Table 4.

Schedule of activities

	Study months (± 2 weeks) a
Timepoint	Screening	On-treatment					Post-treatment
	− 1	0	3	6	9	12	15	18
Enrolment
Eligibility screen “	X
Informed consent	X
Medical history and prior medicationb	X
Randomisationc	X
Interventions
Pharmacological intervention
Placebo		X	X	X	X	X
PIO		X	X	X	X	X
SPIO		X	X	X	X	X
SPIOMET		X	X	X	X	X
Lifestyle intervention d
LIP and LIP-related questionnaires		X	X	X	X	X
Assessments
Ovulation assessment e
0–3 months—start		X
0–3 months—stop			X
9–12 months—start					X
9–12 months—stop						X
12–15 months—start						X
12–15 months—stop							X
Clinical variables
Weight, height, BMI, WHR, SBP, DBPf		X	X	X	X	X	X	X
Hirsutism score		X	X	X	X	X	X	X
Acne score		X	X	X	X	X	X	X
Menstrual regularity		X	X	X	X	X	X	X
Endocrine-metabolic variables
Circulating androgensg		X		X		X		X
Lipidsg		X		X		X		X
Fasting insulin and glycaemiah		X	Xh	X	Xh	X	Xh	X
Glucose-stimulated insulinaemia (OGTT)i		X				X		X
Markers of inflammation & insulin sensitivityg		X		X		X		X
Epigenetic variables
Circulating miR-451a concentrations		X		X		X		X
Imaging variables j
Cardiovascular risk: cIMT (ultrasound)		X				X		X
Body composition: DXA		X				X		X
Abdominal fat distribution and hepatic fat: MRI		X				X		X
Adherence and acceptability
Adherence to treatment		X	X	X	X	X
Acceptability of the tablet			X			X
Safety variables
Laboratory safety variablesk		X		X		X		X
Pregnancy testl		X	X	X	X	X
Adverse events reportingm		X	X	X	X	X	X	X
PROMs on HRQoL n
SF-36		X		X		X		X
PCOSQ		X		X		X		X
Other activities
Concomitant medicationo		X	X	X	X	X	X	X
Patient diary			X	X	X	X	X	X
Online survey (optional)p		X						X

^a1 month is equal to 30 days. Total duration of the clinical study per patient (including 12 months on-treatment and 6 months post-treatment): 18 months

“To verify the inclusion/exclusion criteria, the following parameters will be measured: body mass index (BMI), gynaecological age, hirsutism, acne, menstrual regularity, blood count (haemoglobin, haematocrit, red blood cell count, white blood cell count, platelet count), electrolyte panel (sodium, potassium, chloride, calcium, phosphorus), lipids [total cholesterol, low-density lipoprotein (LDL-cholesterol), high-density lipoprotein (HDL-cholesterol), triglycerides], glucose, insulin, alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyltransferase (GGT), creatinine, urea, vitamin B12, folic acid, progesterone, 17-OH-progesterone, thyroid-stimulating hormone (TSH), androgens [testosterone, sex hormone binding globulin (SHBG), free androgen index (FAI), androstenedione, dehydroepiandrosterone-sulphate], prolactin, ultra-sensitive human chorionic gonadotropin (us-HCG). Androgens will be measured in the early follicular phase of the cycle (days 3 to 7) or after 2 months of amenorrhea

^bMedical history including any clinically significant event during the past 5 years. Only prior medication relevant for in/exclusion criteria and/ or PCOS will be collected

^cThe screening period finalises with randomisation. All patients will be randomised before the basal visit (month 0), including performing any analyses/test related to this visit

^dA trained research nurse will lead lifestyle intervention in a quarterly session through a Lifestyle Intervention Programme (LIP) and LIP-related questionnaires [self-reported Health Behaviour questionnaire, SCOFF & first question from Binge Eating Disorder Screener 7 (BEDS-7), Eating Disorder Examination Questionnaire EDE-Q (only in case the risk is confirmed)]. Patients can be contacted to check their status by phone between the visits at site

^eBy weekly salivary progesterone measurements for 12 consecutive weeks in three periods

^f BMI Body mass index, WHR Wwaist-to-hip ratio, SBP Systolic blood pressure, DBP Diastolic blood pressure

^gCirculating androgens: total testosterone, sex hormone-binding globulin (SHBG), free androgen index (FAI), androstenedione. Lipids: total cholesterol, low-density lipoprotein (LDL-cholesterol), high-density lipoprotein (HDL-cholesterol), triglycerides. Markers of inflammation and insulin sensitivity: ultra-sensitive C-Reactive protein (us-CRP), C-X-C motif chemokine ligand-14 (CXCL14), high-molecular-weight adiponectin (HMW-adip), growth-and-differentiation factor 15 (GDF15)

^hAt visit months 3, 9 and 15, these analyses are to be performed only when they are necessary, namely in the event of clinically relevant hyperglycaemia observed at any time point. For patients with normal glycaemic status, these analyses are not required

ⁱ OGTT, oral glucose tolerance test. Fasting and 2 h after an oral glucose load

^j cIMT, carotid intima media thickness; DXA, dual X-ray absorptiometry; MRI, magnetic resonance imaging

^kLaboratory safety variables: blood count, electrolyte panel (sodium, potassium, chloride, calcium, phosphorus), alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyltransferase (GGT), creatinine, urea, vitamin B12 and folic acid

^lHighly sensitive serum or standard sensitive urine pregnancy tests

^mThe study clinician or designee team member will record all reportable events from treatment start until 6 months post-treatment

ⁿ PROMs, patient-reported outcomes; HRQoL, health-related quality of life; SF-36, short-form 36 health survey; PCOSQ, PCOS health-related quality of life questionnaires

^oConcomitant medication should include both, prescription and over-the-counter medications taken by the patient throughout the study period, including dose, frequency, indication, start and stop dates

^pOptional survey to answer questions about the study conduct