Aortic Stenosis and PhosphodiEsterase Type 5 iNhibition (ASPEN): A Pilot Study

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01275339
• Collaborator: (none)
• Enrollment: 10
• Location: 1
• Arms: 4
• Duration (Months): 52.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Currently, aortic stenosis (AS) is considered a "surgical disease" with no medical therapy available to improve any clinical outcomes, including symptoms, time to surgery, or long-term survival. Thus far, randomized studies involving statins have not been promising with respect to slowing progressive valve stenosis. Beyond the valve, two common consequences of aortic stenosis are hypertrophic remodeling of the left ventricle (LV) and pulmonary venous hypertension; each of these has been associated with worse heart failure symptoms, increased operative mortality, and worse long-term outcomes. Whether altering LV structural abnormalities, improving LV function, and/or reducing pulmonary artery pressures with medical therapy would improve clinical outcomes in patients with AS has not been tested. Animal models of pressure overload have demonstrated that phosphodiesterase type 5 (PDE5) inhibition influences nitric oxide (NO) - cyclic guanosine monophosphate (cGMP) signaling in the LV and favorably impacts LV structure and function, but this has not been tested in humans with AS. Studies in humans with left-sided heart failure and pulmonary venous hypertension have shown that PDE5 inhibition improves functional capacity and quality of life, but patients with AS were not included in those studies. The investigators hypothesize that PDE5 inhibition with tadalafil will have a favorable impact on LV structure and function as well as pulmonary artery pressures. In this pilot study, the investigators anticipate that short-term administration of tadalafil to patients with AS will be safe and well-tolerated.

Condition or Disease	Intervention/Treatment	Phase
Aortic Stenosis; LV Remodeling, Hypertrophy	Drug: Tadalafil; Drug: Placebo	Phase 4

Detailed Description

Subjects with moderately severe to severe aortic stenosis (AS), left ventricular hypertrophy (LVH), diastolic dysfunction, preserved ejection fraction, and no planned aortic valve replacement over the next 6 months will be eligible for this randomized, double-blind, placebo-controlled, pilot study. There will be a diabetic cohort (n=32) and non-diabetic cohort (n=24); each cohort will be randomized 1:1 to tadalafil vs. placebo. During a baseline study visit, the following will be obtained: clinical data, 6 minute walk, quality of life questionnaire, blood draw, and an echocardiogram. A 3-day run-in will occur to initially assess tolerability and compliance. If the drug is tolerated during this run-in period, participants will be randomized. An MRI will also be performed during this randomization visit. Follow-up study visits and testing will occur at 6 and 12 weeks and 6 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Aortic Stenosis and PhosphodiEsterase Type 5 iNhibition (ASPEN): A Pilot Study
• Study Start Date: Dec 1, 2012
• Actual Primary Completion Date: Apr 14, 2017
• Actual Study Completion Date: Apr 14, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Tadalafil in Diabetic Cohort	Drug: Tadalafil; Active drug will be encapsulated to look identical to the placebo pill. Subjects will take a single oral dose of tadalafil once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 20 mg (1 pill) daily for 3 days before having the dose increased to 40 mg (2 pills) once daily. If the increase to 40mg daily is not tolerated, then the dose will be decreased back to 20mg daily.; Other Names: Cialis Adcirca
Placebo Comparator: Placebo in Diabetic Cohort	Drug: Placebo; The placebo pill will be encapsulated to look identical to the active drug pill. Subjects will take a single oral dose of placebo once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 1 pill daily for 3 days before having the dose increased to 2 pills once daily. If the increase to 2 pills is not tolerated, then the dose will be decreased back to 1 pill daily.
Active Comparator: Tadalafil in Non-Diabetic Cohort	Drug: Tadalafil; Active drug will be encapsulated to look identical to the placebo pill. Subjects will take a single oral dose of tadalafil once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 20 mg (1 pill) daily for 3 days before having the dose increased to 40 mg (2 pills) once daily. If the increase to 40mg daily is not tolerated, then the dose will be decreased back to 20mg daily.; Other Names: Cialis Adcirca
Placebo Comparator: Placebo in Non-Diabetic Cohort	Drug: Placebo; The placebo pill will be encapsulated to look identical to the active drug pill. Subjects will take a single oral dose of placebo once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 1 pill daily for 3 days before having the dose increased to 2 pills once daily. If the increase to 2 pills is not tolerated, then the dose will be decreased back to 1 pill daily.

Outcome Measures

Primary Outcome Measures

1. Diastolic Function as Measured by Tissue Doppler e' [Baseline, 12 weeks, and 6 months]

   Measurement of e' (average of septal and lateral) on echo at each of the time points specified.

Secondary Outcome Measures

1. Change in Myocardial Fibrosis (ECV) on MRI [6 months]

2. Change in Other Echocardiographic Indices of Diastolic Function [12 weeks and 6 months]

   E/e' and deceleration time

3. Safety and Tolerability [6 and 12 weeks and 6 months]

   The following with be reported - frequency of the following: hypotension (SBP < 90 mmHg), symptomatic hypotension (symptoms of presyncope or syncope associated with SBP <90), syncope, hospitalization for a cardiac reason, myocardial infarction, new onset or worsening heart failure, and new sustained arrhythmia requiring intervention

4. Change in Indices of Systolic Function [12 weeks and 6 months]

   Stroke volume, EF, LV twist, and stress-corrected midwall shortening by echo and 3D multiparametric strain and EF by MRI

5. Change in LV Hypertrophic Remodeling [12 weeks and 6 months]

   Relative wall thickness, LV chamber dimensions, and wall thickness

6. Change in Novel Echocardiographic Indices of Diastolic Function [12 weeks and 6 months]

   LV stiffness, viscoelasticity, and a load independent index of diastolic filling

7. Change in 6 Minute Walk Distance [6 and 12 weeks and 6 months]

8. Change in Circulating Neurohormonal Markers [6 and 12 weeks and 6 months]

   BNP and systemic markers of collagen turnover and oxidative stress

9. Change in Quality of Life [6 and 12 weeks and 6 months]

   Assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ)

10. Change in Pulmonary Artery Pressure and Pulmonary Vascular Resistance as Assessed by Echo [12 weeks and 6 months]

11. Change in Systemic Blood Pressure [6 and 12 weeks and 6 months]

12. Change in RV Function [12 weeks and 6 months]

    TAPSE, s' tissue Doppler, and Tei index

13. Change in AS Severity [12 weeks and 6 months]

    Aortic valve area, transvalvular pressure gradients

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with moderate to severe aortic stenosis (AVA < 1.5 cm2)

• Left ventricular hypertrophy

• Diastolic dysfunction as evidenced by tissue Doppler e' (average of septal and lateral) ≤ 7 cm/s

• EF ≥ 50%

• None or minimal symptoms related to aortic stenosis (NYHA ≤ 2)

• The subject and treating physician are not planning on a valve replacement procedure to occur during the next 6 months

• Ambulatory

• Normal sinus rhythm

• 18 years of age and older

• Able and willing to comply with all the requirements for the study

Exclusion Criteria:

• Need for ongoing nitrate medications

• SBP < 110mmHg or MAP < 75mmHg

• Moderately severe or severe mitral regurgitation

• Moderately severe or severe aortic regurgitation

• Contraindication to MRI

• Creatinine clearance < 30 mL/min

• Cirrhosis

• Pulmonary fibrosis

• Increased risk of priapism

• Retinal or optic nerve problems or unexplained visual disturbance

• If a subject requires ongoing use of an alpha antagonist typically used for benign prostatic hyperplasia (BPH) (prazosin, terazosin, doxazosin, or tamsulosin), SBP < 120 mmHg or MAP < 80 mmHg is excluded

• Need for ongoing use of a potent CYP3A inhibitor or inducer (ritonavir, ketoconazole, itraconazole, rifampin)

• Current or recent (≤ 30 days) acute coronary syndrome

• O2 sat < 90% on room air

• Females that are pregnant or believe they may be pregnant

• Any condition which the PI determines will place the subject at increased risk or is likely to yield unreliable data

• Unwilling to provide informed consent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington University School of Medicine	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Washington University School of Medicine

Investigators

• Principal Investigator: Brian R. Lindman, MD, MSCI, Washington University School of Medicine

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 1, 2012

More Information

Publications

None provided.

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT01275339
• Other Study ID Numbers: 10-1334b
• First Posted: Jan 12, 2011
• Last Update Posted: Apr 17, 2019
• Last Verified: Apr 1, 2019

• Keywords provided by Washington University School of Medicine: Aortic valve stenosis; Tadalafil; Phosphodiesterase inhibitors; Hypertension, pulmonary; Hypertrophy, left ventricular
• Additional relevant MeSH terms: Aortic Valve Stenosis; Constriction, Pathologic; Hypertrophy; Tadalafil

Study Results

Participant Flow

Arm/Group Title	Tadalafil in Diabetic Cohort	Placebo in Diabetic Cohort	Tadalafil in Non-Diabetic Cohort	Placebo in Non-Diabetic Cohort
Arm/Group Description	Tadalafil: Active drug will be encapsulated to look identical to the placebo pill. Subjects will take a single oral dose of tadalafil once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 20 mg (1 pill) daily for 3 days before having the dose increased to 40 mg (2 pills) once daily. If the increase to 40mg daily is not tolerated, then the dose will be decreased back to 20mg daily.	Placebo: The placebo pill will be encapsulated to look identical to the active drug pill. Subjects will take a single oral dose of placebo once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 1 pill daily for 3 days before having the dose increased to 2 pills once daily. If the increase to 2 pills is not tolerated, then the dose will be decreased back to 1 pill daily.	Tadalafil: Active drug will be encapsulated to look identical to the placebo pill. Subjects will take a single oral dose of tadalafil once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 20 mg (1 pill) daily for 3 days before having the dose increased to 40 mg (2 pills) once daily. If the increase to 40mg daily is not tolerated, then the dose will be decreased back to 20mg daily.	Placebo: The placebo pill will be encapsulated to look identical to the active drug pill. Subjects will take a single oral dose of placebo once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 1 pill daily for 3 days before having the dose increased to 2 pills once daily. If the increase to 2 pills is not tolerated, then the dose will be decreased back to 1 pill daily.
Period Title: Overall Study
STARTED	2	0	4	4
COMPLETED	1	0	3	4
NOT COMPLETED	1	0	1	0

Baseline Characteristics

Arm/Group Title	Tadalafil in Diabetic Cohort	Placebo in Diabetic Cohort	Tadalafil in Non-Diabetic Cohort	Placebo in Non-Diabetic Cohort	Total
Arm/Group Description	Tadalafil: Active drug will be encapsulated to look identical to the placebo pill. Subjects will take a single oral dose of tadalafil once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 20 mg (1 pill) daily for 3 days before having the dose increased to 40 mg (2 pills) once daily. If the increase to 40mg daily is not tolerated, then the dose will be decreased back to 20mg daily.	Placebo: The placebo pill will be encapsulated to look identical to the active drug pill. Subjects will take a single oral dose of placebo once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 1 pill daily for 3 days before having the dose increased to 2 pills once daily. If the increase to 2 pills is not tolerated, then the dose will be decreased back to 1 pill daily.	Tadalafil: Active drug will be encapsulated to look identical to the placebo pill. Subjects will take a single oral dose of tadalafil once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 20 mg (1 pill) daily for 3 days before having the dose increased to 40 mg (2 pills) once daily. If the increase to 40mg daily is not tolerated, then the dose will be decreased back to 20mg daily.	Placebo: The placebo pill will be encapsulated to look identical to the active drug pill. Subjects will take a single oral dose of placebo once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 1 pill daily for 3 days before having the dose increased to 2 pills once daily. If the increase to 2 pills is not tolerated, then the dose will be decreased back to 1 pill daily.	Total of all reporting groups
Overall Participants	2	0	4	4	10
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	65	81.25	75.5	75.7
Sex: Female, Male (Count of Participants)
Female	0 0%	0 NaN	1 25%	1 25%	2 20%
Male	2 100%	0 NaN	3 75%	3 75%	8 80%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 NaN	0 0%	0 0%
Asian	0 0%	0 NaN	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 NaN	0 0%	0 0%
Black or African American	1 50%	1 Infinity	0 0%	2 50%
White	1 50%	3 Infinity	4 100%	8 200%
More than one race	0 0%	0 NaN	0 0%	0 0%
Unknown or Not Reported	0 0%	0 NaN	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Diastolic Function as Measured by Tissue Doppler e'
Description	Measurement of e' (average of septal and lateral) on echo at each of the time points specified.
Time Frame	Baseline, 12 weeks, and 6 months

Outcome Measure Data

Analysis Population Description

There were 0 enrolled that were randomized to placebo in the diabetic cohort; the total number enrolled in the study was small, so this happened randomly.

Arm/Group Title	Tadalafil in Diabetic Cohort	Placebo in Diabetic Cohort	Tadalafil in Non-Diabetic Cohort	Placebo in Non-Diabetic Cohort
Arm/Group Description	Tadalafil: Active drug will be encapsulated to look identical to the placebo pill. Subjects will take a single oral dose of tadalafil once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 20 mg (1 pill) daily for 3 days before having the dose increased to 40 mg (2 pills) once daily. If the increase to 40mg daily is not tolerated, then the dose will be decreased back to 20mg daily.	Placebo: The placebo pill will be encapsulated to look identical to the active drug pill. Subjects will take a single oral dose of placebo once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 1 pill daily for 3 days before having the dose increased to 2 pills once daily. If the increase to 2 pills is not tolerated, then the dose will be decreased back to 1 pill daily.	Tadalafil: Active drug will be encapsulated to look identical to the placebo pill. Subjects will take a single oral dose of tadalafil once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 20 mg (1 pill) daily for 3 days before having the dose increased to 40 mg (2 pills) once daily. If the increase to 40mg daily is not tolerated, then the dose will be decreased back to 20mg daily.	Placebo: The placebo pill will be encapsulated to look identical to the active drug pill. Subjects will take a single oral dose of placebo once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 1 pill daily for 3 days before having the dose increased to 2 pills once daily. If the increase to 2 pills is not tolerated, then the dose will be decreased back to 1 pill daily.
Measure Participants	2	0	4	4
Baseline	4.59	5.97	5.28
12 weeks	3.75	6.44	4.88
6 months	4.63	6.16	5.33

2. Secondary Outcome

Title	Change in Myocardial Fibrosis (ECV) on MRI
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Change in Other Echocardiographic Indices of Diastolic Function
Description	E/e' and deceleration time
Time Frame	12 weeks and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Safety and Tolerability
Description	The following with be reported - frequency of the following: hypotension (SBP < 90 mmHg), symptomatic hypotension (symptoms of presyncope or syncope associated with SBP <90), syncope, hospitalization for a cardiac reason, myocardial infarction, new onset or worsening heart failure, and new sustained arrhythmia requiring intervention
Time Frame	6 and 12 weeks and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Change in Indices of Systolic Function
Description	Stroke volume, EF, LV twist, and stress-corrected midwall shortening by echo and 3D multiparametric strain and EF by MRI
Time Frame	12 weeks and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Change in LV Hypertrophic Remodeling
Description	Relative wall thickness, LV chamber dimensions, and wall thickness
Time Frame	12 weeks and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Change in Novel Echocardiographic Indices of Diastolic Function
Description	LV stiffness, viscoelasticity, and a load independent index of diastolic filling
Time Frame	12 weeks and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Change in 6 Minute Walk Distance
Time Frame	6 and 12 weeks and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Change in Circulating Neurohormonal Markers
Description	BNP and systemic markers of collagen turnover and oxidative stress
Time Frame	6 and 12 weeks and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	Change in Quality of Life
Description	Assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ)
Time Frame	6 and 12 weeks and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Secondary Outcome

Title	Change in Pulmonary Artery Pressure and Pulmonary Vascular Resistance as Assessed by Echo
Time Frame	12 weeks and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Secondary Outcome

Title	Change in Systemic Blood Pressure
Time Frame	6 and 12 weeks and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Secondary Outcome

Title	Change in RV Function
Description	TAPSE, s' tissue Doppler, and Tei index
Time Frame	12 weeks and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Secondary Outcome

Title	Change in AS Severity
Description	Aortic valve area, transvalvular pressure gradients
Time Frame	12 weeks and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	6 months
Adverse Event Reporting Description	In that arm of the study, no patients were enrolled.
Arm/Group Title	Tadalafil in Diabetic Cohort		Placebo in Diabetic Cohort		Tadalafil in Non-Diabetic Cohort		Placebo in Non-Diabetic Cohort
Arm/Group Description	Tadalafil: Active drug will be encapsulated to look identical to the placebo pill. Subjects will take a single oral dose of tadalafil once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 20 mg (1 pill) daily for 3 days before having the dose increased to 40 mg (2 pills) once daily. If the increase to 40mg daily is not tolerated, then the dose will be decreased back to 20mg daily.		Placebo: The placebo pill will be encapsulated to look identical to the active drug pill. Subjects will take a single oral dose of placebo once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 1 pill daily for 3 days before having the dose increased to 2 pills once daily. If the increase to 2 pills is not tolerated, then the dose will be decreased back to 1 pill daily.		Tadalafil: Active drug will be encapsulated to look identical to the placebo pill. Subjects will take a single oral dose of tadalafil once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 20 mg (1 pill) daily for 3 days before having the dose increased to 40 mg (2 pills) once daily. If the increase to 40mg daily is not tolerated, then the dose will be decreased back to 20mg daily.		Placebo: The placebo pill will be encapsulated to look identical to the active drug pill. Subjects will take a single oral dose of placebo once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 1 pill daily for 3 days before having the dose increased to 2 pills once daily. If the increase to 2 pills is not tolerated, then the dose will be decreased back to 1 pill daily.
All Cause Mortality
	Tadalafil in Diabetic Cohort		Placebo in Diabetic Cohort		Tadalafil in Non-Diabetic Cohort		Placebo in Non-Diabetic Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/0 (NaN)		0/4 (0%)		0/4 (0%)
Serious Adverse Events
	Tadalafil in Diabetic Cohort		Placebo in Diabetic Cohort		Tadalafil in Non-Diabetic Cohort		Placebo in Non-Diabetic Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/0 (NaN)		0/4 (0%)		0/4 (0%)
Other (Not Including Serious) Adverse Events
	Tadalafil in Diabetic Cohort		Placebo in Diabetic Cohort		Tadalafil in Non-Diabetic Cohort		Placebo in Non-Diabetic Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/2 (50%)		0/0 (NaN)		2/4 (50%)		2/4 (50%)
Cardiac disorders
lightheadedness	1/2 (50%)	1	1/0 (Infinity)	1	0/4 (0%)	0	0/4 (0%)	0
Gastrointestinal disorders
nausea	0/2 (0%)	0	0/0 (NaN)	0	1/4 (25%)	1	0/4 (0%)	0
Musculoskeletal and connective tissue disorders
fall	0/2 (0%)	0	0/0 (NaN)	0	1/4 (25%)	1	0/4 (0%)	0
unsteady	0/2 (0%)	0	0/0 (NaN)	0	1/4 (25%)	1	0/4 (0%)	0
Respiratory, thoracic and mediastinal disorders
shortness of breath	1/2 (50%)	1	1/0 (Infinity)	1	0/4 (0%)	0	1/4 (25%)	1
orthopnea	1/2 (50%)	1	1/0 (Infinity)	1	0/4 (0%)	0	0/4 (0%)	0
Vascular disorders
dilated aorta	0/2 (0%)	0	0/0 (NaN)	0	0/4 (0%)	0	1/4 (25%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.