A Phase II, randomised, multi-centric, multi-national clinical trial to evaluate the efficacy, tolerability, and safety of a fixed dose combination of Spironolactone, Pioglitazone & Metformin (SPIOMET) for adolescent girls and young adult women (AYAs) with polycystic ovary syndrome (PCOS).

Who can take part

• Age range within the AYAs category (> 12.0 years and ≤ 23.9 years at study start) (96); Given that another inclusion criterium is gynaecological age (years elapsed since menarche) of 2 years or more, and that menarche before age 10.0 years is an exclusion criterium (please see exclusion criteria below), the youngest participant will be older than 12.0 years at study start (97). The upper age limit at study start is set at 23.9 years (thus, 24.9 years when the active treatment ends, see section 7. Conduct), in order to avoid early dropouts due to an increase in the prevalence of pregnancy wish beyond that age in most European countries
• Gynaecological age of 2 years or more
• Clinical and/or biochemical androgen excess (150): Clinical androgen excess, as defined by the presence of hirsutism (modified Ferriman-Gallwey score ≥ 4) (17,98) and/or inflammatory acne (Leeds scale) unresponsive to medications (3,95,99). The scarce normative data existing in adolescents suggest that an adult level of hirsutism is reached around 2 years after menarche (100); and/or biochemical androgen excess, as defined by increased total testosterone (≥45 ng/dL), and/or a FAI higher than 3.5 [FAI, total testosterone (nmol/L) x 100/SHBG (nmol/L)], in the follicular phase of the cycle (days 3–7) or after 2 months of amenorrhea (3,100,101); Measurements of total testosterone and/or FAI are the most recommended assessments to screen for biochemical androgen excess (3,19,95,102). Serum testosterone attains adult levels shortly after menarche; thus, an elevation of serum testosterone concentrations and/or FAI above adult norms and assessed in reliable reference laboratories constitutes biochemical evidence of hyperandrogenism (3,19,95,100). It is accepted that this upper limit can be set at 45 ng/dL for testosterone and at 3.5 for FAI (3,95,100,101,102,103). Direct free testosterone assays, such as radiometric or enzyme-linked assays, preferably should not be used in the assessment of biochemical hyperandrogenism, as they demonstrate poor sensitivity, accuracy and precision (17); free androgen index (FAI) should be derived from testosterone and SHBG: FAI = total testosterone (nmol/L) x 100/SHBG (nmol/L)
• Menstrual irregularity, as defined by ≤ 8 menses per year corresponding to an average inter-menstrual time of ≥45 days (3,95,100); Most adolescents establish a menstrual interval of 20–45 days within the first 2 years after menarche (3,95). Three years after menarche, the 95th percentile for cycle length is 43.6 days (104); thus, cycles longer than 45 days (<8 menses/year) at or beyond this gynaecological age are considered abnormal and are evidence of oligo-anovulation
• Written informed consent obtained from the patient, or assent from the patient and consent by the parents or the legally acceptable representative if she is a minor (for details, see section 7. Conduct, under informed consent)

Who cannot take part

• Use of medications affecting gonadal or adrenal function, or carbohydrate or lipid metabolism in the previous three months (including OCs)
• Pregnancy risk (failure to guarantee the use of non-hormonal contraception in sexually active subjects)
• Cardiac failure or history of cardiac failure
• Hypersensitivity to the study drugs or any of their excipients
• Clinical suspicion of Addison’s disease
• Acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock
• Underweight (BMI<18.5 kg/m2) and eating disorders (anorexia nervosa)
• Any disorder, which may cause tissue hypoxia (especially acute disease or worsening of chronic disease) such as: decompensated heart failure, respiratory failure, recent myocardial infarction, shock
• Current bladder cancer or a history of bladder cancer
• Clinical suspicion of Cushing syndrome
• Clinical suspicion or laboratory confirmation of hyperkalaemia
• Concomitant use of eplerenone or other potassium sparing diuretics
• Concomitant use of other potassium-conserving diuretics and potassium supplements
• Clinical suspicion or laboratory confirmation of anaemia or a bleeding disorder
• Evidence of thyroid, liver, or kidney dysfunction; if the value for a specific variable is not within the normal range for the local lab, the assessment must be repeated. If the subsequent value is within the normal range, the patient can be included in the study. Patients diagnosed with subclinical hypothyroidism or autoimmune thyroiditis can also be included if the condition is treated and the lab values of thyroid variables are within the normal range for the local lab
• Clinical suspicion or laboratory confirmation of glucose intolerance or diabetes mellitus (111,112)
• Gynaecological age < 2.0 years
• Precocious puberty [breast development before age 8 yr and/or precocious menarche (menarche before age 10.0 yr (97,109)]
• Class II obesity or morbid obesity (BMI of 35 kg/m2 or higher) according to published international standard charts for both adolescents and young women (76,77)
• Positive pregnancy test
• Clinical suspicion of any type of acute metabolic acidosis (i.e., lactic acidosis, diabetic ketoacidosis)
• Diabetic pre-coma
• Acute alcohol intoxication, clinical suspicion of alcoholism
• Non-investigated macroscopic haematuria
• Late-onset adrenal hyperplasia due to 21-hydroxylase deficiency [17-hydroxyprogesterone levels >200 ng/dL in the follicular phase of the cycle or after 2 months of amenorrhea] (3,95,110)
• Hyperprolactinaemia (due to any cause including breast-feeding)