Study to Evaluate the Safety and Efficacy of RAD1901 in Postmenopausal Women With Moderate to Severe Vasomotor Symptoms

A Randomized, Double-Blind, Placebo-Controlled, Dose Ranging Study to Evaluate the Safety and Efficacy of RAD1901 in Postmenopausal Women With Moderate to Severe Vasomotor Symptoms

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.

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.

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