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)

Phase 2RecruitingNCT05394142

Fundació Sant Joan de Déu364 enrolled

Overview

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.

Eligibility

Sex: FEMALEMin age: 12 YearsMax age: 23 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. 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; 2. Gynaecological age of 2 years or more; 3. 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); 4. 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); 5. 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; 6. 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: \-

Locations (7)

Universitätsklinik für Innere Medizin

Graz, Austria

RECRUITING

Odense University Hospital (UNIODE)

Odense, Denmark

RECRUITING

Azienda Ospedaliero Universitaria di Bologna

Bologna, Italy

RECRUITING

St. Olavs Hospital

Trondheim, Norway

RECRUITING

Hospital Sant Joan de Deu

Esplugues de Llobregat, Spain

RECRUITING

Hospital Universitari de Girona Dr. Trueta

Girona, Spain

RECRUITING

İstanbul Faculty of Medicine Topkapı

Istanbul, Turkey (Türkiye)

RECRUITING

Outcomes

Primary Outcomes

On-treatment ovulation rate.

Time frame: Following end of each two 12-week on-treatment periods (month 0-3 and month 9-12)

Post-treatment ovulation rate.

Time frame: Following the end of post-treatment period (month 12-15)

Secondary Outcomes

Clinical variable: hirsutism

Presence of hirsutism as measured by the modified Ferriman \& Gallwey score

Time frame: 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

Time frame: Every 3 months from study start to study completion (estimated 18 months)

Clinical variable: menstrual regularity

Assessment of the menstrual regularity

Time frame: Every 3 months from study start to study completion (estimated 18 months)

Circulating androgens

Assessment by measurement of circulating androgens

Time frame: 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;

Time frame: 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);

Time frame: Baseline and at the end of treatment (month 12) and 6 months after treatment

Inflammation markers

Time frame: Baseline and at the end of treatment (month 12) and 6 months after treatment

Insulin sensitivity

Time frame: Baseline and at the end of treatment (month 12) and 6 months after treatment

Ultra-sensitive C-reactive protein (us-CRP);

Time frame: 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);

Time frame: 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),

Time frame: 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);

Time frame: 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);

Time frame: 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

Time frame: 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)

Time frame: 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

Time frame: Baseline and at the end of treatment (month 12) and 6 months after treatment

Imaging:hepatic fat

As measured by MRI

Time frame: 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

Time frame: Baseline and at the end of treatment (month 12) and 6 months after treatment

Weight

Weight measurement

Time frame: Every 3 months from study start to study completion (estimated 18 months)

Improvement of co-morbidities

Time frame: Every 3 months from study start to study completion (estimated 18 months)

Improvement of health behaviour

Time frame: 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

Time frame: 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;

Time frame: 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

Time frame: 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;

Time frame: Every 3 months from study start to study completion (estimated 18 months)

Acceptability of the treatment

Acceptability of the tablet by the study patients

Time frame: Every 3 months from study start to study completion (estimated 18 months)

PROMs (patient-reported outcomes)

Questionnaire SF-36

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment

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)

Overview

Conditions

Interventions

Eligibility

Locations (7)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts