Hot Flashes, Vasomotor Symptoms
Conditions
Brief summary
The primary objective of this study was to determine the clinical safety of RAD1901 and to evaluate whether RAD1901 reduced the frequency and severity of moderate to severe vasomotor symptoms (VMS; hot flashes) in postmenopausal women.
Detailed description
This was a Phase 2b outpatient, prospective, multicenter, double-blind, randomized, placebo-controlled study to determine whether elacestrant reduces the frequency and severity of vasomotor symptoms (VMS; hot flashes) in postmenopausal women with moderate to severe hot flashes. Postmenopausal women who met study criteria were followed for 12 weeks on double-blind study medication and two weeks off study medication. Treatment was randomized 1:1:1:1 to ensure that an approximately equal number of patients were exposed to each of three RAD1901 (elacestrant) doses (5, 10 and 20 mg/day) or placebo. The total period of placebo exposure was 14 weeks. Enrolling approximately 300 patients was expected to provide power for testing superiority of the primary efficacy endpoint outcomes.
Interventions
DRUGRAD1901
RAD1901
OTHERPlacebo
Placebo
Sponsors
Radius Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
40 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
To have participated in this study, a subject MUST: 1. be a postmenopausal woman between 40 and 65 years of age, inclusive 2. be seeking relief or treatment for moderate to severe VMS 3. be willing to discontinue and abstain from the following: vaginal hormonal products; transdermal or oral estrogen or estrogen/progestin combination; progestin implants; injectable estrogen; topical progesterone cream, selective estrogen receptor modulators and intrauterine devices (IUDs) 4. have no clinically significant abnormalities on pelvic exam except for vulvovaginal atrophy (VVA) 5. have a normal or clinically insignificant transvaginal ultrasound (TVU) with an endometrial thickness \<4 mm at screening 6. have a normal endometrial biopsy subsequent to the TVU without clinically relevant results 7. have a normal screening Papanicolaou (Pap) smear 8. have a mammogram within 9 months prior to randomization. Subjects must have had a Breast Imaging Reporting and Data System (BI-RADS) mammography result of 1 or 2 to enroll.
Exclusion criteria
Subjects with any of the following characteristics were not be eligible to participate in the study: 1. have a history of invasive breast cancer or ductal carcinoma in situ, melanoma or any gynecologic cancer. 2. using any of the following: * oral estrogen-, progestin-, androgen-, or selective estrogen receptor modulator (SERM) containing drug products within 8 weeks before screening (visit 1) * transdermal hormone products within 4 weeks before screening (visit 1) * vaginal hormone products (rings, creams, gels) within 4 weeks before screening (visit 1) * progestin implants/injectables, IUDs or estrogen pellets/injectables within 6 months before screening (visit 1) * anabolic steroids 3. have been treated with a gonadotropin-releasing hormone (GnRH) agonist within the last year 4. have been treated with anti-estrogens or aromatase inhibitors within 2 months prior to study entry 5. have been concurrently treated and will abstain from gabapentin and paroxetine or serotonin and norepinephrine reuptake inhibitors (SNRIs) for VMS or other indications for 3 months during the trial and have not taken within 4 weeks prior to screening 6. have unexplained vaginal bleeding within the 3 months prior to study entry 7. have an endometrial biopsy at baseline with a diagnosis by a gynecologic pathologist of proliferative, hyperplasia, polyp or cancer 8. have unresolved cervical cytological smear report of atypical glandular or squamous cells of undetermined significance. Cervical cytologic smear report of ASCUS, low grade squamous intraepithelial lesion or greater, or any reported dysplasia 9. have unresolved findings suspicious for malignancy on the breast examination
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in the Frequency of Moderate to Severe Hot Flashes | Baseline and 12 weeks | Change from baseline to week 12 in the average number of moderate and severe hot flashes per day, where change is calculated as week 12 minus baseline so that negative values indicate a reduction (improvement) of hot flash frequency. Severity of hot flashes was self-assessed and reported as follows: * Mild: sensation of heat without sweating * Moderate: sensation of heat with sweating, able to continue activity * Severe: sensation of heat with sweating, causing cessation of activity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 4 in the Frequency of Moderate to Severe Hot Flashes | Baseline and 4 weeks | Change from baseline to week 4 in the average number of moderate and severe hot flashes per day, where change is calculated as week 4 minus baseline so that negative values indicate a reduction (improvement) of hot flash frequency. |
| Change From Baseline to Week 4 and Week 12 in the Severity of Hot Flashes | Baseline, 4 weeks, and 12 weeks | Change from baseline to week 4 and week 12 in the average daily severity of hot flashes, where change is calculated as week 4 or week 12 minus baseline so that negative values indicate a reduction (improvement) of hot flash severity. Subjects recorded the number of hot flashes per day using an electronic diary. Daily severity score for hot flashes for each subject was calculated as the sum of the number of mild hot flashes, plus 2 times the number of moderate hot flashes, plus 3 times the number of severe hot flashes, divided by the total number of mild, moderate, and severe hot flashes. That is, Daily Severity Score = (Fmild + 2•Fmod + 3•Fsev)/(Fmild + Fmod + Fsev) where Fmild= frequency of mild hot flashes, Fmod = frequency of moderate hot flashes, Fsev = frequency of severe hot flashes. The measure is a weighted average of the frequencies of Hot Flashes. |
| Change From Baseline to Week 4 and Week 12 in the Frequency of All Hot Flashes | Baseline, 4 weeks, and 12 weeks | Change from baseline to week 4 and week 12 in the average number of all hot flashes (mild, moderate, and severe) by eDiary, where change is calculated as week 4 or week 12 minus baseline so that negative values indicate a reduction (improvement) of hot flash frequency. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Regimen 1 RAD1901 5 mg RAD1901 5 mg
RAD1901: RAD1901 | 38 |
| Regimen 2 RAD1901 10 mg RAD1901 10 mg
RAD1901: RAD1901 | 34 |
| Regimen 3 RAD1901 20 mg RAD1901 20 mg
RAD1901: RAD1901 | 28 |
| Regimen 4 Placebo Placebo
Placebo: Placebo | 38 |
| Total | 138 |
Baseline characteristics
| Characteristic | Regimen 1 RAD1901 5 mg | Total | Regimen 4 Placebo | Regimen 3 RAD1901 20 mg | Regimen 2 RAD1901 10 mg |
|---|---|---|---|---|---|
| Age, Continuous | 56.6 years STANDARD_DEVIATION 4.83 | 55.1 years STANDARD_DEVIATION 4.9 | 53.9 years STANDARD_DEVIATION 5.09 | 54.1 years STANDARD_DEVIATION 4.07 | 55.4 years STANDARD_DEVIATION 5.08 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 29 Participants | 6 Participants | 7 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 109 Participants | 32 Participants | 21 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 34 Participants | 10 Participants | 6 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 30 Participants | 100 Participants | 27 Participants | 21 Participants | 22 Participants |
| Region of Enrollment United States | 38 participants | 138 participants | 38 participants | 28 participants | 34 participants |
| Sex: Female, Male Female | 38 Participants | 138 Participants | 38 Participants | 28 Participants | 34 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 38 | 0 / 34 | 0 / 29 | 0 / 38 |
| other Total, other adverse events | 11 / 38 | 3 / 34 | 7 / 29 | 13 / 38 |
| serious Total, serious adverse events | 0 / 38 | 0 / 34 | 0 / 29 | 0 / 38 |
Outcome results
Primary
Change From Baseline to Week 12 in the Frequency of Moderate to Severe Hot Flashes
Change from baseline to week 12 in the average number of moderate and severe hot flashes per day, where change is calculated as week 12 minus baseline so that negative values indicate a reduction (improvement) of hot flash frequency. Severity of hot flashes was self-assessed and reported as follows: * Mild: sensation of heat without sweating * Moderate: sensation of heat with sweating, able to continue activity * Severe: sensation of heat with sweating, causing cessation of activity.
Time frame: Baseline and 12 weeks
Population: The modified intent to treat (mITT) population was used. This included all patients in the safety population who had recorded hot flash data in their eDiaries for at least 5 days during baseline and for at least one day while on double-blind study medication, and was the primary analysis population for all efficacy analyses
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Regimen 1 | Change From Baseline to Week 12 in the Frequency of Moderate to Severe Hot Flashes | -3.48 moderate to severe hot flashes per day | Standard Error 0.793 |
| Regimen 2 | Change From Baseline to Week 12 in the Frequency of Moderate to Severe Hot Flashes | -3.74 moderate to severe hot flashes per day | Standard Error 0.867 |
| Regimen 3 | Change From Baseline to Week 12 in the Frequency of Moderate to Severe Hot Flashes | -4.12 moderate to severe hot flashes per day | Standard Error 0.944 |
| Regimen 4 | Change From Baseline to Week 12 in the Frequency of Moderate to Severe Hot Flashes | -3.66 moderate to severe hot flashes per day | Standard Error 0.808 |
Comparison: Regimen 1 = 5 mg vs Regimen 4 = placebo
Comparison: Regimen 2 = 10 mg vs Regimen 4 = placebo
Comparison: Regimen 3 = 20 mg vs Regimen 4 = placebo
Secondary
Change From Baseline to Week 4 and Week 12 in the Frequency of All Hot Flashes
Change from baseline to week 4 and week 12 in the average number of all hot flashes (mild, moderate, and severe) by eDiary, where change is calculated as week 4 or week 12 minus baseline so that negative values indicate a reduction (improvement) of hot flash frequency.
Time frame: Baseline, 4 weeks, and 12 weeks
Population: mITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Regimen 1 | Change From Baseline to Week 4 and Week 12 in the Frequency of All Hot Flashes | Week 4 change from baseline | -0.99 hot flashes per day | Standard Deviation 3.803 |
| Regimen 1 | Change From Baseline to Week 4 and Week 12 in the Frequency of All Hot Flashes | Week 12 change from baseline | -3.47 hot flashes per day | Standard Deviation 5.076 |
| Regimen 2 | Change From Baseline to Week 4 and Week 12 in the Frequency of All Hot Flashes | Week 12 change from baseline | -2.40 hot flashes per day | Standard Deviation 3.56 |
| Regimen 2 | Change From Baseline to Week 4 and Week 12 in the Frequency of All Hot Flashes | Week 4 change from baseline | -2.23 hot flashes per day | Standard Deviation 4.792 |
| Regimen 3 | Change From Baseline to Week 4 and Week 12 in the Frequency of All Hot Flashes | Week 4 change from baseline | -2.29 hot flashes per day | Standard Deviation 3.754 |
| Regimen 3 | Change From Baseline to Week 4 and Week 12 in the Frequency of All Hot Flashes | Week 12 change from baseline | -3.91 hot flashes per day | Standard Deviation 5.263 |
| Regimen 4 | Change From Baseline to Week 4 and Week 12 in the Frequency of All Hot Flashes | Week 4 change from baseline | -3.27 hot flashes per day | Standard Deviation 4.107 |
| Regimen 4 | Change From Baseline to Week 4 and Week 12 in the Frequency of All Hot Flashes | Week 12 change from baseline | -3.74 hot flashes per day | Standard Deviation 4.228 |
Secondary
Change From Baseline to Week 4 and Week 12 in the Severity of Hot Flashes
Change from baseline to week 4 and week 12 in the average daily severity of hot flashes, where change is calculated as week 4 or week 12 minus baseline so that negative values indicate a reduction (improvement) of hot flash severity. Subjects recorded the number of hot flashes per day using an electronic diary. Daily severity score for hot flashes for each subject was calculated as the sum of the number of mild hot flashes, plus 2 times the number of moderate hot flashes, plus 3 times the number of severe hot flashes, divided by the total number of mild, moderate, and severe hot flashes. That is, Daily Severity Score = (Fmild + 2•Fmod + 3•Fsev)/(Fmild + Fmod + Fsev) where Fmild= frequency of mild hot flashes, Fmod = frequency of moderate hot flashes, Fsev = frequency of severe hot flashes. The measure is a weighted average of the frequencies of Hot Flashes.
Time frame: Baseline, 4 weeks, and 12 weeks
Population: mITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Regimen 1 | Change From Baseline to Week 4 and Week 12 in the Severity of Hot Flashes | Week 4 change from baseline in severity | -0.04 hot flash severity score per day | Standard Deviation 0.25 |
| Regimen 1 | Change From Baseline to Week 4 and Week 12 in the Severity of Hot Flashes | Week 12 change from baseline in severity | -0.09 hot flash severity score per day | Standard Deviation 0.337 |
| Regimen 2 | Change From Baseline to Week 4 and Week 12 in the Severity of Hot Flashes | Week 12 change from baseline in severity | -0.08 hot flash severity score per day | Standard Deviation 0.373 |
| Regimen 2 | Change From Baseline to Week 4 and Week 12 in the Severity of Hot Flashes | Week 4 change from baseline in severity | -0.07 hot flash severity score per day | Standard Deviation 0.26 |
| Regimen 3 | Change From Baseline to Week 4 and Week 12 in the Severity of Hot Flashes | Week 4 change from baseline in severity | -0.13 hot flash severity score per day | Standard Deviation 0.273 |
| Regimen 3 | Change From Baseline to Week 4 and Week 12 in the Severity of Hot Flashes | Week 12 change from baseline in severity | -0.13 hot flash severity score per day | Standard Deviation 0.313 |
| Regimen 4 | Change From Baseline to Week 4 and Week 12 in the Severity of Hot Flashes | Week 4 change from baseline in severity | -0.00 hot flash severity score per day | Standard Deviation 0.28 |
| Regimen 4 | Change From Baseline to Week 4 and Week 12 in the Severity of Hot Flashes | Week 12 change from baseline in severity | -0.01 hot flash severity score per day | Standard Deviation 0.409 |
Secondary
Change From Baseline to Week 4 in the Frequency of Moderate to Severe Hot Flashes
Change from baseline to week 4 in the average number of moderate and severe hot flashes per day, where change is calculated as week 4 minus baseline so that negative values indicate a reduction (improvement) of hot flash frequency.
Time frame: Baseline and 4 weeks
Population: mITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Regimen 1 | Change From Baseline to Week 4 in the Frequency of Moderate to Severe Hot Flashes | -1.15 moderate to severe hot flashes per day | Standard Deviation 3.644 |
| Regimen 2 | Change From Baseline to Week 4 in the Frequency of Moderate to Severe Hot Flashes | -2.22 moderate to severe hot flashes per day | Standard Deviation 4.872 |
| Regimen 3 | Change From Baseline to Week 4 in the Frequency of Moderate to Severe Hot Flashes | -2.70 moderate to severe hot flashes per day | Standard Deviation 3.764 |
| Regimen 4 | Change From Baseline to Week 4 in the Frequency of Moderate to Severe Hot Flashes | -3 moderate to severe hot flashes per day | Standard Deviation 4.075 |