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JOURNAL ONKOLOGIE – STUDIE
SPIOMET4HEALTH

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)

Rekrutierend

NCT-Nummer:
NCT05394142

Studienbeginn:
Mai 2022

Letztes Update:
22.04.2024

Wirkstoff:
Placebo, Pioglitazone, Spironolactone, Metformin

Indikation (Clinical Trials):
Polycystic Ovary Syndrome, Syndrome

Geschlecht:
Frauen

Altersgruppe:
Alle

Phase:
Phase 2

Sponsor:
Fundació Sant Joan de Déu

Collaborator:
-

Studienleiter

Lourdes Ibañez, MD, PhD
Principal Investigator
Investigator

Kontakt

Studienlocations
(3 von 7)

Alle anzeigen

Studien-Informationen

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.

Ein-/Ausschlusskriterien

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:

-

Studien-Rationale

Primary outcome:

1. On-treatment ovulation rate. (Time Frame - Following end of each two 12-week on-treatment periods (month 0-3 and month 9-12)):
On-treatment ovulation rate.

2. Post-treatment ovulation rate. (Time Frame - Following the end of post-treatment period (month 12-15)):
Post-treatment ovulation rate.

Secondary outcome:

1. Clinical variable: hirsutism (Time Frame - Every 3 months from study start to study completion (estimated 18 months)):
Presence of hirsutism as measured by the modified Ferriman & Gallwey score

2. Clinical variable: Acne (Time Frame - Every 3 months from study start to study completion (estimated 18 months)):
Presence of Acne as evaluated using the Leeds Acne Grading Scale

3. Clinical variable: menstrual regularity (Time Frame - Every 3 months from study start to study completion (estimated 18 months)):
Assessment of the menstrual regularity

4. Circulating androgens (Time Frame - Every 3 months from study start to study completion (estimated 18 months)):
Assessment by measurement of circulating androgens

5. Lipids (Time Frame - Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment):
Assessment by measurement of total cholesterol, low-density lipoprotein (LDL-cholesterol), high-density lipoprotein (HDL- cholesterol), triglycerides;

6. Insulinaemia (Time Frame - Baseline and at the end of treatment (month 12) and 6 months after treatment):
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);

7. Inflammation markers (Time Frame - Baseline and at the end of treatment (month 12) and 6 months after treatment):
Inflammation markers

8. Insulin sensitivity (Time Frame - Baseline and at the end of treatment (month 12) and 6 months after treatment):
Insulin sensitivity

9. Ultra-sensitive C-reactive protein (us-CRP); (Time Frame - Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment):
Ultra-sensitive C-reactive protein (us-CRP);

10. Growth-and- differentiation factor-15 (GDF15); (Time Frame - Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment):
Growth-and- differentiation factor-15 (GDF15);

11. High molecular weight adiponectin (HMW-adip), (Time Frame - Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment):
High molecular weight adiponectin (HMW-adip),

12. C-X-C motif chemokine ligand 14 (CXCL14) (69,81); (Time Frame - Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment):
C-X-C motif chemokine ligand 14 (CXCL14) (69,81);

13. Epigenetic variable (Time Frame - Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment):
Circulating microRNA 451-a (miR-451a) concentrations (88);

14. Imaging: Cardiovascular risk (Time Frame - Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment):
As measured by ultrasound

15. Imaging: Body composition (Time Frame - Baseline and at the end of treatment (month 12) and 6 months after treatment):
As measured by dual-energy X-ray absorptiometry (DXA)

16. Imaging: Abdominal fat distribution (subcutaneous and visceral) (Time Frame - Baseline and at the end of treatment (month 12) and 6 months after treatment):
As measured by MRI

17. Imaging:hepatic fat (Time Frame - Baseline and at the end of treatment (month 12) and 6 months after treatment):
As measured by MRI

18. Abdominal fat distribution (Time Frame - Baseline and at the end of treatment (month 12) and 6 months after treatment):
Waist circumference, Waist to hip ratio (WHR), and hepatic fat by MRI

19. Weight (Time Frame - Every 3 months from study start to study completion (estimated 18 months)):
Weight measurement

20. Improvement of co-morbidities (Time Frame - Every 3 months from study start to study completion (estimated 18 months)):
Improvement of co-morbidities

21. Improvement of health behaviour (Time Frame - Every 3 months from study start to study completion (estimated 18 months)):
Improvement of health behaviour

22. Improvement of health-related quality of life (HRQoL) (Time Frame - Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment):
As reported by the patient

23. Safety laboratory tests (Time Frame - Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment):
Blood count, electrolyte panel, urea, alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyltransferase (GGT), creatinine, vitamin B12 and folic acid;

24. Adverse events (AEs) (Time Frame - Every 3 months from study start to study completion (estimated 18 months)):
As reported by the patient

25. Adherence (Time Frame - Every 3 months from study start to study completion (estimated 18 months)):
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;

26. Acceptability of the treatment (Time Frame - Every 3 months from study start to study completion (estimated 18 months)):
Acceptability of the tablet by the study patients

27. PROMs (patient-reported outcomes) (Time Frame - Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment):
Questionnaire SF-36

28. PROMs (patient-reported outcomes) (Time Frame - Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment):
Questionnaire PCOSQ

29. HRQoL (health-related quality of life) (Time Frame - Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment):
Questionnaire SF-36

30. HRQoL (health-related quality of life) (Time Frame - Baseline, at month 3, month 6 and month 12 whiled on treatment and 6 months after the end of treatment):
Questionnaire PCOSQ

Studien-Arme

  • Placebo Comparator: Arm 1 - Placebo
    Placebo
  • Experimental: Arm 1 - PIO
    Pioglitazone
  • Experimental: Arm 1 - SPIO
    Spironolactone and Pioglitazone
  • Experimental: Arm 1 - SPIOMET
    Spironolactone, Pioglitazone and Metformin

Geprüfte Regime

  • Placebo:
    Comparator arm with placebo
  • Pioglitazone (PIO):
    Pioglitazone 7.5 mg/day
  • Spironolactone (S):
    Spironolactone 50 mg/day
  • Metformin (MET):
    Metformin 850 mg/day

Quelle: ClinicalTrials.gov


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