SPIOMET4HEALTH—efficacy, tolerability and safety of lifestyle intervention plus a fixed dose combination of spironolactone, pioglitazone and metformin (SPIOMET) for adolescent girls and young women with polycystic ovary syndrome: study protocol for a multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. The overall prevalence of PCOS is around 5–10% [1] but could be as high as 26% in some populations [2]. The most common features of PCOS include clinical and/or biochemical hyperandrogenism, menstrual irregularities and oligo-anovulation [3, 4]. Women with PCOS also have an elevated prevalence of obesity, and a significant proportion also display insulin resistance, even in the absence of obesity [5].

PCOS is the most frequent cause of anovulatory subfertility and is associated with lifelong co-morbidities including type 2 diabetes (T2D), premature vascular ageing, premenopausal cancer, non-alcoholic fatty liver disease, gestational complications and anxiety/depression, with a negative impact on the health-related quality of life (HRQoL) of these subjects and their offspring [6‐11]. Overweight and obesity amplify the metabolic-reproductive abnormalities and the risks for T2D and cardiovascular complications [5].

Over a quarter of a century, Ibáñez and de Zegher et al. have generated new insights into the pathophysiology of PCOS, including on the developmental sequence of events leading to the disorder [12, 13]. Those evolving concepts have prompted a shift in the therapeutic approach towards interventions guided by the pathophysiology [14, 15]. Nowadays, PCOS is thought to be, in essence, the result of a mismatch between prenatal adipogenesis and postnatal lipogenesis, which can be inferred from a mismatch between prenatal weight gain and postnatal weight gain, and results in a chronic need to store more fat than is safely feasible in the subcutaneous fraction of adipose tissue [12, 13, 16, 17]. The excess fat tends to be stored in ectopic depots, especially in the liver and viscera (hepato-visceral or central fat) [12, 13]. The extent of such storage may be influenced by genetic and epigenetic factors and may be raised by a reduced activity of brown adipose tissue (BAT) that contributes to a more positive energy balance [18‐20].

So far, no treatment for PCOS in adolescent girls or young women (AYAs) has been approved by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA). Oral contraceptives (OCs) are frequently prescribed off-label as first-line treatment in adolescent girls, including in those who do not need contraception [4, 21, 22]. OCs alleviate the clinical symptoms by inducing a combination of anovulatory infertility, regular pseudo-menses and pharmacological elevations of sex hormone-binding globulin (SHBG) [23, 24]. However, they do not revert the underlying pathophysiology so that, upon treatment discontinuation, the entire PCOS phenotype reappears, with risk for subfertility and for potentially lifelong comorbidities that are relevant for public health [25, 26]. Indeed, OC treatment in AYAs with PCOS fails to normalise insulin resistance, the circulating levels of ultra-sensitive C-reactive protein (us-CRP, a marker of low-grade inflammation), the carotid intima-media thickness (cIMT, a marker of subclinical atherosclerosis) or the ectopic fat [13, 27‐30]. Likewise, in the general population, the use of contemporary OCs has been associated with increased risk for breast cancer, glioma and venous thromboembolism, which may vary with oestrogen dose and progestogen type [31‐33]. In women with PCOS, the use of OCs with purportedly low thrombogenic potential has nevertheless been linked to risk for inflammatory and coagulation disorders [34]. Given the hypothesised key role of ectopic (hepato-visceral) fat or central obesity in the pathogenesis of PCOS, the focus of the treatment should be to reduce ectopic fat. In turn, such reduction should have normalising effects on the entire PCOS phenotype.

Pilot studies have been conducted by Ibáñez’ group in AYAs with PCOS and without obesity, leading to the identification of a treatment that consists of a fixed low-dose combination of two insulin sensitisers [pioglitazone (PIO) and metformin (MET), acting through different pathways] and one mixed anti-androgen and anti-mineralocorticoid [spironolactone (SPI)], also acting as BAT activator and thus as driver of energy expenditure. In those studies, the triple low-dose combination of SPI, PIO and MET—so-called SPIOMET—proved to be superior to an OC in normalising the PCOS phenotype, including post-treatment ovulation rate and hepato-visceral fat [14, 15]. The chronological build-up towards SPIOMET started with MET, continued with the addition of a pure anti-androgen (flutamide), and then with the further addition of PIO; in a final step, flutamide was replaced by SPI, in order to take advantage of its mixed anti-androgen, anti-mineralocorticoid and BAT-activating properties [14, 15, 35‐45].

So far, the effects of SPIOMET administered in three separate tablets vs an OC have been investigated in two randomised, controlled, open-label, pilot studies [ISRCTN29234515 and ISRCTN11062950; [14, 15]] performed between 2012 and 2019, that were based in a single centre in Barcelona and that were conducted in adolescents with PCOS and without obesity who did not need contraception [total N = 62; age 16 yr; body mass index (BMI) 24 kg/m²; treatment for 1 year; ovulation assessment during the post-treatment year]. The pooled results from those pilot studies disclosed that SPIOMET has more normalising effects than OCs, particularly in decreasing hepato-visceral fat and insulin resistance, and results in threefold more ovulations after discontinuation of the intervention [14, 15]. In the present clinical trial, SPIOMET will be administered in a single tablet of immediate release containing the three active substances: SPI, 50 mg; PIO, 7.5 mg; MET, 850 mg. The bioequivalence of SPIOMET in a single tablet vs the co-intake of the three separate compounds has been shown in a phase I study [46]. The treatment simplification into the intake of a single daily tablet is expected to raise compliance particularly over the longer term. Studies of other medical conditions have shown that adherence rates are higher with fixed-dose combinations (FDC) than with multiple-tablet therapies [47, 48].

The active substances in the new fixed, low-dose SPIOMET combination (SPI, PIO and MET) are medications that have long been approved for other indications. All three are nowadays available as generic drugs that have been in clinical use for > 25 years, and have been given to millions of humans.

SPI is a steroidal aldosterone antagonist marketed as diuretic but can serve as an anti-androgen if given in higher doses (up to 200 mg/d). SPI has recently been identified as a potent activator of BAT which, in turn, may raise energy expenditure and ultimately result in a lower amount of ectopic fat [45]. SPI was first approved in 1960 and has thus been used in human medicine for > 60 years, primarily for heart failure but also for other cardiovascular conditions. In Europe, SPI has been licensed for oedematous conditions in children at doses of ~ 3 mg/kg. So far, SPI treatment in younger individuals has not been associated with safety concerns [49]. In Europe and in the USA, SPI has for decades been the safe anti-androgen of choice in the treatment of hirsutism with or without hyperandrogenism [50]. SPI treatment in higher dose (100 mg/d or more) is frequently accompanied by menstrual irregularity, and more rarely by abdominal pain, polyuria or dryness of the mouth [51]. There are essentially no safety concerns when spironolactone is dosed at only 50 mg/d (equal or less than 1 mg/kg/d), as will be the case in the present trial. Epidemiologic and cohort-based studies show no evidence of an increased cancer risk associated with SPI use [52].

PIO is a thiazolidinedione (TZD) acting as insulin sensitiser in adipose tissue, liver and muscle. It raises circulating high molecular weight adiponectin (HMW-adip) [43] and also insulin sensitivity via preferentially subcutaneous adipogenesis [53]. In 1999, PIO was approved in monotherapy and, in 2006, in a FDC with MET [54]. In women with PCOS, PIO improves insulin sensitivity, menstrual cyclicity and ovulation rates [55]. Peroxisome proliferator-activated receptor (PPAR)-gamma is generally viewed as the target of TZD class; however, at low dose (7.5 mg/d), PIO may act as an inhibitor of cyclin-dependent kinase 5 (CDK5)-mediated phosphorylation of PPAR-gamma rather than as a PPAR-gamma agonist [56]. The use of PIO has been questioned due to safety concerns, particularly those associated with a purported higher risk for bladder cancer in older men with diabetes. However, FDA performed a 10-year prospective study to establish the connection between pioglitazone and bladder cancer, concluding that it was non-existing [57]. In studies performed in adolescents with PCOS, low-dose PIO (7.5 mg), combined either with MET or with MET plus an anti-androgen, has shown an excellent safety profile [14, 15, 42]. In addition, PIO appears to be well tolerated by children since no side effects were identified in children with autism receiving high doses [58]. In 2008, PIO was flagged for long-term safety and was granted a class waiver by the EMA for paediatric studies for the treatment of type 2 diabetes despite the existing studies. Therefore, it is not licensed in the paediatric population for this indication. However, the Paediatric Committee (PDCO) of the EMA has left the door open for possible future developments of this active substance in other indications. A proof of that is the number of clinical trials using PIO in the paediatric population nowadays [search for “pioglitazone” (search term) and “age group: childbirth – 17 yr” in clinicaltrials.gov]. The safety and efficacy data of PIO in the paediatric population is limited and dosing recommendations are not available; however, the dose ranges investigated in adolescents are 15–45 mg. The proposed dose in the present study (7.5 mg/d) is lower and has been previously used by the present investigators [14, 15, 27, 42, 43]. Therefore, this dose appears to be acceptable in the absence of a standard dose. So far, a total of 31 girls aged 15.7 ± 0.2 years have been exposed to the SPIOMET combination (with three separate tablets) for 1 year [15] and there were no noteworthy adverse events.

MET has anti-diabetic properties by acting via multiple mechanisms. MET is known to raise AMP-activated protein kinase (AMPK) activity and the circulating concentrations of growth-and-differentiation factor 15 (GDF15), a peptide hormone that may reduce appetite by acting via a specific receptor in the brainstem [59‐64]. MET was first approved in 1959, and since then several FDCs containing MET have been approved for the treatment of type 2 diabetes as first and/or second-line therapies [65]. MET is the drug most widely used for the treatment of T2D in adults and in children aged > 10.0 years; its use has significantly increased in non-diabetic younger children and adolescents [66‐68]. Although MET has a limited effect on hirsutism, its benefits on other PCOS-associated features and co-morbidities have long been recognised in adult women; some of these benefits have also been reported in girls and younger women, including for ovulation induction [35, 69]; consequently, MET is commonly used off-label in women with PCOS (https://​www.​nhs.​uk/​conditions/​polycystic-ovary-syndrome-pcos/​treatment/​). Extensive experience has been gathered over the past 60 years in relation to the clinical use and safety of MET [70]. In 2001, the EMA issued a favourable benefit/risk ratio for MET that outlines its safety for use in humans [65]. The main undesirable effects are gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite (> 10%), which usually resolve shortly after initiation of the treatment [69]. Lactic acidosis has been only described in case of inappropriate use, i.e. in the presence of renal, cardiac and hepatic failure, or after intentional overdose [71]. A decrease of vitamin B12 serum levels has been observed in patients treated long-term with metformin but is rarely of clinical significance [72]. The proposed dose of MET (850 mg/d) is at the lower limit of the recommended range (850–2000 mg/d) [73].

Table 1 summarises the targeted efficacy and safety of the separate SPIOMET components and of their ensemble in AYAs with PCOS. The present study aims to strengthen the evidence that SPIOMET can confer additive benefits without eliciting safety concerns [14, 15, 43, 45, 59‐64, 74]. The benefits of each compound on outcomes partly overlap and are essentially present with low doses, whereas the side effects differ and are essentially absent with low doses.

Table 2 provides justification for the dose of each SPIOMET component. Potential interactions of spironolactone and pioglitazone related to cytochrome P450 2C8 (CYP2C8)-mediated metabolism are of little concern, as there is no evidence for clinically relevant drug-drug interactions between these medications [75].

In parallel with the pharmacological intervention, a specific Lifestyle Intervention Programme (LIP) has been developed for AYAs and will be implemented during the time window of medication intake. This intervention is mostly based on the well-established lifestyle intervention “Obeldicks” [76], which is effective to treat hyperandrogenaemia [77] and PCOS-related symptoms [78] in patients with obesity; it focuses on strengths and not on weaknesses and thus, on motivating participants. The contents of “Obeldicks” have been adapted to fit the target population of the study; this intervention aims at increasing the low adherence rates reported in adolescents and adults with obesity [76]. Intervention techniques include motivational interviewing and behavioural training, aiming at changing (family) health behaviour permanently, by methods tailored to the individual requirements. Nutritional education is based on a simple traffic light system [79]. Besides the nutrition education [79, 80], advice for reducing sedentary habits and increasing physical exercise will also be provided by the nurse/clinician caring for the patient. The design of the LIP intervention aims at minimising the daily time burden for participants, and thus at lowering the risk of lack of adherence because the intervention is perceived as too time consuming.

The trial will be conducted in a large and ethnically diverse cohort recruited in 7 institutions from 4 European member states and 2 associated countries.

The principal investigator (PI) or their designee at each centre, in accordance with the institutional policy, will obtain an informed consent previously reviewed and approved by the responsible Ethical Committee (EC). A written consent form bearing the full name and signature of the patient or the patient’s parent/guardian and the assent of the patient (in case of minor patients), together with the name, date and signature of the local investigator, will be obtained. The signed informed consent constitutes a confidential document and therefore will be archived in the study binder. A copy of the consent will be given to the patient or patient’s parent/tutor.

An additional written informed consent for biological sample collection and use of participant data will be obtained from the trial participants or the patient’s parent/tutor.

See Table 4.

Numbers of patients in the four study arms have been calculated to attain 80% statistical power at two-sided 5% alpha level [90‐92], with an expected dropout rate of 27%. The sample size is based on the two-sample t-test (R package “pwr”, functions “pwr.t.test” and “pwr.t2n.test”).

The number of subjects to be included has been determined based on the primary endpoint, namely the number of ovulations over 6 months (from month 9 to month 15). This design will cover to detect a 0.922 mean difference between placebo and SPIOMET arms. The standard deviation of 1.96 is based on previous evidence [14, 15]. The same difference and standard deviation are considered for potentially subsequent hierarchical comparisons (see the section “Trial design {8}”).

A sample size of 364 AYAs with PCOS [at least 180 of whom will be aged < 18.0 years at study start] is required using a 1:1:1:1 allocation ratio for placebo, PIO, SPIO and SPIOMET. The number of participants to be recruited is thus 91 per treatment arm (Table 5). Assuming a 27% dropout rate, approximately 266 patients (~ 66 or 67 per treatment arm) are estimated to complete the study.

A total of 364 AYAs with PCOS will be recruited at the Outpatient Clinic of 7 hospitals from 4 European member states and 2 associated countries; the geographic distribution of the sites ensures ethnic variation.

The number of patients expected to be recruited are respectively:

Medication kits will be packed in boxes with 12 kits per box. For this purpose, kit numbers and treatment arms will be randomly assigned in 12 blocks using PROC PLAN procedure, SAS 9.4.

The randomisation process ensures that all participants and all investigators performing the clinical visits and the assessments will be blinded for the allocated treatment.

Treatment allocation will be done via Interactive Web Randomisation System (IWRS) accessible through the electronic Case Report Form (eCRF) and randomisation codes will be generated. Once a patient is randomised to a planned treatment group, medication kits will be delivered according to the allocated treatment at time 0, 3, 6 and 9 months. Therefore, up to 4 medication kits will be assigned per subject. Each medication kit will contain enough medication for 3 months (3 bottles per kit; each bottle containing 35 pills).

When a patient meets all eligibility criteria, she will be randomised by the principal investigator at each recruiting centre via IWRS, and a randomisation code will be generated. Subsequently, the hospital pharmacy will receive the necessary information for delivering the allocated medication.

The trial is designed as a double-blind study. Participating girls and young women will receive a daily tablet which will be indistinguishable among study groups. The tablets (all with exactly the same size and appearance) will contain placebo or the active compounds (PIO, SPIO or SPIOMET) depending on the study arm to which the patient will be allocated. Study participants, sites and study team members will remain blinded to the treatment allocation. The study blinding will be maintained throughout the clinical trial until data entry and processing are completed and the database has been locked.

In the event of a suspicion of an unexpected serious adverse reaction, the unblinding of the allocation of an individual participant will be requested for regulatory purposes. However, if possible and appropriate, the blinding will be maintained for the investigators and for those who will analyse and interpret the results at the study’s conclusion. The Sponsor will be notified before the blind is broken unless unblinding is required for a medical emergency necessitating knowledge of the blinded medication in the immediate management of the participant’s condition. In the latter case, the investigator will request the unblinding through the IWRS. The timing and rationale for the unblinding must be recorded in the source documentation.

Participants will be seen in person during 3-monthly medical visits. Between such appointments, the study centre will stay in contact with participants (by phone) as to ensure compliance with treatment and follow-up.

If a study participant skips one study visit, then

The following data will be collected in this trial:

Participating girls and young women will be assigned a unique identification code (without any reference to their name), and all patient data will be recorded in an anonymised manner using this code. The list with identification codes will remain at each recruiting centre and will be stored separately from the trial data. Only if needed will this list be used for the re-identification of patients.

The research data of the study will be collected in the Open Clinica eCRF (OpenClinica v3.15.3 system). The investigator(s) or designee(s) will be responsible for the data entry through the eCRF system. The access to the eCRF will be controlled by username and password. Any change conducted in the database will be registered by means of an audit trail. The reason for accessing, username, date and time, table name, old and new values and subject/patient ID will be recorded. Any data transfer will be done using Secure Sockets Layer (SSL) connection with encryption.

For the SPIOMET4HEALTH clinical trial, the Clinical Research Organization (CRO) Optimapharm (Palma de Mallorca, Spain) will be responsible for all tasks related to data management.

The study protocol, documentation, data and all other information generated will be held in strict confidence. No information concerning the study or the data will be released to any unauthorised third party without prior written approval of the Sponsor.

All research activities will be conducted in as private a setting as possible.

The study monitor, other authorised representatives of the Sponsor, representatives of the ECs, regulatory agencies or pharmaceutical company supplying study product will inspect all documents and records required to be maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site will allow access to such records after patients’ written consent.

The study participant’s contact information will be securely stored at each clinical site for internal use during the study. At the end of the study, all records will continue to be kept in a secure location for as long a period as dictated by the reviewing EC, institutional policies or sponsor requirements.

Study participant research data, which are for purposes of statistical analysis and scientific reporting, will be transmitted to and stored at the Optimapharm Biometry Department. This will not include the participant’s contact or identifying information. Rather, individual participants and their research data will be identified by a unique study identification number. The study data entry and study management systems used by clinical sites and by Optimapharm Biometry Department research staff will be secured and password protected. At the end of the study, all study databases will be de-identified and archived at the Optimapharm Biometry Department.

Circulating testosterone and androstenedione, circulating markers (HMW-adip, CXCL14, GDF15 and miR-451a) and salivary progesterone will be analysed centrally at UNIBO and HSJD respectively, and samples will thus be stored in those centres until assessment. The remnant samples will be stored at Biosample Collection located at the Endocrinology Laboratory of HSJD (Barcelona, Spain). These samples can be used in future studies related to PCOS.

The statistical objective of the study will be the assessment of the efficacy, tolerability and safety of SPIOMET in AYAs with PCOS. As explained (see the “Trial design {8}” section), the statistical analysis will be conducted with a hierarchical approach considering the mean number of ovulations (primary outcome) for the different study treatment arms following the predefined order: (1) SPIOMET vs placebo; (2) SPIO vs placebo; (3) PIO vs placebo; (4) SPIOMET vs PIO; and (5) SPIOMET vs SPIO. Therefore, the first comparison will be analysed in the first place, and only if a significant finding is detected for this comparison, a formal statistical conclusion will be reached for the subsequent comparisons (2nd, 3rd, 4th and 5th).

Each null hypothesis will be tested in all randomised patients based on the intention-to-treat (ITT) principle. The analysis will be conducted using an analysis of variance (ANOVA) considering the stratification factors used in the randomisation.

The statistical analysis will be carried out in accordance with the principles specified in the International Conference on Harmonisation (ICH) Topic E9 (CPMP/ICH/363/96) [106] and the addendum on estimands [107]. The SAS System [108] (release 9.4, or an upgraded version), or equivalent validated statistical software, will be used to analyse the data sets. Statistical tests for primary and secondary efficacy outcomes will use a significance level of 0.05; point estimates and two-side 95% confidence intervals for appropriate treatment effects will be provided.

No efficacy interim analyses are planned for this study. Primary and secondary endpoints will be analysed based on the stratification factors applied to the randomisation once the trial is finished.

No subgroup additional analyses will be performed.

The handling of missing data will follow the principles specified in the ICH Topic E9 (CPMP/ICH/363/96), ICH E9 [110] and guidance on missing data [111] guidelines. The main analysis will include all randomised patients following the ITT principle, and thus, patients not completing the 6 months’ assessment period for the primary endpoint will be imputed. If patients have completed ≥ 80% of the 6 months assessment, then the mean value will be imputed for the rest of the missing observations. Otherwise, the 0 to 3 months of follow-up initial period after randomisation will be used for the imputations.

The full protocol, participant-level data and statistical code will be provided on acceptable demand.

The clinical trial is part of the project SPIOMET4HEALTH funded by the European Union’s Horizon 2020 research and innovation programme. SPIOMET4HEALTH will be carried out by a consortium of groups working on PCOS in AYAs. Besides the 7 hospitals where the clinical data will be generated, 10 partners will be part of the consortium: KU Leuven (KUL, Leuven, Belgium), Reig Jofre (Sant Joan Despí, Barcelona, Spain), Optimapharm (Palma de Mallorca, Spain), Vestische Children’s Hospital Children’s Hospital/University of Witten/Herdeck (Witten, Germany), Asphalion (Barcelona, Spain), Outcomes’10 (Castellón de la Plana, Spain), Zabala Innovation (Pamplona, Spain), Universidad Complutense de Madrid (Madrid, Spain), European Institute of Women’s Health (EIWH, Dublin, Ireland), EU delegation of Make Mothers Matter (MMM, Brussels, Belgium).

HSJD – FSJD will be responsible for the coordination of SPIOMET4HEALTH. KU Leuven will function as co-coordinator and will be responsible for the intellectual property management. Reig Jofre will be responsible for manufacturing the study medication. The CRO Optimapharm will lead the management of the clinical trial activities and the Vestische Children's Hospital Children's Hospital/University of Witten/Herdeck will be responsible for the development and implementation of the LIP. Asphalion will perform the regulatory and exploitation activities to define the roadmap towards a marketing authorisation of SPIOMET for the treatment of adolescent PCOS. Outcomes’10 and Universidad Complutense de Madrid will lead the analysis of the costs and health effects of each treatment option as HRQoL. The associations EIWH and MMM will engage activities, stakeholder networks and mapping of current policies on PCOS at national and European levels. Zabala Innovation will be responsible for communication and dissemination of the project.

The trial Sponsor and coordinating centre will be HSJD-FSJD. The General Assembly involves all 17 members of the consortium, will meet at least once yearly and will be the consortium’s ultimate decision-making body. The trial Steering Committee (SC) will be composed of the coordinator (HSJD-FSJD), the co-coordinator (KUL) and a core group composed of UNIBO, Optimapharm and Asphalion. The SC will be responsible for decision-making on the daily running of the project and will meet 3-monthly. The principal investigators as well as the research coordinators at each recruiting centre will meet once monthly to coordinate and supervise all the tasks. At each clinical site, a group of nurses, clinicians and researchers will provide day-to-day support for the trial.

The CRO Optimapharm will be responsible for the trial monitoring, data quality, safety and pharmacovigilance. In addition, an independent Data Safety and Monitoring Board (DSMB) will be established to monitor data quality and patient safety as the study progresses. In order to do so, a DSMB may review unblinded study information (on a patient level or treatment group level) during the conduct of the study. Based on its review, the DSMB provides the Sponsor with recommendations regarding study modification (for example, to strengthen the scientific validity of the trial), continuation or termination. The DSMB will be composed of one external statistician/epidemiologist and two external medical expert consultants.

The nature, severity, treatment and outcome of any potential AE or serious AE (SAE) will be recorded by the investigator or designee team member at each clinical site and will determine the relationship to the treatment or underlying disease. The investigator will collect any unfavourable and unintended sign, symptom or disease temporally associated with the use of the investigational product, whether related to the investigational product or not. All AEs and SAEs, whether expected or unexpected, will be recorded in the medical history and subsequently in the eCRF. The Sponsor will be responsible for determining whether an AE is expected or unexpected. The study clinician or designee team member will record all reportable events from treatment start until 6 months post-treatment.

At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit. Events will be followed for outcome information until resolution or stabilisation. If a participant is found to be pregnant or may have been pregnant at the time of exposure to the tested drugs, then the pregnancy, any AEs associated with maternal exposure and the pregnancy outcome will be recorded on the Pregnancy Surveillance Form and reported to Optimapharm and the Sponsor.

The CRO Optimapharm will be responsible for the auditing of the SPIOMET4HEALTH trial and will conduct the following types of site visits: (1) site initiation visits; (2) monitoring visits; (3) close-out visits. The first one-site monitoring visit will be conducted at each site within 6 weeks after the first subject is randomised. Monitoring frequency will be every 3 months. After the completion of each visit, a report will be provided.

Protocol modifications will be approved by the EC of each recruiting centre and the National Competent Authority in each country.

Worldwide, PCOS is the most prevalent endocrine-metabolic disorder in women of reproductive age, and it is the leading cause of anovulatory subfertility. There is no approved therapy for PCOS in AYAs. New insights into the pathophysiology suggest that PCOS is essentially the result of a mismatch between early adipogenesis and later lipogenesis resulting in an excess of fat in subcutaneous adipose tissue and in an abundance of lipids in ectopic depots such as liver and viscera. The present trial will test—on top of lifestyle measures—the efficacy and safety of a randomised treatment with low-dose generics (PIO, SPIO, SPIOMET) that aim to reduce ectopic fat, to revert the entire PCOS phenotype (and its correlates) towards normal and, ultimately, to decrease PCOS’ economic burden on health care systems.

The strengths include the double-blind, placebo-controlled design of a first multi-centre study in an ethnically diverse study population that bridges adolescence and early adulthood; the combination of a specific lifestyle intervention and different pharmacological treatments; the phase of post-treatment follow-up including an evaluation of ovulatory function; and the pre-, on- and post-treatment assessments with up-to-date markers, imaging techniques and questionnaires. The main limitations relate to the relatively narrow age range, and the exclusion of patients with obesity beyond class I.