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

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02025556
• Collaborator: NCGS, Inc. (Industry)
• Enrollment: 297
• Locations: 63
• Arms: 3
• Actual Duration (Months): 13.9
• Patients Per Site: 4.7
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Episodic Migraine Headache	Drug: LBR-101 High Dose; Drug: LBR-101 Low Dose; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 297 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Study Comparing the Efficacy and Safety of Two Doses of Subcutaneous LBR-101 With Placebo for the Preventive Treatment of High Frequency Episodic Migraine
• Actual Study Start Date: Jan 31, 2014
• Actual Primary Completion Date: Jan 31, 2015
• Actual Study Completion Date: Mar 31, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LBR-101 High Dose Subcutaneous High Dose LBR-101 Administered Monthly x 3	Drug: LBR-101 High Dose; Subcutaneously Administered High Dose LBR-101 Monthly x 3; Other Names: Fremanezumab
Experimental: LBR-101 Low Dose Subcutaneous Low Dose LBR-101 Administered Monthly x 3	Drug: LBR-101 Low Dose; Subcutaneously Administered Low Dose LBR-101 Monthly x 3; Other Names: Fremanezumab
Placebo Comparator: Placebo Subcutaneous Placebo Administered Monthly x 3	Drug: Placebo; Subcutaneously Administered Placebo (Vehicle) Monthly x 3

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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 Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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:

1. History of headaches on more than 8 days per month for at least 3 months prior to screening

1. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Teva Investigational Site 145	Gilbert	Arizona	United States	85234
2	Teva Investigational Site 130	Phoenix	Arizona	United States	85032
3	Teva Investigational Site 117	Scottsdale	Arizona	United States	85259
4	Teva Investigational Site 158	Little Rock	Arkansas	United States	72205
5	Teva Investigational Site 161	Anaheim	California	United States	92801
6	Teva Investigational Site 116	Fullerton	California	United States	92835
7	Teva Investigational Site 119	Long Beach	California	United States	90806
8	Teva Investigational Site 146	Oceanside	California	United States	92056
9	Teva Investigational Site 113	San Francisco	California	United States	94109
10	Teva Investigational Site 108	Stanford	California	United States	94305
11	Teva Investigational Site 112	Walnut Creek	California	United States	94598
12	Teva Investigational Site 132	Boulder	Colorado	United States	80304
13	Teva Investigational Site 162	Stamford	Connecticut	United States	06905
14	Teva Investigational Site 143	DeLand	Florida	United States	32720
15	Teva Investigational Site 137	Hialeah	Florida	United States	33012
16	Teva Investigational Site 159	Hollywood	Florida	United States	33024
17	Teva Investigational Site 101	Jacksonville	Florida	United States	32216
18	Teva Investigational Site 166	Jacksonville	Florida	United States	32256
19	Teva Investigational Site 129	Maitland	Florida	United States	32751
20	Teva Investigational Site 167	Orlando	Florida	United States	32801
21	Teva Investigational Site 139	Ormond Beach	Florida	United States	32174
22	Teva Investigational Site 140	Port Orange	Florida	United States	32127
23	Teva Investigational Site 160	South Miami	Florida	United States	33143
24	Teva Investigational Site 149	Atlanta	Georgia	United States	30342
25	Teva Investigational Site 164	Decatur	Georgia	United States	30030
26	Teva Investigational Site 134	Douglasville	Georgia	United States	30134
27	Teva Investigational Site 125	Evansville	Indiana	United States	47714
28	Teva Investigational Site 133	Lenexa	Kansas	United States	66214
29	Teva Investigational Site 135	Brockton	Massachusetts	United States	02301
30	Teva Investigational Site 124	New Bedford	Massachusetts	United States	02740
31	Teva Investigational Site 151	Springfield	Massachusetts	United States	01104
32	Teva Investigational Site 109	Watertown	Massachusetts	United States	02472
33	Teva Investigational Site 115	Worcester	Massachusetts	United States	01605
34	Teva Investigational Site 110	Ann Arbor	Michigan	United States	48104
35	Teva Investigational Site 114	Kalamazoo	Michigan	United States	49009
36	Teva Investigational Site 150	Golden Valley	Minnesota	United States	55422
37	Teva Investigational Site 152	Kansas City	Missouri	United States	64114
38	Teva Investigational Site 104	Saint Louis	Missouri	United States	63141
39	Teva Investigational Site 107	Springfield	Missouri	United States	65807
40	Teva Investigational Site 148	Reno	Nevada	United States	89502
41	Teva Investigational Site 105	Bronx	New York	United States	10461
42	Teva Investigational Site 131	Greensboro	North Carolina	United States	27405-6962
43	Teva Investigational Site 118	Raleigh	North Carolina	United States	27607
44	Teva Investigational Site 165	Raleigh	North Carolina	United States	27612
45	Teva Investigational Site 168	Winston-Salem	North Carolina	United States	27103
46	Teva Investigational Site 122	Canton	Ohio	United States	44718
47	Teva Investigational Site 141	Cincinnati	Ohio	United States	45227
48	Teva Investigational Site 142	Cincinnati	Ohio	United States	45229-3039
49	Teva Investigational Site 155	Cleveland	Ohio	United States	44195
50	Teva Investigational Site 102	Columbus	Ohio	United States	43221
51	Teva Investigational Site 127	Oklahoma City	Oklahoma	United States	73112
52	Teva Investigational Site 111	Philadelphia	Pennsylvania	United States	19107
53	Teva Investigational Site 120	Goose Creek	South Carolina	United States	29445
54	Teva Investigational Site 153	Bristol	Tennessee	United States	37620
55	Teva Investigational Site 126	Memphis	Tennessee	United States	38119
56	Teva Investigational Site 154	Nashville	Tennessee	United States	37203
57	Teva Investigational Site 128	Arlington	Texas	United States	76012
58	Teva Investigational Site 121	Austin	Texas	United States	78731
59	Teva Investigational Site 136	Austin	Texas	United States	78745
60	Teva Investigational Site 156	Mansfield	Texas	United States	76063
61	Teva Investigational Site 157	Salt Lake City	Utah	United States	84107
62	Teva Investigational Site 123	Charlottesville	Virginia	United States	22911
63	Teva Investigational Site 144	Roanoke	Virginia	United States	24018

Sponsors and Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.
• NCGS, Inc.

Investigators

• Study Director: Teva Medical Expert, MD, Teva Pharmaceuticals USA

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT02025556
• Other Study ID Numbers: LBR-101-022
• First Posted: Jan 1, 2014
• Last Update Posted: Jan 24, 2022
• Last Verified: Jan 1, 2022

• Keywords provided by Teva Branded Pharmaceutical Products R&D, Inc.: High Frequency Episodic Migraine Headache; Episodic Migraine Headache; Migraine Headache
• Additional relevant MeSH terms: Migraine Disorders; Headache; Antibodies, Monoclonal

Study Results

Participant Flow

Recruitment Details	A total of 297 participants with episodic migraine were enrolled in the study.
Pre-assignment Detail	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	104	96	97
Safety Analysis Set	104	96	96
Intent-to-treat (ITT) Set	104	95	96
COMPLETED	98	83	88
NOT COMPLETED	6	13	9

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 Participants	104	96	97	297
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	42.0 (11.62)	40.8 (12.43)	40.7 (12.56)	41.2 (12.17)
Sex: Female, Male (Count of 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) (Count of 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%	1 1%	2 0.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	2 1.9%	1 1%	1 1%	4 1.3%
Native Hawaiian or Other Pacific Islander	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%
Unknown or Not Reported	4 3.8%	2 2.1%	4 4.1%	10 3.4%
Years of migraine (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	21.2 (14.1)	18.9 (12.92)	16.9 (12.25)	19.0 (13.21)
Preventive medication use (Count of Participants)
Yes	28 26.9%	32 33.3%	26 26.8%	86 29%
No	76 73.1%	64 66.7%	71 73.2%	211 71%

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.
Measure Participants	104	95	96
Least Squares Mean (Standard Error) [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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< .0001
	Comments	The threshold for statistical significance was p = .05.
	Method	Mixed Models Analysis
	Comments
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

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, High Dose
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< .0001
	Comments	The threshold for statistical significance was p = .05.
	Method	Mixed Models Analysis
	Comments
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

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.
Measure Participants	104	96	96
Number [Participants]	58 55.8%	44 45.8%	57 58.8%

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.
Measure Participants	58	44	57
Mild	29 27.9%	20 20.8%	31 32%
Moderate	27 26%	20 20.8%	26 26.8%
Severe	1 1%	4 4.2%	0 0%
Unknown severity	1 1%	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.
Measure Participants	104	95	96
Least Squares Mean (Standard Error) [Days]	-3.52 (0.53)	-6.14 (0.56)	-6.10 (0.54)

Adverse Events

Time Frame	Baseline to week 12
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/104 (0%)		0/96 (0%)		0/96 (0%)
Serious Adverse Events
	Placebo		Low Dose		High Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/104 (0%)		2/96 (2.1%)		2/96 (2.1%)
Blood and lymphatic system disorders
Antiphospholipid syndrome	0/104 (0%)	0	0/96 (0%)	0	1/96 (1%)	1
Injury, poisoning and procedural complications
Fibula fracture	0/104 (0%)	0	1/96 (1%)	1	0/96 (0%)	0
Nervous system disorders
Migraine	0/104 (0%)	0	1/96 (1%)	1	0/96 (0%)	0
Tremor	0/104 (0%)	0	0/96 (0%)	0	1/96 (1%)	1
Vascular disorders
Hypertensive crisis	0/104 (0%)	0	1/96 (1%)	1	0/96 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Low Dose		High Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/104 (8.7%)		9/96 (9.4%)		11/96 (11.5%)
General disorders
Injection site pain	6/104 (5.8%)	10	9/96 (9.4%)	13	4/96 (4.2%)	4
Infections and infestations
Sinusitis	3/104 (2.9%)	3	0/96 (0%)	0	5/96 (5.2%)	5
Nervous system disorders
Dizziness	0/104 (0%)	0	1/96 (1%)	2	5/96 (5.2%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.