PrimaryTo evaluate the efficacy of fezolinetant 45 mg versus placebo on the frequency of moderate to severe VMSKey secondaryTo evaluate the efficacy of fezolinetant 45 mg versus placebo on the severity of moderate to severe VMSSecondary• To evaluate…
ID
Source
Brief title
Condition
- Other condition
- Body temperature conditions
- Gender related factors
Synonym
Health condition
hot flashes
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint:
Mean change in the frequency of moderate to severe VMS from baseline to week 24
Secondary outcome
Key Secondary
Mean change in the severity of moderate to severe VMS from baseline to week 24
Secondary
Mean change in the participant-reported sleep disturbance by the PROMIS SD SF
8b 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 reduction 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 AEs, clinical laboratory assessments, vital signs
and ECG
Exploratory
• Change in serum concentrations of sex hormones and SHBG from baseline to
weeks 12 and 24
• Plasma concentration of fezolinetant and ES259564
• Mean change in the PROMIS SD SF 8b from baseline to week 4, 12, and 16
• Score on the PGI-S SD at each visit (weeks 4, 12, 16, and 24)
• Score on the PGI-C SD to each visit (weeks 4, 12, 16, and 24)
• Score on the PGI-C in VMS to at each visit (4, 12, 16, and 24)
• Mean change on the MENQOL total score from baseline to weeks 4, 12, 16, and 24
• Mean change on the MENQOL domain scores from baseline to weeks 4, 12, 16, and
24
• Mean change on the Euro-Qol 5D-5L (EQ-5D-5L) Visual Analog Scale (VAS) from
baseline to weeks 4, 12, 16, and 24
• Mean change on the WPAI-VMS domain scores from baseline to each week up to
weeks 4, 12, 16, and 24
• Mean change on the FSFI total score from baseline to weeks 4, 12, 16, and 24
• Mean change on the FSFI domain scores from baseline to weeks 4, 12, 16, and 24
• Mean change on PHQ-4 score from baseline to weeks 4, 12, 16, and 24
• Mean change in the frequency of mild, moderate and severe VMS from baseline
to each week up to week 24
• Mean change in the severity of mild, moderate and severe VMS from baseline to
each week up to week 24
• Daily mean change in the frequency of moderate to severe VMS from baseline
(day 1) to days 2 to 7 (week 1)
• Daily mean change in the severity of moderate to severe VMS from baseline
(day 1) to days 2 to 7 (week 1)
Background summary
Background
VMS, commonly known as hot flashes (HFs), are the most common complaint among
women entering menopause and for many women, may continue to occur for up to 5
years (although around 20% of women will continue to experience them for up to
15 years) [Stearns et al, 2003; Rossouw et al, 2002; Kronenberg, 1994]. The
large prospective cohort Study of Women's Health Across the Nation found that
overall prevalence of VMS was approximately 70% [Thurston & Joffe, 2011].
VMS can have a significant negative impact on quality of life and are therefore
a major reason for menopausal women to seek medical attention. Despite the vast
numbers of individuals affected, the physiology of VMS is not fully understood,
although a disturbance in normal thermoregulatory function is thought to be the
main underlying cause. The primary presentation of VMS is a subjective and
transient sensation of heat, flushing and sweating that usually last 4 to 10
min and may be followed by a feeling of being chilled. VMS may be accompanied
by palpitations, feelings of anxiety and sleep disruption leading to fatigue or
irritability; in rare occurrence, panic may occur [Kronenberg, 1994;
Kronenberg, 1990].
The most effective and commonly used treatment for VMS is hormone replacement
therapy (HRT), commonly referred to as hormonal treatment (HT), but a Women*s
Health Initiative study raised questions about the long-term safety of this
treatment [Rossouw et al, 2002]. Thus, current guidelines recommend a limited
duration of HRT due to associated risks of breast cancer (BC), coronary artery
disease, stroke and thromboembolism [de Villiers et al, 2016; Rossouw et al,
2002]. Furthermore, the current safety data do not support the use of HRT in
several groups of patients (e.g., those with a history of breast
cancer/endometrial cancer) or those suffering from underlying medical
conditions with a high risk for negative cardiovascular outcome (e.g., coronary
heart disease, diabetes). Women may also stop HRT or make an informed decision
to not take HRT after having a benefit-risk discussion with a healthcare
professional. The perceived limitations of HRT, coupled with the limited
efficacy and adverse effects observed with non-HT (e.g., selective serotonin
reuptake inhibitors) have led clinicians to search for other treatment options
for VMS. Therefore, a non-HT like fezolinetant may be beneficial in patients
with VMS who for a variety of reason are unsuitable for HRT treatment.
A detailed description of the chemistry, pharmacology, as well as clinical
efficacy and safety of fezolinetant is provided in the Investigator*s Brochure
(IB).
Study objective
Primary
To evaluate the efficacy of fezolinetant 45 mg versus placebo on the frequency
of moderate to severe VMS
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
participant-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.
Exploratory
• To evaluate the effect of fezolinetant on pharmacodynamic markers
• To evaluate the pharmacokinetics of fezolinetant and metabolite ES259564
• To evaluate QoL improvement with fezolinetant 45 mg versus placebo on
participant-reported outcomes
• To evaluate the efficacy of fezolinetant 45 mg versus placebo on the
frequency, severity and HF score of mild, moderate and severe VMS.
Study design
This is a 2-arm, randomized, 24-week double-blind, placebo-controlled, parallel
group, multicenter study to assess the efficacy and safety of fezolinetant 45
mg in women suffering from moderate to severe VMS associated with menopause and
considered unsuitable for HRT treatment.
Approximately 440 participants in total will be randomized in a 1:1 ratio
across both treatment arms and stratified by smoking status (smoker or
non-smoker) through IRT.
Participants who complete the 24 weeks of treatment will complete an end of
treatment (EOT) visit and a safety follow-up visit 3 weeks after the
end-of-treatment visit. Data from all remaining visits for participants who
discontinue study investigational medicinal product (IMP) early will be
collected, whenever possible. It is important for participants to complete an
early discontinuation (ED) visit at the time of discontinuation of IMP and
subsequently all planned visits, continue to complete the electronic daily
diary, complete an end of treatment (EOT) visit, and safety follow-up visit.
Home health care visits will be made available to accommodate participants who
have stopped dosing.
Screening will occur up to 21 days prior to randomization. Eligibility during
screening will be assessed via medical history and HRT questionnaire, physical
examination, clinical laboratory testing and vital signs.
At randomization, participants must have a minimum average of 7 moderate to
severe hot flashes (HFs) (VMS) per day. Participants are to record HFs for the
entirety of the screening period. The electronic diary data will be reviewed by
study site staff on Day 1 (visit 2) to confirm study eligibility.
During the 24-week treatment period, visits will be conducted at weeks 2, 4, 8,
12, 16, 20 and 24 as indicated in the schedule of assessments [Table 1].
Participants will record their VMS via an electronic diary on a daily basis.
Site-based patient-reported outcome (PRO) measures will be self-administered
via an electronic device as indicated in the schedule of assessments [Table 1].
Assessments on Day 1 (visit 2) must occur prior to randomization/first dosing;
assessments at weeks 4, 12, 16, 20 and 24 must occur prior to dosing. All
self-administered assessments will be performed first and prior to all other
procedures.
A Data Monitoring Committee (DMC) and a Liver Safety Monitoring Panel (LSMP)
will assess the safety of fezolinetant for the duration of the study.
Intervention
n/a
Study burden and risks
Please refer to section 6. *What side effects could you experience?* and
section 7. *What are the pros and cons if you take part in the study?* in the
Subject Information For Participation In Medical Research Form for an overview
of the risks and side effects.
1 Astellas Way n/a
Northbrook IL 60062
US
1 Astellas Way n/a
Northbrook IL 60062
US
Listed location countries
Age
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).
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 × 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-001685-38-NL |
| CCMO | NL78137.100.21 |