Episodic Migraine Headache
Conditions
Keywords
High Frequency Episodic Migraine Headache, Episodic Migraine Headache, Migraine Headache
Brief summary
The purpose of this study is to determine whether monthly subcutaneous administration of LBR-101 (fremanezumab) is safe and provides migraine prevention in subjects with high frequency episodic migraine.
Interventions
Subcutaneously Administered High Dose LBR-101 Monthly x 3
DRUGLBR-101 Low Dose
Subcutaneously Administered Low Dose LBR-101 Monthly x 3
DRUGPlacebo
Subcutaneously Administered Placebo (Vehicle) Monthly x 3
Sponsors
NCGS, Inc.
Teva Branded Pharmaceutical Products R&D, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Males or females aged 18 to 65 years of age. * A signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study including any known and potential risks and available alternative treatments. * Subjects fulfilling criteria for episodic migraine as per the Second Edition of The International Headache Society (Olesen and Steiner 2004), who experience migraine at high frequency as follows: i. History of headaches on more than 8 days per month for at least 3 months prior to screening ii. Verification of headache frequency through prospectively collected baseline information during the 28-day run-in phase demonstrating headaches (of any type) on at least 8 days with at total of 8 to 14 days\* fulfilling criteria for migraine. \*Operational definition for migraine and probable migraine days are presented in the statistical section of this protocol. * Body Mass Index (BMI) of 17.5 to 37.5 kg/m2, and a total body weight between 50 kg and 120 kg, inclusive. * Demonstrated compliance with the electronic headache diary during the run-in period by entry of headache data on a minimum of 22/28 days (80% compliance).
Exclusion criteria
* Subject has received onabotulinum toxin A for migraine or for any medical or cosmetic reasons requiring injections in the head, face, or neck during the six months prior to screening. * Subject uses medications containing opioids (including codeine) or barbiturates (including Fiorinal®, Fioricet®, or any other combination containing butalbital) on more than 4 days per month for the treatment of migraine or for any other reason. * Failed \> 2 medication categories or \> 3 preventive medications (within two medication categories) due to lack of efficacy for prophylactic treatment of episodic or chronic migraine after an adequate therapeutic trial * Treatment with an investigational drug or device within 30 days of study entry or any prior exposure to a monoclonal antibody targeting the CGRP pathway.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in the Monthly Migraine Days During the 28-day Post Treatment Period Ending With Week 12 | Baseline to week 12 | A migraine day was endorsed when at least 1 of the following situations occurred: 1) A calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache endorsing criteria for migraine, or 2) a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache endorsing criteria for probable migraine, a migraine subtype where only one migraine criterion is missing, or 3) the participant used acute migraine medication (triptans and ergot compounds) to treat a headache of any duration, or 4) any of the above days preceded or followed by a day with a headache of any duration. This calculation was defined as the change from baseline in the number of headache days during the 28-day post treatment period ending at week 12. Headache severity was rated daily by the participant as either no pain, mild, moderate, or severe. |
| Number of Participants With at Least One Adverse Event | Baseline to week 12 | An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Relationship of AE to treatment was determined by the Investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent the previously listed serious outcomes. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. |
| Number of Participants Reporting Mild, Moderate, and Severe Adverse Events (AEs) | Up to week 12 | Adverse events were rated based on the investigator's clinical judgment. Mild: awareness of a sign or symptom that was easily tolerated Moderate: sign or symptom intense enough to interfere with usual activity Severe: interfered significantly with ability to do work or usual activity |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Number of Days With Headache of Any Severity | Baseline to week 12 | A headache day was defined as when at least 1 of the following situations occurred: A calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache of any severity or the participant used acute migraine medication (triptans and ergot compounds) to treat a headache. This calculation was defined as the change from baseline in the number of headache days during the 28-day post treatment period ending at week 12. Headache severity was rated daily by the participant as either no pain, mild, moderate, or severe. |
Countries
United States
Participant flow
Recruitment details
A total of 297 participants with episodic migraine were enrolled in the study.
Pre-assignment details
Participants were assigned to receive either subcutaneous administration of 675 mg of fremanezumab (LBR-101) for three months, subcutaneous administration of 225 mg of fremanezumab (LBR-101) for three months, or subcutaneous administration of placebo for three months.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received subcutaneous placebo injections at one visit per month for three months (Day
1/week 0, Day 29/week 4, and Day 57/week 8). | 104 |
| Low Dose Participants received 225 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8. | 96 |
| High Dose Participants received 675 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8. | 97 |
| Total | 297 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 4 | 2 |
| Overall Study | Lack of Efficacy | 2 | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 4 | 0 |
| Overall Study | Protocol Violation | 2 | 1 | 0 |
| Overall Study | Reason not reported | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 3 | 6 |
Baseline characteristics
| Characteristic | Placebo | Low Dose | High Dose | Total |
|---|---|---|---|---|
| Age, Continuous | 42.0 Years STANDARD_DEVIATION 11.62 | 40.8 Years STANDARD_DEVIATION 12.43 | 40.7 Years STANDARD_DEVIATION 12.56 | 41.2 Years STANDARD_DEVIATION 12.17 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 16 Participants | 17 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 92 Participants | 80 Participants | 79 Participants | 251 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Preventive medication use No | 76 Participants | 64 Participants | 71 Participants | 211 Participants |
| Preventive medication use Yes | 28 Participants | 32 Participants | 26 Participants | 86 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 19 Participants | 18 Participants | 50 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 2 Participants | 4 Participants | 10 Participants |
| Race (NIH/OMB) White | 85 Participants | 74 Participants | 74 Participants | 233 Participants |
| Sex: Female, Male Female | 92 Participants | 87 Participants | 82 Participants | 261 Participants |
| Sex: Female, Male Male | 12 Participants | 9 Participants | 15 Participants | 36 Participants |
| Years of migraine | 21.2 Years STANDARD_DEVIATION 14.1 | 18.9 Years STANDARD_DEVIATION 12.92 | 16.9 Years STANDARD_DEVIATION 12.25 | 19.0 Years STANDARD_DEVIATION 13.21 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 104 | 0 / 96 | 0 / 96 |
| other Total, other adverse events | 9 / 104 | 9 / 96 | 11 / 96 |
| serious Total, serious adverse events | 0 / 104 | 2 / 96 | 2 / 96 |
Outcome results
Primary
Mean Change From Baseline in the Monthly Migraine Days During the 28-day Post Treatment Period Ending With Week 12
A migraine day was endorsed when at least 1 of the following situations occurred: 1) A calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache endorsing criteria for migraine, or 2) a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache endorsing criteria for probable migraine, a migraine subtype where only one migraine criterion is missing, or 3) the participant used acute migraine medication (triptans and ergot compounds) to treat a headache of any duration, or 4) any of the above days preceded or followed by a day with a headache of any duration. This calculation was defined as the change from baseline in the number of headache days during the 28-day post treatment period ending at week 12. Headache severity was rated daily by the participant as either no pain, mild, moderate, or severe.
Time frame: Baseline to week 12
Population: Intent-to-treat (ITT) population includes all randomized participants that received at least one dose and obtained at least one endpoint measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline in the Monthly Migraine Days During the 28-day Post Treatment Period Ending With Week 12 | -3.46 Days | Standard Error 0.53 |
| Low Dose | Mean Change From Baseline in the Monthly Migraine Days During the 28-day Post Treatment Period Ending With Week 12 | -6.27 Days | Standard Error 0.55 |
| High Dose | Mean Change From Baseline in the Monthly Migraine Days During the 28-day Post Treatment Period Ending With Week 12 | -6.09 Days | Standard Error 0.53 |
p-value: <0.000195% CI: [-4.07, -1.55]Mixed Models Analysis
p-value: <0.000195% CI: [-3.9, -1.38]Mixed Models Analysis
Primary
Number of Participants Reporting Mild, Moderate, and Severe Adverse Events (AEs)
Adverse events were rated based on the investigator's clinical judgment. Mild: awareness of a sign or symptom that was easily tolerated Moderate: sign or symptom intense enough to interfere with usual activity Severe: interfered significantly with ability to do work or usual activity
Time frame: Up to week 12
Population: Per planned analysis participants analyzed included all randomized participants who received at least one dose of study drug and reported at least one adverse event.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants Reporting Mild, Moderate, and Severe Adverse Events (AEs) | Mild | 29 Participants |
| Placebo | Number of Participants Reporting Mild, Moderate, and Severe Adverse Events (AEs) | Moderate | 27 Participants |
| Placebo | Number of Participants Reporting Mild, Moderate, and Severe Adverse Events (AEs) | Severe | 1 Participants |
| Placebo | Number of Participants Reporting Mild, Moderate, and Severe Adverse Events (AEs) | Unknown severity | 1 Participants |
| Low Dose | Number of Participants Reporting Mild, Moderate, and Severe Adverse Events (AEs) | Unknown severity | 0 Participants |
| Low Dose | Number of Participants Reporting Mild, Moderate, and Severe Adverse Events (AEs) | Mild | 20 Participants |
| Low Dose | Number of Participants Reporting Mild, Moderate, and Severe Adverse Events (AEs) | Severe | 4 Participants |
| Low Dose | Number of Participants Reporting Mild, Moderate, and Severe Adverse Events (AEs) | Moderate | 20 Participants |
| High Dose | Number of Participants Reporting Mild, Moderate, and Severe Adverse Events (AEs) | Unknown severity | 0 Participants |
| High Dose | Number of Participants Reporting Mild, Moderate, and Severe Adverse Events (AEs) | Moderate | 26 Participants |
| High Dose | Number of Participants Reporting Mild, Moderate, and Severe Adverse Events (AEs) | Severe | 0 Participants |
| High Dose | Number of Participants Reporting Mild, Moderate, and Severe Adverse Events (AEs) | Mild | 31 Participants |
Primary
Number of Participants With at Least One Adverse Event
An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Relationship of AE to treatment was determined by the Investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent the previously listed serious outcomes. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time frame: Baseline to week 12
Population: Safety analysis set included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With at Least One Adverse Event | 58 Participants |
| Low Dose | Number of Participants With at Least One Adverse Event | 44 Participants |
| High Dose | Number of Participants With at Least One Adverse Event | 57 Participants |
Secondary
Change From Baseline in Number of Days With Headache of Any Severity
A headache day was defined as when at least 1 of the following situations occurred: A calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache of any severity or the participant used acute migraine medication (triptans and ergot compounds) to treat a headache. This calculation was defined as the change from baseline in the number of headache days during the 28-day post treatment period ending at week 12. Headache severity was rated daily by the participant as either no pain, mild, moderate, or severe.
Time frame: Baseline to week 12
Population: Intent-to-treat (ITT) population includes all randomized participants who received at least one dose of study medication and obtained at least one endpoint measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Number of Days With Headache of Any Severity | -3.52 Days | Standard Error 0.53 |
| Low Dose | Change From Baseline in Number of Days With Headache of Any Severity | -6.14 Days | Standard Error 0.56 |
| High Dose | Change From Baseline in Number of Days With Headache of Any Severity | -6.10 Days | Standard Error 0.54 |