A Multicenter Assessment of LBR-101 in High Frequency Episodic Migraine

• ClinicalTrials.gov Identifier: NCT02025556
• Recruitment Status: Completed
• First Posted: January 1, 2014
• Results First Posted: January 24, 2022
• Last Update Posted: January 24, 2022
• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
• Collaborator: NCGS, Inc.
• Information provided by (Responsible Party): Teva Branded Pharmaceutical Products R&D, Inc.

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Episodic Migraine Headache
• Interventions: Drug: LBR-101 High Dose; Drug: LBR-101 Low Dose; Drug: Placebo
• Enrollment: 297

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.

Arm/Group Title	Placebo	Low Dose	High Dose
Arm/Group Description	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).	Participants received 225 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.	Participants received 675 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.
Period Title: Overall Study
Started [1]	104	96	97
Safety Analysis Set [2]	104	96	96
Intent-to-treat (ITT) Set [3]	104	95	96
Completed	98	83	88
Not Completed	6	13	9
Reason Not Completed
Adverse Event	0	4	2
Lack of Efficacy	2	1	0
Protocol Violation	2	1	0
Withdrawal by Subject	0	3	6
Lost to Follow-up	2	4	0
Reason not reported	0	0	1
[1] All randomized participants; [2] All randomized participants who received at least one dose of study drug; [3] Received at least one dose of study drug and obtained at least one efficacy measurement

Baseline Characteristics

Arm/Group Title		Placebo	Low Dose	High Dose	Total
Arm/Group Description		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).	Participants received 225 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.	Participants received 675 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.	Total of all reporting groups
Overall Number of Baseline Participants		104	96	97	297
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	104 participants	96 participants	97 participants	297 participants
		42.0 (11.62)	40.8 (12.43)	40.7 (12.56)	41.2 (12.17)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	104 participants	96 participants	97 participants	297 participants
	Female	92 88.5%	87 90.6%	82 84.5%	261 87.9%
	Male	12 11.5%	9 9.4%	15 15.5%	36 12.1%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	104 participants	96 participants	97 participants	297 participants
	Hispanic or Latino	11 10.6%	16 16.7%	17 17.5%	44 14.8%
	Not Hispanic or Latino	92 88.5%	80 83.3%	79 81.4%	251 84.5%
	Unknown or Not Reported	1 1.0%	0 0.0%	1 1.0%	2 0.7%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	104 participants	96 participants	97 participants	297 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	2 1.9%	1 1.0%	1 1.0%	4 1.3%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	13 12.5%	19 19.8%	18 18.6%	50 16.8%
	White	85 81.7%	74 77.1%	74 76.3%	233 78.5%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	4 3.8%	2 2.1%	4 4.1%	10 3.4%
Years of migraine; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	104 participants	96 participants	97 participants	297 participants
		21.2 (14.1)	18.9 (12.92)	16.9 (12.25)	19.0 (13.21)
Preventive medication use [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	104 participants	96 participants	97 participants	297 participants
	Yes	28 26.9%	32 33.3%	26 26.8%	86 29.0%
	No	76 73.1%	64 66.7%	71 73.2%	211 71.0%
		[1] Measure Description: Participants reported preventive migraine medication use at the time of randomization

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline in the Monthly Migraine Days During the 28-day Post Treatment Period Ending With Week 12
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Low Dose	High Dose
Arm/Group Description:	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).	Participants received 225 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.	Participants received 675 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.
Overall Number of Participants Analyzed	104	95	96
Least Squares Mean (Standard Error); Unit of Measure: Days
	-3.46 (0.53)	-6.27 (0.55)	-6.09 (0.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Low Dose
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< .0001
	Comments	The threshold for statistical significance was p = .05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.81
	Confidence Interval	(2-Sided) 95%; -4.07 to -1.55
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.64
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, High Dose
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< .0001
	Comments	The threshold for statistical significance was p = .05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.64
	Confidence Interval	(2-Sided) 95%; -3.9 to -1.38
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.64
	Estimation Comments	[Not Specified]

2. Primary Outcome

Title	Number of Participants With at Least One Adverse Event
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Low Dose	High Dose
Arm/Group Description:	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).	Participants received 225 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.	Participants received 675 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.
Overall Number of Participants Analyzed	104	96	96
Measure Type: Number; Unit of Measure: Participants
	58	44	57

3. Primary Outcome

Title	Number of Participants Reporting Mild, Moderate, and Severe Adverse Events (AEs)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Low Dose	High Dose
Arm/Group Description:	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).	Participants received 225 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.	Participants received 675 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.
Overall Number of Participants Analyzed	58	44	57
Measure Type: Count of Participants; Unit of Measure: Participants
Mild	29 50.0%	20 45.5%	31 54.4%
Moderate	27 46.6%	20 45.5%	26 45.6%
Severe	1 1.7%	4 9.1%	0 0.0%
Unknown severity	1 1.7%	0 0.0%	0 0.0%

4. Secondary Outcome

Title	Change From Baseline in Number of Days With Headache of Any Severity
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Low Dose	High Dose
Arm/Group Description:	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).	Participants received 225 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.	Participants received 675 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.
Overall Number of Participants Analyzed	104	95	96
Least Squares Mean (Standard Error); Unit of Measure: Days
	-3.52 (0.53)	-6.14 (0.56)	-6.10 (0.54)

Adverse Events

Time Frame	Baseline to week 12
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Placebo		Low Dose		High Dose
Arm/Group Description	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).		Participants received 225 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.		Participants received 675 mg fremanezumab subcutaneously on Day 1/week 0, Day 29/week 4, and on Day 57/week 8.
All-Cause Mortality
	Placebo		Low Dose		High Dose
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/104 (0.00%)		0/96 (0.00%)		0/96 (0.00%)
Serious Adverse Events
	Placebo		Low Dose		High Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/104 (0.00%)		2/96 (2.08%)		2/96 (2.08%)
Blood and lymphatic system disorders
Antiphospholipid syndrome † 1	0/104 (0.00%)	0	0/96 (0.00%)	0	1/96 (1.04%)	1
Injury, poisoning and procedural complications
Fibula fracture † 1	0/104 (0.00%)	0	1/96 (1.04%)	1	0/96 (0.00%)	0
Nervous system disorders
Migraine † 1	0/104 (0.00%)	0	1/96 (1.04%)	1	0/96 (0.00%)	0
Tremor † 1	0/104 (0.00%)	0	0/96 (0.00%)	0	1/96 (1.04%)	1
Vascular disorders
Hypertensive crisis † 1	0/104 (0.00%)	0	1/96 (1.04%)	1	0/96 (0.00%)	0
1 Term from vocabulary, MedDra 17.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo		Low Dose		High Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/104 (8.65%)		9/96 (9.38%)		11/96 (11.46%)
General disorders
Injection site pain † 1	6/104 (5.77%)	10	9/96 (9.38%)	13	4/96 (4.17%)	4
Infections and infestations
Sinusitis † 1	3/104 (2.88%)	3	0/96 (0.00%)	0	5/96 (5.21%)	5
Nervous system disorders
Dizziness † 1	0/104 (0.00%)	0	1/96 (1.04%)	2	5/96 (5.21%)	6
1 Term from vocabulary, MedDra 17.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.

Results Point of Contact

• Name/Title: Director, Clinical Research
• Organization: Teva Branded Pharmaceutical Products R&D, Inc.
• Phone: 1-888-483-8279
• EMail: USMedInfo@tevapharm.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

VanderPluym J, Dodick DW, Lipton RB, Ma Y, Loupe PS, Bigal ME. Fremanezumab for preventive treatment of migraine: Functional status on headache-free days. Neurology. 2018 Sep 18;91(12):e1152-e1165. doi: 10.1212/01.wnl.0000544321.19316.40. Epub 2018 Aug 17.

Halker Singh RB, Aycardi E, Bigal ME, Loupe PS, McDonald M, Dodick DW. Sustained reductions in migraine days, moderate-to-severe headache days and days with acute medication use for HFEM and CM patients taking fremanezumab: Post-hoc analyses from phase 2 trials. Cephalalgia. 2019 Jan;39(1):52-60. doi: 10.1177/0333102418772585. Epub 2018 May 3.

Cohen JM, Dodick DW, Yang R, Newman LC, Li T, Aycardi E, Bigal ME. Fremanezumab as Add-On Treatment for Patients Treated With Other Migraine Preventive Medicines. Headache. 2017 Oct;57(9):1375-1384. doi: 10.1111/head.13156. Epub 2017 Sep 1.

Bigal ME, Dodick DW, Rapoport AM, Silberstein SD, Ma Y, Yang R, Loupe PS, Burstein R, Newman LC, Lipton RB. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol. 2015 Nov;14(11):1081-90. doi: 10.1016/S1474-4422(15)00249-5. Epub 2015 Sep 30.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT02025556
• Other Study ID Numbers: LBR-101-022
• First Submitted: December 20, 2013
• First Posted: January 1, 2014
• Results First Submitted: December 1, 2021
• Results First Posted: January 24, 2022
• Last Update Posted: January 24, 2022