A Phase 3 Study of Tezacaftor (VX-661) in Combination With Ivacaftor (VX-770) in Subjects Aged 12 Years and Older With Cystic Fibrosis (CF), Who Have One F508del-CFTR Mutation and a Second Mutation That Has Been Demonstrated to be Clinically Responsive to Ivacaftor

• Sponsor: Vertex Pharmaceuticals Incorporated (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02412111
• Collaborator: (none)
• Enrollment: 156
• Locations: 68
• Arms: 3
• Actual Duration (Months): 27
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a Phase 3, randomized, double-blind, ivacaftor-controlled, parallel-group, multicenter study of tezacaftor in combination with ivacaftor in subjects aged 12 years and older with CF who are heterozygous for the F508del-CFTR mutation and a second CFTR allele with a gating defect that is clinically demonstrated to be ivacaftor responsive.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis	Drug: Ivacaftor; Drug: Tezacaftor/Ivacaftor	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 156 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-Blind, Ivacaftor-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of VX-661 in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Heterozygous for the F508del-CFTR Mutation and a Second CFTR Allele With a Gating Defect That Is Clinically Demonstrated to be Ivacaftor Responsive
• Actual Study Start Date: Jun 1, 2015
• Actual Primary Completion Date: Sep 1, 2017
• Actual Study Completion Date: Sep 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ivacaftor (Run-in Period) Ivacaftor 150 milligram (mg) tablet orally every 12 hours for 4 weeks.	Drug: Ivacaftor; Other Names: VX-770
Experimental: VX-661 + Ivacaftor (Active comparator period) VX-661 100 mg and ivacaftor 150 mg fixed-dose combination tablet orally once daily in the morning and ivacaftor 150 mg tablet orally once daily in the evening for 8 weeks.	Drug: Ivacaftor; Other Names: VX-770 ; Drug: Tezacaftor/Ivacaftor; Other Names: VX-661/VX-770
Active Comparator: Ivacaftor monotherapy (Active comparator period) Ivacaftor 150 mg tablet orally every 12 hours as monotherapy for 8 weeks.	Drug: Ivacaftor; Other Names: VX-770

Outcome Measures

Primary Outcome Measures

1. Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 8 [Baseline, Through Week 8]

   FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.

Secondary Outcome Measures

1. Relative Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 8 [Baseline, Through Week 8]

   FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.

2. Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline Through Week 8 [Baseline, Through Week 8]

   The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.

3. Absolute Change From Baseline in Sweat Chloride Through Week 8 [Baseline, Through Week 8]

   Sweat samples were collected using an approved collection device.

4. Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [Baseline up to Week 16]

5. Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1-VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) [Predose on Week -2 for Run-in period; Pre-dose on Week 2 for Active comparator period]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Heterozygous for F508del-CFTR mutation and a second CFTR allele with a gating defect that is clinically demonstrated to be ivacaftor responsive

• FEV1 ≥40% and ≤90% of predicted normal for age, sex, and height during screening

• Stable CF disease as judged by the investigator.

Exclusion Criteria:

• History of any comorbidity that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject.

• Pregnant and nursing females (females of childbearing potential must have a negative pregnancy test at Screening and Week -4 Visits).

• Sexually active subjects of reproductive potential who are not willing to follow the contraception requirements

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Oakland	California	United States
3		San Diego	California	United States
4		Aurora	Colorado	United States
5		Washington	District of Columbia	United States
6		Orlando	Florida	United States
7		Augusta	Georgia	United States
8		Indianapolis	Indiana	United States
9		Lexington	Kentucky	United States
10		Boston	Massachusetts	United States
11		Ann Arbor	Michigan	United States
12		Detroit	Michigan	United States
13		Grand Rapids	Michigan	United States
14		Saint Louis	Missouri	United States
15		Omaha	Nebraska	United States
16		Lebanon	New Hampshire	United States
17		Manchester	New Hampshire	United States
18		Morristown	New Jersey	United States
19		New Brunswick	New Jersey	United States
20		Albany	New York	United States
21		New York	New York	United States
22		Cincinnati	Ohio	United States
23		Toledo	Ohio	United States
24		Oklahoma City	Oklahoma	United States
25		Portland	Oregon	United States
26		Philadelphia	Pennsylvania	United States
27		Pittsburgh	Pennsylvania	United States
28		Charleston	South Carolina	United States
29		Knoxville	Tennessee	United States
30		Nashville	Tennessee	United States
31		Houston	Texas	United States
32		Salt Lake City	Utah	United States
33		Morgantown	West Virginia	United States
34		Chermside		Australia
35		Clayton		Australia
36		Melbourne		Australia
37		South Brisbane		Australia
38		Westmead		Australia
39		Innsbruck		Austria
40		Bruxelles		Belgium
41		Gent		Belgium
42		Leuven		Belgium
43		Calgary		Canada
44		Toronto		Canada
45		Vancouver		Canada
46		Paris Cedex 14		France
47		Dresden		Germany
48		Erlangen		Germany
49		Essen		Germany
50		Frankfurt		Germany
51		Giessen		Germany
52		Heidelberg		Germany
53		Jena		Germany
54		Munchen		Germany
55		Cork		Ireland
56		Dublin		Ireland
57		Bari		Italy
58		Milano		Italy
59		Roma		Italy
60		Belfast		United Kingdom
61		Birmingham		United Kingdom
62		Cardiff		United Kingdom
63		Glasgow		United Kingdom
64		Leeds		United Kingdom
65		London		United Kingdom
66		Manchester		United Kingdom
67		Newcastle		United Kingdom
68		Southampton		United Kingdom

Sponsors and Collaborators

• Vertex Pharmaceuticals Incorporated

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Apr 18, 2017
• Statistical Analysis Plan - Jul 28, 2017

More Information

Publications

None provided.

• Responsible Party: Vertex Pharmaceuticals Incorporated
• ClinicalTrials.gov Identifier: NCT02412111
• Other Study ID Numbers: VX14-661-109
• First Posted: Apr 8, 2015
• Last Update Posted: Jan 8, 2019
• Last Verified: Jan 1, 2019

• Additional relevant MeSH terms: Cystic Fibrosis; Fibrosis; Ivacaftor

Study Results

Participant Flow

Pre-assignment Detail	The study consisted of 2 periods: an Ivacaftor Run-in Period and an Active Comparator Treatment Period. Participants were randomized in a ratio of 1:1 to receive either VX-661/ivacaftor combination therapy or ivacaftor monotherapy for 8 weeks during the Active Comparator Treatment Period after completion of 4 weeks Ivacaftor Run-in Period.

Arm/Group Title	Ivacaftor (Run-in Period)	VX-661 + Ivacaftor (Active Comparator Period)	Ivacaftor Monotherapy (Active Comparator Period)
Arm/Group Description	Ivacaftor 150 milligram (mg) tablet orally every 12 hours for 4 weeks.	VX-661 100 mg and ivacaftor 150 mg fixed-dose combination tablet orally once daily in the morning and ivacaftor 150 mg tablet orally once daily in the evening for 8 weeks.	Ivacaftor 150 mg tablet orally every 12 hours as monotherapy for 8 weeks.
Period Title: Ivacaftor Run-in Period (4 Weeks)
STARTED	156	0	0
COMPLETED	153	0	0
NOT COMPLETED	3	0	0
Period Title: Ivacaftor Run-in Period (4 Weeks)
STARTED	0	76	75
Full Analysis Set	0	76	74
COMPLETED	0	75	69
NOT COMPLETED	0	1	6

Baseline Characteristics

Arm/Group Title	VX-661 + Ivacaftor (Active Comparator Period)	Ivacaftor Monotherapy (Active Comparator Period)	Total
Arm/Group Description	VX-661 100 mg and ivacaftor 150 mg fixed-dose combination tablet orally once daily in the morning and ivacaftor 150 mg tablet orally once daily in the evening for 8 weeks.	Ivacaftor 150 mg tablet orally every 12 hours as monotherapy for 8 weeks.	Total of all reporting groups
Overall Participants	76	74	150
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33.0 (13.1)	31.8 (11.1)	32.4 (12.2)
Sex: Female, Male (Count of Participants)
Female	32 42.1%	34 45.9%	66 44%
Male	44 57.9%	40 54.1%	84 56%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 1.4%	1 0.7%
Not Hispanic or Latino	76 100%	72 97.3%	148 98.7%
Unknown or Not Reported	0 0%	1 1.4%	1 0.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 2.6%	0 0%	2 1.3%
White	73 96.1%	72 97.3%	145 96.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 1.3%	2 2.7%	3 2%

Outcome Measures

1. Primary Outcome

Title	Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 8
Description	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time Frame	Baseline, Through Week 8

Outcome Measure Data

Analysis Population Description

Full Analysis Set was defined as all randomized participants who have received at least 1 dose of blinded study drug during the active comparator treatment period. Here "Overall number of participants analyzed" signifies those participants who were evaluable for this outcome.

Arm/Group Title	VX-661 + Ivacaftor (Active Comparator Period)	Ivacaftor Monotherapy (Active Comparator Period)
Arm/Group Description	VX-661 100 mg and ivacaftor 150 mg fixed-dose combination tablet orally once daily in the morning and ivacaftor 150 mg tablet orally once daily in the evening for 8 weeks.	Ivacaftor 150 mg tablet orally every 12 hours as monotherapy for 8 weeks.
Measure Participants	76	72
Least Squares Mean (Standard Error) [Percent predicted of FEV1]	0.5 (0.4)	0.2 (0.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VX-661 + Ivacaftor (Active Comparator Period), Ivacaftor Monotherapy (Active Comparator Period)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.5846
	Comments
	Method	Mixed Model for Repeated Measures (MMRM)
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) mean difference
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -0.8 to 1.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Relative Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 8
Description	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time Frame	Baseline, Through Week 8

Outcome Measure Data

Analysis Population Description

Full Analysis Set was defined as all randomized participants who have received at least 1 dose of blinded study drug during the active comparator treatment period. Here "Overall number of participants analyzed" signifies those participants who were evaluable for this outcome.

Arm/Group Title	VX-661 + Ivacaftor (Active Comparator Period)	Ivacaftor Monotherapy (Active Comparator Period)
Arm/Group Description	VX-661 100 mg and ivacaftor 150 mg fixed-dose combination tablet orally once daily in the morning and ivacaftor 150 mg tablet orally once daily in the evening for 8 weeks.	Ivacaftor 150 mg tablet orally every 12 hours as monotherapy for 8 weeks.
Measure Participants	76	72
Least Squares Mean (Standard Error) [Percent change]	1.3 (0.6)	0.5 (0.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VX-661 + Ivacaftor (Active Comparator Period), Ivacaftor Monotherapy (Active Comparator Period)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.3860
	Comments
	Method	Mixed models Repeated Measures (MMRM)
	Comments
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; -1.0 to 2.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline Through Week 8
Description	The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.
Time Frame	Baseline, Through Week 8

Outcome Measure Data

Analysis Population Description

Full Analysis Set was defined as all randomized participants who have received at least 1 dose of blinded study drug during the active comparator treatment period. Here "Overall number of participants analyzed" signifies those participants who were evaluable for this outcome.

Arm/Group Title	VX-661 + Ivacaftor (Active Comparator Period)	Ivacaftor Monotherapy (Active Comparator Period)
Arm/Group Description	VX-661 100 mg and ivacaftor 150 mg fixed-dose combination tablet orally once daily in the morning and ivacaftor 150 mg tablet orally once daily in the evening for 8 weeks.	Ivacaftor 150 mg tablet orally every 12 hours as monotherapy for 8 weeks.
Measure Participants	76	73
Least Squares Mean (Standard Error) [units on a scale]	0.7 (1.3)	-2.1 (1.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VX-661 + Ivacaftor (Active Comparator Period), Ivacaftor Monotherapy (Active Comparator Period)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.1236
	Comments
	Method	Mixed models Repeated Measures (MMRM)
	Comments
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	2.8
	Confidence Interval	(2-Sided) 95%; -0.8 to 6.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Absolute Change From Baseline in Sweat Chloride Through Week 8
Description	Sweat samples were collected using an approved collection device.
Time Frame	Baseline, Through Week 8

Outcome Measure Data

Analysis Population Description

Full Analysis Set was defined as all randomized participants who have received at least 1 dose of blinded study drug during the active comparator treatment period. Here "Overall number of participants analyzed" signifies those participants who were evaluable for this outcome.

Arm/Group Title	VX-661 + Ivacaftor (Active Comparator Period)	Ivacaftor Monotherapy (Active Comparator Period)
Arm/Group Description	VX-661 100 mg and ivacaftor 150 mg fixed-dose combination tablet orally once daily in the morning and ivacaftor 150 mg tablet orally once daily in the evening for 8 weeks.	Ivacaftor 150 mg tablet orally every 12 hours as monotherapy for 8 weeks.
Measure Participants	74	70
Least Squares Mean (Standard Error) [Millimoles per liter]	-7.9 (1.7)	-2.1 (1.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VX-661 + Ivacaftor (Active Comparator Period), Ivacaftor Monotherapy (Active Comparator Period)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0216
	Comments
	Method	Mixed models Repeated Measures (MMRM)
	Comments
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	-5.8
	Confidence Interval	(2-Sided) 95%; -10.7 to -0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame	Baseline up to Week 16

Outcome Measure Data

Analysis Population Description

The Safety Set included all participants who received at least 1 dose of study drug during Ivacaftor (Run-in period) and active comparator treatment period.

Arm/Group Title	Ivacaftor (Run-in Period)	VX-661 + Ivacaftor (Active Comparator Period)	Ivacaftor Monotherapy (Active Comparator Period)
Arm/Group Description	Ivacaftor 150 milligram (mg) tablet orally every 12 hours for 4 weeks.	VX-661 100 mg and ivacaftor 150 mg fixed-dose combination tablet orally once daily in the morning and ivacaftor 150 mg tablet orally once daily in the evening for 8 weeks.	Ivacaftor 150 mg tablet orally every 12 hours as monotherapy for 8 weeks.
Measure Participants	156	76	75
Participants with AEs	66 86.8%	50 67.6%	54 36%
Participants with SAEs	2 2.6%	4 5.4%	7 4.7%

6. Secondary Outcome

Title	Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1-VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA)
Time Frame	Predose on Week -2 for Run-in period; Pre-dose on Week 2 for Active comparator period

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set included participants who received study drug and had PK assessment. Here 'Overall number of participants analyzed' signifies participants who were evaluable for this outcome. "Number Analyzed=0" indicates no participants were analyzed for specified categories because VX-661 was not administered in the specified arms.

Arm/Group Title	Ivacaftor (Run-in Period)	VX-661 + Ivacaftor (Active Comparator Period)	Ivacaftor Monotherapy (Active Comparator Period)
Arm/Group Description	Ivacaftor 150 milligram (mg) tablet orally every 12 hours for 4 weeks.	VX-661 100 mg and ivacaftor 150 mg fixed-dose combination tablet orally once daily in the morning and ivacaftor 150 mg tablet orally once daily in the evening for 8 weeks.	Ivacaftor 150 mg tablet orally every 12 hours as monotherapy for 8 weeks.
Measure Participants	143	75	68
IVA	812 (615)	1000 (742)	740 (464)
M1-IVA	1590 (956)	1830 (1010)	1450 (828)
VX-661	2520 (1490)
M1-VX-661	4870 (1750)

Adverse Events

Time Frame	Baseline up to Week 16
Arm/Group Title	Ivacaftor (Run-in Period)		VX-661 + Ivacaftor (Active Comparator Period)		Ivacaftor Monotherapy (Active Comparator Period)
Arm/Group Description	Ivacaftor 150 milligram (mg) tablet orally every 12 hours for 4 weeks.		VX-661 100 mg and ivacaftor 150 mg fixed-dose combination tablet orally once daily in the morning and ivacaftor 150 mg tablet orally once daily in the evening for 8 weeks.		Ivacaftor 150 mg tablet orally every 12 hours as monotherapy for 8 weeks.
All Cause Mortality
	Ivacaftor (Run-in Period)		VX-661 + Ivacaftor (Active Comparator Period)		Ivacaftor Monotherapy (Active Comparator Period)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/156 (0%)		0/76 (0%)		0/75 (0%)
Serious Adverse Events
	Ivacaftor (Run-in Period)		VX-661 + Ivacaftor (Active Comparator Period)		Ivacaftor Monotherapy (Active Comparator Period)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/156 (1.3%)		4/76 (5.3%)		7/75 (9.3%)
Gastrointestinal disorders
Pancreatitis	1/156 (0.6%)		0/76 (0%)		0/75 (0%)
General disorders
Face oedema	0/156 (0%)		1/76 (1.3%)		0/75 (0%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	1/156 (0.6%)		2/76 (2.6%)		5/75 (6.7%)
Infective exacerbation of bronchiectasis	0/156 (0%)		1/76 (1.3%)		0/75 (0%)
Influenza	0/156 (0%)		1/76 (1.3%)		0/75 (0%)
Investigations
Human rhinovirus test positive	1/156 (0.6%)		0/76 (0%)		0/75 (0%)
Nervous system disorders
Idiopathic intracranial hypertension	0/156 (0%)		0/76 (0%)		1/75 (1.3%)
Psychiatric disorders
Suicidal ideation	0/156 (0%)		0/76 (0%)		1/75 (1.3%)
Renal and urinary disorders
Acute kidney injury	0/156 (0%)		1/76 (1.3%)		0/75 (0%)
Skin and subcutaneous tissue disorders
Urticaria	0/156 (0%)		1/76 (1.3%)		0/75 (0%)
Other (Not Including Serious) Adverse Events
	Ivacaftor (Run-in Period)		VX-661 + Ivacaftor (Active Comparator Period)		Ivacaftor Monotherapy (Active Comparator Period)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/156 (15.4%)		25/76 (32.9%)		32/75 (42.7%)
Gastrointestinal disorders
Nausea	3/156 (1.9%)		0/76 (0%)		4/75 (5.3%)
Diarrhoea	2/156 (1.3%)		4/76 (5.3%)		1/75 (1.3%)
General disorders
Fatigue	4/156 (2.6%)		5/76 (6.6%)		2/75 (2.7%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	2/156 (1.3%)		6/76 (7.9%)		4/75 (5.3%)
Viral upper respiratory tract infection	1/156 (0.6%)		4/76 (5.3%)		6/75 (8%)
Nervous system disorders
Dizziness	2/156 (1.3%)		4/76 (5.3%)		0/75 (0%)
Headache	10/156 (6.4%)		6/76 (7.9%)		4/75 (5.3%)
Respiratory, thoracic and mediastinal disorders
Cough	12/156 (7.7%)		12/76 (15.8%)		12/75 (16%)
Sputum increased	8/156 (5.1%)		4/76 (5.3%)		7/75 (9.3%)
Haemoptysis	3/156 (1.9%)		3/76 (3.9%)		4/75 (5.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

PI is free to publish results of the study after (1)first multi-center publication, (2)if sponsor elects not to publish the results, or(3)18 months after close of the study, whichever occurs first. Proposed publications are to be submitted to the sponsor for review and comment for a period of at least 45 days (which may be extended under certain circumstances related to protection of intellectual property); the sponsor cannot require changes to the proposed publications.