A Clinical Trial to Evaluate the Efficacy, Tolerability, and Safety of a Fixed Dose Combination of Spironolactone, Pioglitazone & Metformin (SPIOMET) in Polycystic Ovary Syndrome (PCOS)

Study Overview
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Brief Summary
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This is a multi-centre, multi-national, double-blinded, placebo-controlled, parallel, randomised Phase II clinical trial to evaluate the efficacy, tolerability, and safety of a fixed dose combination of Spironolactone, Pioglitazone and Metformin (SPIOMET) for adolescent girls and young adult women with polycystic ovary syndrome. Study description: Currently, there is no European Medicines Agency /U.S. Food and Drug Administration (FDA)-approved therapy for polycystic ovary syndrome in adolescent girls and young adult women. Oral contraceptives (OCs) are prescribed off-label to approximately 98% of AYAs with PCOS, including those without pregnancy risk. OCs alleviate key symptoms by inducing a pharmacological combination of anovulatory subfertility, regular pseudo-menses, and extreme elevations of sex hormone-binding globulin (SHBG), but OCs do not revert the underlying pathophysiology, and patients remain at risk for post-treatment subfertility and possibly, for lifelong co-morbidities. Given the key role of hepato-visceral fat excess in the pathogenesis of PCOS, the prime aim of the treatment should be to achieve a preferential loss of central fat, which should in turn normalise the entire PCOS phenotype. Recent evidence disclosed that a treatment consisting of a fixed low-dose combination of two insulin sensitisers [pioglitazone (PIO) and metformin (MET), with different modes of action], and one mixed anti-androgen and anti-mineralocorticoid (spironolactone), was superior to an OC in normalising the PCOS phenotype, including ovulation rates and hepato-visceral fat. The study's main goals are to assess the efficacy, tolerability and safety of a new treatment (SPIOMET) for adolescent girls and young adult women with polycistic ovarian syndrome; the comparison (in this order) of each SPIOMET, spironolactone and pioglitazone (SPIO) and PIO over placebo; and in addition, the comparison of SPIOMET over PIO and over SPIO (in this order). Primary Objective: To test the efficacy of SPIOMET in normalising ovulation rate in adolescents and young adult women with PCOS. Secondary Objectives: To test the efficacy of SPIOMET in normalising the endocrine-metabolic status, to describe the drug safety profile and to assess the adherence and subjective acceptability, as well as the quality of life of the participating subjects.

Detailed Description
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This is a multi-centre, multi-national, double-blinded, placebo-controlled, parallel, randomised Phase II clinical trial to evaluate the efficacy, tolerability, and safety of a fixed dose combination of Spironolactone, Pioglitazone and Metformin (SPIOMET) for adolescent girls and young adult women (AYAs) with polycystic ovary syndrome (PCOS). Study description: Currently, there is no European Medicines Agency (EMA)/U.S. Food and Drug Administration (FDA)-approved therapy for PCOS in AYAs. Oral contraceptives (OCs) are prescribed off-label to approximately 98% of AYAs with PCOS, including those without pregnancy risk. OCs alleviate key symptoms by inducing a pharmacological combination of anovulatory subfertility, regular pseudo-menses, and extreme elevations of sex hormone-binding globulin (SHBG), but OCs do not revert the underlying pathophysiology, and patients remain at risk for post-treatment subfertility and possibly, for lifelong co-morbidities. Given the key role of hepato-visceral fat excess in the pathogenesis of PCOS, the prime aim of the treatment should be to achieve a preferential loss of central fat, which should in turn normalise the entire PCOS phenotype. Recent evidence disclosed that a treatment consisting of a fixed low-dose combination of two insulin sensitisers [pioglitazone (PIO) and metformin (MET), with different modes of action], and one mixed anti-androgen and anti-mineralocorticoid (spironolactone), was superior to an OC in normalising the PCOS phenotype, including ovulation rates and hepato-visceral fat.

Official Title
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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)

Conditions
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Polycystic Ovary Syndrome (PCOS)

Intervention / Treatment
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* Drug: Placebo
* Drug: Pioglitazone
* Drug: Spironolactone
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 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); Biochemical androgen excess, as defined by increased total testosterone (≥50 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 hyperandrogenaemia (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); 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 periods/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). Exclusion Criteria: -

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 23 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a multi-centre, multi-national, double-blinded, placebo-controlled, parallel, randomised Phase 2 clinical trial with four subgroups
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Arm 1 - Placebo<br>Placebo | Drug: Placebo<br>* Comparator arm with placebo<br>|
| Experimental: Arm 1 - PIO<br>Pioglitazone | Drug: Pioglitazone<br>* Pioglitazone 7.5 mg/day<br>* Other names: PIO;|
| Experimental: Arm 1 - SPIO<br>Spironolactone and Pioglitazone | Drug: Pioglitazone<br>* Pioglitazone 7.5 mg/day<br>* Other names: PIO;Drug: Spironolactone<br>* Spironolactone 50 mg/day<br>* Other names: S;|
| Experimental: Arm 1 - SPIOMET<br>Spironolactone, Pioglitazone and Metformin | Drug: Pioglitazone<br>* Pioglitazone 7.5 mg/day<br>* Other names: PIO;Drug: Spironolactone<br>* Spironolactone 50 mg/day<br>* Other names: S;Drug: Metformin<br>* Metformin 850 mg/day<br>* Other names: MET;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| On-treatment ovulation rate. | On-treatment ovulation rate. | Following end of each two 12-week on-treatment periods (month 0-3 and month 9-12) | 
| Post-treatment ovulation rate. | Post-treatment ovulation rate. | Following the end of post-treatment period (month 12-15) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical variable: hirsutism | Presence of hirsutism as measured by the modified Ferriman & Gallwey score | Every 3 months from study start to study completion (estimated 18 months) | 
| Clinical variable: Acne | Presence of Acne as evaluated using the Leeds Acne Grading Scale | Every 3 months from study start to study completion (estimated 18 months) | 
| Clinical variable: menstrual regularity | Assessment of the menstrual regularity | Every 3 months from study start to study completion (estimated 18 months) | 
| Circulating androgens | Assessment by measurement of circulating androgens | Every 3 months from study start to study completion (estimated 18 months) | 
| Lipids | Assessment by measurement of total cholesterol, low-density lipoprotein (LDL-cholesterol), high-density lipoprotein (HDL- cholesterol), triglycerides; | Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment | 
| Insulinaemia | Fasting and 2 hours after a 75-gr oral glucose load [oral glucose tolerance test (oGTT). Estimation of insulin resistance from fasting insulin and glucose levels using the homeostasis model assessment (HOMA); | Baseline and at the end of treatment (month 12) and 6 months after treatment | 
| Inflammation markers | Inflammation markers | Baseline and at the end of treatment (month 12) and 6 months after treatment | 
| Insulin sensitivity | Insulin sensitivity | Baseline and at the end of treatment (month 12) and 6 months after treatment | 
| Ultra-sensitive C-reactive protein (us-CRP); | Ultra-sensitive C-reactive protein (us-CRP); | Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment | 
| Growth-and- differentiation factor-15 (GDF15); | Growth-and- differentiation factor-15 (GDF15); | Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment | 
| High molecular weight adiponectin (HMW-adip), | High molecular weight adiponectin (HMW-adip), | Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment | 
| C-X-C motif chemokine ligand 14 (CXCL14) (69,81); | C-X-C motif chemokine ligand 14 (CXCL14) (69,81); | Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment | 
| Epigenetic variable | Circulating microRNA 451-a (miR-451a) concentrations (88); | Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment | 
| Imaging: Cardiovascular risk | As measured by ultrasound | Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment | 
| Imaging: Body composition | As measured by dual-energy X-ray absorptiometry (DXA) | Baseline and at the end of treatment (month 12) and 6 months after treatment | 
| Imaging: Abdominal fat distribution (subcutaneous and visceral) | As measured by MRI | Baseline and at the end of treatment (month 12) and 6 months after treatment | 
| Imaging:hepatic fat | As measured by MRI | Baseline and at the end of treatment (month 12) and 6 months after treatment | 
| Abdominal fat distribution | Waist circumference, Waist to hip ratio (WHR), and hepatic fat by MRI | Baseline and at the end of treatment (month 12) and 6 months after treatment | 
| Weight | Weight measurement | Every 3 months from study start to study completion (estimated 18 months) | 
| Improvement of co-morbidities | Improvement of co-morbidities | Every 3 months from study start to study completion (estimated 18 months) | 
| Improvement of health behaviour | Improvement of health behaviour | Every 3 months from study start to study completion (estimated 18 months) | 
| Improvement of health-related quality of life (HRQoL) | As reported by the patient | Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment | 
| Safety laboratory tests | Blood count, electrolyte panel, urea, alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyltransferase (GGT), creatinine, vitamin B12 and folic acid; | Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment | 
| Adverse events (AEs) | As reported by the patient | Every 3 months from study start to study completion (estimated 18 months) | 
| Adherence | Adherence will be calculated as the ratio between the number of tablets prescribed and dispensed for the period between hospital appointments and the number of tablets returned by the patient at the following appointment; | Every 3 months from study start to study completion (estimated 18 months) | 
| Acceptability of the treatment | Acceptability of the tablet by the study patients | Every 3 months from study start to study completion (estimated 18 months) | 
| PROMs (patient-reported outcomes) | Questionnaire SF-36 | Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment | 
| PROMs (patient-reported outcomes) | Questionnaire PCOSQ | Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment | 
| HRQoL (health-related quality of life) | Questionnaire SF-36 | Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment | 
| HRQoL (health-related quality of life) | Questionnaire PCOSQ | Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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polycystic ovary syndrome, spironolactone, pioglitazone, metformin, peadiatric, PCOS