Impact of Chronic Kidney Disease on the Effects of Ticagrelor in Patients With Diabetes and Coronary Artery Disease

• Sponsor: University of Florida (Other)
• Overall Status: Completed
• CT.gov ID: NCT02539160
• Collaborator: (none)
• Enrollment: 101
• Location: 1
• Arms: 4
• Actual Duration (Months): 52.5
• Patients Per Site Per Month: 1.9

Study Details

Study Description

Brief Summary

Patients with diabetes mellitus (DM) are at increased risk of atherothrombotic events. Importantly, DM is a key risk factor for the development of chronic kidney disease (CKD), which further enhances atherothrombotic risk. Clopidogrel is the most widely used platelet P2Y12 receptor inhibitor. However, despite its clinical benefit, patients with DM and CKD frequently experience recurrent atherothrombotic events. Ticagrelor is an oral, reversible, non-competitive P2Y12 receptor inhibitor with more potent and consistent platelet inhibition than clopidogrel. In large-scale clinical investigation, ticagrelor significantly reduced ischemic events to a greater extent than clopidogrel, a finding that was consistent also among DM patients. To date there has been no analysis on the efficacy of ticagrelor in DM patients according to CKD status. Moreover, although pharmacodynamic (PD) studies showed enhanced platelet inhibition associated with ticagrelor, it is unknown how this may be affected by CKD status. Ultimately, how PK/PD profiles of different ticagrelor dosing regimens may be affected by DM and CKD status is also unknown. The proposed study is aimed to show the impact of CKD status among patients with DM and coronary artery disease) CAD on PD and PK profiles of ticagrelor used at 2 doses (90mg bid and 60mg bid) in the setting of a prospective, randomized, cross-over trial.

Condition or Disease	Intervention/Treatment	Phase
Coronary Artery Disease; Diabetes Mellitus	Drug: ticagrelor	Phase 4

Detailed Description

Patients with diabetes mellitus (DM) are at increased risk of atherothrombotic events. Importantly, DM is a key risk factor for the development of chronic kidney disease (CKD), which further enhances atherothrombotic risk. These observations underscore the importance of antiplatelet therapy for prevention of atherothrombotic recurrences in these high-risk patients. Clopidogrel is the most widely used platelet P2Y12 receptor inhibitor. However, despite its clinical benefit, patients with DM and CKD frequently experience recurrent atherothrombotic events. This may be in part due to the impaired pharmacokinetic (PK) and pharmacodynamic (PD) effects of clopidogrel in patients with DM and CKD. Since both DM and CKD represent pandemic public health problems, the prevalence of which will double over the next 20 years, identifying antiplatelet agents with more favorable PK/PD profiles is of key importance.

Ticagrelor is an oral, reversible, non-competitive P2Y12 receptor inhibitor with more potent and consistent platelet inhibition than clopidogrel. In large-scale clinical investigation, ticagrelor significantly reduced ischemic events to a greater extent than clopidogrel, a finding that was consistent also among DM patients. In patients with CKD, ticagrelor led to an even greater relative risk reduction of ischemic events, including cardiovascular mortality, compared to patients without CKD. However, to date there has been no analysis on the efficacy of ticagrelor in DM patients according to CKD status. Moreover, although PD studies showed enhanced platelet inhibition associated with ticagrelor, it is unknown how this may be affected by CKD status. Ultimately, how PK/PD profiles of different ticagrelor dosing regimens may be affected by DM and CKD status is also unknown. The proposed study is aimed to show the impact of CKD status among patients with DM and CAD on PD and PK profiles of ticagrelor used at 2 doses (90mg bid and 60mg bid) in the setting of a prospective, randomized, cross-over trial.

Study Design

• Study Type: Interventional
• Actual Enrollment: 101 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Impact of Chronic Kidney Disease on the Pharmacodynamic and Pharmacokinetic Effects of Ticagrelor in Patients With Diabetes Mellitus and Coronary Artery Disease
• Actual Study Start Date: Feb 1, 2016
• Actual Primary Completion Date: Nov 14, 2019
• Actual Study Completion Date: Jun 17, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: CKD - Ticagrelor 90 Patients with chronic kidney disease will receive ticagrelor 90mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 60mg twice/daily for 7-10 days.	Drug: ticagrelor; Diabetic patients with or without chronic kidney disease will be randomized 1:1 to either (A) standard dose (90mg twice daily of ticagrelor) for 7-10 days and then cross-over to low dose (60mg twice daily of ticagrelor) for 7-10 days; (B) low dose (60mg twice daily of ticagrelor) for 7-10 days (phase 1) and then cross-over to standard dose (90mg twice daily of ticagrelor) for 7-10 days (phase 2).; Other Names: brilinta
Experimental: CKD - Ticagrelor 60 Patients with chronic kidney disease will receive ticagrelor 60mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 90mg twice/daily for 7-10 days.	Drug: ticagrelor; Diabetic patients with or without chronic kidney disease will be randomized 1:1 to either (A) standard dose (90mg twice daily of ticagrelor) for 7-10 days and then cross-over to low dose (60mg twice daily of ticagrelor) for 7-10 days; (B) low dose (60mg twice daily of ticagrelor) for 7-10 days (phase 1) and then cross-over to standard dose (90mg twice daily of ticagrelor) for 7-10 days (phase 2).; Other Names: brilinta
Active Comparator: Non-CKD - Ticagrelor 90 Patients without chronic kidney disease will receive ticagrelor 90mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 60mg twice/daily for 7-10 days.	Drug: ticagrelor; Diabetic patients with or without chronic kidney disease will be randomized 1:1 to either (A) standard dose (90mg twice daily of ticagrelor) for 7-10 days and then cross-over to low dose (60mg twice daily of ticagrelor) for 7-10 days; (B) low dose (60mg twice daily of ticagrelor) for 7-10 days (phase 1) and then cross-over to standard dose (90mg twice daily of ticagrelor) for 7-10 days (phase 2).; Other Names: brilinta
Experimental: Non-CKD - Ticagrelor 60 Patients without chronic kidney disease will receive ticagrelor 60mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 90mg twice/daily for 7-10 days.	Drug: ticagrelor; Diabetic patients with or without chronic kidney disease will be randomized 1:1 to either (A) standard dose (90mg twice daily of ticagrelor) for 7-10 days and then cross-over to low dose (60mg twice daily of ticagrelor) for 7-10 days; (B) low dose (60mg twice daily of ticagrelor) for 7-10 days (phase 1) and then cross-over to standard dose (90mg twice daily of ticagrelor) for 7-10 days (phase 2).; Other Names: brilinta

Outcome Measures

Primary Outcome Measures

1. Platelet Reactivity Measured by Vasodilator Stimulated Phosphoprotein (VASP) Platelet Reactivity Index (PRI %) [7 days]

   The primary end point of the study was platelet reactivity assessed by VASP-PRI following treatment with ticagrelor 90mg between DM-CKD and DM-non-CKD cohorts. PRI % is a measure of platelet reactivity, where higher PRI levels represent higher platelet reactivity and lower effect of antiplatelet medications. PRI greater than 50% represents inadequate response to antiplatelet medications.

Secondary Outcome Measures

1. Platelet Reactivity Measured by VerifyNow P2Y12 [7 days]

   Platelet reactivity assessed by VerifyNow P2Y12 following treatment with ticagrelor 90mg or 60 mg between DM-CKD and DM-non-CKD cohorts. Results are expressed in P2Y12 reaction units (PRU). PRU is a measure of platelet reactivity, where higher PRU levels represent higher platelet reactivity and lower effect of antiplatelet medications. PRU greater than 208 represents inadequate response to antiplatelet medications.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Age >18 years.

• Type 2 DM, defined according to World Health Organization (WHO) definition, on treatment with oral hypoglycemic agents and/or insulin for at least 2 months without any changes in treatment regimen;

• Angiographically documented CAD.

• On treatment with low-dose aspirin (81mg/day) and clopidogrel (75mg/day) for at least 30 days as part of standard of care.

Exclusion Criteria:

• Patients with end-stage renal disease on hemodialysis.

• Use of any antiplatelet therapy (except aspirin and clopidogrel) in past 30 days.

• Use of parenteral or oral anticoagulation in past 30 day.

• Active pathological bleeding.

• History of intracranial hemorrhage with prior hemorrhage stroke.

• Blood dyscrasia or bleeding diathesis.

• Any active malignancy.

• Platelet count < 80x106/µl.

• Hemoglobin <10 g/dl.

• Known hepatic dysfunction (known moderate and severe hepatic dysfunction).

• Hemodynamic instability.

• Known allergy or hypersensitivity to ticagrelor or any excipients.

• Pregnant / lactating females (women of childbearing age must use reliable birth control while in the study).

• Strong inhibitors of cytochrome CYP3A4 and potent inducers of cytochrome CYP3A4 (to avoid interaction with ticagrelor): ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromycin.

• Patients with sick sinus syndrome (SSS) or high degree atrio-ventricular block without pacemaker protection.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Florida	Jacksonville	Florida	United States	32209

Sponsors and Collaborators

• University of Florida

Investigators

• Principal Investigator: Dominick J Angiolillo, MD, PhD, University of Florida College of Medicine-Jacksonville

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 31, 2018
• Informed Consent Form - Jul 5, 2018

More Information

Publications

None provided.

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT02539160
• Other Study ID Numbers: ESR-15-10953
• First Posted: Sep 2, 2015
• Last Update Posted: Jan 28, 2022
• Last Verified: Jan 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by University of Florida: coronary artery disease; diabetes mellitus; chronic kidney disease; ticagrelor
• Additional relevant MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Diabetes Mellitus; Ticagrelor

Study Results

Participant Flow

Recruitment Details	Subjects were recruited between February 2016 and November 2019 at the outpatient clinics of University of Florida Health - Jacksonville (Jacksonville, Florida, USA).
Pre-assignment Detail	101 patients were consented and enrolled in the study; 9 patients were not eligible for randomization due to the presence of exclusion criteria. A total of 92 patients (non-CKD, n=48; CKD, n=44) were randomized and exposed to at least one dose of study medication.

Arm/Group Title	DM-Non-CKD Ticagrelor 90 First	DM-Non-CKD Ticagrelor 60 First	DM-CKD Ticagrelor 90 First	DM-CKD Ticagrelor 60 First
Arm/Group Description	Patients with diabetes mellitus (DM) and coronary artery disease (CAD) were stratified according to chronic kidney disease (CKD) status. Non-CKD was defined by a glomerular filtrate rate (GFR) ≥ 60 ml/min/1.73m2. Non-CKD patients were randomized 1:1 to a) standard dose ticagrelor (90mg twice daily) for 7-10 days or b) low dose ticagrelor (60mg twice daily) for 7-10 days (phase 1). After 7-10 days of randomized treatment patients were crossed over to the alternative treatment, which was maintained for additional 7-10 days (phase 2).No wash out was performed.	Patients with diabetes mellitus (DM) and coronary artery disease (CAD) were stratified according to chronic kidney disease (CKD) status. CKD was defined by a glomerular filtrate rate (GFR) < 60 ml/min/1.73m2. CKD patients were randomized 1:1 to a) standard dose ticagrelor (90mg twice daily) for 7-10 days or b) low dose ticagrelor (60mg twice daily) for 7-10 days (phase 1). After 7-10 days of randomized treatment patients were crossed over to the alternative treatment, which was maintained for additional 7-10 days (phase 2). No wash out was performed.	Patients with diabetes mellitus (DM) and coronary artery disease (CAD) were stratified according to chronic kidney disease (CKD) status. CKD was defined by a glomerular filtrate rate (GFR) < 60 ml/min/1.73m2. CKD patients were randomized 1:1 to a) standard dose ticagrelor (90mg twice daily) for 7-10 days or b) low dose ticagrelor (60mg twice daily) for 7-10 days (phase 1). After 7-10 days of randomized treatment patients were crossed over to the alternative treatment, which was maintained for additional 7-10 days (phase 2). No wash out was performed.	Patients with diabetes mellitus (DM) and coronary artery disease (CAD) were stratified according to chronic kidney disease (CKD) status. CKD was defined by a glomerular filtrate rate (GFR) < 60 ml/min/1.73m2. CKD patients were randomized 1:1 to a) standard dose ticagrelor (90mg twice daily) for 7-10 days or b) low dose ticagrelor (60mg twice daily) for 7-10 days (phase 1). After 7-10 days of randomized treatment patients were crossed over to the alternative treatment, which was maintained for additional 7-10 days (phase 2). No wash out was performed.
Period Title: Phase 1 Pre-crossover
STARTED	24	24	22	22
COMPLETED	19	20	19	19
NOT COMPLETED	5	4	3	3
Period Title: Phase 1 Pre-crossover
STARTED	19	20	19	19
COMPLETED	19	20	19	19
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	DM-Non-CKD (All Participants Regardless of Sequence)	DM-CKD (All Participants Regardless of Sequence)	Total
Arm/Group Description	Patients with diabetes mellitus (DM) and coronary artery disease (CAD) were stratified according to chronic kidney disease (CKD) status. Non-CKD was defined by a glomerular filtrate rate (GFR) ≥ 60 ml/min/1.73m2. Non-CKD patients were randomized 1:1 to a) standard dose ticagrelor (90mg twice daily) for 7-10 days or b) low dose ticagrelor (60mg twice daily) for 7-10 days (phase 1). After 7-10 days of randomized treatment patients were crossed over to the alternative treatment, which was maintained for additional 7-10 days (phase 2). This is a crossover study where participants in each cohort received both treatments but in difference sequences. Therefore, baseline characteristics are presented for the two separate cohorts but combining patients together regardless of treatment sequence.	Patients with diabetes mellitus (DM) and coronary artery disease (CAD) were stratified according to chronic kidney disease (CKD) status. CKD was defined by a glomerular filtrate rate (GFR) < 60 ml/min/1.73m2. CKD patients were randomized 1:1 to a) standard dose ticagrelor (90mg twice daily) for 7-10 days or b) low dose ticagrelor (60mg twice daily) for 7-10 days (phase 1). After 7-10 days of randomized treatment patients were crossed over to the alternative treatment, which was maintained for additional 7-10 days (phase 2). This is a crossover study where participants in each cohort received both treatments but in difference sequences. Therefore, baseline characteristics are presented for the two separate cohorts but combining patients together regardless of treatment sequence.	Total of all reporting groups
Overall Participants	39	38	77
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62 (8)	66 (9)	64 (8)
Sex: Female, Male (Count of Participants)
Female	14 35.9%	15 39.5%	29 37.7%
Male	25 64.1%	23 60.5%	48 62.3%
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	15 38.5%	12 31.6%	27 35.1%
White	20 51.3%	26 68.4%	46 59.7%
More than one race	4 10.3%	0 0%	4 5.2%
Unknown or Not Reported	0 0%	0 0%	0 0%
GFR (ml/min/1.73m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ml/min/1.73m^2]	88 (17)	46 (9)	67 (25)
Prior myocardial infarction (Count of Participants)
Count of Participants [Participants]	18 46.2%	23 60.5%	41 53.2%

Outcome Measures

1. Primary Outcome

Title	Platelet Reactivity Measured by Vasodilator Stimulated Phosphoprotein (VASP) Platelet Reactivity Index (PRI %)
Description	The primary end point of the study was platelet reactivity assessed by VASP-PRI following treatment with ticagrelor 90mg between DM-CKD and DM-non-CKD cohorts. PRI % is a measure of platelet reactivity, where higher PRI levels represent higher platelet reactivity and lower effect of antiplatelet medications. PRI greater than 50% represents inadequate response to antiplatelet medications.
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

The pharmacodynamic (PD) population included all patients with any PD data on study drug and without a major protocol deviation thought to affect significantly the PD findings. The PD population was used for analysis of all primary and secondary PD variables.

Arm/Group Title	CKD - Ticagrelor 90	CKD - Ticagrelor 60	Non-CKD - Ticagrelor 90	Non-CKD - Ticagrelor 60
Arm/Group Description	Patients with chronic kidney disease will receive ticagrelor 90mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 60mg twice/daily for 7-10 days.	Patients with chronic kidney disease will receive ticagrelor 60mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 90mg twice/daily for 7-10 days.	Patients without chronic kidney disease will receive ticagrelor 90mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 60mg twice/daily for 7-10 days.	Patients without chronic kidney disease will receive ticagrelor 60mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 90mg twice/daily for 7-10 days.
Measure Participants	38	38	39	39
Mean (Standard Deviation) [PRI%]	25 (14)	32 (13)	31 (20)	38 (20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CKD - Ticagrelor 90, Non-CKD - Ticagrelor 90
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.105
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	6.4
	Confidence Interval	(2-Sided) 95%; -1.1 to 14.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CKD - Ticagrelor 60, Non-CKD - Ticagrelor 60
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.112
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6
	Confidence Interval	(2-Sided) 95%; -1.5 to 13.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Platelet Reactivity Measured by VerifyNow P2Y12
Description	Platelet reactivity assessed by VerifyNow P2Y12 following treatment with ticagrelor 90mg or 60 mg between DM-CKD and DM-non-CKD cohorts. Results are expressed in P2Y12 reaction units (PRU). PRU is a measure of platelet reactivity, where higher PRU levels represent higher platelet reactivity and lower effect of antiplatelet medications. PRU greater than 208 represents inadequate response to antiplatelet medications.
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	CKD - Ticagrelor 90	CKD - Ticagrelor 60	Non-CKD - Ticagrelor 90	Non-CKD - Ticagrelor 60
Arm/Group Description	Patients with chronic kidney disease will receive ticagrelor 90mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 60mg twice/daily for 7-10 days.	Patients with chronic kidney disease will receive ticagrelor 60mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 90mg twice/daily for 7-10 days.	Patients without chronic kidney disease will receive ticagrelor 90mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 60mg twice/daily for 7-10 days.	Patients without chronic kidney disease will receive ticagrelor 60mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 90mg twice/daily for 7-10 days.
Measure Participants	38	38	39	39
Mean (Standard Deviation) [PRU]	39 (57)	59 (56)	51 (52)	74 (65)

Adverse Events

Time Frame	Any adverse event during the study period (any time from enrollment until completion of the study, up to 20 days) was recorded.
Arm/Group Title	CKD - Ticagrelor 90		CKD - Ticagrelor 60		Non-CKD - Ticagrelor 90		Non-CKD - Ticagrelor 60
Arm/Group Description	Patients with chronic kidney disease will receive ticagrelor 90mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 60mg twice/daily for 7-10 days.		Patients with chronic kidney disease will receive ticagrelor 60mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 90mg twice/daily for 7-10 days.		Patients without chronic kidney disease will receive ticagrelor 90mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 60mg twice/daily for 7-10 days.		Patients without chronic kidney disease will receive ticagrelor 60mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 90mg twice/daily for 7-10 days.
All Cause Mortality
	CKD - Ticagrelor 90		CKD - Ticagrelor 60		Non-CKD - Ticagrelor 90		Non-CKD - Ticagrelor 60
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/38 (0%)		0/38 (0%)		0/38 (0%)		0/38 (0%)
Serious Adverse Events
	CKD - Ticagrelor 90		CKD - Ticagrelor 60		Non-CKD - Ticagrelor 90		Non-CKD - Ticagrelor 60
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/38 (2.6%)		1/38 (2.6%)		0/39 (0%)		1/39 (2.6%)
Cardiac disorders
hypotension	0/38 (0%)	0	1/38 (2.6%)	1	0/39 (0%)	0	0/39 (0%)	0
syncope	1/38 (2.6%)	1	0/38 (0%)	0	0/39 (0%)	0	0/39 (0%)	0
Metabolism and nutrition disorders
hyperglycemia	0/38 (0%)	0	1/38 (2.6%)	1	0/39 (0%)	0	0/39 (0%)	0
Renal and urinary disorders
hypokalemia	0/38 (0%)	0	0/38 (0%)	0	0/39 (0%)	0	1/39 (2.6%)	1
Other (Not Including Serious) Adverse Events
	CKD - Ticagrelor 90		CKD - Ticagrelor 60		Non-CKD - Ticagrelor 90		Non-CKD - Ticagrelor 60
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/38 (23.7%)		6/38 (15.8%)		9/39 (23.1%)		7/39 (17.9%)
Blood and lymphatic system disorders
minor bleeding	2/38 (5.3%)	2	0/38 (0%)	0	1/39 (2.6%)	1	1/39 (2.6%)	1
Respiratory, thoracic and mediastinal disorders
dyspnea	7/38 (18.4%)	7	6/38 (15.8%)	6	8/39 (20.5%)	8	6/39 (15.4%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.