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).

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacio Sant Joan De Deu

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Female

Therapeutic area

Diseases [C] - Female Urogenital Diseases and Pregnancy Complications [C13]

Trial duration

24 May 2022 → 27 Feb 2026

Decision date (initial)

2024-12-02

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Fundacion Sant Joan de Deu

External identifiers

EU CT number

2024-518527-29-00

EudraCT number

2021-003177-58

ClinicalTrials.gov

NCT05394142

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To test the efficacy of SPIOMET in normalising ovulation in adolescents and young adult women with PCOS.

Secondary objectives 1

1. To test the efficacy of SPIOMET in normalising the endocrine-metabolic status, body composition and abdominal fat distribution, on-treatment and post-treatment; to assess the safety of SPIOMET and the adherence and subjective acceptability, and the quality of life of participating subjects.

Conditions and MedDRA coding

Polycystic ovary syndrome (PCOS)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002187-PIP01-17

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

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 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).
4. 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;
5. 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 26

1. 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);
2. Underweight (BMI<18.5 kg/m2) and eating disorders (anorexia nervosa);
3. Clinical suspicion or laboratory confirmation of anaemia or a bleeding disorder;
4. 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
5. Precocious puberty [breast development before age 8 yr and/or precocious menarche (menarche before age 10.0 yr (97,109)];
6. Clinical suspicion of Cushing syndrome;
7. 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);
8. Hyperprolactinaemia (due to any cause including breast-feeding);
9. Clinical suspicion or laboratory confirmation of glucose intolerance or diabetes mellitus (111,112);
10. Use of medications affecting gonadal or adrenal function, or carbohydrate or lipid metabolism in the previous three months (including OCs);
11. Gynaecological age < 2.0 years;
12. Positive pregnancy test;
13. Pregnancy risk (failure to guarantee the use of non-hormonal contraception in sexually active subjects);
14. Cardiac failure or history of cardiac failure;
15. Hypersensitivity to the study drugs or any of their excipients.
16. Clinical suspicion of Addison’s disease.
17. Clinical suspicion of any type of acute metabolic acidosis (i.e., lactic acidosis, diabetic ketoacidosis).
18. Diabetic pre-coma.
19. Acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock.
20. 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.
21. Acute alcohol intoxication, clinical suspicion of alcoholism.
22. Clinical suspicion or laboratory confirmation of hyperkalaemia.
23. Concomitant use of eplerenone or other potassium sparing diuretics.
24. Concomitant use of other potassium-conserving diuretics and potassium supplements
25. Current bladder cancer or a history of bladder cancer.
26. Non-investigated macroscopic haematuria.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. On-treatment and post-treatment ovulation rate.

Secondary endpoints 8

1. Clinical variables: weight, height, BMI, WHR, SBP, DBP, hirsutism score (modified Ferriman & Gallwey score), acne score (evaluated using the Leeds Acne Grading Scale), menstrual regularity (3,17)
2. Endocrine-metabolic variables: • Circulating androgens: total testosterone, SHBG, FAI, androstenedione; • Lipids: total cholesterol, LDL-cholesterol, high-density lipoprotein HDL- cholesterol, triglycerides; • Insulinaemia: fasting and 2 hours after a 75-gr oGTT. Estimation of insulin resistance from fasting insulin and glucose levels using the homeostasis model assessment (HOMA); • Markers of inflammation & insulin sensitivity: us-CRP; GDF15; HMW-adip; CXCL14(69,81);
3. Epigenetic variable: circulating miR-451a concentrations (88);
4. Imaging variables: • Cardiovascular risk – cIMT (ultrasound); • Body composition DXA; • Abdominal fat distribution (subcutaneous and visceral) and hepatic fat (MRI);
5. Lifestyle assessment parameters, including changes in 1): imaging variables; 2) clinical variables; 3) endocrine-metabolic variables; 4) health behaviour assessed through LIP-related self-reported Health Behaviour in School-aged Children (HBSC) questionnaire; 5) minimisation of adverse side effects and evaluation of the risk of eating disorders assessed through LIP-related questionnaires “Sick-Control-One-Fat-Food” (SCOFF) and Binge Eating Disorder Screener 7 (BEDS-7)
6. Safety variables: • Blood count (haemoglobin, haematocrit, red blood cell count, white blood cell count, platelet count), electrolyte panel (sodium, potassium, chloride, calcium, phosphorus), urea, ALT, AST, GGT, creatinine, vitamin B12 and folic acid; • Report of AEs;
7. Adherence and acceptability: • 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; • Acceptability of the tablet by the study patients;
8. PROMs & HRQoL: assessed through generic (SF-36) and specific (PCOSQ) questionnaires.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacio Sant Joan De Deu

Sponsor organisation

Fundacio Sant Joan De Deu

Address

Calle Santa Rosa 39-57 3a Planta

City

Esplugues De Llobregat

Postcode

08950

Country

Spain

Scientific contact point

Organisation

Fundacio Sant Joan De Deu

Contact name

Joana Claverol

Public contact point

Organisation

Fundacio Sant Joan De Deu

Contact name

Joana Claverol

Third parties 1

Locations

5 EU/EEA countries · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 27 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications