| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Vulvovaginal atrophy in postmenopausal women |
| Atrofia vulvovaginale nelle donne in post-menopausa |
|
| E.1.1.1 | Medical condition in easily understood language |
| The combination of symptoms such as vaginal dryness, dyspareunia, burning, itching, as well as urinary complaints or infections of the lower urinary tract presented during menopause |
| La combinazione di sintomi quali secchezza vaginale, dispareunia, bruciore, prurito, così come disturbi urinari o infezioni del tratto urinario inferiore presenti durante la menopausa |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10047782 |
| E.1.2 | Term | Vulvovaginal atrophy |
| 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 |
| Evaluate the efficacy of 0.005%, 0.002%, and 0.0008% estriol vaginal gel and determine the minimal effective dose for the treatment of postmenopausal vaginal atrophy in women who report moderate to severe vaginal dryness as the most bothersome symptom |
| Valutare l’efficacia del gel vaginale con 0,005%, 0,002% e 0,0008% di estriolo e determinare la dose minima efficace per il trattamento dell’atrofia vaginale post-menopausale nelle donne che riferiscono secchezza vaginale da moderata a grave come sintomo più fastidioso |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives:
Evaluate the efficacy of the three formulations of estriol vaginal gel in the improvement of other symptoms and signs of vulvovaginal atrophy.
Evaluate the safety and tolerability of the three formulations of estriol vaginal gel
Exploratory objectives:
Evaluate the final subjective global perception of efficacy of the three formulations of estriol vaginal gel.
Evaluate the subject`s acceptability of the three formulations. |
Obiettivi secondari:
Valutare l’efficacia delle tre formulazioni di gel vaginale a base di estriolo nel miglioramento di altri sintomi e segni di atrofia vulvovaginale.
Valutare la sicurezza e la tollerabilità delle tre formulazioni di gel vaginale a base di estriolo
Obiettivi esplorativi:
Valutare la percezione globale soggettiva finale dell’efficacia delle tre formulazioni di gel vaginale a base di estriolo.
Valutare l’accettabilità delle tre formulazioni da parte del soggetto. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Capable of understanding the written informed consent, provides signed and witnessed written informed consent, and agrees to comply with the protocol procedures and assessments
2.Age >40 and <80 years
3.Postmenopausal (≥12 months since last spontaneous menstrual period, or having 6 months of spontaneous amenorrhea with serum FSH levels >40 IU/L, or ≥6 weeks since bilateral oophorectomy with or without hysterectomy)
4.BMI ≤ 36 kg/m2
5.Vaginal Maturation Index ≤ 5% superficial cells on a vaginal smear
6.Vaginal pH >5
7.Moderate to severe vaginal dryness currently reported as the most bothersome symptom of vaginal atrophy.
8.Documented negative mammogram within 9 months prior to randomization, with normal breast examination at screening.
9.Negative Papanicolau test at screening (in women with cervix). |
•Capacità di comprendere il consenso informato scritto, fornire un consenso informato scritto firmato in presenza di un testimone, accettare di conformarsi alle procedure e alle valutazioni previste dal protocollo
•Età compresa tra >40 e <80 anni
•Periodo post-menopausale (≥ 12 mesi dall’ultimo ciclo mestruale spontaneo o 6 mesi di amenorrea spontanea con livelli sierici di FSH [ormone follicolo-stimolante] > 40 IU/l o ≥ 6 settimane dall’ultima ovariectomia bilaterale con o senza isterectomia)
•IMC 36 kg/m2
•Indice di maturazione vaginale con ≤ 5% di cellule superficiali come da Pap-test
•pH vaginale > 5
•Secchezza vaginale da moderata a grave attualmente indicata essere il sintomo più fastidioso di atrofia vaginale.
•Mammografia negativa documentata nei 9 mesi precedenti la randomizzazione, con esame del seno normale allo screening.
•Pap-test negativo allo screening (nelle donne con cervice).
|
|
| E.4 | Principal exclusion criteria |
.Subjects with contraindications for hormone therapy with estrogens such as those diagnosed or history of: malignant and premalignant lesions of the breast and/or endometrium, malignancy of the colon, malignant melanoma, hepatic tumor, venous thromboembolic conditions (including deep vein thrombosis or pulmonary embolism), arterial thromboembolic conditions (including angina pectoris, myocardial infarction, or cerebrovascular accident), coagulopathies, vaginal bleeding of unknown etiology, acute liver disease or a history of liver disease as long as liver function tests have failed to return to normal, or porphyria
2.Subjects who have abnormal laboratory values at screening that the investigator considers clinically relevant for the purposes of the study.
3.Subjects with any medical-surgical pathology which is not controlled at the time of inclusion in the study.
4.Subjects with any acute or chronic condition whose management or progression may interfere with the subject´s participation in the study.
5.Subject with uncontrolled hypertension (>140 mmHg systolic blood pressure and/or ≥90 mmHg diastolic blood pressure).
6.Subjects with Grade II or higher utero-vaginal prolapse.
7.Subjects with uterine polyps.
8.Subjects with symptomatic and/or large uterine fibroids (>3 cm) and/or palpable fibroids at gynecological examination.
9.Subjects who have had urogenital surgery within 3 months of baseline visit.
10.Subjects with signs and symptoms suggestive of infection of the genital or urinary tract requiring treatment at the start of the study.
11.In women who have a uterus, evidence of hyperplasia, cancer or other endometrial pathology in endometrial biopsy.
12.Subjects who have received the following treatments within the specified time periods prior to screening procedures: any type of non-hormonal vulvovaginal treatment in the 7 days (including cosmetics expected to have an impact on vaginal pH such as special feminine wash gels); phytoestrogens by any route within 1 month; vaginal hormone therapy within 1 month; hormone therapy (estrogen alone, progestin alone or estrogen/progestin combination) by oral, intrauterine or transdermal route within 2 months; progestational implants, estrogen, or estrogen/progestational injectable within 3 months; estrogen pellet therapy or progestin injectable drug therapy within 6 months; percutaneous estrogen lotions or gels within 1 month; testosterone or testosterone derivatives, DHEA, tibolone, or SERMs by any route within 2 months;
13.Subjects receiving antiepileptic drugs (barbiturates, hydantoins, carbamazepine), certain antibiotics and other antiinfective medicinal products; phenylbutazone; preparations based on medicinal plants that contain St. John’s Wort.
14.Subjects who are allergic to any of the components of the medication under study.
15.Subjects who are currently participating or have participated in the experimental evaluation of any product within 8 weeks of the start of the study.
|
•Soggetti con controindicazione alla terapia ormonale estrogenica, come le pazienti con diagnosi o anamnesi di: lesioni maligne e premaligne del seno e/o dell’endometrio, tumore maligno del colon, melanoma maligno, tumore epatico, condizioni tromboemboliche venose (inclusa trombosi venosa profonda o embolia polmonare), condizioni tromboemboliche arteriose (inclusa angina pectoris, infarto del miocardio o incidente cerebrovascolare), coagulopatie, sanguinamento vaginale di eziologia sconosciuta, malattia epatica acuta o anamnesi di malattia epatica, che test di funzionalità epatica non sono riusciti a riportare alla normalità, o porfiria.
•Soggetti con valori di laboratorio anomali allo screening considerati dallo sperimentatore clinicamente rilevanti ai fini dello studio.
•Soggetti con qualsiasi patologia medico-chirurgica non controllata al momento dell’inclusione nello studio.
•Soggetti con condizioni acute o croniche la cui gestione o progressione può interferire con la partecipazione del soggetto allo studio.
•Soggetto con ipertensione non controllata (pressione arteriosa sistolica>140 mmHg e/o pressione arteriosa diastolica ≥90 mmHg).
•Soggetti con prolasso utero-vaginale di grado II o superiore.
•Soggetti con polipi uterini.
•Soggetti con fibromi uterini sintomatici e/o di grandi dimensioni (>3 cm) e/o fibromi palpabili all’esame ginecologico.
•Soggetti sottoposti a intervento urogenitale 3 mesi prima della visita basale.
•Soggetti con segni e sintomi che indicano infezione del tratto genitale o urinario che richiedono il trattamento all’inizio dello studio.
•Nelle donne con utero, evidenza di iperplasia, tumore o altra patologia endometriale rilevata con la biopsia dell’endometrio.
•Soggetti che abbiano ricevuto i seguenti trattamenti entro i periodi di tempo specificati, prima delle procedura di screening: qualsiasi tipo di trattamento non ormonale per la vulvovaginite nei 7 giorni precedenti (compresi i cosmetici che potrebbero avere un impatto sul pH vaginale, come specifici gel lavanti femminili), fitoestrogeni per qualsiasi via di somministrazione nel mese precedente, terapia ormonale vaginale nel mese precedente, terapia ormonale (solo estrogeni, solo progestinici o estro/progestinici in combinazione) per via orale, intrauterina o transdermica nei 2 mesi precedenti, impianti progestinici, estrogeno o estro/progestinici per iniezione nei 3 mesi precedenti, terapia estrogenica con pellet o terapia con progestinici iniettabili nei 6 mesi precedenti, lozioni o gel percutanei nel mese precedente, testosterone o suoi derivati, deidroepiandrosterone (DHEA), tibolone o i modulatori selettivi del recettore degli estrogeni (SERM, selective estrogen receptor modulator) per qualsiasi via di somministrazione nei 2 mesi precedenti.
•Soggetti trattati con farmaci antiepilettici (barbiturici, idantoine, carbamazepina), alcuni antibiotici o altri prodotti medicinali per il trattamento delle infezioni, fenilbutazone, preparazioni a base di piante medicinali che contengono erba di San Giovanni.
•Soggetti allergici a uno qualsiasi dei componenti del farmaco in studio.
•Soggetti attualmente partecipanti o che abbiano partecipato alla valutazione sperimentale di un qualsiasi prodotto nelle 8 settimane precedenti l’inizio dello studio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary Efficacy Endpoints The 4 co-primary efficacy endpoints in this study are: •change from Baseline to Week 12 in the severity of vaginal dryness; •change from Baseline to Week 12 in vaginal pH; •change from Baseline to Week 12 in the proportion of parabasal cells of the vaginal epithelium; •and change from Baseline to Week 12 in the proportion of superficial cells of the vaginal epithelium. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints in this study are:
•change from Baseline to Week 12 in the severity of individual vaginal
symptoms including dyspareunia, pruritus, burning and dysuria;
•change from Baseline to Week 12 in the Global Symptom Score
•change from Baseline to Week 12 in the severity of individual vaginal
signs including pallor, friability, thinning or flattening of folds, petechiae
and dry mucosa;
•change from Baseline to Week 3 in the proportion of superficial cells of
the vaginal epithelium;
•change from Baseline to Week 3 in the proportion of parabasal cells of
the vaginal epithelium;
•change from Baseline to Week 3 in the severity of vaginal dryness;
•change from Baseline to Week 3 in vaginal pH;
•change from Baseline to Week 3 in the severity of individual vaginal
symptoms including dyspareunia, pruritus, burning and dysuria;
•change from Baseline to Week 3 in the severity of individual vaginal
signs including pallor, friability, thinning or flattening of folds, petechiae
and dry mucosa;
•change from Baseline to Week 3 in the Global Symptom Score
Exploratory Efficacy Endpoints
The following exploratory endpoints will be analyzed:
•evaluation of the final subjective global perception of efficacy at Week
12;
•evaluation of the acceptability of the therapy at Week 12.
Safety Endpoints
The following safety variables will be analyzed:
•laboratory parameters
- biochemistry, hematology and urinalysis at Week 12;
- serum lipids, and coagulation parameters at Week 12;
- change from Baseline in hormone levels (estradiol, estrone, estriol,
FSH, LH);
•change from Baseline in uterine evaluation by transvaginal ultrasound
at Week 12 for women with an intact uterus;
•change from Baseline in endometrial histology at Week 12 for women
with an intact uterus;
•frequency and severity of AEs. |
| Refer to the EN |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| please refer to the timepoint specified in each variable |
| Refer to the EN |
|
| 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 | 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 | Yes |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 | Information not present in EudraCT |
| 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
|
| LVLS (including End of Study phone call at week 16) |
| LVLS (inclusa la telefonata di Fine Studio alla settimana 16) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 10 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
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