A Study of ALKS 5461 for the Treatment of Major Depressive Disorder (MDD) - the FORWARD-3 Study

• Sponsor: Alkermes, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02158546
• Collaborator: (none)
• Enrollment: 447
• Locations: 58
• Arms: 2
• Duration (Months): 19
• Patients Per Site: 7.7
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This study will evaluate the efficacy and safety of ALKS 5461.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: ALKS 5461; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 447 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Efficacy and Safety Study of ALKS 5461 for the Adjunctive Treatment of Major Depressive Disorder (the FORWARD-3 Study)
• Study Start Date: May 1, 2014
• Actual Primary Completion Date: Dec 1, 2015
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ALKS 5461	Drug: ALKS 5461; Sublingual tablet, taken once daily (in addition to open-label treatment with a commercially available antidepressant)
Placebo Comparator: Placebo	Drug: Placebo; Sublingual tablet, taken once daily (in addition to open-label treatment with a commercially available antidepressant)

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to End of Treatment (Week 6) in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score [Baseline and week 6]

   The MADRS-10 scale is a clinician-administered questionnaire comprised of 10 items used to measure the severity of MDD symptoms. Scores range from 0 (no apparent symptoms) to 60 (most severe symptoms). Individual questionnaire items include: Apparent Sadness, Reported Sadness, Inner Tension, Reduced Sleep, Reduced Appetite, Concentration Difficulties, Lassitude, Inability to Feel, Pessimistic Thoughts, and Suicidal Thoughts.

Secondary Outcome Measures

1. Proportion of Patients Who Exhibited Treatment Response (MADRS-10) [6 weeks]

   The proportion of subjects demonstrating MADRS-10 treatment response, defined as a ≥ 50% reduction in MADRS-10 score from baseline to the end of the efficacy period (week 6).

2. Remission Rate [6 weeks]

   The proportion of subjects achieving remission, defined as a MADRS-10 score of ≤ 10 at the end of the efficacy period.

3. Number of Subjects With Adverse Events (AEs) [6 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Have a Body Mass Index (BMI) of 18.0 to 40.0 kg/m2, inclusive

• Agree to use an acceptable method of contraception for the duration of the study

• Have a Major Depressive Disorder (MDD) primary diagnosis

• Have no more than 2 inadequate responses to antidepressant therapy (ADT) in the current Major Depressive Episode (MDE)

• Additional criteria may apply

Exclusion Criteria:

• Have a current primary Axis-I disorder other than MDD

• Have used opioid agonists (eg, codeine, oxycodone, tramadol, morphine) or opioid antagonists (eg, naloxone, naltrexone) within 14 days

• Have received electroconvulsive therapy treatment within the last 2 years or received more than one course of electroconvulsive treatment during lifetime

• Have attempted suicide within the past 2 years

• Have a positive test for drugs of abuse

• Are pregnant, planning to become pregnant, or breastfeeding

• Have a history of intolerance, allergy, or hypersensitivity to buprenorphine or opioid antagonists (eg, naltrexone, naloxone)

• Have had a significant blood loss or blood donation within 60 days

• Additional criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alkermes Investigational Site	Little Rock	Arkansas	United States	72211
2	Alkermes Investigational Site	Bellflower	California	United States	90706
3	Alkermes Investigational Site	Beverly Hills	California	United States	90210
4	Alkermes Investigational Site	Glendale	California	United States	91206
5	Alkermes Investigational Site	Los Alamitos	California	United States	90720
6	Alkermes Investigational Site	Orange	California	United States	92868
7	Alkermes Investigational Site	Redlands	California	United States	92374
8	Alkermes Investigational Site	Temecula	California	United States	92591
9	Alkermes Investigational Site	Washington	District of Columbia	United States	20016
10	Alkermes Investigational Site	Hallandale Beach	Florida	United States	33009
11	Alkermes Investigational Site	Hialeah	Florida	United States	33016
12	Alkermes Investigational Site	Jacksonville	Florida	United States	32256
13	Alkermes Investigational Site	Leesburg	Florida	United States	34748
14	Alkermes Investigational Site	Maitland	Florida	United States	32751
15	Alkermes Investigational Site	Tampa	Florida	United States	33613
16	Alkermes Investigational Site	Atlanta	Georgia	United States	30331
17	Alkermes Investigational Site	Chicago	Illinois	United States	60634
18	Alkermes Investigational Site	Oak Brook	Illinois	United States	60523
19	Alkermes Investigational Site	Vernon Hills	Illinois	United States	60061
20	Alkermes Investigational Site	Indianapolis	Indiana	United States	46260
21	Alkermes Investigational Site	Lafayette	Indiana	United States	47905
22	Alkermes Investigational Site	Edgewood	Kentucky	United States	41017
23	Alkermes Investigational	Washington DC	Maryland	United States	20016
24	Alkermes Investigational Site	Brockton	Massachusetts	United States	02301
25	Alkermes Investigational Site	Watertown	Massachusetts	United States	02472
26	Alkermes Investigational Site	Kansas City	Missouri	United States	64114
27	Alkermes Investigational Site	O'Fallon	Missouri	United States	63368
28	Alkermes Investigational Site	Saint Louis	Missouri	United States	63109
29	Alkermes Investigational Site	Cherry Hill	New Jersey	United States	08002
30	Alkermes Investigational Site	Albuquerque	New Mexico	United States	87109
31	Alkermes Investigational Site	Jamaica	New York	United States	11432
32	Alkermes Investigational Site	New York	New York	United States	10023
33	Alkermes Investigational Site	Staten Island	New York	United States	10312
34	Alkermes Investigational Site	Charlotte	North Carolina	United States	28204
35	Alkermes Investigational Site	Beachwood	Ohio	United States	44122
36	Alkermes Investigational Site	Cincinnati	Ohio	United States	45215
37	Alkermes Investigational Site	Cincinnati	Ohio	United States	45227
38	Alkermes Investigational Site	Mason	Ohio	United States	45040
39	Alkermes Investigational Site	Middleburg Heights	Ohio	United States	44130
40	Alkermes Investigational Site	Portland	Oregon	United States	97210
41	Alkermes Investigational Site	Salem	Oregon	United States	97301
42	Alkermes Investigational Site	Philadelphia	Pennsylvania	United States	19104
43	Alkermes Investigational Site	Charleston	South Carolina	United States	29407
44	Alkermes Investigational Site	Memphis	Tennessee	United States	38119
45	Alkermes Investigational Site	Dallas	Texas	United States	75231
46	Alkermes Investigational Site	Dallas	Texas	United States	75309
47	Alkermes Investigational Site	Houston	Texas	United States	77098
48	Alkermes Investigational Site	Sugar Land	Texas	United States	77478
49	Alkermes Investigational Site	Bellevue	Washington	United States	98007
50	Alkermes Investigational Site	Waukesha	Wisconsin	United States	53188
51	Alkermes Investigational Site	Bourgas		Bulgaria	8001
52	Alkermes Investigational Site	Kazanlak		Bulgaria	6100
53	Alkermes Investigational Site	Sofia		Bulgaria	1113
54	Alkermes Investigational Site	Sofia		Bulgaria	1431
55	Alkermes Investigational Site	Sofia		Bulgaria	1632
56	Alkermes Investigational Site	Varna		Bulgaria	9020
57	Alkermes Investigational Site	Veliko Tarnovo		Bulgaria	5000
58	Alkermes Investigational Site	Vratza		Bulgaria	3000

Sponsors and Collaborators

• Alkermes, Inc.

Investigators

• Study Director: Sanjeev Pathak, MD, Alkermes, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Alkermes, Inc.
• ClinicalTrials.gov Identifier: NCT02158546
• Other Study ID Numbers: ALK5461-206
• First Posted: Jun 9, 2014
• Last Update Posted: Jun 25, 2019
• Last Verified: May 1, 2019

• Keywords provided by Alkermes, Inc.: Major Depressive Disorder; Depression; Alkermes; ALKS 5461; Samidorphan
• Additional relevant MeSH terms: Disease; Depressive Disorder; Depression; Depressive Disorder, Major

Study Results

Participant Flow

Recruitment Details	Subjects were diagnosed with major depressive disorder (MDD) and had an inadequate response to 1 or 2 adequate courses of treatment with a commercially available antidepressant therapy (ADT) during the current major depressive episode (MDE). All subjects continued ADT for the duration of the study.
Pre-assignment Detail	2 cohorts of subjects were enrolled: Group 1- subjects with baseline HAM-D17 score ≥ 20; Group 2- subjects with baseline HAM-D17 score 18-19. Only Group 1 was included in the efficacy analysis. Study included a 4-week pbo run-in period prior to the 6-week treatment period. In Group 1, 102 subjects did not meet criteria for randomization.

Arm/Group Title	Group 1 - ALKS 5461 2mg/2mg	Group 1 - Placebo	Group 2 ALKS 5461 2mg/2mg	Group 2 - Placebo
Arm/Group Description	Randomized to ALKS 5461 2mg/2mg	Randomized to Placebo	Randomized to ALKS 5461 2mg/2mg	Randomized to placebo
Period Title: Overall Study
STARTED	152	153	18	19
COMPLETED	133	136	14	13
NOT COMPLETED	19	17	4	6

Baseline Characteristics

Arm/Group Title	Group 1 ALKS 5461 2mg/2mg	Group 1 Placebo	Group 2 ALKS 5461 2mg/2mg	Group 2 Placebo	Total
Arm/Group Description	Randomized to ALKS 5461 2mg/2mg	Randomized to placebo	Randomized to ALKS 5461 2mg/2mg	Randomized to placebo	Total of all reporting groups
Overall Participants	147	148	15	15	325
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.4 (12.31)	48.1 (12.51)	47.5 (12.63)	45.9 (11.44)	47.7 (12.33)
Sex: Female, Male (Count of Participants)
Female	88 59.9%	94 63.5%	8 53.3%	7 46.7%	197 60.6%
Male	59 40.1%	54 36.5%	7 46.7%	8 53.3%	128 39.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	23 15.6%	29 19.6%	2 13.3%	1 6.7%	55 16.9%
Not Hispanic or Latino	124 84.4%	119 80.4%	13 86.7%	14 93.3%	270 83.1%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 1.4%	0 0%	0 0%	0 0%	2 0.6%
Asian	5 3.4%	0 0%	0 0%	0 0%	5 1.5%
Native Hawaiian or Other Pacific Islander	1 0.7%	0 0%	0 0%	0 0%	1 0.3%
Black or African American	33 22.4%	33 22.3%	3 20%	2 13.3%	71 21.8%
White	106 72.1%	115 77.7%	12 80%	13 86.7%	246 75.7%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	118 80.3%	128 86.5%	14 93.3%	12 80%	272 83.7%
Bulgaria	29 19.7%	20 13.5%	1 6.7%	3 20%	53 16.3%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to End of Treatment (Week 6) in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score
Description	The MADRS-10 scale is a clinician-administered questionnaire comprised of 10 items used to measure the severity of MDD symptoms. Scores range from 0 (no apparent symptoms) to 60 (most severe symptoms). Individual questionnaire items include: Apparent Sadness, Reported Sadness, Inner Tension, Reduced Sleep, Reduced Appetite, Concentration Difficulties, Lassitude, Inability to Feel, Pessimistic Thoughts, and Suicidal Thoughts.
Time Frame	Baseline and week 6

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of subjects in the Group 1 Safety Population who have at least 1 post-randomization assessment of MADRS total score.

Arm/Group Title	ALKS 5461 2mg/2mg	Placebo
Arm/Group Description	Randomized to ALKS 5461 2mg/2mg	Randomized to placebo
Measure Participants	142	146
Least Squares Mean (Standard Error) [units on a scale]	-4.8 (0.67)	-4.6 (0.66)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ALKS 5461 2mg/2mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.782
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least square means difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -2.1 to 1.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.95
	Estimation Comments

2. Secondary Outcome

Title	Proportion of Patients Who Exhibited Treatment Response (MADRS-10)
Description	The proportion of subjects demonstrating MADRS-10 treatment response, defined as a ≥ 50% reduction in MADRS-10 score from baseline to the end of the efficacy period (week 6).
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

The FAS consists of subjects in the Group 1 Safety Population who have at least 1 post-randomization assessment of MADRS total score.

Arm/Group Title	ALKS 5461 2mg/2mg	Placebo
Arm/Group Description	Randomized to ALKS 5461 2mg/2mg	Randomized to placebo
Measure Participants	142	146
Count of Participants [Participants]	24 16.3%	21 14.2%

3. Secondary Outcome

Title	Remission Rate
Description	The proportion of subjects achieving remission, defined as a MADRS-10 score of ≤ 10 at the end of the efficacy period.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

The FAS consists of subjects in the Group 1 Safety Population who have at least 1 post-randomization assessment of MADRS total score.

Arm/Group Title	ALKS 5461 2mg/2mg	Placebo
Arm/Group Description	Randomized to ALKS 5461 2mg/2mg	Randomized to placebo
Measure Participants	142	146
Count of Participants [Participants]	20 13.6%	18 12.2%

4. Secondary Outcome

Title	Number of Subjects With Adverse Events (AEs)
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Safety population consisted of subjects who were identified as placebo non-responders at the end of the double-blind placebo run-in period and received at least one dose of randomized study drug (ie, placebo or ALKS 5461) subsequent to randomization.

Arm/Group Title	ALKS 5461 2mg/2mg	Placebo	Group 2 ALKS 5461 2mg/2mg	Group 2 Placebo
Arm/Group Description	Randomized to ALKS 5461 2mg/2mg	Randomized to placebo	Randomized to ALKS 5461 2mg/2mg	Randomized to placebo
Measure Participants	147	148	15	15
Count of Participants [Participants]	63 42.9%	51 34.5%	11 73.3%	8 53.3%

Adverse Events

Time Frame	AE reporting includes the 6-week double-blind, placebo-controlled period.
Arm/Group Title	Group 1 ALKS 5461 2mg/2mg		Group 1 Placebo		Group 2 ALKS 5461 2mg/2mg		Group 2 Placebo
Arm/Group Description	Randomized to ALKS 5461 2mg/2mg		Randomized to placebo		Randomized to ALKS 5461 2mg/2mg		Randomized to placebo
All Cause Mortality
	Group 1 ALKS 5461 2mg/2mg		Group 1 Placebo		Group 2 ALKS 5461 2mg/2mg		Group 2 Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/147 (0%)		0/148 (0%)		0/15 (0%)		0/15 (0%)
Serious Adverse Events
	Group 1 ALKS 5461 2mg/2mg		Group 1 Placebo		Group 2 ALKS 5461 2mg/2mg		Group 2 Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/147 (0%)		1/148 (0.7%)		0/15 (0%)		0/15 (0%)
Cardiac disorders
Atrial fibrillation	0/147 (0%)	0	1/148 (0.7%)	1	0/15 (0%)	0	0/15 (0%)	0
Other (Not Including Serious) Adverse Events
	Group 1 ALKS 5461 2mg/2mg		Group 1 Placebo		Group 2 ALKS 5461 2mg/2mg		Group 2 Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/147 (26.5%)		24/148 (16.2%)		11/15 (73.3%)		8/15 (53.3%)
Blood and lymphatic system disorders
Anaemia	0/147 (0%)	0	0/148 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1
Cardiac disorders
Bradycardia	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0
Palpitations	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0
Tachycardia	0/147 (0%)	0	0/148 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1
Eye disorders
Eyelid oedema	0/147 (0%)	0	0/148 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1
Gastrointestinal disorders
Nausea	13/147 (8.8%)	14	1/148 (0.7%)	1	4/15 (26.7%)	7	2/15 (13.3%)	2
Vomiting	4/147 (2.7%)	4	2/148 (1.4%)	2	1/15 (6.7%)	2	0/15 (0%)	0
Constipation	3/147 (2%)	3	1/148 (0.7%)	1	3/15 (20%)	3	0/15 (0%)	0
Dry mouth	3/147 (2%)	3	2/148 (1.4%)	2	2/15 (13.3%)	2	1/15 (6.7%)	1
Diarrhoea	1/147 (0.7%)	1	3/148 (2%)	3	1/15 (6.7%)	2	0/15 (0%)	0
Flatulence	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0
Food poisoning	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0
Gingival pain	0/147 (0%)	0	0/148 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	2
General disorders
Fatigue	4/147 (2.7%)	4	3/148 (2%)	3	1/15 (6.7%)	1	0/15 (0%)	0
Infections and infestations
Upper respiratory tract infection	4/147 (2.7%)	5	3/148 (2%)	4	1/15 (6.7%)	1	0/15 (0%)	0
Nasopharyngitis	3/147 (2%)	3	3/148 (2%)	3	0/15 (0%)	0	1/15 (6.7%)	1
Influenza	0/147 (0%)	0	0/148 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1
Injury, poisoning and procedural complications
Epicondylitis	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0
Tooth fracture	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0
Investigations
Blood creatine phosphokinase increased	4/147 (2.7%)	4	0/148 (0%)	0	0/15 (0%)	0	0/15 (0%)	0
Blood pressure increased	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0
Urine output increased	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0
Metabolic syndorome	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0
Musculoskeletal and connective tissue disorders
Muscle spasms	3/147 (2%)	3	0/148 (0%)	0	0/15 (0%)	0	0/15 (0%)	0
Arthralgia	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0
Musculoskeletal chest pain	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0
Pain in extremity	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0
Nervous system disorders
Headache	6/147 (4.1%)	7	5/148 (3.4%)	7	4/15 (26.7%)	4	1/15 (6.7%)	1
Dizziness	1/147 (0.7%)	1	3/148 (2%)	3	2/15 (13.3%)	2	0/15 (0%)	0
Somnolence	0/147 (0%)	0	0/148 (0%)	0	2/15 (13.3%)	2	0/15 (0%)	0
Burning sensation	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0
Disturbance in attention	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0
Hypersomnia	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0
Hypoaesthesia	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	2	0/15 (0%)	0
Memory impairment	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0
Paraesthesia	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	2	0/15 (0%)	0
Tension headache	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0
Psychiatric disorders
Abnormal dreams	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0
Insomnia	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0
Nightmare	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0
Sleep disorder	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0
Initial insomnia	0/147 (0%)	0	0/148 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0
Skin and subcutaneous tissue disorders
Dermatitis contact	0/147 (0%)	0	0/148 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0
Vascular disorders
Hypertension	3/147 (2%)	3	2/148 (1.4%)	2	0/15 (0%)	0	0/15 (0%)	0

Limitations/Caveats

Pre-specified primary population data are shown. Data from one trial site were excluded as pre-specified due to data integrity concerns (18 subjects). Other excluded subjects did not receive randomized study drug.

More Information

Certain Agreements

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

Should an Investigator desire to disclose study results, Sponsor will review the results disclosure prior to public release and can embargo the disclosure for a period of at least 60 days. Revisions to the disclosure will be negotiated in good faith. For a multicenter study the Investigators agree to publish/publicly present the results together with the other sites for the 12 month period after study results are available unless Sponsor grants written permission in advance.