| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to Severe Vasomotor Symptoms (Hot Flashes) Associated with Menopause |
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| E.1.1.1 | Medical condition in easily understood language |
| Hot Flashes Associated with Menopause |
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| 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 |
To evaluate the efficacy of fezolinetant versus placebo on the frequency and severity of moderate to severe vasomotor symptoms (VMS).
● The estimand of the primary objective will use a hypothetical strategy and compare patients as though they had continued on the assigned treatment.
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| E.2.2 | Secondary objectives of the trial |
Key secondary objective:
● To evaluate the efficacy of fezolinetant versus placebo on patient-reported sleep disturbance.
Secondary objectives:
● To evaluate the effect of fezolinetant versus placebo on the frequency and severity of moderate to severe VMS at weekly time points.
● To evaluate the safety and tolerability of fezolinetant.
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved written informed consent and privacy language as per national regulations must be obtained from the subject or legally authorized representative prior to any study-related procedures.
2. Subject is born female, aged ≥ 40 years and ≤ 65 years of age at the screening visit.
3. Subject has a body mass index ≥ 18 kg/m2 and ≤ 38 kg/m2.
4. Subject must be seeking treatment or relief for VMS associated with menopause and confirmed as menopausal per 1 of the following criteria at the screening visit:
● Spontaneous amenorrhea for≥ 12 consecutive months
● Spontaneous amenorrhea for ≥ 6 months with biochemical criteria of menopause (FSH > 40 IU/L); or
● Having had bilateral oophorectomy ≥ 6 weeks prior to the screening visit (with or without hysterectomy).
5. Within the 10 days prior to randomization, subject must have a minimum average of 7 to
8 moderate to severe HFs (VMS) per day, or 50 to 60 per week.
6. Subject is in good general health as determined on the basis of medical history and general physical examination, including a bimanual clinical pelvic examination and clinical breast examination devoid of relevant clinical findings, performed at the screening visit; hematology and biochemistry parameters, pulse rate and/or blood pressure and ECG within the reference range for the population studied, or showing no clinically relevant deviations, as judged by the investigator.
7. Subject has documentation of a normal/negative or no clinically significant findings mammogram (obtained at screening or within the prior 12 months of study enrollment). Appropriate documentation includes a written report or an electronic report indicating normal/negative or no clinically significant mammographic findings.
8. Subject is willing to undergo a TVU to evaluate the uterus and ovaries at screening and at week 52 (EOT), and for subjects who are withdrawn from the study prior to completion, a TVU at the ED visit. This is not required for subjects who have had a partial (supra-cervical) or full hysterectomy.
Subject is willing to undergo an endometrial biopsy at screening and at week 52 (EOT), for subjects with uterine bleeding, and for subjects who are withdrawn from the study prior to completion. This is not required for subjects who have had a partial
(supracervical) or full hysterectomy.
10. Subject has documentation of a normal or not clinically significant Pap test (or equivalent cervical cytology) in the opinion of the investigator within the previous 12 months or at screening. This is not required for subjects who have had a fully hysterectomy.
11. Subject has a negative urine pregnancy test at screening.
12. Subject has a negative serology panel (i.e., negative hepatitis B surface antigen, negative
hepatitis C virus antibody and negative human immunodeficiency virus antibody screens) at screening.
13. Subject agrees not to participate in another interventional study while participating in the present study.
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|
| E.4 | Principal exclusion criteria |
1. Subject uses a prohibited therapy (strong or moderate CYP1A2 inhibitors, HRT, hormonal contraceptive or any treatment for VMS [prescription, over the counter or herbal]) or is not willing to wash out and discontinue use of such drugs for the full duration of study conduct.
2. Subject has known substance abuse or alcohol addiction within 6 months of screening, as assessed by the investigator.
3. Subject has previous or current history of a malignant tumor, except for basal cell carcinoma.
4. Subject's systolic blood pressure is ≥ 130 mmHg or diastolic blood pressure is ≥ 80 mmHg based on an the average of 2 to 3 readings on at least 2 different occasions within the screening period.
- Subjects who do not meet these criteria may at the discretion of the investigator, be re-assessed after initiation or review of antihypertensive measures.
- Subjects with a medical history of hypertension can be enrolled at the discretion of the investigator, once they are medically clear (stable and compliant).
5. Subject has history of severe allergy, hypersensitivity or intolerance to drugs in general, including the study drug and any of its excipients.
6. For subjects with a uterus: Subject has an unacceptable result from the TVU assessment at screening (i.e., full length of endometrial cavity cannot be visualized or presence of a clinically significant finding).
7. For subjects with a uterus: Subject has an endometrial biopsy confirming presence of disordered proliferative endometrium, endometrial hyperplasia, endometrial cancer or other clinically significant findings in the opinion of the investigator at screening. A biopsy with insufficient material for evaluation, or unevaluable material, is acceptable provided the endometrial thickness is less than 4 mm.
8. Subject has a history within the last 6 months of undiagnosed uterine bleeding.
9. Subject has a history of seizures or other convulsive disorders.
10. Subject has a medical condition or chronic disease (including history of neurological [including cognitive], hepatic, renal, cardiovascular, gastrointestinal, pulmonary [e.g., moderate asthma], endocrine or gynecological disease) or malignancy that could confound interpretation of the study outcome in the opinion of the investigator.
11. Subject has active liver disease, jaundice, elevated liver aminotransferases (ALT or AST), elevated total or direct bilirubin, elevated INR, or elevated alkaline phosphatase (ALP). Patients with mildly elevated ALT or AST up to <1.5 times the upper limit of normal (ULN) can be enrolled if total and direct bilirubin are normal. Patients with mildly elevated ALP (up to <1.5 x ULN) can be enrolled if cholestatic liver disease is excluded and no cause other than fatty liver is diagnosed. Patients with Gilbert’s syndrome with elevated total bilirubin may be enrolled as long as direct bilirubin, hemoglobin, and reticulocytes are normal.
12. Subject has creatinine > 1.5 × ULN; or estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula 59 mL/min per 1.73 m2 at screening.
13. Subject has a history of suicide attempt or suicidal behavior within the last 12 months or has suicidal ideation within the last 12 months (a response of “yes” to question 4 or 5 on the suicidal ideation portion of the Columbia Suicide Severity Rating Scale [C-SSRS]), or who is at significant risk to commit suicide, as assessed by the investigator at screening and at visit 2 (randomization).
14. Subject has previous been enrolled in a clinical trial with fezolinetant.
15. Subject is participating concurrently in another interventional study or participated in an interventional study within 28 days prior to screening, or received any investigational drug within 28 days or within 5 half-lives prior to screening, whichever is longer. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Co-primary:
● Mean change in the frequency of moderate to severe VMS from baseline to week 4
● Mean change in the frequency of moderate to severe VMS from baseline to week 12
● Mean change in the severity of moderate to severe VMS from baseline to week 4
● Mean change in the severity of moderate to severe VMS from baseline to week 12
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key Secondary:
The key secondary efficacy objective examines the effect of fezolinetant versus placebo on the following:
● Mean change in the Patient-reported Outcomes Measurement Information System Sleep Disturbance – Short Form 8b (PROMIS SD SF 8b) Total Score from baseline to week 12
Secondary:
The secondary efficacy objectives examine the effect of fezolinetant versus placebo on the following:
● Mean change in the frequency of moderate and severe VMS from baseline to each week up to week 12
● Mean change in the severity of moderate and severe VMS from baseline to each week up to week 12
● Mean percent reduction in the frequency of moderate and severe VMS from baseline to each week up to week 12
● Percent reduction ≥ 50% and at 100% in the frequency of moderate and severe VMS from baseline to each week up to week 12
● Mean change in the frequency of moderate to severe VMS from baseline to week 24 (descriptive)
● Mean change in the severity of moderate to severe VMS from baseline to week 24 (descriptive) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 |
| After 12 weeks of treatment, all subjects will receive active treatment through end of study |
|
| 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 | 3 |
| 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 | 30 |
| 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 |
| Canada |
| Czech Republic |
| Germany |
| Hungary |
| Latvia |
| Poland |
| Spain |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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