ASTRO-CM: Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis

• Sponsor: University of Minnesota (Other)
• Overall Status: Completed
• CT.gov ID: NCT01802385
• Collaborator: Infectious Disease Institute, Kampala, Uganda (Other), National Institute of Neurological Disorders and Stroke (NINDS) (NIH), Mbarara University of Science and Technology (Other), Medical Research Council (Other), Wellcome Trust (Other), Makerere University (Other)
• Enrollment: 460
• Locations: 2
• Arms: 2
• Actual Duration (Months): 30.7
• Patients Per Site: 230
• Patients Per Site Per Month: 7.5

Study Details

Study Description

Brief Summary

This is a phase III trial to determine whether adjunctive sertraline will lead to improved survival 18-week survival.

There was an initial phase I/II unmasked dose finding pharmacokinetic study of CSF concentrations in 172 persons conducted from August 2013 to August 2014. See NCT03002012.

Condition or Disease	Intervention/Treatment	Phase
Cryptococcal Meningitis; Fungal Meningitis	Drug: Sertraline	Phase 3

Detailed Description

This is a phase III randomized trial to evaluate whether sertraline when added to standard amphotericin-based therapy for cryptococcal meningitis, will lead to improved survival . Cryptococcal meningitis diagnosis will be made via CSF cryptococcal antigen (CRAG) at time of lumbar puncture (LP) with confirmation by CSF culture. After informed consent, subjects that meet eligibility requirements will be able to enter study. A non-randomized phase I dose-escalation study will first be conducted to help optimize dosing for a larger randomized phase II study.

Phase III Design: Subjects will be randomized to standard induction therapy with masked placebo or sertraline at 400mg/day. We will use a permutated block randomization in a 1:1 allocation (n=275 per arm). Total anticipated enrollment: 550 subjects.

Study Design

• Study Type: Interventional
• Actual Enrollment: 460 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis
• Actual Study Start Date: Mar 9, 2015
• Actual Primary Completion Date: Sep 1, 2017
• Actual Study Completion Date: Sep 27, 2017

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Placebo Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day) + placebo
Experimental: Sertraline 400mg Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks.	Drug: Sertraline; Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.; Other Names: Zoloft Lustral

Outcome Measures

Primary Outcome Measures

1. Survival [18 weeks]

   18-week survival. The comparison will be between sertraline 400mg group and placebo

Secondary Outcome Measures

1. Safety (Occurence of Adverse Events) [18 weeks]

   Safety and tolerability of adjunctive sertraline (grade 4-5) adverse reactions

2. Count of Participants With Cerebrospinal Fluid Sterility [14 days]

   Number of participants with sterile cerebrospinal fluid at 2 weeks

3. Center for Epidemiologic Studies in Depression (CES-D) Scale [14 weeks]

   Center for Epidemiologic Studies in Depression (CES-D) scale at 14 weeks. CES-D scores are based on a 20 item survey with total scores ranging from 0 to 60. Higher scores suggest a greater presence of depressive symptoms. A CES-D score of 16 or higher is interpreted to indicate a risk for depression.

4. Quantitative Neurocognitive Performance Score (QNPZ-8) [14 weeks]

   Quantitative neurocognitive performance Z-score (QNPZ-8) at 14 weeks. The QNPZ-8 is a mean score of testing of 8 neurocognitive domains. Eqach domain is scaled based on a Z-score where the mean = 0 for the HIV-negative Ugandan population, accounting for age and educational status. Each +1 unit is one standard deviation better than the population norm. Each -1 unit is one standard deviation worse than the population norm.

5. Fungal Clearance as Determined by Early Fungicidal Activity of CDF [14 days]

   To determine whether adjunctive sertraline will lead to a faster rate of fungal clearance from cerebrospinal fluid (CSF), as measured by early fungicidal activity (EFA) of clearance of the Cryptococcus colony forming units (cfu) per mL of CSF per day, compared to standard therapy alone.

6. Number of Participants Experiencing IRIS OR Relapse [18 weeks]

   Cumulative incidence of central nervous system (CNS) cryptococcal-related paradoxical immune reconstitution inflammatory syndrome (IRIS) or culture-positive relapse

7. Event Free Survival [18 weeks]

   Event free survival of composite events of: death,central nervous system (CNS) cryptococcal-related paradoxical immune reconstitution inflammatory syndrome (IRIS) or culture-positive relapse.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Cryptococcal meningitis diagnosed by CSF cryptococcal antigen (CRAG)

• HIV-1 infection

• Ability and willingness of the participant or legal guardian/representative to provide informed consent

• Willing to receive protocol-specified lumbar punctures

Exclusion Criteria:

• Age < 18 years

• Receipt of >=3 doses of amphotericin therapy

• Cannot or unlikely to attend regular clinic visits

• History of known liver cirrhosis

• Presence of jaundice

• Pregnancy

• Current breastfeeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Infectious Disease Institute	Kampala		Uganda
2	Mbarara University of Science and Technology	Mbarara		Uganda

Sponsors and Collaborators

• University of Minnesota
• Infectious Disease Institute, Kampala, Uganda
• National Institute of Neurological Disorders and Stroke (NINDS)
• Mbarara University of Science and Technology
• Medical Research Council
• Wellcome Trust
• Makerere University

Investigators

• Principal Investigator: David B Meya, MBCHB MMed, Infectious Disease Institute
• Study Director: Joshua Rhein, MD, University of Minnesota
• Study Chair: David R Boulware, MD MPH, University of Minnesota

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 1, 2015

More Information

Additional Information:

• Infectious Disease Institute
• Accordia Global Health Foundation

Publications

• Rhein J, Morawski BM, Hullsiek KH, Nabeta HW, Kiggundu R, Tugume L, Musubire A, Akampurira A, Smith KD, Alhadab A, Williams DA, Abassi M, Bahr NC, Velamakanni SS, Fisher J, Nielsen K, Meya DB, Boulware DR; ASTRO-CM Study Team. Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study. Lancet Infect Dis. 2016 Jul;16(7):809-818. doi: 10.1016/S1473-3099(16)00074-8. Epub 2016 Mar 10.
• Smith KD, Achan B, Hullsiek KH, McDonald TR, Okagaki LH, Alhadab AA, Akampurira A, Rhein JR, Meya DB, Boulware DR, Nielsen K; ASTRO-CM/COAT Team. Increased Antifungal Drug Resistance in Clinical Isolates of Cryptococcus neoformans in Uganda. Antimicrob Agents Chemother. 2015 Dec;59(12):7197-204. doi: 10.1128/AAC.01299-15. Epub 2015 Aug 31.
• Zhai B, Wu C, Wang L, Sachs MS, Lin X. The antidepressant sertraline provides a promising therapeutic option for neurotropic cryptococcal infections. Antimicrob Agents Chemother. 2012 Jul;56(7):3758-66. doi: 10.1128/AAC.00212-12. Epub 2012 Apr 16.

• Responsible Party: University of Minnesota
• ClinicalTrials.gov Identifier: NCT01802385
• Other Study ID Numbers: S4 0296-01; R01NS086312-01
• First Posted: Mar 1, 2013
• Last Update Posted: Jun 9, 2020
• Last Verified: Jun 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by University of Minnesota: cryptococcal meningitis; cryptococcus; meningitis; yeast; fungus
• Additional relevant MeSH terms: Meningitis, Cryptococcal; Meningitis, Fungal; Meningitis; Sertraline

Study Results

Participant Flow

Arm/Group Title	Placebo	Sertraline 400mg
Arm/Group Description	Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
Period Title: Overall Study
STARTED	231	229
COMPLETED	125	109
NOT COMPLETED	106	120

Baseline Characteristics

Arm/Group Title	Placebo	Sertraline 400mg	Total
Arm/Group Description	Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Total of all reporting groups
Overall Participants	231	229	460
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	231 100%	229 100%	460 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	35	35	35
Sex: Female, Male (Count of Participants)
Female	87 37.7%	97 42.4%	184 40%
Male	144 62.3%	132 57.6%	276 60%
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	231 100%	229 100%	460 100%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Uganda	231 100%	229 100%	460 100%

Outcome Measures

1. Primary Outcome

Title	Survival
Description	18-week survival. The comparison will be between sertraline 400mg group and placebo
Time Frame	18 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Sertraline 400mg
Arm/Group Description	Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
Measure Participants	231	229
Count of Participants [Participants]	125 54.1%	109 47.6%

2. Secondary Outcome

Title	Safety (Occurence of Adverse Events)
Description	Safety and tolerability of adjunctive sertraline (grade 4-5) adverse reactions
Time Frame	18 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Sertraline 400mg
Arm/Group Description	Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
Measure Participants	231	229
Number [events]	121	141

3. Secondary Outcome

Title	Count of Participants With Cerebrospinal Fluid Sterility
Description	Number of participants with sterile cerebrospinal fluid at 2 weeks
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Sertraline 400mg
Arm/Group Description	Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
Measure Participants	231	229
Count of Participants [Participants]	90 39%	101 44.1%

4. Secondary Outcome

Title	Center for Epidemiologic Studies in Depression (CES-D) Scale
Description	Center for Epidemiologic Studies in Depression (CES-D) scale at 14 weeks. CES-D scores are based on a 20 item survey with total scores ranging from 0 to 60. Higher scores suggest a greater presence of depressive symptoms. A CES-D score of 16 or higher is interpreted to indicate a risk for depression.
Time Frame	14 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Sertraline 400mg
Arm/Group Description	Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
Measure Participants	231	229
Mean (95% Confidence Interval) [score on a scale]	16.6	13.2

5. Secondary Outcome

Title	Quantitative Neurocognitive Performance Score (QNPZ-8)
Description	Quantitative neurocognitive performance Z-score (QNPZ-8) at 14 weeks. The QNPZ-8 is a mean score of testing of 8 neurocognitive domains. Eqach domain is scaled based on a Z-score where the mean = 0 for the HIV-negative Ugandan population, accounting for age and educational status. Each +1 unit is one standard deviation better than the population norm. Each -1 unit is one standard deviation worse than the population norm.
Time Frame	14 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Sertraline 400mg
Arm/Group Description	Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
Measure Participants	231	229
Mean (95% Confidence Interval) [score]	-1.4	-1.3

6. Secondary Outcome

Title	Fungal Clearance as Determined by Early Fungicidal Activity of CDF
Description	To determine whether adjunctive sertraline will lead to a faster rate of fungal clearance from cerebrospinal fluid (CSF), as measured by early fungicidal activity (EFA) of clearance of the Cryptococcus colony forming units (cfu) per mL of CSF per day, compared to standard therapy alone.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Sertraline 400mg
Arm/Group Description	Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
Measure Participants	231	229
General Linear Regression	0.47	.43
Mixed-Effects Regression	0.33	.33

7. Secondary Outcome

Title	Number of Participants Experiencing IRIS OR Relapse
Description	Cumulative incidence of central nervous system (CNS) cryptococcal-related paradoxical immune reconstitution inflammatory syndrome (IRIS) or culture-positive relapse
Time Frame	18 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Sertraline 400mg
Arm/Group Description	Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
Measure Participants	231	229
Count of Participants [Participants]	9 3.9%	5 2.2%

8. Secondary Outcome

Title	Event Free Survival
Description	Event free survival of composite events of: death,central nervous system (CNS) cryptococcal-related paradoxical immune reconstitution inflammatory syndrome (IRIS) or culture-positive relapse.
Time Frame	18 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Sertraline 400mg
Arm/Group Description	Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
Measure Participants	231	229
Count of Participants [Participants]	116 50.2%	103 45%

Adverse Events

Time Frame	18 weeks
Adverse Event Reporting Description	Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
Arm/Group Title	Placebo		Sertraline 400mg
Arm/Group Description	Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.		Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
All Cause Mortality
	Placebo		Sertraline 400mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	106/231 (45.9%)		120/229 (52.4%)
Serious Adverse Events
	Placebo		Sertraline 400mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	121/231 (52.4%)		141/229 (61.6%)
Blood and lymphatic system disorders
Thrombosis	1/231 (0.4%)		0/229 (0%)
Elevated Creatinine	9/231 (3.9%)		13/229 (5.7%)
Hypokalemia	4/231 (1.7%)		13/229 (5.7%)
Hyperkalemia	2/231 (0.9%)		0/229 (0%)
Hyponatremia	13/231 (5.6%)		16/229 (7%)
Hypernatremia	0/231 (0%)		2/229 (0.9%)
Hypomagnesemia	2/231 (0.9%)		0/229 (0%)
Acidosis	0/231 (0%)		3/229 (1.3%)
Anemia	49/231 (21.2%)		54/229 (23.6%)
Leukopenia	0/231 (0%)		1/229 (0.4%)
Neutropenia	0/231 (0%)		4/229 (1.7%)
Thrombocytopenia	0/231 (0%)		2/229 (0.9%)
Lymphopenia	9/231 (3.9%)		10/229 (4.4%)
Elevated ALT	2/231 (0.9%)		0/229 (0%)
Elevated AST	3/231 (1.3%)		0/229 (0%)
Elevated Bilirubin	10/231 (4.3%)		9/229 (3.9%)
Gastrointestinal disorders
Diarrhea	1/231 (0.4%)		0/229 (0%)
Vomiting	0/231 (0%)		1/229 (0.4%)
General disorders
Fever	4/231 (1.7%)		1/229 (0.4%)
Hypotension	1/231 (0.4%)		2/229 (0.9%)
Headache	1/231 (0.4%)		0/229 (0%)
Anorexia	1/231 (0.4%)		0/229 (0%)
Infections and infestations
Infection	3/231 (1.3%)		1/229 (0.4%)
Nervous system disorders
Seizure	2/231 (0.9%)		2/229 (0.9%)
Psychiatric disorders
Altered Mental Status	1/231 (0.4%)		3/229 (1.3%)
Respiratory, thoracic and mediastinal disorders
Respiratory Distress	3/231 (1.3%)		4/229 (1.7%)
Other (Not Including Serious) Adverse Events
	Placebo		Sertraline 400mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	65/231 (28.1%)		66/229 (28.8%)
General disorders
Non-serious Adverse Events	65/231 (28.1%)		66/229 (28.8%)

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.