| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to Severe Vasomotor Symptoms (VMS) in Postmenopausal Women |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hot flushes associated with menopause |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020407 |
| E.1.2 | Term | Hot flashes |
| E.1.2 | System Organ Class | 100000004866 |
|
| 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 |
Arms 1-3: To measure the effect of treatment with E4 15 mg or E4 20 mg compared to placebo on the frequency and severity of moderate to severe VMS in postmenopausal women at 4 and 12 weeks
Arm 4: To evaluate the effect of treatment with E4 20 mg / P4 100 mg on the endometrium |
|
| E.2.2 | Secondary objectives of the trial |
Arms 1-3: Treatment with E4 15 mg or E4 20 mg:
- To measure the effect of treatment compared to placebo on the frequency and severity of moderate to severe VMS in postmenopausal women weekly up to 12 weeks, on symptoms of vulvovaginal atrophy (VVA), lipid and glucose metabolism, health-related quality of life (HRQoL) and treatment satisfaction (TS), and on the endometrium and vaginal bleeding in non-hysterectomized subjects
- To measure the clinical meaningfulness compared to placebo on the reduction of VMS at weeks 4 and 12
- To evaluate the general safety of treatment compared to placebo
Arm 4: Treatment with E4 20 mg / P4 100 mg:
- To evaluate the general safety of treatment
- To evaluate the effect of treatment on vaginal bleeding, HRQoL and TS, lipid and glucose metabolism |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed and dated written informed consent form and any required privacy authorization prior to the initiation of any trial procedure, after the nature of the trial has been explained according to local regulatory requirements;
2. Females, ≥ 40 up to ≤ 65 years of age at randomization/treatment allocation;
3. For hysterectomized subjects: documented hysterectomy must have occurred at least 6 weeks prior to the start of screening. Hysterectomy can be total or subtotal (i.e., cervix was not removed).
4. For non-hysterectomized subjects: uterus with bi-layer endometrial
thickness ≤ 4 mm on transvaginal ultrasound (TVUS) (Amendment 1,
November 28, 2019);
5. For non-hysterectomized subjects: an evaluable endometrial biopsy
taken during screening that reveals no abnormal results, i.e., presence
of hyperplasia (simple or complex, with or without atypia), presence of
carcinoma, and presence of disordered proliferative findings. The
screening biopsy should have sufficient endometrial tissue for diagnosis;
6. Seeking treatment for relief of VMS associated with menopause;
a) For the Efficacy Study part: at least 7 moderate to severe bothersome VMS per day or at least 50 moderate to severe bothersome VMS per week in the last 7 consecutive days during the Screening period;
b) For the Endometrial and General Safety Study part: at least 1 moderate to severe VMS per week;
7. Body mass index ≥ 18.0 kg/m² to ≤ 38.0 kg/m²;
8. A mammogram that shows no sign of significant disease performed during screening or within 9 months prior to the start of screening;
9. Post-menopausal status defined as any of the following:
a) For non-hysterectomized subjects:
- at least 12 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) >40 mIU/mL (value obtained after washout of estrogen/progestin containing drugs, see exclusion criteria 18 and 20);
- or at least 6 months of spontaneous amenorrhea with serum FSH >40 mIU/mL and E2 <20 pg/mL (<73.4 pmol/L, value obtained after washout of estrogen/progestin containing drugs, see exclusion criteria 18 and 20); (Amendment 2, February 24, 2020);
- or at least 6 weeks postsurgical bilateral oophorectomy;
b) For hysterectomized subjects:
- serum FSH >40 mIU/mL and E2 <20 pg/mL (<73.4 pmol/L values obtained after washout of estrogen/progestin containing drug see exclusion criteria 18 and 20) (Amendment 2, February 24, 2020);
- or at least 6 weeks post-surgical bilateral oophorectomy;
10. Good physical and mental health, in the judgement of the Investigator as based on medical history, physical and gynecological examination and clinical assessments performed prior Visit 1;
11. Able to understand and comply with the protocol requirements, instructions, and protocol-stated restrictions;
12. Able and willing to complete trial daily paper diaries (if applicable, see protocol Section 10.1.7) and questionnaires. |
|
| E.4 | Principal exclusion criteria |
1. History of malignancy with the exception of basal cell or squamous
cell carcinoma of the skin if diagnosed more than 1 year prior to the
Screening visit;
2. Any clinically significant findings found by the Investigator at the
breast examination and/or on mammography suspicious of breast
malignancy that would require additional clinical testing to rule out
breast cancer (however, simple cysts confirmed by ultrasound are
allowed);
3. PAP test with atypical squamous cells undetermined significance
(ASC-US) or higher (low-grade squamous intraepithelial lesion [LSIL],
atypical squamous cells- cannot exclude high-grade squamous
intraepithelial lesion [HSIL] [ASC-H], HSIL, dysplastic or malignant
cells) in sub-totally hysterectomized and non-hysterectomized subjects.
Note: ASC-US is allowed if a reflex human papilloma virus (HPV) testingis performed and is negative for high risk oncogene HPV;
4. For non-hysterectomized subjects:
a) History or presence of uterine cancer, endometrial hyperplasia,
disordered proliferative findings; b) Presence of endometrial polyps; c)
Undiagnosed vaginal bleeding or undiagnosed abnormal uterine
bleeding; d) Endometrial ablation; e) Any uterine/endometrial
abnormality that in the judgment of the investigator contraindicates the
use of estrogen and/or progestin therapy. This includes presence or
history of adenomyosis or significant myoma (Amendment 2, February
24, 2020);
5. Systolic blood pressure (BP) higher than 130 mmHg, diastolic BP
higher than 80 mmHg during screening;
6. History of venous or arterial thromboembolic disease (e.g., superficial
or deep vein thrombosis, pulmonary embolism, stroke, myocardial
infarction, angina pectoris, etc.), or first degree family history of VTE;
7. History of known acquired or congenital coagulopathy or abnormal
coagulation factors, including known thrombophilia's;
8. Laboratory values of fasting glucose ranges above 125 mg/dL (>6.94
mmol/L) and/or glycated hemoglobin above 7% (Amendment 2,
February 24, 2020);
9. Dyslipoproteinemia (LDL >190 mg/dL [>4.91 mmol/L] and/or
triglycerides >300 mg/dL [>3.39 mmol/L]) (Amendment 1, November
28, 2019 and Amendment 2, February 24, 2020);
10. Subjects smoking >15 cigarettes per day (Amendment 1, November
28, 2019);
11. Presence or history of gallbladder disease, unless cholecystectomy
has been performed;
12. Systemic lupus erythematosus;
13. Any malabsorption disorders including gastric bypass surgery;
14. History of acute liver disease in the preceding 12 months before the
start of screening or presence or history of chronic or severe liver
disease [alanine transaminase (ALT) or aspartate transaminase (AST)
>2x upper limit of normal (ULN), bilirubin >1.5 ULN], or liver tumors;
15. Chronic or current acute renal impairment (estimated glomerular
filtration rate <60 ml/min);
16. Porphyria;
17. Diagnosis or treatment of major psychiatric disorder (e.g.,
schizophrenia, bipolar disorder, etc.), in the judgement of the
Investigator;
18. Use of estrogen/progestin containing drug(s) up to:
a) 1 week before screening start for vaginal non systemic hormonal
products (rings, creams, gels); b) 4 weeks before screening start for
vaginal or transdermal estrogen or estrogen/progestin products; c) 8
weeks before screening start for oral estrogen and/or progestin
products and/or selective estrogen receptor modulator therapy; d) 8
weeks before screening start for intrauterine progestin therapy; e) 3
months before screening start for progestin implants or estrogen alone
injectable drug therapy; f) 6 months before screening start for estrogen
pellet therapy or progestin injectable drug therapy;
19. Use of androgen/DHEA containing drugs:
a) 8 weeks before screening start for oral, topical, vaginal or
transdermal androgen; b) 6 months before screening start for
implantable or injectable androgen therapy;
20. Use of phytoestrogens or black cohosh for the treatment of VMS up
to 2 weeks before the start of screening;
21. For the women participating in the Efficacy Study part: use of
prescription or over-the-counter products used for the treatment of VMS,
e.g., anti-depressants: paroxetine, escitalopram, methyldopa, opioid and
clonidine up to 4 weeks before the start of screening, and venlafaxine
and desvenlafaxine up to 3 months before the start of screening, and not
willing to stop these during their participation in the trial;
22. Not willing to stop any hormonal products as described in exclusion
criteria 18, 19 and 20, during their participation in the trial;
23. Inadequately treated hyperthyroidism with abnormal TSH and free
T4 at screening. Subjects with low TSH are allowed if free T4 at
screening is within normal range. (Amendment 1, November 28, 2019);
24. History or presence of allergy/intolerance per the protocol;
25. History of alcohol or substance abuse per the protocol;
Refer to the study protocol for additional exclusion criteria 26 - 29 and
footnotes. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Arm 1-3:
Mean change in weekly frequency of moderate to severe VMS from baseline to week 4 and week 12
Mean change in severity of moderate to severe VMS from baseline to week 4 and week 12
Arm 4:
- Change from baseline to each measured time point in endometrial thickness measured by ultrasound
- Frequency of disordered proliferative endometrium, benign simple hyperplasia or hyperplasia with atypia or higher anomalies after 12 months of treatment based on endometrial biopsies
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Arm 1-3: Week 4 and week 12
Arm 4: Day 1, week 13, 29, 53 |
|
| E.5.2 | Secondary end point(s) |
Arm 1-3:
For Objective 1
- Change from baseline to week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 in the weekly frequency of moderate to severe VMS, and in the severity of moderate to severe VMS
- Change from baseline to weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 in the weekly frequency and severity of mild, moderate and severe VMS
- Percentage of subjects with 50% and 75% reduction from baseline in the weekly frequency of moderate to severe VMS at weeks 4 and 12
For Objective 2
- Percentage of subjects with a clinically important difference (CID) compared to baseline in the weekly frequency of moderate to severe VMS at weeks 4 and 12 using the Clinical Global Impression (CGI) questionnaire
For Objective 3
- Change from baseline to week 12 in VVA symptoms (subject self-assessment) using VVA questionnaire
- Change from baseline to week 12 in the VVA symptoms (subject self-assessment) that is initially identified by the subject as being the most bothersome using the VVA questionnaire at baseline
For Objective 4
- Change from baseline to week 12 in triglycerides, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, total cholesterol, lipoprotein(a), total cholesterol/HDL-cholesterol ratio, fasting glycemia, insulin, glycated hemoglobin and homeostasis model assessment estimated insulin resistance (HOMA-IR)
For Objective 5
- Change from baseline to week 12 in HRQoL using the Menopause-specific Quality of Life (MENQOL) questionnaire
- Total score in TS after 4 and 12 weeks of treatment using the Clinical Global Impression (CGI) questionnaire
For Objective 6
- Frequency of treatment emergent adverse events (TEAE) (including treatment emergent serious adverse event [SAE] monitoring)
- Frequency of changes in results in physical and gynecological examination, vital signs, electrocardiogram (ECG) and breast examination at each measured time point
- Frequency of changes in routine clinical laboratory tests results (hematology and chemistry) at each measured time point
For Objective 7
- Change from baseline to each measured time point in endometrial thickness measured by ultrasound
- Frequency of subjects in the different endometrial categories according to the Blaustein's pathology (see Appendix 16.4 of protocol) in subjects for whom an endometrial biopsy has been taken
For Objective 8
- Frequency of women with vaginal bleeding and/or spotting during each 28-day cycle of treatment with E4 based on recording in the patient diary
- Frequency of women with amenorrhea (absence of any bleeding or spotting) during each 28-day cycle of treatment with E4 based on recording in the patient diary
Arm 4
For Objective 1
- Frequency of TEAEs (including SAEs)
- Frequency of changes in results in physical and gynecological examination, vital signs, ECG, mammography, and breast examination at each measured time point
- Frequency of changes in routine clinical laboratory tests results (hematology and chemistry) at each measured time point
For Objective 2
- Frequency of women with vaginal bleeding and/or spotting during each 28-day cycle of treatment based on recording in the patient diary
- Frequency of women with amenorrhea (absence of any bleeding or spotting) during each 28-day cycle of treatment based on recording in the patient diary
For Objective 3
- Change from baseline to week 12 and week 52 in HRQoL using the MENQOL questionnaire
- Total score in TS assessed after 4, 12 and 52 weeks of treatment using the CGI questionnaire
For Objective 4
- Change from baseline to week 12 and week 52 in : triglycerides, HDL-cholesterol, LDL-cholesterol, total cholesterol, lipoprotein(a), total cholesterol/HDL-cholesterol ratio, fasting glycemia, insulin, glycated hemoglobin and HOMA-IR |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Arm 1-3:
For Objective 1 - up to 12 weeks
For Objective 2 - weeks 4 and 12
For Objective 3 - day 1 and week 12
For Objective 4 - day 1 and week 12
For Objective 5 - day 1 and week 12; - 4 and 12 weeks
For Objective 6 - day 1, week 5, 9, 13, 15/16
For Objective 7 - day 1, week 13, week 15/16; - week 13
For Objective 8 - each 28 day cycle
Arm4:
For Objective 1 - day 1, Week 5, 13, 29, 41 and 53
For Objective 2 - each 28 day cycle
For Objective 3 - day 1, week 12 and 52; - Week 4, 12 and 52
For Objective 4 - day 1, week 12 and 52 |
|
| 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 | Yes |
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| The Endometrial and General Safety Study has an open label design. |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 78 |
| 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 |
| Argentina |
| Brazil |
| Czech Republic |
| Hungary |
| Italy |
| Lithuania |
| Poland |
| Romania |
| Russian Federation |
| Slovakia |
| Spain |
| United Kingdom |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 16 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 16 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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