussion on future treatment and follow up (continuation of metformin etc) 
 
5.5 End-of-trial 
5.5.1 
Definition 
The clinical trial will end after the last participant has attended the last visit (Visit 3). If one of the 
participants in the trial falls pregnant, the clinical trial will end at the latest 38 weeks after Visit 3 
of the last pregnant participant. For pregnant participants, we will search the hospital charts to 
evaluate the endpoint of the pregnancy (miscarriage, extrauterine pregnancy, induced abortion 
or live birth).  
The Sponsors and/or the trial steering committee have the right at any time to terminate the 
study for clinical or administrative reasons. 
5.5.2 
Premature termination of the study 
The study or a part of the study may be stopped if new information about safety or efficacy is 
received. 
If a participant becomes pregnant, starts a medication on “the exclusion list” (Table 1) or gets 
sever adverse events (acute metabolic acidosis,  renal impairment, hepatic insufficiency, heart- 
or respiratory failure), they will be instructed to withdraw from the interventional component of 
the study (discontinue the metformin medication), but we will still include them in the study and 
analyse blood samples and results from clinical examination and questionnaires, already 
performed. 
Participants have the right to voluntarily discontinue study treatment or withdraw from the 
study at any time for any reason without any consequences. 
5.5.3 
Reporting the end of trial 
The end of the study will be reported in the CTIS (Clinical Trials Information System) within 15 
days from the end of the clinical trial.  
 
5.6 Discontinuation/withdrawal of subjects from study protocol 
Participants have the right to voluntarily discontinue study treatment or withdraw from the 
study at any time for any reason without any consequences. The participant is not obliged to 
disclose the reason for discontinuation. The investigator has the right to discontinue a subject 
from study treatment or withdraw a subject from the study at any time if it is in the best interest 
of the subject. 

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Subjects can be withdrawn from the study or the interventional component for any of the 
following reasons: 
- withdrawal of consent by the subject  
- any medical condition that the investigator or sponsor determines may jeopardize the 
subject’s safety if she or he continues receiving the study treatment 
- pregnancy 
- ineligibility (either arising during the study or retrospectively having been overlooked at 
screening) 
- an adverse event which requires discontinuation of the study medication  
- lack of compliance with the study or study procedures (e.g., dosing, study visits) 
- lost to follow-up (at least three documented attempts must be made to contact any 
subject lost to follow-up) 
If a subject is withdrawn before completing the study, the reason for withdrawal will be entered 
on the appropriate case report form (CRF) page. 
If a subject is withdrawn due to an adverse event, the investigator will arrange for follow-up 
visits until the adverse event has resolved or stabilise 
If a subject is withdrawn before visit 2 (less than 14 weeks metformin use), she will be replaced 
by another subject. If she is withdrawn later, she will not be replaced. We will use intention-to 
treat-analyses in this study. 
 
5.7 Participant care after the trial 
During the last visit, we will inform the participant on the recommended follow up for 
individuals with PCOS, which is generally clinical examination and laboratory tests every 1-3 
years. If the participant is willing to continue and fulfils the criteria for metformin medication, a 
prescription will be written. The follow-up should be arranged at the participants health care 
centre or in private care by the participant herself.  
 
6 
TREATMENT OF TRIAL SUBJECTS 
6.1 Description of study treatment(s) 
Participants in the study will be divided into two arms, receiving a different dose of metformin: 
1. Metforem depotablet (extended release) 500 mg, containing 500 mg of metformin 
hydrochloride, used at a maximum dose of one tablet in the morning and two in the evening. 
Size: 19 x 8,8 mm 
Colour: White 
2. Metforem depotablet (extended release) 750 mg, containing 750 mg of metformin 
hydrochloride, used at a maximum dose of one tablet in the morning and two in the evening 
Size: 20,3 x 9,4 mm 
Colour: White  
Metformin is a low cost, readily available medication that has been extensively used as an insulin 
sensitiser for over seven decades in type 2 diabetes mellitus and for several decades in PCOS.  

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The optimal metformin dose for adults with PCOS is unclear but the suggested maximum daily 
dose according to the International PCOS Guideline is 2.5 g in adults (6). Metformin should be 
taken together with a meal. 
6.2 Formulation, packaging and handling 
The packing and labelling of the metformin medication will be done by Meilahti University 
Pharmacy (address: Siltasairaalan aula, Haartmaninkatu 4, 00290 Helsinki). We are currently 
negotiating with the pharmaceutical company Orion Pharma, whether they would be willing to 
donate metformin medication for the study. 
6.3 Storage and disposition of study treatment(s) 
The metformin medication will be stored according to instructions from the pharmaceutical 
company at the Meilahti University Pharmacy. We anticipate doing research visits once per week 
and the metformin medication will be brought from Meilahti University Pharmacy earlier at the 
same day of the research visits. The metformin medication will be stored and locked in a secure 
place until they are dispensed for subject use or are returned to the sponsor. There are no 
specific instructions for storage conditions of metformin medication by the pharmaceutical 
company. The metformin medication is for investigational use only and is to be used only within 
the context of this study. 
6.4 Accountability of the study treatment(s) 
The investigator is responsible for the control of the metformin medication during the 
investigation. A table of distributed and returned number of metformin tablets, with dates and 
package identification number, per each subject will be used for documenting the 
accountability. 
The study medication will be supplied to Meilahti University Pharmacy by Orion Pharma and 
retrieved at the end of the study. 
The investigator will use a standard prescription manner of the institution, and the investigator 
will collect the medication from the pharmacy. 
6.5 Assessment of compliance 
The participants will be asked to bring all unused metformin tablets to their next visit. 
Compliance will be assessed by maintaining dispensing records.  
If a participant has used less than an average of 2,5 metformin tablets per day (after expected to 
use 3 tablets per day), it will be regarded as significant non-compliance. 
When significant non-compliance is observed, the reason behind non-compliance will be 
evaluated (forgetting medication, side-effects etc). Efforts to find ways to minimize non-
compliance will be taken (alarm if forgetting medication, timing of medicine intake if side-
effects etc). 
Participants will also be encouraged to contact the research team if they are bothered by or 
experiences severe side effects or have difficulties with using the medication as instructed.  
6.6 Overdose of study treatment 
If overdose of metformin is observed or comes to the knowledge of the research team, the 
situation will be handled according to the dose of metformin. According to information received 
from the national Poison Center (Myrkytystietokeskus), if a suspected dose of over 6000mg per 
day has been used (8 tablets or more), the participant will be asked to contact the emergency 

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unit. If a dose of more than 3000mg (4 tablets or more) has been used and the participant 
experiences serious side effects (signs of acute metabolic acidosis,  renal impairment, hepatic 
insufficiency, heart- or respiratory failure) the participant will be asked to contact the emergency 
unit. 
6.7 Prior and concomitant treatment 
Any non-study medication during the trial will be recorded during the study period. Medication 
use will be documented at the screening call, screening visit, visit 1, 2, and 3. 
6.7.1 
Permitted medications 
Permitted medications are described in Table 1 
6.7.2 
Prohibited medications 
Prohibited medications are described in Table 1. If a prohibited medication is commenced 
during the study, the participant will be excluded from the interventional component of the 
study, starting from the intake of the prohibited medication.  
7 
SAFETY REPORTING 
The safety and tolerability will be evaluated throughout the study based on adverse events, vital 
signs and physical exam findings. The appearance of adverse events will be asked in a 
questionnaire and documented on visit 2 and 3. In addition, the participants will be instructed to 
contact the research team (by phone or email) if adverse events occur during the study period. 
7.1 Definitions 
7.1.1 
Adverse event 
Adverse events are any untoward medical occurrence in a patient or clinical trial participant 
administered a medicinal product, which do not necessarily have a causal relationship with this 
treatment. 
An adverse event can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding, for example), symptom or disease temporally associated with the use of a 
medicinal product, even if not considered related to the medicinal product. 
7.1.2 
Adverse reaction 
All untoward and unintended responses to a medicinal product related to any dose count as 
adverse reactions. The phrase ‘responses to a medicinal product’ means that a causal relationship 
between a study medication and an adverse event is at least a reasonable possibility, i.e., the 
relationship cannot be ruled out. All cases judged by either the reporting medically qualified 
professional or the sponsor as having a reasonable suspected causal relationship to the study 
medication qualify as adverse reactions.   
7.1.3 
Serious adverse event (SAE) 
Any untoward medical occurrence or affect that at any dose:  
- results in death,  
- is life-threatening*,  
- requires hospitalisation or prolongation of existing hospitalisation,  
- results in persistent or significant disability or incapacity,  
- is a congenital anomaly or birth defect 
- counts as an important medical event** 

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*Regarding a life-threatening event, this refers to an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might have caused death 
if it were more severe.  
**Some medical events may jeopardise the subject or may require an intervention to prevent one 
of the above characteristics/consequences. Such events (hereinafter referred to as ‘important 
medical events’) should also be considered as ‘serious’ in accordance with the definition  
7.1.4 
Suspected unexpected serious adverse reactions (SUSARs) 
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g. undesirable events listed in the SmPC section 4.8) 
 
7.2 Evaluation of adverse events and SAEs 
7.2.1 
Assessment of seriousness 
In previous studies the reported adverse effects with metformin are usually mild and self-limiting 
including nausea, vomiting, diarrhoea and abdominal pain. Lactic acidosis, a previously feared 
serious adverse effect, is very rare in women with PCOS, 1 in 30,000 patients using metformin (9). 
Adverse effects can be minimized by starting metformin treatment at a lower dose with 500mg 
increments 1-2 times weekly and by using extended-release preparations (3, 10). 
7.2.2 
Assessment of causality 
All adverse events judged by either the investigator or the sponsor as having a reasonable 
suspected causal relationship to an investigational medicinal product qualify as adverse reactions.  
All adverse events judged as being related to an interaction between the study medication and 
another medication will also be considered adverse reactions. 
Alternative causes such as natural history of the underlying disease, concomitant therapy, other 
risk factors and the temporal relationship of the event to the treatment should be considered. 
7.2.3 
Assessment of intensity 
The investigator will assess severity for each adverse event and record this on the Case report 
form (CRF) according to one of the following categories: 
Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities (grade 1-3 in the questionnaire) 
Moderate: An event that is sufficiently discomforting to interfere with normal everyday activities 
(grade 4 in the questionnaire) 
Severe: An event that prevents normal everyday activities (grade 5 in the questionnaire) 
7.2.4 
Assessment of expectedness 
Adverse gastrointestinal effects, such as diarrhoea, nausea, loss of appetite and vomiting, are 
relatively common, affecting up to 30% of patients who take metformin. Lactic acidosis is a rare, 
yet severe adverse effect with an incidence rate of approximately 1 in 30,000 patients using 
metformin.  Several risk factors contribute to developing lactic acidosis, including hepatic or 
renal impairment, advanced age and alcoholism. Participants with these risk factors will be 
excluded from the study. Overall Metformin is generally considered safe and well-tolerated. For 

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more details, please see the SmPC section 4.8., which will be considered as reference safety 
information (RSI) for this trial for the assessment of expectedness. 
7.2.5 
Emergency unblinding procedures 
In case of a serious adverse event or overdosing, where the participant will receive emergency 
medical care, the study blind will be broken. This can be done by contacting the research team by 
phone, who will make the decision and perform the unblinding. Participants will be provided with 
and encouraged to carry a card with sponsor contact details in case emergency unblinding 
becomes necessary. 
 
7.3 Reporting procedures for all adverse events 
All adverse events occurring during the study observed by the investigator or reported by the 
subject will be recorded on the CRF. 
Serious adverse events considered related to the study medication as judged by an investigator 
will be followed until resolution or until the event is considered stable. All related serious 
adverse events that result in a subject’s withdrawal from the interventional component of the 
study or are present at the end of the study, will be followed up until a satisfactory resolution 
occurs. 
It will be left to the investigator’s clinical judgment whether an adverse event is of sufficient 
severity to require the subject’s removal from treatment. A subject may also voluntarily withdraw 
from treatment due to what he or she perceives as an intolerable adverse event. If either of 
these occurs, the subject will undergo an end-of-study assessment and be given appropriate 
care under medical supervision until symptoms cease or the condition becomes stable. 
Any pregnancy occurring during the clinical study and the outcome (e.g., delivery of healthy child 
at term, spontaneous abortion) of the pregnancy will be recorded and followed. 
 
7.4 Reporting procedures for serious adverse events (SAE) 
The investigator will report all SAE immediately to the sponsor. The immediate report will be 
followed by detailed, written reports. The immediate and follow-up reports will identify subjects 
by unique code numbers assigned to the latter. The immediate report will be made by the 
investigator to the sponsor within 24 h following knowledge of the serious adverse event. 
All SAE information must be recorded on an SAE form and sent expeditiously to the sponsor. 
Additional information received for a case (follow-up or corrections to the original case) need to 
be detailed on a new SAE form and sent expeditiously to the sponsor. 
The sponsor will keep detailed records of all adverse events reported by the investigator or 
investigators. 
In cases where reporting is not required immediately the investigator will report within the 
appropriate time frame, taking account of the specificities of the trial and of the serious adverse 
event, as well as possible guidance in the protocol or the investigator’s brochure. 
The academic sponsors will report all SUSARs to FIMEA, using CIOMS-I template. Fatal or life-
threatening SUSARs must be reported within 7 days. SUSARs which are not fatal and not life-
threatening are to be reported within 15 days. The sponsor will also inform all investigators 

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concerned of relevant information about SUSARs that could adversely affect the safety of 
subjects. 
If the initial report is incomplete, e.g. if the sponsor has not provided all the information within 
seven days, the sponsor will submit a completed report based on the initial information within 
an additional eight days. 
If significant new information on an already reported case is received by the sponsor, the clock 
starts again at day zero, i.e. the date of receipt of new information. This information will be 
reported as a follow-up report within 15 days. 
In addition to the expedited reporting above, the sponsor will, once a year throughout the 
clinical trial or on request, submit a safety report to the competent authority and ethics 
committees.  
 
7.5 Pregnancy 
The investigators will collect pregnancy information on all participants. All pregnancies during 
the trial will be followed to outcome. 
 
8 
STATISTICS 
8.1 Description of statistical methods 
 
Continuous variables will be summarised by number of patients, mean, standard deviation, 
median, minimum, and maximum values and by reporting mean differences. Categorical 
variables will be summarized by counts and percentages.  
Primary analysis: For normally distributed variables, independent-sample t-tests will be used to 
evaluate changes between measurements at baseline and after 14 and 26 weeks of treatment 
and to compare the different metformin doses. Mann-Whitney will be performed for variables 
with skewed distribution.  
Supplementary analysis: We will also use repeated measures ANOVA and linear mixed-effects 
models when comparing the two metformin doses regarding change from baseline 
measurement and when comparing the two groups to each other.  
Adverse event rates between the two treatment arms will be calculated using Poisson regression 
models. We will follow the intention-to-treat principle and adjust/perform sub-analyses 
according to age, BMI and PCOS phenotype.  
 
8.2 Determination of sample size subjects 
As we have found only one previous RCT comparing different metformin doses in PCOS (11) 
where standard deviations (SD) were not calculated, it is impossible to use previous RCT studies 
on different metformin doses to base decisions on SD and margin on. 
In the research group we have agreed on 6 primary endpoints with the following standard 
deviations and non-inferiority limits. For non-inferiority analyses we have used a power 
calculator found on www.sealedenvelope.com/power/continuous-noninferior/ 

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For superiority analyses we have used G Power 3.1. 
Weight: For this outcome we have used a non-inferiority test. In the study by Harborne et al. 
(11), a weight difference of 2.1 kg was non-significant. Generally, a weight reduction of 5%, 
being 4 kg for a person with the weight of 80 kg, is regarded as a significant weight reduction 
(12), which is why the research team decided to use 4 kg as a margin. Power analysis has 
indicated that a total number of 156 participants (78 in each group) will be needed to reveal a 
4kg weight reduction difference between the groups, with an 80% power. Here we have used a 
non-inferiority limit of 4kg, a SD of 10 and a 5% p-value. We have estimated a 15% drop-out 
making the total number of participants needed to 184 (92 participants in each group). 
HOMA-IR (Homeostatic model assessment for insulin resistance): For this outcome we have 
used a non-inferiority test. We have not found any studies on what is considered a significant 
HOMA-IR reduction. Based on an expert opinion by endocrinologist and adjunct professor 
Heikki Koistinen we decided on a reduction of 20%. According to a recent study (13), the cut-off 
value for HOMA-IR to discriminate insulin resistance in women with PCOS is 2.1 and based on 
this we have decided on a margin of 0.42. Power analysis has indicated that a total number of 
142 participants (71 in each group) will be needed to reveal a 0.5 reduction difference of 
HOMA-IR between the groups, with an 80% power. Here we have used a non-inferiority limit of 
0.42, a SD of 1.0 and a 5% p-value. We have estimated a 15% drop-out, making the total 
number of participants needed to 168 (84 participants in each group). 
Hirsutism: For this outcome we have used a non-inferiority test. According to a study by 
Harborne et al. (12), a reduction of 2 mFG-score was significant when studying the effect of 
metformin on hirsutism, which is why the research team decided to use this margin. Power 
analysis has indicated that a total number of 156 participants (78 in each group) will be needed 
to reveal a reduction difference of 2 mFG scores between the groups, with an 80% power. Here 
we have used a non-inferiority limit of 2, a SD of 5 and a 5% p-value. We have estimated a 15% 
drop-out, making the total number of participants needed to 184 (92 participants in each 
group). 
Testosterone: For this outcome we have used a non-inferiority test. In a study comparing 
different metformin doses (1000mg and 1500mg) in breast cancer patients (14), a testosterone 
decrease of 0.41 was considered significant, which is why the research team decided to use this 
margin. Power analysis has indicated that a total number of 148 participants (74 in each group) 
will be needed to reveal a 0.41 reduction difference of Testosterone between the groups, with 
an 80% power. Here we have used a non-inferiority limit of 0.41, a SD of 1.0 and a 5% p-value. 
We have estimated a 15% drop-out, making the total number of participants needed to 174 (87 
participants in each group). 
AMH (anti-Mullerian hormone): For this outcome we have used a non-inferiority test. Several 
factors affect AMH in the general population, including laboratory assays, age, BMI, ethnicity, 
menstrual cycle stage and ovarian surgery (15). A recent study has showed that for the Elecsys 
assay (used by HUSLAB) AMH varies 0.7-0.31 pmol/l per year according to age (17). The 
intercycle variation is expected to be small (16). In our research team, we decided on a reduction 
of 0.5 pmol/l. Power analysis has indicated that a total number of 100 participants (50 in each 
group) will be needed to reveal a 0.5 reduction difference of AMH between the groups, with an 
80% power. Here we have used a non-inferiority limit of 0.5, a SD of 1.0 and a 5% p-value. We 
have estimated a 15% drop-out, making the total number of participants needed to 118 (59 
participants in each group). 

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Gastrointestinal side-effects: Gastrointestinal adverse events of metformin are the most 
common and are assessed to affect up to 20% of patients (18). For this outcome we have used a 
superiority test (Fisher’s exact test). Power analysis has indicated that a total number of 138 
participants (69 in each group) will be needed to reveal a 20% difference in side-effect between 
the groups, with an 80% power. Here we have used a two tailed test with proportions of 0,30 
and 0,10 and a 5% p-value. We have estimated a 15% drop-out, making the total number of 
participants needed to 164 (82 participants in each group). 
The publication on quality of life/mental health and weight stigma in women with PCOS is more 
of exploratory than confirmatory nature, which is why we have not defined a primary outcome 
for this publication.  
In this study we will have 1-2 primary outcome per publication, the rest will be secondary 
outcomes of more exploratory nature. Hence, we have not planned to perform multiplicity 
adjustments in our analyses. For the publication on hyperandrogenism, where two primary 
outcomes (hirsutism and total testosterone) are listed, hirsutism as a marker of clinical 
hyperandrogenism will be of higher hierarchy. 
Our hypothesis is that individuals using the lower metformin dose (1500 mg/day) might improve 
their biochemical and clinical outcomes to the same extent than those using a higher metformin 
dose (2250 mg/day) but with fewer gastrointestinal side effects. 
8.3 Analysis sets 
The set of participants whose data are to be included in the analyses are defined in the statistical 
section of the protocol, 8.1 and 8.2 
8.4 Demographic and baseline disease characteristics 
Demographic and baseline disease characteristics will be summarised descriptively by treatment 
group. 
8.5 Efficacy analysis 
8.5.1 
Primary and secondary efficacy endpoint 
Anthropometric:  
Primary outcome: Weight 
Secondary outcomes:  BMI, WC, WHR, BAI, body composition, BP, pulse  
Here we will measure change in outcomes from baseline to 14 and 26 weeks. We will summarise 
the outcomes by number of patients, mean, standard deviation, median, minimum, and 
maximum values and report mean differences. We will follow the intention-to-treat principle 
and adjust/perform sub-analyses according to age, BMI and PCOS phenotype.  
Primary analysis: For normally distributed variables, independent-sample t-tests will be used to 
compare values between and within the two treatment groups at baseline and 26 weeks. Mann-
Whitney will be performed for variables with skewed distribution.  
Supplementary analysis: Repeated measures ANOVA will be performed to estimate the within-
group modifications (baseline, 14 and 26 weeks). We will also use linear mixed-effects models 
when comparing the two metformin doses regarding change from baseline measurement and 
when comparing the two groups to each other.  
 

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Metabolic:  
Primary outcome: HOMA-IR 
Secondary outcomes: fasting glucose, fasting insulin, HbA1C, lipids (cholesterol and its 
subclasses, triglycerides), CRP, 2-hour OGTT, ALAT, G-GT, FLI, Matsuda Index, TyG index  
For all outcomes we will measure change from baseline to 14 and 26 weeks. We will summarise 
the outcomes by number of patients, mean, standard deviation, median, minimum, and 
maximum values and report mean differences. We will follow the intention-to-treat principle 
and adjust/perform sub-analyses according to age, BMI and PCOS phenotype. 
Primary analysis: For normally distributed variables, independent-sample t-tests will be used to 
compare values between and within the two treatment groups at baseline and 26 weeks. Mann-
Whitney will be performed for variables with skewed distribution.  
Supplementary analysis: Repeated measures ANOVA will be performed to estimate the within-
group modifications (baseline, 14 and 26 weeks). We will also use linear mixed-effects models 
when comparing the two metformin doses regarding change from baseline measurement and 
when comparing the two groups to each other.  
 
Androgenicity:  
Clinical: 
Primary outcome: hirsutism 
Secondary outcome: acne, alopecia 
For hirsutism, we will measure modified Ferriman-Gallwey score as a part of the clinical 
examination and for acne we will use the PCOS-Q to ask about facial hirsutism and alopecia 
(score 1-7). We will report change from baseline to 14 and 26 weeks by number of patients, 
mean, standard deviation, median, minimum, and maximum values and report mean differences. 
We will follow the intention-to-treat principle and adjust/perform sub-analyses according to 
age, BMI and PCOS phenotype. 
Primary analysis: For normally distributed variables, independent-sample t-tests will be used to 
compare values between and within the two treatment groups at baseline and 26 weeks. Mann-
Whitney will be performed for variables with skewed distribution.  
Supplementary analysis: Repeated measures ANOVA will be performed to estimate the within-
group modifications (baseline, 14 and 26 weeks). We will also use linear mixed-effects models 
when comparing the two metformin doses regarding change from baseline measurement and 
when comparing the two groups to each other.  
Biochemical: 
Primary outcome: total testosterone 
Secondary outcomes: FAI, SHBG, DHEAS, androstenedione, free testosterone 
For all outcomes we will measure change from baseline to 14 and 26 weeks. We will summarise 
the outcomes by number of patients, mean, standard deviation, median, minimum, and 
maximum values and report mean differences. We will follow the intention-to-treat principle 
and adjust/perform sub-analyses according to age, BMI and PCOS phenotype.  

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Primary analysis: For normally distributed variables, independent-sample t-tests will be used to 
compare values between and within the two treatment groups at baseline and 26 weeks. Mann-
Whitney will be performed for variables with skewed distribution.  
Supplementary analysis: Repeated measures ANOVA will be performed to estimate the within-
group modifications (baseline, 14 and 26 weeks). We will also use linear mixed-effects models 
when comparing the two metformin doses regarding change from baseline measurement and 
when comparing the two groups to each other.  
 
Menstrual Cyclicity: 
Secondary outcomes: questionnaire, where asking if the menstrual cycle is regular (defined as 21 
days or more but under 36 days) and how long the previous two cycles were (days).  
Continuous variables (cycle length) will be summarised by number of patients, mean, standard 
deviation, median, minimum, and maximum values and by reporting mean differences. 
Categorical variables (regular cycle – yes/no) will be summarized by counts and percentages.  
We will follow the intention-to-treat principle and adjust/perform sub-analyses according to 
age, BMI and PCOS phenotype. 
Primary analysis: Rates of regular menstrual cycle between the two treatment arms will be 
calculated using Poisson regression models. For normally distributed variables, independent-
sample t-tests will be used to compare continuous variables between and within the two 
treatment groups at baseline and 26 weeks. Mann-Whitney will be performed for variables with 
skewed distribution.  
Supplementary analysis: Repeated measures ANOVA will be performed to estimate the within-
group modifications (baseline, 14 and 26 weeks). We will also use linear mixed-effects models 
when comparing the two metformin doses regarding change from baseline measurement and 
when comparing the two groups to each other.  
 
Gastrointestinal side-effects: 
Primary outcome: Appearance of severe of adverse effects.  
Secondary outcomes: Appearance of GI AE (never/everything else but never), subanalyses on the 
appearance of different adverse effects (abdominal pain, reflux, nausea, diarrhoea, loss of 
appetite) and discontinuation of metformin due to GI AE. 
In our questionnaire we will ask the participants whether they have experienced abdominal pain, 
reflux, nausea, diarrhoea or loss of appetite during the last two weeks and grade the symptoms 
from 1-5 (1 being never and 5 being all the time). We will count the scores and give each 
participant a score between 5-25. A severe adverse effect is defined as a score of 4 or more in 
one of the questions (indicating a daily experience of abdominal pain, reflux, nausea, diarrhoea 
or loss of appetite during the last two weeks). We will measure change from baseline to 14 and 
26 weeks and summarise the outcomes by number of patients, mean, standard deviation, 
median, minimum, and maximum values and report mean differences. We will follow the 
intention-to-treat principle and adjust/perform sub-analyses according to age, BMI and PCOS 
phenotype.  

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Primary analysis: Adverse event rates between the two treatment arms will be calculated using 
Poisson regression models. For normally distributed variables, independent-sample t-tests will 
be used to compare values between and within the two treatment groups at baseline and 26 
weeks. Mann-Whitney will be performed for variables with skewed distribution.  
Supplementary analysis: Repeated measures ANOVA will be performed to estimate the within-
group modifications (baseline, 14 and 26 weeks). We will also use linear mixed-effects models 
when comparing the two metformin doses regarding change from baseline measurement and 
when comparing the two groups to each other.  
 
Quality of life and weight stigma: 
Secondary outcomes: The PCOS-Q is a questionnaire that was specifically designed to measure 
quality of life for women with PCOS. Questions on depression, anxiety, fear etc will be given 
scores from 1-7, depending on severity. In our own questionnaire we will ask about weight 
stigma and ask for examples on it. This publication will be of more exploratory nature. We will, 
however, count the scores and measure change from baseline to 14 and 26 weeks and 
summarise the outcomes by number of patients, mean, standard deviation, median, minimum, 
and maximum values and report mean differences. 
Primary analysis: Rates between the two treatment arms will be calculated using Poisson 
regression models. For normally distributed continuous variables, independent-sample t-tests 
will be used to compare values between and within the two treatment groups at baseline and 26 
weeks. Mann-Whitney will be performed for variables with skewed distribution. 
Supplementary analysis: Repeated measures ANOVA will be performed to estimate the within-
group modifications (baseline, 14 and 26 weeks). We will also use linear mixed-effects models 
when comparing the two metformin doses regarding change from baseline measurement and 
when comparing the two groups to each other. 
 
Polycystic ovary morphology:  
Primary outcome: AMH  
Secondary outcomes: Follicle number per ovary, antral follicle count (AFC) and ovarian volume 
For all outcomes we will measure change from baseline to 14 and 26 weeks. We will summarise 
the outcomes by number of patients, mean, standard deviation, median, minimum, and 
maximum values and report mean differences.  
Primary analysis: For normally distributed variables, independent-sample t-tests will be used to 
compare values between and within the two treatment groups at baseline and 26 weeks. Mann-
Whitney will be performed for variables with skewed distribution.  
Supplementary analysis: Repeated measures ANOVA will be performed to estimate the within-
group modifications (baseline, 14 and 26 weeks). We will also use linear mixed-effects models 
when comparing the two metformin doses regarding change from baseline measurement and 
when comparing the two groups to each other. We will follow the intention-to-treat principle 
and adjust/perform sub-analyses according to age, BMI and PCOS phenotype. 
 

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8.6 Safety analysis 
The appearance of adverse events is asked in the questionnaire on visit 2 and 3 and grouped 
into five different categories (see questionnaires attached). 
8.7 The level of statistical significance 
The level of statistical significance to be used in this study is <0,05 
8.8 Criteria for the termination of the trial 
The trial will be terminated when at least 92 participants per treatment arm have attended visit 
2. 
Since Metformin is generally considered a safe and well-tolerated medication, the risk for having 
to terminate the trial due to too many serious adverse events is small. 
8.9 Procedure for accounting for missing, unused and spurious data 
We will perform intention-to-treat analyses. To reduce the number of participants without any 
treatment data, we will measure outcomes at 14 weeks to have some data available if the 
participant falls pregnant or decides to terminate the study. 
8.10 
Procedure for reporting any deviation(s) from the original statistical plan 
Any deviations from the original statistical plan will be discussed with the other research 
members. 
 
9 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
Direct access to study documents and source data will be granted to authorised representatives 
from the sponsor, host institution and the regulatory authorities to permit trial-related 
monitoring, audits and inspections. 
 
10 DATA HANDLING AND RECORD KEEPING 
10.1 
Data collection, source documents and case report forms 
Source documents for this study will include hospital records, procedure reports and data 
collection forms. These documents will be used to enter data on the CRFs. All data entered on 
CRFs will be entered legibly. If an error is made, the error will be crossed through with a single 
line in such a way that the original entry can still be read. The correct entry will then be clearly 
inserted, and the alterations will be initialled and dated by the investigator.  
Data reported on the CRF that are derived from source documents must be consistent with the 
source documents or the discrepancies must be explained. 
All documents will be stored safely in confidential conditions. On all study-specific documents 
other than the signed consent, the subject will be referred to by the study subject identification 
code. 

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10.2 
Data reporting  
All study visits will be documented in the participant’s hospital records. Information on QoL and 
adverse effects will be documented in the questionnaire, filled by the participant. There will be 
source data on all data recorded on the CRF. On all study-specific documents other than the 
signed consent, the subject will be referred to by the study subject identification code. 
 
11 RETENTION OF ESSENTIAL DOCUMENTS 
Essential documents will be retained for at least 25 years from study end. We will retain the trial-
related essential documents as required by the applicable regulatory requirements and until the 
sponsor informs us or the institution that these documents are no longer necessary. 
 
12 QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
To ensure that the data obtained from this research are accurate, complete, and reliable, data 
entered on the CRF will be independently double checked by two investigators. 
13 AUDITS AND INSPECTIONS 
This trial may be subject to internal or external auditing or inspections procedure to ensure 
adherence to GCP. Access to all trial-related documents will be given at that time. 
 
14 ETHICAL CONSIDERATIONS 
Metformin, especially in the early stages of treatment, can cause gastrointestinal side effects, 
such as diarrhea, nausea and loss of appetite. Most of the time, the side effects are mild and 
self-limiting and disappear as the treatment continues. 
In our opinion, this study meets the regulations and principles set for medical research and the 
safety of the subjects has been considered. We consider the research to be ethical. 
14.1 
Declaration of Helsinki 
The sponsor will ensure that this study is conducted in accordance with the ethical principles 
that have their origins in the Declaration of Helsinki. 
14.2 
Good Clinical Practice 
This study will be conducted in accordance with Good Clinical Practice, as defined by the 
International Conference on Harmonisation and set out in directive 2005/28/EC as well as in 
accordance with the ethical principles underlying European Union Regulation (EU) No 536/2014. 
14.3 
Approvals 
Required documents including the protocol, informed consent form, subject information leaflet, 
investigational medicinal product dossier, investigators brochure and any other required 
documents will be submitted to the ethical committee at Helsinki University for written approval.  
The sponsor will submit and obtain approval from the above parties for substantial 
modifications to the original approved documents. 

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14.4 
Informed consent 
The investigators will take informed consent and explain the nature of the study to the subject 
and answer all questions regarding this study. Prior to any study-related screening procedures 
being performed on the subject, the informed consent statement will be reviewed and signed 
and dated by the subject and the investigator who administered the informed consent form. 
A representative subject information leaflet and a sample subject consent form is attached as a 
separate document. 
14.5 
Benefits and risks assessment  
The benefits of this study for the participants with PCOS is that they will receive a thorough 
medical examination, information and treatment for their condition. The risks and burden 
associated with participation include gastrointestinal side effects from the medication and minor 
pain related to the blood samples. The risks connected to this study can be considered minimal. 
14.6 
Subject confidentiality 
The trial staff will ensure that the subjects’ anonymity is maintained. The subjects will be 
identified only by initials and a subject’s identification number on the CRF and any database. All 
documents will be stored securely. The study will comply with the EU General Data Protection 
Regulation 2016/679. 
The sponsor shall be notified immediately upon a data security breach observed. The sponsor 
will promptly analyse the case and notify regulatory bodies as indicated. 
14.7 
Retention of biological samples 
Please see the separate document “compliance_with_use_biological_samp_en” 
 
15 FINANCING AND INSURANCE 
Helsinki University holds an insurance for the participants. 
At the moment two grants have been received: 
1. Valtion tutkimusraha (VTR) - 65,311€ 
2. Finska Läkaresällskapet – 11,250€ 
Altogether: 76561€ for the first year 
We are also negotiating with pharmaceutical companies to get the metformin medication 
sponsored. 
 
16 CLINICAL STUDY REPORT AND PUBLICATION POLICY 
A summary report of the study will be provided to the CTIS portal within a year after the end of 
the trial. 
 
 
 

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