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)

NCT ID: NCT05394142

Last Updated: 2024-04-22

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 364 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-05-24
• Study Completion Date: 2025-04-30

Brief Summary

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

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.

Conditions

Polycystic Ovary Syndrome (PCOS)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Arm 1 - Placebo

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Comparator arm with placebo

Arm 1 - PIO

Pioglitazone

Group Type: EXPERIMENTAL

Pioglitazone

Intervention Type: DRUG

Pioglitazone 7.5 mg/day

Arm 1 - SPIO

Spironolactone and Pioglitazone

Group Type: EXPERIMENTAL

Pioglitazone

Intervention Type: DRUG

Pioglitazone 7.5 mg/day

Spironolactone

Intervention Type: DRUG

Spironolactone 50 mg/day

Arm 1 - SPIOMET

Spironolactone, Pioglitazone and Metformin

Group Type: EXPERIMENTAL

Pioglitazone

Intervention Type: DRUG

Pioglitazone 7.5 mg/day

Spironolactone

Intervention Type: DRUG

Spironolactone 50 mg/day

Metformin

Intervention Type: DRUG

Metformin 850 mg/day

Interventions

Placebo

Comparator arm with placebo

Intervention Type: DRUG

Pioglitazone

Pioglitazone 7.5 mg/day

Intervention Type: DRUG

Spironolactone

Spironolactone 50 mg/day

Intervention Type: DRUG

Metformin

Metformin 850 mg/day

Intervention Type: DRUG

Other Intervention Names

PIO; S; MET

Eligibility Criteria

Exclusion Criteria

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).

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• Minimum Eligible Age: 12 Years
• Maximum Eligible Age: 23 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Fundació Sant Joan de Déu

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Lourdes Ibañez, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Investigator

Locations

Universitätsklinik für Innere Medizin

Graz, , Austria

Site Status: RECRUITING

Odense University Hospital (UNIODE)

Odense, , Denmark

Site Status: RECRUITING

Azienda Ospedaliero Universitaria di Bologna

Bologna, , Italy

Site Status: RECRUITING

St. Olavs Hospital

Trondheim, , Norway

Site Status: RECRUITING

Hospital Sant Joan de Deu

Esplugues de Llobregat, , Spain

Site Status: RECRUITING

Hospital Universitari de Girona Dr. Trueta

Girona, , Spain

Site Status: RECRUITING

İstanbul Faculty of Medicine Topkapı

Istanbul, , Turkey (Türkiye)

Site Status: RECRUITING

Countries

Austria; Denmark; Italy; Norway; Spain; Turkey (Türkiye)

Central Contacts

Rita Malpique, PhD

Role: CONTACT

rita.malpique@sjd.es

+34936 00 97 51 ext. 77806

Elizabeth García Pérez, PhD

Role: CONTACT

+34936 00 97 51 ext. 77848

Facility Contacts

Barbara Obermayer-Pietsch

Role: primary

Pernille Ravn

Role: primary

Alessandra Gambineri

Role: primary

Eszter Vanky

Role: primary

Lourdes Ibañez

Role: primary

Abel López Bermejo

Role: primary

Feyza Darendeliler

Role: primary

Other Identifiers

2021-003177-58

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

SPIOMET4HEALTH

Identifier Type: -

Identifier Source: org_study_id