Vasomotor Symptoms; Hot Flashes
Conditions
Keywords
Vasomotor symptoms; Hot Flashes; Menopause
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.
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.
Interventions
BIOLOGICALErenumab
Administered via subcutaneous injection.
DRUGPlacebo
Administered via subcutaneous injection
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
45 Years to 65 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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 | — |
| 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 | — |
| 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. |
| 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 | — |
| 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: 1. Have you wished you were dead or wished you could go to sleep and not wake up? 2. Have you actually had any thoughts of killing yourself? |
| 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. |
| 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 | — |
Countries
United States
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 details
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).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received a single dose of placebo administered by subcutaneous injection. | 52 |
| Erenumab Participants received a single dose of 70 mg erenumab administered by subcutaneous injection. | 50 |
| Total | 102 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 3 |
Baseline characteristics
| Characteristic | Placebo | Total | Erenumab |
|---|---|---|---|
| Age, Continuous | 55.5 years STANDARD_DEVIATION 4.8 | 55.6 years STANDARD_DEVIATION 4.3 | 55.6 years STANDARD_DEVIATION 3.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 14 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 46 Participants | 88 Participants | 42 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Number of Hot Flashes at Baseline ≤ 11.5 hot flashes/24 hours | 26 Participants | 51 Participants | 25 Participants |
| Number of Hot Flashes at Baseline > 11.5 hot flashes/24 hours | 26 Participants | 51 Participants | 25 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 15 Participants | 25 Participants | 10 Participants |
| Race/Ethnicity, Customized Mixed Race | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 36 Participants | 72 Participants | 36 Participants |
| Sex: Female, Male Female | 52 Participants | 102 Participants | 50 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 52 | 9 / 50 |
| serious Total, serious adverse events | 0 / 52 | 0 / 50 |
Outcome results
Primary
Ratio of Week 4 to Baseline Average Number of Daily Moderate to Severe Hot Flashes
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)
Population: All participants for whom at least 1 postdose hot flash response measure was recorded.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Ratio of Week 4 to Baseline Average Number of Daily Moderate to Severe Hot Flashes | 0.35 ratio |
| Erenumab | Ratio of Week 4 to Baseline Average Number of Daily Moderate to Severe Hot Flashes | 0.38 ratio |
Comparison: 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.p-value: 0.72395% CI: [0.66, 1.83]Repeated Measures Analysis of Covariance
Secondary
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for Erenumab | 190 day*μg/mL | Standard Deviation 96.3 |
Secondary
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
Population: All participants who received erenumab and for whom at least 1 pharmacokinetic (PK) parameter or endpoint could be adequately estimated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUClast) for Erenumab | 173 day*μg/mL | Standard Deviation 84.6 |
Secondary
Maximum Observed Concentration (Cmax) of Erenumab After a Single Dose
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
Population: All participants who received erenumab and for whom at least 1 pharmacokinetic (PK) parameter or endpoint could be adequately estimated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximum Observed Concentration (Cmax) of Erenumab After a Single Dose | 6.13 μg/mL | Standard Deviation 2.86 |
Secondary
Number of Participants Who Developed Anti-erenumab Antibodies After a Single Dose
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
Population: All participants who received study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants Who Developed Anti-erenumab Antibodies After a Single Dose | Binding antibody positive | 0 Participants |
| Placebo | Number of Participants Who Developed Anti-erenumab Antibodies After a Single Dose | Neutralizing antibody positive | 0 Participants |
| Erenumab | Number of Participants Who Developed Anti-erenumab Antibodies After a Single Dose | Binding antibody positive | 5 Participants |
| Erenumab | Number of Participants Who Developed Anti-erenumab Antibodies After a Single Dose | Neutralizing antibody positive | 4 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events
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
Population: All participants who received study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Treatment-emergent Adverse Events | Treatment-emergent adverse events (TEAEs) | 23 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events | TEAE leading to discontinuation of study drug | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events | Fatal adverse events | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events | Treatment-related adverse events (TRAEs) | 5 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events | Treatment-related serious adverse events | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events | TRAE leading to discontinuation of study drug | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events | TRAE leading to discontinuation of study | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events | Treatment-related fatal adverse events | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events | TEAE leading to discontinuation of study | 0 Participants |
| Erenumab | Number of Participants With Treatment-emergent Adverse Events | Treatment-related adverse events (TRAEs) | 3 Participants |
| Erenumab | Number of Participants With Treatment-emergent Adverse Events | Treatment-emergent adverse events (TEAEs) | 24 Participants |
| Erenumab | Number of Participants With Treatment-emergent Adverse Events | Treatment-related fatal adverse events | 0 Participants |
| Erenumab | Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Erenumab | Number of Participants With Treatment-emergent Adverse Events | Treatment-related serious adverse events | 0 Participants |
| Erenumab | Number of Participants With Treatment-emergent Adverse Events | TEAE leading to discontinuation of study drug | 0 Participants |
| Erenumab | Number of Participants With Treatment-emergent Adverse Events | TEAE leading to discontinuation of study | 0 Participants |
| Erenumab | Number of Participants With Treatment-emergent Adverse Events | TRAE leading to discontinuation of study | 0 Participants |
| Erenumab | Number of Participants With Treatment-emergent Adverse Events | Fatal adverse events | 0 Participants |
| Erenumab | Number of Participants With Treatment-emergent Adverse Events | TRAE leading to discontinuation of study drug | 0 Participants |
Secondary
Number of Participants With Treatment-emergent Suicidal Ideation
The Columbia Suicide Severity Rating Scale (C-SSRS) was used to assess suicidal ideation during the study based on the following Yes/No questions: 1. Have you wished you were dead or wished you could go to sleep and not wake up? 2. Have you actually had any thoughts of killing yourself?
Time frame: 16 weeks
Population: All participants who received study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Treatment-emergent Suicidal Ideation | 0 Participants |
| Erenumab | Number of Participants With Treatment-emergent Suicidal Ideation | 0 Participants |
Secondary
Ratio of Week 4 to Baseline Daily Hot Flash Severity Score
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)
Population: All participants for whom at least 1 postdose hot flash response measure was recorded.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Ratio of Week 4 to Baseline Daily Hot Flash Severity Score | 0.40 ratio |
| Erenumab | Ratio of Week 4 to Baseline Daily Hot Flash Severity Score | 0.45 ratio |
Comparison: 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.p-value: 0.55195% CI: [0.74, 1.74]Repeated Measures Analysis of Covariance
Secondary
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Terminal Half-life (T1/2) of Erenumab | 12.1 days | Standard Deviation 3 |
Secondary
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
Population: All participants who received erenumab and for whom at least 1 pharmacokinetic (PK) parameter or endpoint could be adequately estimated.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Maximum Observed Concentration (Tmax) of Erunumab After a Single Dose | 7.0 days |