Study of Erenumab (AMG 334) in Women With Hot Flashes

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01890109
• Collaborator: (none)
• Enrollment: 103
• Locations: 7
• Arms: 2
• Actual Duration (Months): 9.9
• Patients Per Site: 14.7
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

The primary objective of this study was to evaluate the frequency of moderate to severe daily hot flashes 4 weeks after a single dose of erenumab (AMG 334) in women with hot flashes associated with menopause.

Condition or Disease	Intervention/Treatment	Phase
Vasomotor Symptoms; Hot Flashes	Biological: Erenumab; Drug: Placebo	Phase 1

Detailed Description

This study will test the hypothesis that the vasodilation associated with capsaicin-induced dermal blood flow (DBF) provides a good model for the vasodilation associated with hot flashes; therefore erenumab doses that cause DBF inhibition will be safe and well tolerated, and will be effective in the reduction of the frequency and/or severity of HFs.

Study Design

• Study Type: Interventional
• Actual Enrollment: 103 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Randomized, Stratified, Parallel-group, Double-blind, Placebo-controlled, Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of AMG 334 in Women With Hot Flashes Associated With Menopause
• Actual Study Start Date: May 13, 2013
• Actual Primary Completion Date: Mar 11, 2014
• Actual Study Completion Date: Mar 11, 2014

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants received a single dose of placebo administered by subcutaneous injection.	Drug: Placebo; Administered via subcutaneous injection
Experimental: Erenumab Participants received a single dose of 70 mg erenumab administered by subcutaneous injection.	Biological: Erenumab; Administered via subcutaneous injection.; Other Names: AMG 334 Aimovig™

Outcome Measures

Primary Outcome Measures

1. Ratio of Week 4 to Baseline Average Number of Daily Moderate to Severe Hot Flashes [Baseline (days -7 to day 1 predose) and week 4 (days 21 to 27)]

   The severity of hot flashes was assessed by participants based on the following categories: Mild: sensation of heat without sweating, mild flushing; Moderate: sensation of heat, face flushed, slightly clammy, some sweating, able to continue activity, may want to remove layers of clothing or covers at night; Severe: sensation of heat with more severe sweating, have to stop current activity, may have to change clothing. Baseline (BL) number of hot flashes is the average number of moderate or severe hot flashes per 24 hours from day -7 to day 1 predose based on geometric mean, and the week 4 number of hot flashes is the average number of moderate or severe hot flashes per 24 hours from day 21 to day 27 based on geometric mean. The ratio of week 4 to BL was used to assess change from BL to week 4 via a log transformation (log[week4/BL] = log[week4] - log[BL]), which was estimated using a repeated measures analysis. The ratio was obtained via an exponential back-transformation.

Secondary Outcome Measures

1. Ratio of Week 4 to Baseline Daily Hot Flash Severity Score [Baseline (days -7 to day 1 predose) and week 4 (days 21 to 27)]

   The daily severity score was calculated according to the following: (Number of mild hot flashes * 1) + (number of moderate hot flashes * 2) + (number of severe hot flashes * 3). The baseline daily hot flash severity score is the geometric mean daily hot flash severity score from day -7 to day 1 predose, and the week 4 daily hot flash severity score is the geometric mean daily hot flash severity score from day 21 to day 27. The ratio of week 4 to baseline (week 4 / baseline) was used to assess change from baseline to week 4 via a log transformation (log[week4/BL] = log[week4] - log[baseline]), which was estimated using a repeated measures analysis. The ratio was obtained via an exponential back-transformation.

2. Number of Participants With Treatment-emergent Adverse Events [16 weeks]

   A treatment-emergent adverse event is any adverse event that began or worsened after the initial dose of study drug and before the end of study. A serious adverse event is an adverse event that met at least 1 of the following serious criteria: fatal life threatening required inpatient hospitalization or prolongation of existing hospitalization resulted in persistent or significant disability/incapacity congenital anomaly/birth defect. other medically important serious event A treatment-related adverse event (TRAE) is any treatment-emergent adverse event that per investigator review had a reasonable possibility of being caused by the study drug.

3. Maximum Observed Concentration (Cmax) of Erenumab After a Single Dose [Predose and 4 hours, 2, 3, 4, 8, 12, 15, 22, 29, 43, 50, 57, 64, 78, 85, and 113 days post-dose]

   Blood samples were analyzed using an enzyme-linked immunosorbent assay (ELISA) following a validated analytical procedure.

4. Time to Maximum Observed Concentration (Tmax) of Erunumab After a Single Dose [Predose and 4 hours, 2, 3, 4, 8, 12, 15, 22, 29, 43, 50, 57, 64, 78, 85, and 113 days post-dose]

5. Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUClast) for Erenumab [Predose and 4 hours, 2, 3, 4, 8, 12, 15, 22, 29, 43, 50, 57, 64, 78, 85, and 113 days post-dose]

6. Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for Erenumab [Predose and 4 hours, 2, 3, 4, 8, 12, 15, 22, 29, 43, 50, 57, 64, 78, 85, and 113 days post-dose]

7. Terminal Half-life (T1/2) of Erenumab [Predose and 4 hours, 2, 3, 4, 8, 12, 15, 22, 29, 43, 50, 57, 64, 78, 85, and 113 days post-dose]

8. Number of Participants With Treatment-emergent Suicidal Ideation [16 weeks]

   The Columbia Suicide Severity Rating Scale (C-SSRS) was used to assess suicidal ideation during the study based on the following Yes/No questions: Have you wished you were dead or wished you could go to sleep and not wake up? Have you actually had any thoughts of killing yourself?

9. Number of Participants Who Developed Anti-erenumab Antibodies After a Single Dose [16 weeks]

   Two validated assays were used to detect the presence of anti-erenumab antibodies. First, an electrochemiluminescent (ECL) bridging immunoassay was used to detect antibodies capable of binding erenumab. Second, a cell based bioassay was used to test positive binding antibody samples for neutralizing activity against erenumab. A participant was defined as positive for developing anti-erenumab antibodies if they were binding antibody positive postbaseline with a negative or no result at baseline. If a sample was positive for binding antibodies and demonstrated neutralizing activity at the same time point, the participant was defined as positive for neutralizing antibodies.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years to 65 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• female subjects with hot flashes associated with menopause between 45 and 65 years of age, inclusive, with no history or evidence of clinically relevant medical disorders as determined by the investigator in consultation with the Amgen physician.

Exclusion Criteria:

• History or evidence of clinically significant disorder (including psychiatric), condition or disease that, in the opinion of the Investigator or Amgen physician would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	San Diego	California	United States	92108
2	Research Site	Miami	Florida	United States	33186
3	Research Site	Winston-Salem	North Carolina	United States	27103
4	Eugene Andruczyk	Philadelphia	Pennsylvania	United States	19114
5	Research Site	Philadelphia	Pennsylvania	United States	19114
6	Research Site	Mount Pleasant	South Carolina	United States	29464
7	Research Site	Seattle	Washington	United States	98105

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

None provided.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT01890109
• Other Study ID Numbers: 20120180
• First Posted: Jul 1, 2013
• Last Update Posted: Jan 14, 2019
• Last Verified: Jan 1, 2019

• Keywords provided by Amgen: Vasomotor symptoms; Hot Flashes; Menopause
• Additional relevant MeSH terms: Hot Flashes; Erenumab

Study Results

Participant Flow

Recruitment Details	This study was conducted at 6 centers in the United States from 13 May 2013 to 11 March 2014. Screening included completion of a 7-day diary to record hot flashes.
Pre-assignment Detail	Participants meeting the eligibility criteria were randomized in a 1:1 ratio to erenumab or placebo. Participants were stratified based on the average number of hot flashes per 24 hours during the screening period (≤ 11.5 or > 11.5).

Arm/Group Title	Placebo	Erenumab
Arm/Group Description	Participants received a single dose of placebo administered by subcutaneous injection.	Participants received a single dose of 70 mg erenumab administered by subcutaneous injection.
Period Title: Overall Study
STARTED	52	51
Received Study Treatment	52	50
COMPLETED	51	46
NOT COMPLETED	1	5

Baseline Characteristics

Arm/Group Title	Placebo	Erenumab	Total
Arm/Group Description	Participants received a single dose of placebo administered by subcutaneous injection.	Participants received a single dose of 70 mg erenumab administered by subcutaneous injection.	Total of all reporting groups
Overall Participants	52	50	102
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.5 (4.8)	55.6 (3.8)	55.6 (4.3)
Sex: Female, Male (Count of Participants)
Female	52 100%	50 100%	102 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 11.5%	8 16%	14 13.7%
Not Hispanic or Latino	46 88.5%	42 84%	88 86.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	0 0%	1 2%	1 1%
Asian	1 1.9%	0 0%	1 1%
Black or African American	15 28.8%	10 20%	25 24.5%
Mixed Race	0 0%	1 2%	1 1%
Native Hawaiian or Other Pacific Islander	0 0%	2 4%	2 2%
White	36 69.2%	36 72%	72 70.6%
Number of Hot Flashes at Baseline (Count of Participants)
≤ 11.5 hot flashes/24 hours	26 50%	25 50%	51 50%
> 11.5 hot flashes/24 hours	26 50%	25 50%	51 50%

Outcome Measures

1. Primary Outcome

Title	Ratio of Week 4 to Baseline Average Number of Daily Moderate to Severe Hot Flashes
Description	The severity of hot flashes was assessed by participants based on the following categories: Mild: sensation of heat without sweating, mild flushing; Moderate: sensation of heat, face flushed, slightly clammy, some sweating, able to continue activity, may want to remove layers of clothing or covers at night; Severe: sensation of heat with more severe sweating, have to stop current activity, may have to change clothing. Baseline (BL) number of hot flashes is the average number of moderate or severe hot flashes per 24 hours from day -7 to day 1 predose based on geometric mean, and the week 4 number of hot flashes is the average number of moderate or severe hot flashes per 24 hours from day 21 to day 27 based on geometric mean. The ratio of week 4 to BL was used to assess change from BL to week 4 via a log transformation (log[week4/BL] = log[week4] - log[BL]), which was estimated using a repeated measures analysis. The ratio was obtained via an exponential back-transformation.
Time Frame	Baseline (days -7 to day 1 predose) and week 4 (days 21 to 27)

Outcome Measure Data

Analysis Population Description

All participants for whom at least 1 postdose hot flash response measure was recorded.

Arm/Group Title	Placebo	Erenumab
Arm/Group Description	Participants received a single dose of placebo administered by subcutaneous injection.	Participants received a single dose of 70 mg erenumab administered by subcutaneous injection.
Measure Participants	52	50
Number (95% Confidence Interval) [ratio]	0.35	0.38

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erenumab
	Comments	Repeated measures analysis of covariance was performed on the log transformed ratio to baseline of the number of daily moderate to severe hot flashes. Independent variables included treatment, week, and the treatment-by-week interaction; subject served as a random effect; and the log transformed baseline number of daily moderate to severe hot flashes was used as a covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.723
	Comments
	Method	Repeated Measures Analysis of Covariance
	Comments
Method of Estimation	Estimation Parameter	Least Square Geometric Mean Ratio
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Ratio of Week 4 to Baseline Daily Hot Flash Severity Score
Description	The daily severity score was calculated according to the following: (Number of mild hot flashes * 1) + (number of moderate hot flashes * 2) + (number of severe hot flashes * 3). The baseline daily hot flash severity score is the geometric mean daily hot flash severity score from day -7 to day 1 predose, and the week 4 daily hot flash severity score is the geometric mean daily hot flash severity score from day 21 to day 27. The ratio of week 4 to baseline (week 4 / baseline) was used to assess change from baseline to week 4 via a log transformation (log[week4/BL] = log[week4] - log[baseline]), which was estimated using a repeated measures analysis. The ratio was obtained via an exponential back-transformation.
Time Frame	Baseline (days -7 to day 1 predose) and week 4 (days 21 to 27)

Outcome Measure Data

Analysis Population Description

All participants for whom at least 1 postdose hot flash response measure was recorded.

Arm/Group Title	Placebo	Erenumab
Arm/Group Description	Participants received a single dose of placebo administered by subcutaneous injection.	Participants received a single dose of 70 mg erenumab administered by subcutaneous injection.
Measure Participants	52	50
Number (95% Confidence Interval) [ratio]	0.40	0.45

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erenumab
	Comments	Repeated measures analysis of covariance was performed on the log transformed ratio to baseline of the daily hot flash severity score. Independent variables included treatment, week, and the treatment-by-week interaction; subject served as a random effect; and the log transformed baseline daily hot flash severity score was used as a covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.551
	Comments
	Method	Repeated Measures Analysis of Covariance
	Comments
Method of Estimation	Estimation Parameter	Least Square Geometric Mean Ratio
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 0.74 to 1.74
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events
Description	A treatment-emergent adverse event is any adverse event that began or worsened after the initial dose of study drug and before the end of study. A serious adverse event is an adverse event that met at least 1 of the following serious criteria: fatal life threatening required inpatient hospitalization or prolongation of existing hospitalization resulted in persistent or significant disability/incapacity congenital anomaly/birth defect. other medically important serious event A treatment-related adverse event (TRAE) is any treatment-emergent adverse event that per investigator review had a reasonable possibility of being caused by the study drug.
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

All participants who received study drug

Arm/Group Title	Placebo	Erenumab
Arm/Group Description	Participants received a single dose of placebo administered by subcutaneous injection.	Participants received a single dose of 70 mg erenumab administered by subcutaneous injection.
Measure Participants	52	50
Treatment-emergent adverse events (TEAEs)	23 44.2%	24 48%
Serious adverse events	0 0%	0 0%
TEAE leading to discontinuation of study drug	0 0%	0 0%
TEAE leading to discontinuation of study	0 0%	0 0%
Fatal adverse events	0 0%	0 0%
Treatment-related adverse events (TRAEs)	5 9.6%	3 6%
Treatment-related serious adverse events	0 0%	0 0%
TRAE leading to discontinuation of study drug	0 0%	0 0%
TRAE leading to discontinuation of study	0 0%	0 0%
Treatment-related fatal adverse events	0 0%	0 0%

4. Secondary Outcome

Title	Maximum Observed Concentration (Cmax) of Erenumab After a Single Dose
Description	Blood samples were analyzed using an enzyme-linked immunosorbent assay (ELISA) following a validated analytical procedure.
Time Frame	Predose and 4 hours, 2, 3, 4, 8, 12, 15, 22, 29, 43, 50, 57, 64, 78, 85, and 113 days post-dose

Outcome Measure Data

Analysis Population Description

All participants who received erenumab and for whom at least 1 pharmacokinetic (PK) parameter or endpoint could be adequately estimated.

Arm/Group Title	Erenumab
Arm/Group Description	Participants received a single dose of 70 mg erenumab administered by subcutaneous injection.
Measure Participants	50
Mean (Standard Deviation) [μg/mL]	6.13 (2.86)

5. Secondary Outcome

Title	Time to Maximum Observed Concentration (Tmax) of Erunumab After a Single Dose
Time Frame	Predose and 4 hours, 2, 3, 4, 8, 12, 15, 22, 29, 43, 50, 57, 64, 78, 85, and 113 days post-dose

Outcome Measure Data

Analysis Population Description

All participants who received erenumab and for whom at least 1 pharmacokinetic (PK) parameter or endpoint could be adequately estimated.

Arm/Group Title	Erenumab
Arm/Group Description	Participants received a single dose of 70 mg erenumab administered by subcutaneous injection.
Measure Participants	50
Median (Full Range) [days]	7.0

6. Secondary Outcome

Title	Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUClast) for Erenumab
Time Frame	Predose and 4 hours, 2, 3, 4, 8, 12, 15, 22, 29, 43, 50, 57, 64, 78, 85, and 113 days post-dose

Outcome Measure Data

Analysis Population Description

All participants who received erenumab and for whom at least 1 pharmacokinetic (PK) parameter or endpoint could be adequately estimated.

Arm/Group Title	Erenumab
Arm/Group Description	Participants received a single dose of 70 mg erenumab administered by subcutaneous injection.
Measure Participants	50
Mean (Standard Deviation) [day*μg/mL]	173 (84.6)

7. Secondary Outcome

Title	Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for Erenumab
Time Frame	Predose and 4 hours, 2, 3, 4, 8, 12, 15, 22, 29, 43, 50, 57, 64, 78, 85, and 113 days post-dose

Outcome Measure Data

Analysis Population Description

All participants who received erenumab and for whom at least 1 pharmacokinetic (PK) parameter or endpoint could be adequately estimated. AUCinf could not be accurately estimated for 23 participants who are excluded from the analysis.

Arm/Group Title	Erenumab
Arm/Group Description	Participants received a single dose of 70 mg erenumab administered by subcutaneous injection.
Measure Participants	27
Mean (Standard Deviation) [day*μg/mL]	190 (96.3)

8. Secondary Outcome

Title	Terminal Half-life (T1/2) of Erenumab
Time Frame	Predose and 4 hours, 2, 3, 4, 8, 12, 15, 22, 29, 43, 50, 57, 64, 78, 85, and 113 days post-dose

Outcome Measure Data

Analysis Population Description

All participants who received erenumab and for whom at least 1 PK parameter or endpoint could be adequately estimated. T1/2 could not be accurately estimated for 23 participants who are excluded from the analysis. The terminal half-life calculated from this single dose study may not be representative of a clinically relevant half-life of erenumab.

Arm/Group Title	Erenumab
Arm/Group Description	Participants received a single dose of 70 mg erenumab administered by subcutaneous injection.
Measure Participants	27
Mean (Standard Deviation) [days]	12.1 (3.00)

9. Secondary Outcome

Title	Number of Participants With Treatment-emergent Suicidal Ideation
Description	The Columbia Suicide Severity Rating Scale (C-SSRS) was used to assess suicidal ideation during the study based on the following Yes/No questions: Have you wished you were dead or wished you could go to sleep and not wake up? Have you actually had any thoughts of killing yourself?
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

All participants who received study drug

Arm/Group Title	Placebo	Erenumab
Arm/Group Description	Participants received a single dose of placebo administered by subcutaneous injection.	Participants received a single dose of 70 mg erenumab administered by subcutaneous injection.
Measure Participants	52	50
Count of Participants [Participants]	0 0%	0 0%

10. Secondary Outcome

Title	Number of Participants Who Developed Anti-erenumab Antibodies After a Single Dose
Description	Two validated assays were used to detect the presence of anti-erenumab antibodies. First, an electrochemiluminescent (ECL) bridging immunoassay was used to detect antibodies capable of binding erenumab. Second, a cell based bioassay was used to test positive binding antibody samples for neutralizing activity against erenumab. A participant was defined as positive for developing anti-erenumab antibodies if they were binding antibody positive postbaseline with a negative or no result at baseline. If a sample was positive for binding antibodies and demonstrated neutralizing activity at the same time point, the participant was defined as positive for neutralizing antibodies.
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

All participants who received study drug.

Arm/Group Title	Placebo	Erenumab
Arm/Group Description	Participants received a single dose of placebo administered by subcutaneous injection.	Participants received a single dose of 70 mg erenumab administered by subcutaneous injection.
Measure Participants	52	50
Binding antibody positive	0 0%	5 10%
Neutralizing antibody positive	0 0%	4 8%

Adverse Events

Time Frame	16 Weeks
Adverse Event Reporting Description	Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	Placebo		Erenumab 70 mg
Arm/Group Description	Participants received a single dose of placebo administered by subcutaneous injection.		Participants received a single dose of 70 mg erenumab administered by subcutaneous injection.
All Cause Mortality
	Placebo		Erenumab 70 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Erenumab 70 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/52 (0%)		0/50 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Erenumab 70 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/52 (21.2%)		9/50 (18%)
Infections and infestations
Upper respiratory tract infection	2/52 (3.8%)		3/50 (6%)
Urinary tract infection	3/52 (5.8%)		0/50 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/52 (0%)		4/50 (8%)
Back pain	0/52 (0%)		3/50 (6%)
Nervous system disorders
Headache	4/52 (7.7%)		3/50 (6%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	3/52 (5.8%)		0/50 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.