E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
ovarian hyperandrogenism with hyperinsulinaemia |
hiperandrogenismo ovárico con hiperinsulinismo |
|
E.1.1.1 | Medical condition in easily understood language |
Polycystic Ovary Syndrome |
Síndrome del ovario poliquístico |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
MedDRA Classification |
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 assess the benefit of the treatment with low doses of PioSpiMet vs EE-LNG in adolescent with hiperandrogenism without risk of pregnancy in terms of: menstruation cycle, insulin sensitivity, the thickness of the carotid artery, visceral and hepatic fat. To assess the maintenance of the effects after treatment with PioSpiMet and to evaluate if the patients treated with EE-lng back to the basal state.
- To characterize the profile of miRNA, intestinal microbiota, telomeric length in leucocytes and the Telomerase activity in patients and controls. To determine changes along time in these parameters to identify prognostic and effectiveness treatment markers.
- To study the polimorphism of the DENND1A in blood between patients and controls. To assess changes along time in inflamatory gene in subcutaneous white adipose tissue and insuline action after the treatment. |
Determinar los beneficios del tratamiento a dosis bajas con PioSpiMet (Pioglitazona+Espironolactona+Metmorfina)vsEE-LNG(etinil-estradiol+levonorgestrel) en adolescentes hiperandrogénicas sin riesgo de embarazo sobre: la ciclicidad menstrual y ovulación; sensibilidad a la insulina , cIMT , la grasa visceral y hepática. Evaluar si los beneficios de PioSpiMet se mantienen al suspender el tratamiento y si se produce una regresión a la situación basal después de EE-LNG.
-Caracterizar el perfil de miRNAs circulantes, del microbioma intestinal, LTL y la AT en pacientes y controles. Determinar los cambios longitudinales en los parámetros mencionados en las pacientes después de PioSpiMet o EE-LNG.
-Determinar si los polimorfismos de DENND1A en sangre periférica difieren en pacientes y controles. Estudiar cambios longitudinales en la expresión en tejido adiposo blanco subcutáneo de genes de inflamación y de acción de la insulina después del tratamiento. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Age equal to or more than 12 years and less than 18 years
2) Menarche at least two years before
3) Body mass index (BMI) below 97th percentile and above the 10th percentile according to age
4) Clinical hyperandrogenism:
a)Hirsutism and/or acne
b)Oligomenorrhea or amenorrhea
and Biochemical hyperandrogenism:
a)Total testosterone > 60 ng/dL and/or free androgen index > 5
b)Androstenedione > 160 ng/dL
5) Hyperinsulinemia:
a)Basal insulin > 15 µU/mL
b)Glucose/insulin ratio < 7 or insulin peak in the oral glucose test> 100 µUmL |
1) Edad igual o superior a los 12 años e inferior a los 18 años
2) Menarquia al menos 2 años antes
3) Índice de masa corporal (IMC) inferior al percentil 97 y superior al percentil 10 para la edad
4) Hiperandrogenismo clínico:
a)Hirsutismo y/o acné
b)Oligomenorrea o amenorrea
Y Hiperandrogenismo bioquímico:
a)Testosterona total > 60ng/dL y/o índice de andrógenos libres (IAL) > 5
b)Androstendiona > 160 ng/Dl
5) Hiperinsulinismo:
a)Insulina basal > 15 µmU/mL
b)Cociente glucosa/insulina <7 ó pico de insulina en el test de tolerancia oral a la glucosa > 100 µmUmL |
|
E.4 | Principal exclusion criteria |
1)Pregnancy or pregnancy risk
2)Congenital adrenal hyperplasia due to 21-hydroxylase deficiency
3)Hyperprolactinemia
4)Cushing's syndrome
5)Uncontrolled hypothyroidism
6)Liver dysfunction, renal dysfunction of the CPK or the LDH
7)Diabetes or glucose intolerance
8)Known skin allergies
9)Treatment during the previous six months with antiandrogens, estro-progestins, or drugs that interfere with the lipid and carbohydrate metabolism.
10)The existence of known bacterial infections.
11)Inflammatory bowel disease. |
1)Embarazo o riesgo de embarazo
2)Hiperplasia suprarrenal congénita por déficit de 21-hidroxilasa
3)Hiperprolactinemia
4)Síndrome de Cushing
5)Hipotiroidismo no controlado
6)Alteración hepática, renal, de Creatin-fosfoquinasa (CPK) o de lactato deshidrogenasa (LDH)
7)Diabetes o intolerancia a la glucosa
8)Alergias cutáneas conocidas
9)Tratamiento con antiandrógenos, estro-progestágenos, o fármacos que interfieran con el metabolismo lipídico e hidrocarbonado en los 6 meses previos.
10)Infecciones bacterianas conocidas.
11)Enfermedad inflamatoria intestinal. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
ovulatory frequency (at least one ovulatory cycle after PioSpiMet vs none with EE-LNG),insulin sensitivity (HOMA), visceral abdominal fat and intrahepatic lipid content, IMTc . A reduction in HOMA equal to or more than 10%, accompanied by a decrease in basal insulin amounts equal to or more than 10%, and two or more of the following changes: a decrease of visceral fat > 20%, a decrease of the intrahepatic lipid content > 30%, or a decrease of the IMT > 20% will be considered as a positive and discriminative response. |
Frecuencia ovulatoria (al menos un ciclo ovulatorio después de PioSpiMet vs ninguno con EE-LNG), sensibilidad a la insulina (HOMA), grasa visceral y hepática, cIMT. Se considerará una respuesta positiva y discriminativa una disminución del HOMA > o = 10%, acompañada de una reducción de las cifras de insulina basal > o = 10%, y de dos o más de los cambios siguientes: disminución de la grasa visceral >20%, hepática >30%, o del cIMT > 20%. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
baseline, 6 months, 12 months, 18 months and 24 months. |
basal, 6 meses, 12 meses,18 meses y 24 meses |
|
E.5.2 | Secondary end point(s) |
Ferriman and Gallwey score, androgens, triglicerides, high molecular weight adiponectine, IRA, PCRus,menstrual cycle. |
Puntuación de Ferriman y Gallwey, andrógenos, triglicéridos, adiponectina alto peso molecular, IRA, PCRus, regularidad menstrual. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline, 6 months, 12 months, 18 months and 24 months |
Basal, 6 meses, 12 meses,18 meses y 24 meses |
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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 | No |
E.6.4 | Safety | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |