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)

NCT05394142 | Recruiting Phase 2 DMC

• 2 other identifiers: SPIOMET4HEALTH2021-003177-58
• Study Type: interventional
• Target: 364
• Locations: 6 countries
• Sites: 7

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.

Conditions

Polycystic Ovary Syndrome (PCOS)

Keywords

polycystic ovary syndrome; spironolactone; pioglitazone; metformin; peadiatric; PCOS

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (30)

• Clinical variable: hirsutism

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

• Clinical variable: Acne

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

• Clinical variable: menstrual regularity

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

• Circulating androgens

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

• Lipids

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

Study Arms (4)

Arm 1 - Placebo

PLACEBO COMPARATOR

Placebo

Drug: Placebo

Arm 1 - PIO

EXPERIMENTAL

Pioglitazone

Drug: Pioglitazone

Arm 1 - SPIO

EXPERIMENTAL

Spironolactone and Pioglitazone

Drug: Pioglitazone; Drug: Spironolactone

Arm 1 - SPIOMET

EXPERIMENTAL

Spironolactone, Pioglitazone and Metformin

Drug: Pioglitazone; Drug: Spironolactone; Drug: Metformin

Interventions

Placebo DRUG

Comparator arm with placebo

Arm 1 - Placebo

Pioglitazone DRUG

Pioglitazone 7.5 mg/day

Also known as: PIO

Arm 1 - PIO; Arm 1 - SPIO; Arm 1 - SPIOMET

Spironolactone DRUG

Spironolactone 50 mg/day

Also known as: S

Arm 1 - SPIO; Arm 1 - SPIOMET

Metformin DRUG

Metformin 850 mg/day

Also known as: MET

Arm 1 - SPIOMET

Eligibility Criteria

• Age: 12 Years - 23 Years
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may not qualify if:

• 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).

Sponsors & Collaborators

• Fundació Sant Joan de Déu: lead

Study Sites (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

MeSH Terms

Conditions

Polycystic Ovary Syndrome

Interventions

Pioglitazone; Spironolactone; Metformin

Condition Hierarchy (Ancestors)

Ovarian Cysts; Cysts; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Gonadal Disorders; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Thiazolidinediones; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Lactones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Biguanides; Guanidines; Amidines

Study Officials

• Lourdes Ibañez, MD, PhD

  Investigator

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Rita Malpique, PhD

CONTACT

+34936 00 97 51; rita.malpique@sjd.es

Elizabeth García Pérez, PhD

CONTACT

+34936 00 97 51

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a multi-centre, multi-national, double-blinded, placebo-controlled, parallel, randomised Phase 2 clinical trial with four subgroups

Study Record Dates

• First Submitted: May 9, 2022
• First Posted: May 27, 2022
• Study Start: May 24, 2022
• Primary Completion: April 1, 2025
• Study Completion: April 1, 2025
• Last Updated: April 22, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1); NO (1); IT (1); ES (2); TU (1); DK (1)