Clinical trial NCT05394142: 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)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Polycystic Ovary Syndrome (PCOS)
Keywords: polycystic ovary syndrome
spironolactone
pioglitazone
metformin
peadiatric
PCOS
Lead sponsor: Fundació Sant Joan de Déu
Sponsor class: OTHER
First posted: 2022-05-27
Enrollment: 364
Sex: FEMALE
Minimum age (years): 12
Maximum age (years): 23
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a multi-centre, multi-national, double-blinded, placebo-controlled, parallel, randomised Phase 2 clinical trial with four subgroups
Primary purpose: TREATMENT

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.

Eligibility criteria: 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:

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Primary outcomes:
measure: On-treatment ovulation rate.
timeFrame: Following end of each two 12-week on-treatment periods (month 0-3 and month 9-12)
measure: Post-treatment ovulation rate.
timeFrame: Following the end of post-treatment period (month 12-15)
Secondary outcomes:
measure: Clinical variable: hirsutism
timeFrame: Every 3 months from study start to study completion (estimated 18 months)
measure: Clinical variable: Acne
timeFrame: Every 3 months from study start to study completion (estimated 18 months)
measure: Clinical variable: menstrual regularity
timeFrame: Every 3 months from study start to study completion (estimated 18 months)
measure: Circulating androgens
timeFrame: Every 3 months from study start to study completion (estimated 18 months)
measure: Lipids
timeFrame: Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment
measure: Insulinaemia
timeFrame: Baseline and at the end of treatment (month 12) and 6 months after treatment
measure: Inflammation markers
timeFrame: Baseline and at the end of treatment (month 12) and 6 months after treatment
measure: Insulin sensitivity
timeFrame: Baseline and at the end of treatment (month 12) and 6 months after treatment
measure: Ultra-sensitive C-reactive protein (us-CRP);
timeFrame: Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment
measure: Growth-and- differentiation factor-15 (GDF15);
timeFrame: Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment
measure: High molecular weight adiponectin (HMW-adip),
timeFrame: Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment
measure: C-X-C motif chemokine ligand 14 (CXCL14) (69,81);
timeFrame: Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment
measure: Epigenetic variable
timeFrame: Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment
measure: Imaging: Cardiovascular risk
timeFrame: Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment
measure: Imaging: Body composition
timeFrame: Baseline and at the end of treatment (month 12) and 6 months after treatment
measure: Imaging: Abdominal fat distribution (subcutaneous and visceral)
timeFrame: Baseline and at the end of treatment (month 12) and 6 months after treatment
measure: Imaging:hepatic fat
timeFrame: Baseline and at the end of treatment (month 12) and 6 months after treatment
measure: Abdominal fat distribution
timeFrame: Baseline and at the end of treatment (month 12) and 6 months after treatment
measure: Weight
timeFrame: Every 3 months from study start to study completion (estimated 18 months)
measure: Improvement of co-morbidities
timeFrame: Every 3 months from study start to study completion (estimated 18 months)
measure: Improvement of health behaviour
timeFrame: Every 3 months from study start to study completion (estimated 18 months)
measure: Improvement of health-related quality of life (HRQoL)
timeFrame: Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment
measure: Safety laboratory tests
timeFrame: Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment
measure: Adverse events (AEs)
timeFrame: Every 3 months from study start to study completion (estimated 18 months)
measure: Adherence
timeFrame: Every 3 months from study start to study completion (estimated 18 months)
measure: Acceptability of the treatment
timeFrame: Every 3 months from study start to study completion (estimated 18 months)
measure: PROMs (patient-reported outcomes)
timeFrame: Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment
measure: PROMs (patient-reported outcomes)
timeFrame: Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment
measure: HRQoL (health-related quality of life)
timeFrame: Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment
measure: HRQoL (health-related quality of life)
timeFrame: Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Universitätsklinik für Innere Medizin
city: Odense
country: Denmark
facility: Odense University Hospital (UNIODE)
city: Bologna
country: Italy
facility: Azienda Ospedaliero Universitaria di Bologna
city: Trondheim
country: Norway
facility: St. Olavs Hospital
city: Esplugues De Llobregat
country: Spain
facility: Hospital Sant Joan de Deu
city: Girona
country: Spain
facility: Hospital Universitari de Girona Dr. Trueta
city: Istanbul
country: Turkey
facility: İstanbul Faculty of Medicine Topkapı
Study officials:
affiliation: Investigator
name: Lourdes Ibañez, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: