Evaluation of Efficacy, Tolerability, and Safety of Spironolactone, Pioglitazone, and Metformin in Adolescents and Young Adults with Polycystic Ovary Syndrome
- Trial ID
- 2024-518527-29-00
- Protocol
- SPIOMET4HEALTH
- Sponsor
- Fundacio Sant Joan De Deu
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase II, randomised, multi-centric, multi-national clinical trial is to evaluate the **efficacy** of a fixed dose combination of Spironolactone, Pioglitazone, and Metformin (SPIOMET) in normalising ovulation in adolescent girls and young adult women with **polycystic ovary syndrome (PCOS)**. This is clinically relevant as PCOS is a common endocrine disorder that can lead to infertility due to anovulation. Addressing ovulation normalization can significantly impact reproductive health and improve fertility outcomes in this population.
Secondary objectives include:
- Testing the efficacy of SPIOMET in normalising the endocrine-metabolic status, body composition, and abdominal fat distribution both during and after treatment.
- Assessing the safety profile of SPIOMET.
- Evaluating adherence, subjective acceptability, and quality of life of the participants.
Participants
The clinical trial involves a total of **42 participants** who are adolescents and young adult women diagnosed with **polycystic ovary syndrome (PCOS)**. The study population is exclusively female, with an age range from over 12.0 years to 23.9 years at the start of the study. Participants were selected based on specific criteria, including a gynaecological age of 2 years or more, clinical and/or biochemical androgen excess, and menstrual irregularity. The trial focuses on a vulnerable population, as it includes adolescents. Participants are required to provide written informed consent, or assent with parental consent if they are minors. The study does not specify any particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that the participants have a consistent diagnosis of PCOS, characterized by symptoms such as hirsutism, inflammatory acne, and irregular menstrual cycles.
Plans and Procedures
The clinical trial is a **Phase II**, randomized, multi-centric, multi-national study designed to evaluate the efficacy, tolerability, and safety of a fixed-dose combination of **spironolactone**, **pioglitazone**, and **metformin** (SPIOMET) in adolescent girls and young adult women with **polycystic ovary syndrome (PCOS)**. The trial employs a **double-blind** and **controlled** design to ensure unbiased results. The estimated duration of the trial is from May 25, 2022, to February 25, 2026, with a maximum treatment period of 18 weeks for the SPIOMET group.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, gynaecological age, and clinical or biochemical androgen excess. Following successful screening, participants will be randomized into treatment groups. The trial includes regular follow-up visits to monitor clinical variables, endocrine-metabolic variables, and safety parameters. The primary endpoint is the on-treatment and post-treatment ovulation rate, while secondary endpoints include clinical, endocrine-metabolic, epigenetic, imaging, lifestyle assessment, and safety variables. The end-of-study visit will evaluate the overall outcomes and collect final data.
The expected length of participant involvement is approximately 18 weeks, with conditions for early termination including non-compliance with the study protocol, adverse events, or withdrawal of consent. Participants will be monitored for adherence and acceptability of the treatment, with adherence calculated as the ratio of tablets prescribed to those returned. Safety assessments will include blood counts, electrolyte panels, and reports of adverse events. The trial aims to provide comprehensive data on the efficacy and safety of SPIOMET in normalizing ovulation in the target population.
Treatment
The clinical trial involves the administration of several experimental medications, each formulated as a **tablet** for **oral** administration. The first experimental medication, **SPIO**, contains the active substances **pioglitazone** and **spironolactone**. This combination is designed to be administered orally, with a maximum treatment period of 52 weeks. The specific dosage and frequency of administration are not detailed in the provided data, but compliance with the dosing schedule will be monitored throughout the trial.
The second experimental medication, **SPIOMET**, is a fixed-dose combination tablet containing **metformin**, **pioglitazone**, and **spironolactone**. This formulation is also administered orally, with a maximum treatment period of 18 weeks. As with SPIO, the exact dosage and administration frequency are not specified, but participant adherence to the treatment regimen will be closely monitored to ensure compliance.
The third experimental medication, **PIO**, consists solely of **pioglitazone** in tablet form. It is administered orally, with a treatment duration of up to 52 weeks. The trial will include measures to monitor participant compliance with the prescribed dosing schedule, although specific dosage details are not provided.
In addition to the experimental medications, a **placebo** formulation is included in the trial. The placebo is designed to match the experimental treatments in appearance and administration route, ensuring blinding of participants and investigators. The compatibility and stability of the placebo formulation are extrapolated from the SPIOMET compatibility study, ensuring consistency across the trial.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the **ovulation rate** during and after treatment. This primary endpoint will provide a direct measure of the treatment's effectiveness in normalizing ovulation in adolescent girls and young adult women with polycystic ovary syndrome (PCOS). Secondary endpoints will include a range of clinical, endocrine-metabolic, epigenetic, imaging, lifestyle, safety, and patient-reported outcomes. Clinical variables such as weight, height, body mass index (BMI), waist-to-hip ratio (WHR), systolic and diastolic blood pressure (SBP, DBP), hirsutism score, acne score, and menstrual regularity will be evaluated. Endocrine-metabolic assessments will measure circulating androgens, lipid profiles, insulinaemia, and markers of inflammation and insulin sensitivity. Epigenetic analysis will focus on circulating miR-451a concentrations. Imaging variables will assess cardiovascular risk, body composition, abdominal fat distribution, and hepatic fat using techniques such as ultrasound, dual-energy X-ray absorptiometry (DXA), and magnetic resonance imaging (MRI).
Lifestyle assessment parameters will include changes in imaging, clinical, and endocrine-metabolic variables, as well as health behavior through self-reported questionnaires. Safety variables will be monitored through blood counts, electrolyte panels, liver and kidney function tests, and reports of adverse events. Adherence to the treatment will be calculated based on the ratio of tablets prescribed and returned, while acceptability will be evaluated through patient feedback. Patient-reported outcomes and health-related quality of life (HRQoL) will be assessed using generic (SF-36) and specific (PCOSQ) questionnaires. These comprehensive assessments will be conducted at various time points throughout the trial to ensure a thorough evaluation of the treatment's efficacy and safety.
Inclusion and Exclusion Criteria
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 and/or biochemical androgen excess (150): 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); and/or biochemical androgen excess, as defined by increased total testosterone (≥45 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 biochemical androgen excess (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); free androgen index (FAI) should be derived from testosterone and SHBG: FAI = total testosterone (nmol/L) x 100/SHBG (nmol/L).
- 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 menses/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
- Class II obesity or morbid obesity (BMI of 35 kg/m2 or higher) according to published international standard charts for both adolescents and young women (76,77);
- Underweight (BMI<18.5 kg/m2) and eating disorders (anorexia nervosa);
- Clinical suspicion or laboratory confirmation of anaemia or a bleeding disorder;
- Evidence of thyroid, liver, or kidney dysfunction; if the value for a specific variable is not within the normal range for the local lab, the assessment must be repeated. If the subsequent value is within the normal range, the patient can be included in the study. Patients diagnosed with subclinical hypothyroidism or autoimmune thyroiditis can also be included if the condition is treated and the lab values of thyroid variables are within the normal range for the local lab
- Precocious puberty [breast development before age 8 yr and/or precocious menarche (menarche before age 10.0 yr (97,109)];
- Clinical suspicion of Cushing syndrome;
- Late-onset adrenal hyperplasia due to 21-hydroxylase deficiency [17-hydroxyprogesterone levels >200 ng/dL in the follicular phase of the cycle or after 2 months of amenorrhea] (3,95,110);
- Hyperprolactinaemia (due to any cause including breast-feeding);
- Clinical suspicion or laboratory confirmation of glucose intolerance or diabetes mellitus (111,112);
- Use of medications affecting gonadal or adrenal function, or carbohydrate or lipid metabolism in the previous three months (including OCs);
- Gynaecological age < 2.0 years;
- Positive pregnancy test;
- Pregnancy risk (failure to guarantee the use of non-hormonal contraception in sexually active subjects);
- Cardiac failure or history of cardiac failure;
- Hypersensitivity to the study drugs or any of their excipients.
- Clinical suspicion of Addison’s disease.
- Clinical suspicion of any type of acute metabolic acidosis (i.e., lactic acidosis, diabetic ketoacidosis).
- Diabetic pre-coma.
- Acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock.
- Any disorder, which may cause tissue hypoxia (especially acute disease or worsening of chronic disease) such as: decompensated heart failure, respiratory failure, recent myocardial infarction, shock.
- Acute alcohol intoxication, clinical suspicion of alcoholism.
- Clinical suspicion or laboratory confirmation of hyperkalaemia.
- Concomitant use of eplerenone or other potassium sparing diuretics.
- Concomitant use of other potassium-conserving diuretics and potassium supplements
- Current bladder cancer or a history of bladder cancer.
- Non-investigated macroscopic haematuria.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 25 May 2022 | 50 |
 Denmark | Not Recruiting | 25 May 2022 | 50 |
 Italy | Not Recruiting | 25 May 2022 | 50 |
 Norway | Not Recruiting | 25 May 2022 | 50 |
 Spain | Not Recruiting | 25 May 2022 | 116 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
SPIO | Test | TABLET | ORAL | 00 | 52 | PRD9639901 |
SPIOMET | Test | TABLET | ORAL | 00 | 18 | PRD9639900 |
The current SPIOMET, SPIO, PIO and Placebo formulation was defined based on the compatibility study for SPIOMET carried out by Kern Pharma (see section 2.1.P.2.2.1 of IMPD).
SPIO, PIO and Placebo formulations are considered compatible. As they have the same qualitative composition as SPIOMET, the compatibility and stability can be extrapolated from SPIOMET. | Placebo | N/A | — | — | — | N/A |
PIO | Test | TABLET | ORAL | 00 | 52 | PRD9639902 |