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

• Sponsor: Radius Pharmaceuticals, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02653417
• Collaborator: (none)
• Enrollment: 139
• Location: 1
• Arms: 4
• Duration (Months): 29
• Patients Per Site Per Month: 4.8

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Vasomotor Symptoms; Hot Flashes	Drug: RAD1901; Other: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 139 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Dec 1, 2015
• Actual Primary Completion Date: Dec 12, 2016
• Actual Study Completion Date: May 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Regimen 1 RAD1901 5 mg/day	Drug: RAD1901; RAD1901; Other Names: Elacestrant
Experimental: Regimen 2 RAD1901 10 mg/day	Drug: RAD1901; RAD1901; Other Names: Elacestrant
Experimental: Regimen 3 RAD1901 20 mg/day	Drug: RAD1901; RAD1901; Other Names: Elacestrant
Placebo Comparator: Regimen 4 Placebo	Other: Placebo; Placebo

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 65 Years
• Sexes Eligible for Study: Female
• Accepts 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

1. have been treated with a gonadotropin-releasing hormone (GnRH) agonist within the last year

2. have been treated with anti-estrogens or aromatase inhibitors within 2 months prior to study entry

3. 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

4. have unexplained vaginal bleeding within the 3 months prior to study entry

5. have an endometrial biopsy at baseline with a diagnosis by a gynecologic pathologist of proliferative, hyperplasia, polyp or cancer

6. 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

7. have unresolved findings suspicious for malignancy on the breast examination

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Women's Health Care Specialists P.C. - Beyer Research	Kalamazoo	Michigan	United States	49009

Sponsors and Collaborators

• Radius Pharmaceuticals, Inc.

Investigators

• Study Director: Clinical Operations, Radius Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Radius Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02653417
• Other Study ID Numbers: VMRAD1901-203
• First Posted: Jan 12, 2016
• Last Update Posted: Mar 13, 2019
• Last Verified: Mar 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Hot Flashes

Study Results

Participant Flow

Arm/Group Title	Regimen 1	Regimen 2	Regimen 3	Regimen 4
Arm/Group Description	RAD1901 5 mg RAD1901: RAD1901	RAD1901 10 mg RAD1901: RAD1901	RAD1901 20 mg RAD1901: RAD1901	Placebo Placebo: Placebo
Period Title: Overall Study
STARTED	38	34	29	38
COMPLETED	37	32	26	33
NOT COMPLETED	1	2	3	5

Baseline Characteristics

Arm/Group Title	Regimen 1 RAD1901 5 mg	Regimen 2 RAD1901 10 mg	Regimen 3 RAD1901 20 mg	Regimen 4 Placebo	Total
Arm/Group Description	RAD1901 5 mg RAD1901: RAD1901	RAD1901 10 mg RAD1901: RAD1901	RAD1901 20 mg RAD1901: RAD1901	Placebo Placebo: Placebo	Total of all reporting groups
Overall Participants	38	34	28	38	138
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.6 (4.83)	55.4 (5.08)	54.1 (4.07)	53.9 (5.09)	55.1 (4.9)
Sex: Female, Male (Count of Participants)
Female	38 100%	34 100%	28 100%	38 100%	138 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	8 21.1%	8 23.5%	7 25%	6 15.8%	29 21%
Not Hispanic or Latino	30 78.9%	26 76.5%	21 75%	32 84.2%	109 79%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 2.6%	0 0%	1 3.6%	1 2.6%	3 2.2%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	6 15.8%	12 35.3%	6 21.4%	10 26.3%	34 24.6%
White	30 78.9%	22 64.7%	21 75%	27 71.1%	100 72.5%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	1 2.6%	0 0%	0 0%	0 0%	1 0.7%
Region of Enrollment (participants) [Number]
United States	38 100%	34 100%	28 100%	38 100%	138 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 12 in the Frequency of Moderate to Severe Hot Flashes
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Regimen 1	Regimen 2	Regimen 3	Regimen 4
Arm/Group Description	RAD1901 5 mg RAD1901: RAD1901	RAD1901 10 mg RAD1901: RAD1901	RAD1901 20 mg RAD1901: RAD1901	Placebo Placebo: Placebo
Measure Participants	38	34	28	38
Least Squares Mean (Standard Error) [moderate to severe hot flashes per day]	-3.48 (0.793)	-3.74 (0.867)	-4.12 (0.944)	-3.66 (0.808)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regimen 1, Regimen 4
	Comments	Regimen 1 = 5 mg vs Regimen 4 = placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.18
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Regimen 2, Regimen 4
	Comments	Regimen 2 = 10 mg vs Regimen 4 = placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.08
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Regimen 3, Regimen 4
	Comments	Regimen 3 = 20 mg vs Regimen 4 = placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.46
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline to Week 4 in the Frequency of Moderate to Severe Hot Flashes
Description	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

Outcome Measure Data

Analysis Population Description

mITT population

Arm/Group Title	Regimen 1 RAD1901 5 mg	Regimen 2 RAD1901 10 mg	Regimen 3 RAD1901 20 mg	Regimen 4 Placebo
Arm/Group Description	RAD1901 5 mg RAD1901: RAD1901	RAD1901 10 mg RAD1901: RAD1901	RAD1901 20 mg RAD1901: RAD1901	Placebo Placebo: Placebo
Measure Participants	38	34	28	38
Mean (Standard Deviation) [moderate to severe hot flashes per day]	-1.15 (3.644)	-2.22 (4.872)	-2.70 (3.764)	-3 (4.075)

3. Secondary Outcome

Title	Change From Baseline to Week 4 and Week 12 in the Severity of Hot Flashes
Description	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

Outcome Measure Data

Analysis Population Description

mITT population

Arm/Group Title	Regimen 1 RAD1901 5 mg	Regimen 2 RAD1901 10 mg	Regimen 3 RAD1901 20 mg	Regimen 4 Placebo
Arm/Group Description	RAD1901 5 mg RAD1901: RAD1901	RAD1901 10 mg RAD1901: RAD1901	RAD1901 20 mg RAD1901: RAD1901	Placebo Placebo: Placebo
Measure Participants	38	34	28	38
Week 4 change from baseline in severity	-0.04 (0.25)	-0.07 (0.26)	-0.13 (0.273)	-0.00 (0.280)
Week 12 change from baseline in severity	-0.09 (0.337)	-0.08 (0.373)	-0.13 (0.313)	-0.01 (0.409)

4. Secondary Outcome

Title	Change From Baseline to Week 4 and Week 12 in the Frequency of All Hot Flashes
Description	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

Outcome Measure Data

Analysis Population Description

mITT population

Arm/Group Title	Regimen 1 RAD1901 5 mg	Regimen 2 RAD1901 10 mg	Regimen 3 RAD1901 20 mg	Regimen 4 Placebo
Arm/Group Description	RAD1901 5 mg RAD1901: RAD1901	RAD1901 10 mg RAD1901: RAD1901	RAD1901 20 mg RAD1901: RAD1901	Placebo Placebo: Placebo
Measure Participants	38	34	28	38
Week 4 change from baseline	-0.99 (3.803)	-2.23 (4.792)	-2.29 (3.754)	-3.27 (4.107)
Week 12 change from baseline	-3.47 (5.076)	-2.40 (3.560)	-3.91 (5.263)	-3.74 (4.228)

Adverse Events

Time Frame	Up to 14 weeks
Arm/Group Title	Regimen 1 RAD1901 5 mg		Regimen 2 RAD1901 10 mg		Regimen 3 RAD1901 20 mg		Regimen 4 Placebo
Arm/Group Description	RAD1901 5 mg RAD1901: RAD1901		RAD1901 10 mg RAD1901: RAD1901		RAD1901 20 mg RAD1901: RAD1901		Placebo Placebo: Placebo
All Cause Mortality
	Regimen 1 RAD1901 5 mg		Regimen 2 RAD1901 10 mg		Regimen 3 RAD1901 20 mg		Regimen 4 Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/38 (0%)		0/34 (0%)		0/29 (0%)		0/38 (0%)
Serious Adverse Events
	Regimen 1 RAD1901 5 mg		Regimen 2 RAD1901 10 mg		Regimen 3 RAD1901 20 mg		Regimen 4 Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/38 (0%)		0/34 (0%)		0/29 (0%)		0/38 (0%)
Other (Not Including Serious) Adverse Events
	Regimen 1 RAD1901 5 mg		Regimen 2 RAD1901 10 mg		Regimen 3 RAD1901 20 mg		Regimen 4 Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/38 (28.9%)		3/34 (8.8%)		7/29 (24.1%)		13/38 (34.2%)
Gastrointestinal disorders
Nausea	1/38 (2.6%)		0/34 (0%)		0/29 (0%)		4/38 (10.5%)
Diarrhoea	1/38 (2.6%)		0/34 (0%)		1/29 (3.4%)		2/38 (5.3%)
Dyspepsia	0/38 (0%)		1/34 (2.9%)		2/29 (6.9%)		1/38 (2.6%)
Abdominal Pain	0/38 (0%)		1/34 (2.9%)		0/29 (0%)		2/38 (5.3%)
General disorders
Chills	0/38 (0%)		0/34 (0%)		0/29 (0%)		2/38 (5.3%)
Infections and infestations
Upper respiratory tract infection	1/38 (2.6%)		0/34 (0%)		2/29 (6.9%)		2/38 (5.3%)
Sinusitis	0/38 (0%)		0/34 (0%)		1/29 (3.4%)		2/38 (5.3%)
Musculoskeletal and connective tissue disorders
Back pain	2/38 (5.3%)		1/34 (2.9%)		0/29 (0%)		0/38 (0%)
Arthralgia	2/38 (5.3%)		0/34 (0%)		0/29 (0%)		0/38 (0%)
Pain in extremity	0/38 (0%)		0/34 (0%)		0/29 (0%)		2/38 (5.3%)
Nervous system disorders
Headache	2/38 (5.3%)		1/34 (2.9%)		1/29 (3.4%)		2/38 (5.3%)
Psychiatric disorders
Insomnia	2/38 (5.3%)		0/34 (0%)		0/29 (0%)		0/38 (0%)
Reproductive system and breast disorders
Vaginal haemorrhage	2/38 (5.3%)		1/34 (2.9%)		1/29 (3.4%)		4/38 (10.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.