Healthy Subjects
Conditions
Brief summary
The primary objective of this study was to assess the effects of subcutaneous sumatriptan alone and the effects of a single dose of erenumab (AMG 334) intravenous (IV) and sumatriptan concomitant therapy on resting blood pressure in healthy adults.
Interventions
DRUGPlacebo
Administered by intravenous infusion
DRUGSumatriptan
Administered by two 6 mg subcutaneous injections 1 hour apart on day 2 and day 5
DRUGErenumab
Administered by intravenous infusion
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male and female subjects ≥ 18 to ≤ 55 years old * Good general health * Laboratory results within range * Other Inclusion Criteria May Apply
Exclusion criteria
* Female subjects pregnant or breastfeeding * An unstable medical condition * History of cancer * Active liver disease * Positive Hepatitis B or Hepatitis C * Unwilling or unable to limit alcohol consumption * Unable to refrain from strenuous exercise * Other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time-weighted Averages of Mean Arterial Pressure | Days 2 and 5 from predose to 2.5 hours after sumatriptan dosing. | Mean arterial pressure (MAP) is the average arterial pressure during a single cardiac cycle. MAP was calculated as diastolic blood pressure (DBP) + 0.33 \* (systolic blood pressure \[SBP\]-DBP). Individual time-weighted average in MAP were calculated as area under the measurement-time curve from predose through 2.5 hours of MAP divided by the time period over which the measurements were made (ie, AUCmap0-2.5 hr /2.5 hours). Data were analyzed using a linear mixed effects regression model with fixed effects for treatment and period and random effect for subject; Sumatriptan Alone data include participants from both Groups A (Parts 1 and 2) and B (Part 1 only). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | From the first dose of study drug (sumatriptan, placebo or erenumab) until 84 days after the last dose (89 days). Part 1 includes AEs from day 1 to predose on day 4 and Part 2 includes AEs from day 4 through day 89. | Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and according to the following: Grade 1 = Mild AE, asymptomatic or mild symptoms; Grade 2 = Moderate, minimal, local or noninvasive intervention indicated; Grade 3 = Severe or medically significant but not immediately life-threatening; Grade 4 = Life-threatening consequences, urgent intervention indicated; Grade 5 = Death related to AE. |
| Area Under the Concentration-time Curve From Time 0 to 6 Hours for Sumatriptan | Day 2 and day 5 at 1 hour (prior to 2nd sumatriptan injection), 1 hour 10 minutes, 1.25, 1.5, 2, 3, 4.5, and 7 hours relative to the first 6 mg dose of sumatriptan. | Plasma concentrations of sumatriptan were quantified using a validated high performance liquid chromatographic method with tandem mass spectrometry detection. Area under the plasma concentration-time curve from time 0 to 6 hours post dose (AUC6hr) after the 2nd 6 mg dose of sumatriptan was estimated using the linear trapezoidal method. Sumatriptan plasma concentrations below the lower limit of quantification (LLOQ; 0.100 ng/mL) were set to 0 before data analysis. Log-transformed AUC6hr was analyzed using a linear mixed effects model with treatment as a fixed effect and subject as a random effect. Sumatriptan Alone data include participants from both Groups A (Parts 1 and 2) and B (Part 1 only). |
| Area Under the Concentration-time Curve From Time 0 to Infinity for Sumatriptan | Day 2 and day 5 at 1 hour (prior to 2nd sumatriptan injection), 1 hour 10 minutes, 1.25, 1.5, 2, 3, 4.5, and 7 hours relative to the first 6 mg dose of sumatriptan. | Plasma concentrations of sumatriptan were quantified using a validated high performance liquid chromatographic method with tandem mass spectrometry detection. The area under the plasma concentration-time curve from time 0 to infinity (AUCinf) after the 2nd 6 mg dose of sumatriptan was estimated as the sum of AUClast and Clast/λz where Clast is the last observed concentration and λz is the first-order terminal rate constant estimated via linear regression of the terminal log-linear decay phase. Sumatriptan plasma concentrations below the lower limit of quantification (LLOQ) (0.100 ng/mL) were set to 0 before data analysis. Log-transformed AUCinf was analyzed using a linear mixed effects model with treatment as a fixed effect and subject as a random effect. Sumatriptan Alone data include participants from both Groups A (Parts 1 and 2) and B (Part 1 only). |
| Maximum Observed Plasma Concentration (Cmax) of Sumatriptan | Day 2 and day 5 at predose, 1 hour (prior to 2nd sumatriptan injection), 1 hour 10 minutes, 1.25, 1.5, 2, 3, 4.5, and 7 hours relative to the first 6 mg dose of sumatriptan. | Plasma concentrations of sumatriptan were quantified using a validated high performance liquid chromatographic method with tandem mass spectrometry detection. Sumatriptan plasma concentrations below the lower limit of quantification (LLOQ) (0.100 ng/mL) were set to 0 before data analysis. Log-transformed maximum observed plasma concentration (Cmax) was analyzed using a linear mixed effects model with treatment as a fixed effect and subject as a random effect. Sumatriptan Alone data include participants from both Groups A (Parts 1 and 2) and B (Part 1 only). |
| Number of Participants Who Developed Anti-erenumab Antibodies | Baseline and day 89 | Two validated assays were used to detect the presence of anti-erenumab antibodies. All samples were first tested in an electrochemiluminescence-based bridging assay to detect antibodies capable of binding to erenumab (Binding Antibody Assay). Samples confirmed to be positive for binding antibodies were subsequently tested in a cell-based assay to determine neutralizing activity against erenumab (Neutralizing Antibody Assay). If a post-dose sample was positive for binding antibodies and demonstrated neutralizing activity at the same time point, the sample was defined as positive for neutralizing antibodies. Binding/neutralizing antibody positive is defined as participants with an antibody positive postbaseline results and with a negative or no result at baseline. |
Countries
Belgium
Participant flow
Recruitment details
This study was conducted at 1 center in Belgium; participants were enrolled from 22 February 2016 to 11 May 2016.
Pre-assignment details
Eligible participants were randomized on day 1 to receive either erenumab or matching placebo in a 2:1 allocation ratio.
Participants by arm
| Arm | Count |
|---|---|
| Group A: Placebo + Sumatriptan Participants received a placebo intravenous (IV) infusion on day 1 then 12 mg subcutaneous (SC) sumatriptan (6 mg, followed by 6 mg at least 1 hour later) on day 2 (Part 1). After a 2-day washout participants received another placebo IV infusion on day 4 followed by 12 mg SC sumatriptan (6 mg, followed by 6 mg at least 1 hour later) on day 5 (Part 2). | 12 |
| Group B: Erenumab + Sumatriptan Participants received a placebo IV infusion on day 1 then 12 mg SC sumatriptan (6 mg, followed by 6 mg at least 1 hour later) on day 2 (Part 1). After a 2-day washout participants received 140 mg erenumab IV infusion on day 4 followed by 12 mg SC sumatriptan (6 mg, followed by 6 mg at least 1 hour later) on day 5 (Part 2). | 22 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Sponsor Decision | 2 | 2 |
Baseline characteristics
| Characteristic | Group A: Placebo + Sumatriptan | Group B: Erenumab + Sumatriptan | Total |
|---|---|---|---|
| Age, Continuous | 27.3 years STANDARD_DEVIATION 8.6 | 29.1 years STANDARD_DEVIATION 10.3 | 28.5 years STANDARD_DEVIATION 9.6 |
| Age, Customized 18 - 24 years | 6 Participants | 9 Participants | 15 Participants |
| Age, Customized 25 - 55 years | 6 Participants | 13 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 22 Participants | 33 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black (or African American) | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 12 Participants | 21 Participants | 33 Participants |
| Sex: Female, Male Female | 4 Participants | 6 Participants | 10 Participants |
| Sex: Female, Male Male | 8 Participants | 16 Participants | 24 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 | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 11 / 12 | 17 / 22 | 9 / 10 | 17 / 20 |
| serious Total, serious adverse events | 0 / 12 | 0 / 22 | 0 / 10 | 0 / 20 |
Outcome results
Primary
Time-weighted Averages of Mean Arterial Pressure
Mean arterial pressure (MAP) is the average arterial pressure during a single cardiac cycle. MAP was calculated as diastolic blood pressure (DBP) + 0.33 \* (systolic blood pressure \[SBP\]-DBP). Individual time-weighted average in MAP were calculated as area under the measurement-time curve from predose through 2.5 hours of MAP divided by the time period over which the measurements were made (ie, AUCmap0-2.5 hr /2.5 hours). Data were analyzed using a linear mixed effects regression model with fixed effects for treatment and period and random effect for subject; Sumatriptan Alone data include participants from both Groups A (Parts 1 and 2) and B (Part 1 only).
Time frame: Days 2 and 5 from predose to 2.5 hours after sumatriptan dosing.
Population: All participants who received at least 1 dose of study drug (placebo, sumatriptan, or erenumab) and with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sumatriptan Alone | Time-weighted Averages of Mean Arterial Pressure | 87.40 mmHg | Standard Error 0.98 |
| Erenumab + Sumatriptan | Time-weighted Averages of Mean Arterial Pressure | 87.36 mmHg | Standard Error 1.22 |
Comparison: A linear mixed effects regression analysis was performed to assess if the time-weighted average in MAP for erenumab with sumatriptan is similar to sumatriptan alone. A two-sided 90% confidence interval (equivalent to a one-sided upper 95% CI) for the mean treatment difference was calculated using a linear mixed-effects model with fixed effects for treatment and period and a random effect for subject.90% CI: [-2.16, 2.08]
Secondary
Area Under the Concentration-time Curve From Time 0 to 6 Hours for Sumatriptan
Plasma concentrations of sumatriptan were quantified using a validated high performance liquid chromatographic method with tandem mass spectrometry detection. Area under the plasma concentration-time curve from time 0 to 6 hours post dose (AUC6hr) after the 2nd 6 mg dose of sumatriptan was estimated using the linear trapezoidal method. Sumatriptan plasma concentrations below the lower limit of quantification (LLOQ; 0.100 ng/mL) were set to 0 before data analysis. Log-transformed AUC6hr was analyzed using a linear mixed effects model with treatment as a fixed effect and subject as a random effect. Sumatriptan Alone data include participants from both Groups A (Parts 1 and 2) and B (Part 1 only).
Time frame: Day 2 and day 5 at 1 hour (prior to 2nd sumatriptan injection), 1 hour 10 minutes, 1.25, 1.5, 2, 3, 4.5, and 7 hours relative to the first 6 mg dose of sumatriptan.
Population: All participants who received at least 1 dose of study drug (placebo, sumatriptan, or erenumab) and have at least one pharmacokinetic (PK) sample collected or one PK parameter.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sumatriptan Alone | Area Under the Concentration-time Curve From Time 0 to 6 Hours for Sumatriptan | 133.33 hr*ng/mL | Standard Error 1.03 |
| Erenumab + Sumatriptan | Area Under the Concentration-time Curve From Time 0 to 6 Hours for Sumatriptan | 130.59 hr*ng/mL | Standard Error 1.04 |
Comparison: The mean for each treatment was compared using a linear mixed effects model with group A (sumatriptan alone) as the reference treatment group. The linear mixed effects model included treatment (erenumab with sumatriptan vs sumatriptan alone) and period as a fixed effect and subject as a random effect.90% CI: [0.93, 1.03]
Secondary
Area Under the Concentration-time Curve From Time 0 to Infinity for Sumatriptan
Plasma concentrations of sumatriptan were quantified using a validated high performance liquid chromatographic method with tandem mass spectrometry detection. The area under the plasma concentration-time curve from time 0 to infinity (AUCinf) after the 2nd 6 mg dose of sumatriptan was estimated as the sum of AUClast and Clast/λz where Clast is the last observed concentration and λz is the first-order terminal rate constant estimated via linear regression of the terminal log-linear decay phase. Sumatriptan plasma concentrations below the lower limit of quantification (LLOQ) (0.100 ng/mL) were set to 0 before data analysis. Log-transformed AUCinf was analyzed using a linear mixed effects model with treatment as a fixed effect and subject as a random effect. Sumatriptan Alone data include participants from both Groups A (Parts 1 and 2) and B (Part 1 only).
Time frame: Day 2 and day 5 at 1 hour (prior to 2nd sumatriptan injection), 1 hour 10 minutes, 1.25, 1.5, 2, 3, 4.5, and 7 hours relative to the first 6 mg dose of sumatriptan.
Population: All participants who received at least 1 dose of study drug (placebo, sumatriptan, or erenumab) and have at least one pharmacokinetic (PK) sample collected or one PK parameter.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sumatriptan Alone | Area Under the Concentration-time Curve From Time 0 to Infinity for Sumatriptan | 144.32 hr*ng/mL | Standard Error 1.03 |
| Erenumab + Sumatriptan | Area Under the Concentration-time Curve From Time 0 to Infinity for Sumatriptan | 144.81 hr*ng/mL | Standard Error 1.04 |
Comparison: The mean for each treatment was compared using a linear mixed effects model with group A (sumatriptan alone) as the reference treatment group. The linear mixed effects model included treatment (erenumab with sumatriptan vs sumatriptan alone) and period as a fixed effect and subject as a random effect.90% CI: [0.96, 1.05]
Secondary
Maximum Observed Plasma Concentration (Cmax) of Sumatriptan
Plasma concentrations of sumatriptan were quantified using a validated high performance liquid chromatographic method with tandem mass spectrometry detection. Sumatriptan plasma concentrations below the lower limit of quantification (LLOQ) (0.100 ng/mL) were set to 0 before data analysis. Log-transformed maximum observed plasma concentration (Cmax) was analyzed using a linear mixed effects model with treatment as a fixed effect and subject as a random effect. Sumatriptan Alone data include participants from both Groups A (Parts 1 and 2) and B (Part 1 only).
Time frame: Day 2 and day 5 at predose, 1 hour (prior to 2nd sumatriptan injection), 1 hour 10 minutes, 1.25, 1.5, 2, 3, 4.5, and 7 hours relative to the first 6 mg dose of sumatriptan.
Population: All participants who received at least 1 dose of study drug (placebo, sumatriptan, or erenumab) and have at least one pharmacokinetic (PK) sample collected or one PK parameter.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sumatriptan Alone | Maximum Observed Plasma Concentration (Cmax) of Sumatriptan | 83.50 ng/mL | Standard Error 1.05 |
| Erenumab + Sumatriptan | Maximum Observed Plasma Concentration (Cmax) of Sumatriptan | 79.00 ng/mL | Standard Error 1.07 |
Comparison: The mean for each treatment was compared using a linear mixed effects model with group A (sumatriptan alone) as the reference treatment group. The linear mixed effects model included treatment (erenumab with sumatriptan vs sumatriptan alone) and period as a fixed effect and subject as a random effect.90% CI: [0.82, 1.09]
Secondary
Number of Participants Who Developed Anti-erenumab Antibodies
Two validated assays were used to detect the presence of anti-erenumab antibodies. All samples were first tested in an electrochemiluminescence-based bridging assay to detect antibodies capable of binding to erenumab (Binding Antibody Assay). Samples confirmed to be positive for binding antibodies were subsequently tested in a cell-based assay to determine neutralizing activity against erenumab (Neutralizing Antibody Assay). If a post-dose sample was positive for binding antibodies and demonstrated neutralizing activity at the same time point, the sample was defined as positive for neutralizing antibodies. Binding/neutralizing antibody positive is defined as participants with an antibody positive postbaseline results and with a negative or no result at baseline.
Time frame: Baseline and day 89
Population: Participants who received at least 1 dose of study drug (placebo, sumatriptan, or erenumab) with a postbaseline antibody result.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sumatriptan Alone | Number of Participants Who Developed Anti-erenumab Antibodies | Binding antibody positive | 0 Participants |
| Sumatriptan Alone | Number of Participants Who Developed Anti-erenumab Antibodies | Neutralizing antibody positive | 0 Participants |
| Erenumab + Sumatriptan | Number of Participants Who Developed Anti-erenumab Antibodies | Binding antibody positive | 1 Participants |
| Erenumab + Sumatriptan | Number of Participants Who Developed Anti-erenumab Antibodies | Neutralizing antibody positive | 1 Participants |
Secondary
Number of Participants With Adverse Events
Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and according to the following: Grade 1 = Mild AE, asymptomatic or mild symptoms; Grade 2 = Moderate, minimal, local or noninvasive intervention indicated; Grade 3 = Severe or medically significant but not immediately life-threatening; Grade 4 = Life-threatening consequences, urgent intervention indicated; Grade 5 = Death related to AE.
Time frame: From the first dose of study drug (sumatriptan, placebo or erenumab) until 84 days after the last dose (89 days). Part 1 includes AEs from day 1 to predose on day 4 and Part 2 includes AEs from day 4 through day 89.
Population: All participants who received at least 1 dose of study drug (placebo, sumatriptan, or erenumab).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sumatriptan Alone | Number of Participants With Adverse Events | Fatal adverse events | 0 Participants |
| Sumatriptan Alone | Number of Participants With Adverse Events | AE leading to discontinuation of study drug | 2 Participants |
| Sumatriptan Alone | Number of Participants With Adverse Events | Serious adverse events | 0 Participants |
| Sumatriptan Alone | Number of Participants With Adverse Events | Adverse event ≥ grade 3 | 0 Participants |
| Sumatriptan Alone | Number of Participants With Adverse Events | Adverse event ≥ grade 2 | 1 Participants |
| Sumatriptan Alone | Number of Participants With Adverse Events | Any adverse event | 11 Participants |
| Sumatriptan Alone | Number of Participants With Adverse Events | Adverse event ≥ grade 4 | 0 Participants |
| Erenumab + Sumatriptan | Number of Participants With Adverse Events | Adverse event ≥ grade 2 | 0 Participants |
| Erenumab + Sumatriptan | Number of Participants With Adverse Events | Serious adverse events | 0 Participants |
| Erenumab + Sumatriptan | Number of Participants With Adverse Events | AE leading to discontinuation of study drug | 2 Participants |
| Erenumab + Sumatriptan | Number of Participants With Adverse Events | Any adverse event | 19 Participants |
| Erenumab + Sumatriptan | Number of Participants With Adverse Events | Adverse event ≥ grade 3 | 0 Participants |
| Erenumab + Sumatriptan | Number of Participants With Adverse Events | Adverse event ≥ grade 4 | 0 Participants |
| Erenumab + Sumatriptan | Number of Participants With Adverse Events | Fatal adverse events | 0 Participants |
| Part 2 Group A: Placebo + Sumatriptan | Number of Participants With Adverse Events | Fatal adverse events | 0 Participants |
| Part 2 Group A: Placebo + Sumatriptan | Number of Participants With Adverse Events | Any adverse event | 9 Participants |
| Part 2 Group A: Placebo + Sumatriptan | Number of Participants With Adverse Events | Adverse event ≥ grade 3 | 0 Participants |
| Part 2 Group A: Placebo + Sumatriptan | Number of Participants With Adverse Events | Adverse event ≥ grade 2 | 0 Participants |
| Part 2 Group A: Placebo + Sumatriptan | Number of Participants With Adverse Events | Adverse event ≥ grade 4 | 0 Participants |
| Part 2 Group A: Placebo + Sumatriptan | Number of Participants With Adverse Events | Serious adverse events | 0 Participants |
| Part 2 Group A: Placebo + Sumatriptan | Number of Participants With Adverse Events | AE leading to discontinuation of study drug | 0 Participants |
| Part 2 Group B: Erenumab + Sumatriptan | Number of Participants With Adverse Events | Fatal adverse events | 0 Participants |
| Part 2 Group B: Erenumab + Sumatriptan | Number of Participants With Adverse Events | Adverse event ≥ grade 3 | 0 Participants |
| Part 2 Group B: Erenumab + Sumatriptan | Number of Participants With Adverse Events | Adverse event ≥ grade 2 | 3 Participants |
| Part 2 Group B: Erenumab + Sumatriptan | Number of Participants With Adverse Events | Adverse event ≥ grade 4 | 0 Participants |
| Part 2 Group B: Erenumab + Sumatriptan | Number of Participants With Adverse Events | Any adverse event | 17 Participants |
| Part 2 Group B: Erenumab + Sumatriptan | Number of Participants With Adverse Events | Serious adverse events | 0 Participants |
| Part 2 Group B: Erenumab + Sumatriptan | Number of Participants With Adverse Events | AE leading to discontinuation of study drug | 0 Participants |