Acute Anxiolytic Effects of Riluzole on Subjects With Social Anxiety Disorder

• Sponsor: Yale University (Other)
• Overall Status: Completed
• CT.gov ID: NCT03017508
• Collaborator: Biohaven Pharmaceuticals, Inc. (Industry)
• Enrollment: 22
• Location: 1
• Arms: 2
• Duration (Months): 48.9
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The goal of the current proposal is to examine if sublingual riluzole can reduce anxiety in people with social anxiety disorder during a public speaking task.

Condition or Disease	Intervention/Treatment	Phase
Social Anxiety Disorder; Performance Anxiety	Drug: BHV-0223; Drug: Placebo	Phase 2/Phase 3

Detailed Description

The investigators propose conducting a double-blind, placebo controlled crossover study examining the effects of BHV-0223 on public speaking anxiety. Twenty participants with DSM-5 defined social anxiety disorder and clinically significant public speaking anxiety on the Impromptu Speech Task will be enrolled in a challenge study. Participants will be given BHV-0223 (or placebo) under double-blind crossover conditions 1 hour prior to performing each of 2 impromptu speech tasks. The two study days involving BHV-0223 (or placebo) administration and impromptu speech task will be separated by 2 to 10 days to allow for medication washout. There will be a final follow-up visit 2 to 10 days later to perform a complete Physical exam and do follow-up liver function testing and a Complete Blood Count. Our primary outcome will examine BHV-0223's effects (compared to placebo) on self-rated anxiety during the impromptu speech task. The investigators will also collect physiological measures of anxiety, clinician-rated measures of anxiety, and measures of speech performance as secondary outcomes.

Study Design

• Study Type: Interventional
• Actual Enrollment: 22 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: Double-Blind, Placebo-Controlled, Single-Dose Crossover Study Examining the Effects of Sublingual Riluzole (BHV-0223) on Public Speaking in Social Anxiety Disorder
• Study Start Date: Jan 1, 2017
• Actual Primary Completion Date: Dec 1, 2019
• Actual Study Completion Date: Jan 29, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BHV-0223 (Sublingual Riluzole) Participants will be given one dose of BHV-0223 (sublingual riluzole) 35mg before performing a 10 minute speech task. Participants will then be assessed every hour for the next three hours. There will be 2 to 10 days of washout period between the randomly assigned arms of the study.	Drug: BHV-0223; 35mg of sublingual riluzole before performing an anxiety provoking speech task. Participants will then be clinically assessed every hour for 3 hours.; Other Names: sublingual riluzole
Placebo Comparator: Placebo Participants will be given one dose of an identical looking sublingual placebo before performing a 10 minute speech task. Participants will then be assessed every hour for the next three hours. There will be 2 to 10 days of washout period between the randomly assigned arms of the study.	Drug: Placebo; a sublingual tablet identical to the active drug will be given before performing an anxiety provoking speech task. Participants will then be clinically assessed every hour for three hours.

Outcome Measures

Primary Outcome Measures

1. VAS-anxiety Immediately After the Impromptu Speech Task [up to 60 minutes]

   Measure Description: In the Visual Analogue Scale (VAS) participants are presented with a straight horizontal line of 100 mm in length and asked to mark the placement that would best describe the intensity of the anxiety felt at that moment. The left end (0mm) represents "no anxiety" and the right end (100mm) represents "the worst anxiety ever felt" by the participant.The VAS score is determined by measuring in millimeters from the left hand end of the line to the point that the patient marks, generating a numerical score along a continuum

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female (post-menopausal, surgically sterile, or negative pregnancy test at screening and agreement to utilize an established birth control, including complete abstinence, during the testing period) between the age of 18 and 65 yrs.

2. Meet DSM-5 criteria for social anxiety disorder by structured clinical interview (SCID) and have a LSAS public speaking subscale score >6.

3. Stable psychiatric medications. Participants must have had stable doses of all psychiatric medications for the month prior to treatment and have been on stable doses of SSRI and antidepressants for at least 1 month prior to study enrollment. As needed benzodiazepine use will be permitted as long as subjects refrain from using benzodiazepines for the 48 hours prior to the study.

4. Medically and neurologically healthy on the basis of physical examination, SMAC-20 (including LFT's, TFT's), VDRL, CBC w/ diff, urinalysis, urine toxicology, EKG, and medical history. Individuals with stable medical problems that do not have CNS effects or interfere with medications administered (e.g., oral hypoglycemics) may be included if their medications have not been adjusted in the month prior to entry;

5. Urine toxicology screen negative for drug of abuse.

6. Able to provide written informed consent according to the Yale Human Investigation Committee (HIC) guidelines.

Exclusion Criteria:

1. Positive pregnancy test

2. Breastfeeding females

3. History of substance abuse disorder (ETOH, cocaine, opiates, PCP) within the last 6 months or positive urine toxicology on screening (within the previous 6 months).

4. History of pervasive developmental disorder or psychotic disorder by DSM-IV-TR criteria.

5. Presence of dentures, braces, piercings at the time of dosing, or any physical findings in the mouth or tongue that, in the opinion of the Principal Investigator, would be likely to interfere with successful completion of the dosing procedure.

6. Participants with a medical condition that might interfere with the physiological absorption and motility (ie, gastric bypass, duodenectomy) or gastric bands.

7. Participants with any clinically significant abnormality or abnormal laboratory test results.

8. Participant has a current diagnosis of viral hepatitis (HBsAG or HVC) or a history of liver disease.

9. Participant has significant history of seizure disorder other than a single childhood febrile seizure (eg. Epilepsy)

10. Participant using any drugs known to induce or inhibit CYP 1A2 metabolism (examples of inducers: rifampin, carbamazepine, etc.; examples of inhibitors: fluvoxamine, ciprofloxacin, fluoroquinolones, etc.) within 30 days prior to the first study drug administration.

11. Participants with a history of allergic reactions to riluzole or other related drugs.

12. Participant has a history of anaphylaxis, a documented hypersensitivity reaction, or a clinically important reaction to any drug.

13. Participant has received another investigational drug or device within the 30 days (90 days for biologics) prior to the first dosing or is currently participating in an investigational study involving no drug administration.

14. Participant with clinically significant electrocardiogram (ECG) abnormalities (QTcF

450 msec) or vital sign abnormalities (systolic blood pressure lower than 90 or over 140 mmHg, diastolic blood pressure lower than 50 or over 90 mmHg, or heart rate less than 50 or over 100 bpm) at Screening or Baseline (Day -1).

1. Any reason which, in the opinion of the Principal Investigator, would prevent the participant from being in the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Connecticut Mental Health Center	New Haven	Connecticut	United States	06508

Sponsors and Collaborators

• Yale University
• Biohaven Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Michael H. Bloch, MD, MS, Associate Professor

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 28, 2017

More Information

Publications

• Baker SL, Heinrichs N, Kim HJ, Hofmann SG. The liebowitz social anxiety scale as a self-report instrument: a preliminary psychometric analysis. Behav Res Ther. 2002 Jun;40(6):701-15.
• Davidson JR. Use of benzodiazepines in social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder. J Clin Psychiatry. 2004;65 Suppl 5:29-33. Review.
• Mathew SJ, Amiel JM, Coplan JD, Fitterling HA, Sackeim HA, Gorman JM. Open-label trial of riluzole in generalized anxiety disorder. Am J Psychiatry. 2005 Dec;162(12):2379-81.
• Pittenger C, Coric V, Banasr M, Bloch M, Krystal JH, Sanacora G. Riluzole in the treatment of mood and anxiety disorders. CNS Drugs. 2008;22(9):761-86. Review.
• Ries BJ, McNeil DW, Boone ML, Turk CL, Carter LE, Heimberg RG. Assessment of contemporary social phobia verbal report instruments. Behav Res Ther. 1998 Oct;36(10):983-94.
• Sanacora G, Kendell SF, Levin Y, Simen AA, Fenton LR, Coric V, Krystal JH. Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry. 2007 Mar 15;61(6):822-5. Epub 2006 Dec 4.

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT03017508
• Other Study ID Numbers: 1605017768
• First Posted: Jan 11, 2017
• Last Update Posted: May 20, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Yale University: Cross-over study; Riluzole; Double-blind study; Speech task; Social Anxiety Disorder
• Additional relevant MeSH terms: Disease; Anxiety Disorders; Phobia, Social; Riluzole

Study Results

Participant Flow

Recruitment Details	28 participants were screened in person at the Yale Child Study Center. Of these, 22 were enrolled and 6 were excluded (2 did not have a diagnosis of Public Speaking Anxiety, 3 had a positive utox and 1 had uncontrolled hypertension).

Arm/Group Title	Participants Randomized to BHV-0223 First and After a Washout Period of 2-10 Days Received Placebo	Participants Randomized to Placebo First and After a Washout Period of 2-10 Days Received BHV-0223
Arm/Group Description	Participants that were randomized to receive sublingual BHV-0223 before performing a 10 minute speech task and were then followed for 3 hours. Participants were then assessed every hour for the next three hours. There was a 2 to 10 days of washout period. These participants would then receive an identical looking sublingual placebo before performing a 10 minute speech task and were followed for 3 hours.	Participants that were randomized to receive sublingual placebo before performing a 10 minute speech task and were then followed for 3 hours. Participants were then assessed every hour for the next three hours. There was a 2 to 10 days of washout period. These participants would then receive sublingual BHV-0223 before performing a 10 minute speech task and were followed for 3 hours.
Period Title: Overall Study
STARTED	12	10
First Intervention (1 Day)	12	10
Washout (2-10 Days)	12	10
Second Intervention (1 Day)	12	10
COMPLETED	12	10
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Participants That Were Randomized to Receive BHV-0223 (Sublingual Riluzole) First	Participants That Were Randomized to Receive Placebo First	Total
Arm/Group Description	Participants were given one dose of BHV-0223 (sublingual riluzole) 35mg before performing a 10 minute speech task. Participants will then be assessed every hour for the next three hours. There will be 2 to 10 days of washout period between the randomly assigned arms of the study. BHV-0223: 35mg of sublingual riluzole before performing an anxiety provoking speech task. Participants will then be clinically assessed every hour for 3 hours.	Participants were given one dose of an identical looking sublingual placebo before performing a 10 minute speech task. Participants will then be assessed every hour for the next three hours. There will be 2 to 10 days of washout period between the randomly assigned arms of the study. Placebo: a sublingual tablet identical to the active drug will be given before performing an anxiety provoking speech task. Participants will then be clinically assessed every hour for three hours.	Total of all reporting groups
Overall Participants	12	10	22
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	12 100%	10 100%	22 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	34	29	31.7
Sex: Female, Male (Count of Participants)
Female	5 41.7%	3 30%	8 36.4%
Male	7 58.3%	7 70%	14 63.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 8.3%	1 10%	2 9.1%
Not Hispanic or Latino	11 91.7%	9 90%	20 90.9%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 16.7%	0 0%	2 9.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 16.7%	2 20%	4 18.2%
White	8 66.7%	7 70%	15 68.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 10%	1 4.5%
Region of Enrollment (participants) [Number]
United States	12 100%	10 100%	22 100%
Visual Analogue Scale Baseline Score (millimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [millimeters]	62.25 (17.05)	46.6 (22.5)	55.1 (20.9)

Outcome Measures

1. Primary Outcome

Title	VAS-anxiety Immediately After the Impromptu Speech Task
Description	Measure Description: In the Visual Analogue Scale (VAS) participants are presented with a straight horizontal line of 100 mm in length and asked to mark the placement that would best describe the intensity of the anxiety felt at that moment. The left end (0mm) represents "no anxiety" and the right end (100mm) represents "the worst anxiety ever felt" by the participant.The VAS score is determined by measuring in millimeters from the left hand end of the line to the point that the patient marks, generating a numerical score along a continuum
Time Frame	up to 60 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	BHV-0223 (Sublingual Riluzole)	Placebo
Arm/Group Description	Participants will be given one dose of BHV-0223 (sublingual riluzole) 35mg before performing a 10 minute speech task. Participants will then be assessed immediately after finishing speech task. BHV-0223: 35mg of sublingual riluzole before performing an anxiety provoking speech task. Participants will then be clinically assessed immediately after finishing the speech task.	Participants will be given one dose of an identical looking sublingual placebo before performing a 10 minute speech task. Participants will then be assessed immediately after finishing the speech task. Placebo: a sublingual tablet identical to the active drug will be given before performing an anxiety provoking speech task. Participants will then be clinically assessed immediately after finishing the speech task.
Measure Participants	22	22
Mean (Standard Deviation) [millimeters (units on a scale)]	54.3 (23.6)	62.6 (13.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BHV-0223 (Sublingual Riluzole), Placebo
	Comments	Paired t-test on VAS scores during speech comparing sublingual riluzole to placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.056
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-8.34
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 18.34
	Estimation Comments

Adverse Events

Time Frame	Up to 1 hour.
Arm/Group Title	BHV-0223 (Sublingual Riluzole)		Placebo
Arm/Group Description	Participants will be given one dose of BHV-0223 (sublingual riluzole) 35mg before performing a 10 minute speech task. Participants will then be assessed immediately after finishing speech task. BHV-0223: 35mg of sublingual riluzole before performing an anxiety provoking speech task. Participants will then be clinically assessed immediately after finishing the speech task.		Participants will be given one dose of an identical looking sublingual placebo before performing a 10 minute speech task. Participants will then be assessed immediately after finishing the speech task. Placebo: a sublingual tablet identical to the active drug will be given before performing an anxiety provoking speech task. Participants will then be clinically assessed immediately after finishing the speech task.
All Cause Mortality
	BHV-0223 (Sublingual Riluzole)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/22 (0%)
Serious Adverse Events
	BHV-0223 (Sublingual Riluzole)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/22 (0%)
Other (Not Including Serious) Adverse Events
	BHV-0223 (Sublingual Riluzole)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/22 (59.1%)		0/22 (0%)
General disorders
Temporary perioral numbing	13/22 (59.1%)	13	0/22 (0%)	0

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.