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 |
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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 45 mg versus placebo on the frequency of moderate to severe VMS |
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E.2.2 | Secondary objectives of the trial |
Key secondary: - To evaluate the efficacy of fezolinetant 45 mg versus placebo on the severity of moderate to severe VMS; Secondary: - To evaluate the effect of fezolinetant 45 mg versus placebo on patient-reported sleep disturbance - To evaluate the efficacy of fezolinetant 45 mg versus placebo on the frequency and severity of moderate to severe VMS - To evaluate the safety and tolerability of fezolinetant 45 mg |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. IRB/IEC approved written informed consent and privacy language as per national regulations must be obtained from the participant prior to any study-related procedures. 2. Participant is born female, aged ≥ 40 years and ≤ 65 years of age at the screening visit 3. Participant must be seeking treatment or relief for VMS associated with menopause and confirmed as menopausal per one of the following criteria at the screening visit: • Spontaneous amenorrhea for ≥ 12 consecutive months • Spontaneous amenorrhea for ≥ 6 months with biochemical criterion of menopause (follicle-stimulating hormone [FSH] > 40 IU/L) • Had bilateral oophorectomy ≥ 6 weeks prior to the screening visit (with or without hysterectomy) • Had hysterectomy without oophorectomy and who meets the biochemical criterion of menopause (FSH > 40 IU/L) 4. Participant has VMS and is unsuitable to receive HRT (HRT contraindicated, HRT caution, HRT stoppers and HRT averse participants). The definitions for HRT unsuitable categories are provided below: • HRT Contraindicated: participants with undiagnosed vaginal bleeding, history of breast cancer or estrogen dependent tumors; arterial thromboembolic disease (e.g., angina, myocardial infarction, cerebrovascular accident, transient ischemic attack, venous thrombophilic disorder [e.g., deep vein thrombosis, pulmonary embolism]); hypersensitivity to estrogen and progesterone therapy or any of the excipients; or porphyria. Note: Participants with undiagnosed vaginal bleeding will be allowed in the study after appropriate assessment has been performed at the investigator’s discretion. • HRT Caution: participants with history of diabetes mellitus, hyperlipidemia, smoking (current), migraine, obesity (body mass index > 29.9 kg/m2), systemic lupus erythematosus, epilepsy, family history of breast cancer in the first degree relative or mutation of breast cancer gene (BRCA1 and BRCA2) • HRT Stoppers: participants who have discontinued HRT due to lack of efficacy, HRT-related side effects, advised by healthcare provider to stop due to length of time on HRT or due to participant’s age ≥ 60 years old • HRT Averse: participants who made an informed choice to not take HRT after a consultation about the benefit risks of HRT For HRT Contraindicated and HRT Caution participants, written documentation regarding the conditions listed must be present in the medical files of participants to qualify under these definitions. For HRT Stoppers for lack of efficacy and HRT-related side effects, accurate and exhaustive documentation must be provided, for example (and as applicable) length of HRT treatment and reason for determining inefficacy, type and duration of HRT-related side effects, etc. For HRT Averse participants, documentation must be provided regarding the nature and extent of the participant’s consultation with her healthcare provider, participant’s reason not to take HRT, etc. 5. Participant has a minimum average of 7 moderate to severe HFs (VMS) per day as recorded in the electronic diary during the last 10 days prior to randomization. 6. Participant is in good general health as determined on the basis of medical history, general physical examination, laboratory and other medical assessments in the opinion of the investigator. 7. Participant has a negative serology panel (including hepatitis B surface antigen, hepatitis C virus antibody and human immunodeficiency virus antibody screens).
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E.4 | Principal exclusion criteria |
1. Participant uses a prohibited therapy for VMS (e.g., prescription, over-the-counter or herbal) prior to screening and for the duration of treatment with IP. Refer to [Section 6.8 Concomitant Therapy and Section 10.4 Appendix 4: List of Excluded Concomitant Medications] for a list of prohibited therapies. 2. Participant has known documented substance abuse or alcohol addiction within 6 months of screening. 3. Participant has history of a malignant tumor within the last 5 years, except for basal cell carcinoma. 4. Participant has endometrial thickness > 8 mm on the locally read screening transvaginal ultrasound (TVU) or any clinically significant findings that that would make the participant ineligible in the opinion of the investigator. 5. Participant has history of severe allergy, hypersensitivity or intolerance to the IP and/or any of its excipients. 6. Participant has a history of seizures or other convulsive disorders unless well controlled. 7. Participant has a medical condition or chronic disease (including history of neurological [including cognitive], 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. 8. Participant has any of the following: • active liver disease, • jaundice, • elevated liver aminotransferases at screening (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]), • elevated total bilirubin (TBL) or direct bilirubin (DBL) > 1.5 x upper limit of normal (ULN), • elevated International Normalized Ratio (INR) >1.5 (unless participant is receiving anticoagulant therapy) or • elevated alkaline phosphatase (ALP). Participants with mildly elevated ALT or AST up to 1.5 × upper limit of normal (ULN) can be enrolled if TBL and DBL are normal. Participants with mildly elevated ALP (up to 1.5 × ULN) can be enrolled if cholestatic liver disease is excluded and no cause other than fatty liver is diagnosed. Participants with Gilbert’s syndrome with elevated TBL may be enrolled as long as DBL, hemoglobin and reticulocytes are normal. 9. Participant has creatinine > 1.5 × ULN or estimated glomerular filtration rate using the Modification of Diet in Renal Disease formula ≤ 59 mL/min per 1.73 m2 at the screening visit. 10. Participant has a history of suicide attempt or suicidal behavior within the last 12 months. 11. Participant has participated in another interventional study within the last 30 days prior to screening and for the duration of the study. 12. Participant who has been previously enrolled in a clinical study with fezolinetant. 13. Participant is unable or unwilling to complete the study procedures. 14. Participant has any condition, which in the investigator’s opinion, makes the participant unsuitable for study participation.
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E.5 End points |
E.5.1 | Primary end point(s) |
- Mean change in the frequency of moderate to severe Vasomotor Symptoms (VMS) from baseline to week 24 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- Mean change in the severity of moderate to severe VMS from baseline to week 24; - Mean change in the patient-reported sleep disturbance by the Patient-Reported Outcomes Measurement Information System Sleep Disturbance – Short Form 8b (PROMIS SD SF 8b) total score from baseline to week 24; - Mean change in the frequency of moderate to severe VMS from baseline to weeks 1, 4, 8, 12, 16 and 20; - Mean change in the severity of moderate to severe VMS from baseline to weeks 1, 4, 8, 12, 16 and 20; - Mean percent change in the frequency of moderate and severe VMS from baseline to weeks 1, 4, 8, 12, 16, 20 and 24; - Responder of percent reduction ≥ 50%, ≥ 75% and at 100% in the frequency of moderate and severe VMS from baseline to weeks 1, 4, 8, 12, 16, 20 and 24; - Frequency and severity of treatment-emergent adverse events (TEAEs), clinical laboratory assessments, vital signs and electrocardiogram (ECG);
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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 | Yes |
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 | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | 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 | 2 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 65 |
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 |
Finland |
France |
Poland |
Sweden |
Netherlands |
Spain |
Czechia |
Germany |
Italy |
Belgium |
Denmark |
Hungary |
Norway |
Russian Federation |
Turkey |
United Kingdom |
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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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Last subject last visit/procedure |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |