A Multicenter Assessment of LBR-101 in High Frequency Epi... | NCT02025556

Status Module

Name	Class
NCGS, Inc.	INDUSTRY

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
LBR-101 High Dose	Experimental	Subcutaneous High Dose LBR-101 Administered Monthly x 3	Drug: LBR-101 High Dose
LBR-101 Low Dose	Experimental	Subcutaneous Low Dose LBR-101 Administered Monthly x 3	Drug: LBR-101 Low Dose
Placebo	Placebo Comparator	Subcutaneous Placebo Administered Monthly x 3	Drug: Placebo

Name	Type	Description	Arm Group Labels	Other Names
LBR-101 High Dose	Drug	Subcutaneously Administered High Dose LBR-101 Monthly x 3	LBR-101 High Dose

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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.	Baseline to week 12
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.	Baseline to week 12
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	Up to week 12

Secondary Outcomes

Measure	Description	Time Frame
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.

Eligibility Module

Eligibility Criteria

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.

Name	Affiliation	Role
Teva Medical Expert, MD	Teva Pharmaceuticals USA	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Teva Investigational Site 145		Gilbert	Arizona	85234	United States
Teva Investigational Site 130

PubMed Identifier	Type	Citation	Retractions
30450545	Derived	Silberstein SD, Rapoport AM, Loupe PS, Aycardi E, McDonald M, Yang R, Bigal ME. The Effect of Beginning Treatment With Fremanezumab on Headache and Associated Symptoms in the Randomized Phase 2 Study of High Frequency Episodic Migraine: Post-Hoc Analyses on the First 3 Weeks of Treatment. Headache. 2019 Mar;59(3):383-393. doi: 10.1111/head.13446. Epub 2018 Nov 18.
30120138

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	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).
FG001	Low Dose	Participants received 225 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Arm/Group Information

ID	Title	Description
BG000	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).
BG001	Low Dose	Participants received 225 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.
BG002	High Dose	Participants received 675 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.
BG003	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

Years

Title

Denominators

Categories

Title	Measurements
	BG00042.0± 11.62 BG00140.8± 12.43 BG00240.7± 12.56 BG003

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00092 BG00187 BG002

Ethnicity (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Hispanic or Latino	BG00011 BG00116 BG002

Race (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0000 BG0010 BG002

Years of migraine

Mean

Standard Deviation

Years

Title

Denominators

Categories

Title	Measurements
	BG00021.2± 14.1 BG00118.9± 12.92 BG002

Preventive medication use

Participants reported preventive migraine medication use at the time of randomization

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Yes	BG00028 BG00132 BG002

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

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.

Intent-to-treat (ITT) population includes all randomized participants that received at least one dose and obtained at least one endpoint measurement.

Posted

Least Squares Mean

Standard Error

Days

Baseline to week 12

ID	Title	Description
OG000	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).
OG001	Low Dose	Participants received 225 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.
OG002	High Dose	Participants received 675 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.

Units	Counts
Participants	OG000104 OG00195 OG00296

Title

Denominators

Categories

Title	Measurements
	OG000-3.46± 0.53 OG001-6.27± 0.55 OG002-6.09± 0.53

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Mixed Models Analysis		< .0001	The threshold for statistical significance was p = .05.	Mean Difference (Final Values)	-2.81	Standard Error of the Mean	0.64	2-Sided	95	-4.07	-1.55					Superiority
OG000 OG002		Mixed Models Analysis

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.

Safety analysis set included all randomized participants who received at least one dose of study drug.

Posted

Number

Participants

Baseline to week 12

ID	Title	Description
OG000	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).
OG001	Low Dose	Participants received 225 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.
OG002	High Dose

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

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.

Posted

Count of Participants

Participants

Up to week 12

ID	Title	Description
OG000	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).
OG001	Low Dose	Participants received 225 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.
OG002	High Dose	Participants received 675 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.

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.

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.

Posted

Least Squares Mean

Standard Error

Days

Baseline to week 12

ID	Title	Description
OG000	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).
OG001	Low Dose	Participants received 225 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.
OG002	High Dose	Participants received 675 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	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	0	104	9	104
EG001	Low Dose	Participants received 225 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.	96	2	96	9	96
EG002	High Dose	Participants received 675 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.	96	2	96	11	96

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Antiphospholipid syndrome	Blood and lymphatic system disorders	MedDra 17.0	Systematic Assessment	EG0000 events0 affected104 at risk EG0010 events0 affected96 at risk EG0021 events1 affected96 at risk
Fibula fracture	Injury, poisoning and procedural complications	MedDra 17.0	Systematic Assessment	EG0000 events0 affected104 at risk EG0011 events1 affected96 at risk EG0020 events0 affected96 at risk
Migraine	Nervous system disorders	MedDra 17.0	Systematic Assessment	EG0000 events0 affected104 at risk EG0011 events1 affected96 at risk EG0020 events0 affected96 at risk
Tremor	Nervous system disorders	MedDra 17.0	Systematic Assessment	EG0000 events0 affected104 at risk EG0010 events0 affected96 at risk EG0021 events1 affected96 at risk
Hypertensive crisis	Vascular disorders	MedDra 17.0	Systematic Assessment	EG0000 events0 affected104 at risk EG0011 events1 affected96 at risk EG0020 events0 affected96 at risk

ID	Term
D051270	Headache Disorders, Primary
D020773	Headache Disorders
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Injection site pain	General disorders	MedDra 17.0	Systematic Assessment	EG00010 events6 affected104 at risk EG00113 events9 affected96 at risk EG0024 events4 affected96 at risk
Sinusitis	Infections and infestations	MedDra 17.0	Systematic Assessment	EG0003 events3 affected104 at risk EG0010 events0 affected96 at risk EG0025 events5 affected96 at risk
Dizziness	Nervous system disorders	MedDra 17.0	Systematic Assessment	EG0000 events0 affected104 at risk EG0012 events1 affected96 at risk EG0026 events5 affected96 at risk