| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Polycystic Ovary Syndrome (PCOS) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Polycystic Ovary Syndrome (PCOS) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065161 |
| E.1.2 | Term | Polycystic ovarian syndrome |
| E.1.2 | System Organ Class | 100000004872 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To test the efficacy of SPIOMET in normalising ovulation in adolescents and young adult women with PCOS. |
|
| E.2.2 | Secondary objectives of the trial |
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. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age range within the AYAs category (> 12.0 years and ≤ 23.9 years at study start);
2. Gynaecological age of 2 years or more;
3. Clinical androgen excess, as defined by the presence of hirsutism (modified Ferriman-Gallwey score ≥ 4) and/or inflammatory acne (Leeds scale) unresponsive to medications. The scarce normative data existing in adolescents suggest that an adult level of hirsutism is reached around 2 years after menarche;
4. 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;
5. Menstrual irregularity, as defined by ≤ 8 menses per year corresponding to an average intermenstrual time of ≥45 days;
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 |
|
| E.4 | Principal exclusion criteria |
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;
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);
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];
8. Hyperprolactinaemia (due to any cause including breast-feeding);
9. Clinical suspicion or laboratory confirmation of glucose intolerance or diabetes mellitus;
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 (such asi.e., lactic acidosis, diabetic ketoacidosis);
18. Diabetic pre-coma;
20. Acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock;
21. Any disorders which may cause tissue hypoxia (especially acute disease or worsening of chronic disease) such as: decompensated heart failure, respiratory failure, recent myocardial infarction, shock;
22. Acute alcohol intoxication, Clinical suspicion of alcoholism;
23. Clinical suspicion or laboratory confirmation of Hyperkalaemia;
24. Concomitant use of eplerenone or other potassium sparing diuretics;
25. Concomitant use of other potassium- conserving diuretics and potassium supplements should not be given routinely;
26. Current bladder cancer or a history of bladder cancer;
27. Non-investigated macroscopic haematuria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| On-treatment and post-treatment ovulation rate. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Following end of each two 12-week on-treatment periods (month 0-3 and month 9-12), and following the end of post-treatment period (month 12-15) |
|
| E.5.2 | Secondary end point(s) |
1. Clinical variables: weight, height, BMI, WHR, SBP, DBP, hirsutism (modified Ferriman & Gallwey score), Acne (evaluated using the Leeds Acne Grading Scale), menstrual regularity
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 oral glucose load [oral glucose tolerance test (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;
3. Epigenetic variable: circulating miR-451a concentrations;
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-OneFat-Food”
(SCOFF) and Binge EatingDisorder Screener 7 (BEDS-7);only in case the risk is confirmed,then,the Eating Disorder Examination Questionnaire (EDE-Q) will be used; 6) PROMs on HRQoL (SF-36, PCOSQ).
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 two 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 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 40 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 40 |
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