RELIEF: A Study To Evaluate The Efficacy And Safety Of TNX-102 SL In Patients With Fibromyalgia

• Sponsor: Tonix Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04172831
• Collaborator: (none)
• Enrollment: 503
• Locations: 39
• Arms: 2
• Actual Duration (Months): 10.7
• Patients Per Site: 12.9
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

This is a Phase 3, randomized, parallel-group, double-blind, placebo-controlled, 14-week study designed to evaluate the efficacy and safety of TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) taken daily at bedtime for the treatment of fibromyalgia.

Condition or Disease	Intervention/Treatment	Phase
Fibromyalgia	Drug: TNX-102 SL; Drug: Placebo SL Tablet	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 503 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Double-Blind, Randomized, Multicenter, Placebo-Controlled Study To Evaluate The Efficacy And Safety Of TNX-102 SL Taken Daily At Bedtime In Patients With Fibromyalgia
• Actual Study Start Date: Dec 9, 2019
• Actual Primary Completion Date: Oct 29, 2020
• Actual Study Completion Date: Oct 29, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TNX-102 SL Tablets, 5.6 mg 1 x TNX-102 SL 2.8 mg Tablet taken sublingually each day at bedtime for 2 weeks then 2 x TNX-102 SL 2.8 mg (5.6 mg) Tablet taken sublingually each day at bedtime for 12 weeks.	Drug: TNX-102 SL; Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks.; Other Names: Low dose cyclobenzaprine sublingual tablets
Placebo Comparator: Placebo SL Tablet 1 x Placebo Tablet taken sublingually each day at bedtime for 2 weeks then 2 x Placebo Tablet taken sublingually each day at bedtime for 12 weeks.	Drug: Placebo SL Tablet; Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks.; Other Names: Placebo sublingual tablets

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Week 14 in the Numerical Rating Scale (NRS) Weekly Average of Daily Self-reported Average Pain Severity Scores. [14 weeks]

   Patients provide a daily numeric assessment of their average pain (24-hour recall), via an electronic diary, using an 11-point NRS. Scores range from 0 (no pain) to 10 (worst possible pain).

Secondary Outcome Measures

1. Number of Patients With a Patient's Global Impression of Change (PGIC) Rating of "Very Much Improved" or "Much Improved" [14 weeks]

   The PGIC is a fibromyalgia specific validated instrument on a scale of 1 to 7, where a score of 1 indicates the highest level of improvement and a score of 7 indicates a much worse outcome.

2. Change From Baseline to Week 14 in the Fibromyalgia Impact Questionnaire - Revised (FIQR) Symptoms Domain Score [14 weeks]

   The FIQ-R is a validated questionnaire. Scores on the symptoms domain range from 0 to 100 where a higher score means worse outcome.

3. Change From Baseline to Week 14 in the FIQR Function Domain Score [14 weeks]

   The FIQ-R is a validated questionnaire. Scores on the function domain range from 0 to 90 where a higher score means worse outcome.

4. Change From Baseline to Week 14 in the Patient Reported Outcomes Measurement Information System (PROMIS) Score for Sleep Disturbance [14 weeks]

   The PROMIS Sleep disturbance short form 8a consists of 8 questions on a 5-point scale (1 to 5) where a higher score indicates a worse outcome. The total score is reported on a range of 8 to 40.

5. Change From Baseline to Week 14 in the PROMIS Score for Fatigue [14 weeks]

   The PROMIS fatigue short form 8a consists of 8 questions on a 5 point scale (1 to 5) where a higher score indicates a worse outcome. The total score is reported on a range of 8 to 40.

6. Change From Baseline to Week 14 in the Weekly Average of the Daily Diary Assessment of Sleep Quality [14 weeks]

   Patients provide a daily numeric assessment of their sleep quality for the previous night, via an electronic diary, using an 11-point NRS. Scores range from 0 (best possible sleep) to 10 (worst possible sleep).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• The patient is male or female 18 to 65 years of age, inclusive.

• The patient has a diagnosis of primary FM as defined by the 2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria (American College of Rheumatology Preliminary Diagnostic Criteria)

• The in-clinic 7-day recall NRS average daily pain intensity score at Screening Visit within protocol specified range.

Exclusion Criteria:

• History of or evidence for a diagnosis of borderline personality disorder (BPD).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tonix Clinical Site	Birmingham	Alabama	United States	35216
2	Tonix Clinical Site	Phoenix	Arizona	United States	85016
3	Tonix Clinical Site	Oceanside	California	United States	92056
4	Tonix Clinical Site	Sacramento	California	United States	95831
5	Tonix Clinical Site	San Diego	California	United States	92103
6	Tonix Clinical Site	Temecula	California	United States	32591
7	Tonix Clinical Site	Cromwell	Connecticut	United States	06416
8	Tonix Clinical Site	Fort Myers	Florida	United States	33912
9	Tonix Clinical Site	Jacksonville	Florida	United States	32256
10	Tonix Clinical Site	North Miami	Florida	United States	33161
11	Tonix Clinical Site	Ocala	Florida	United States	34470
12	Tonix Clinical Site	Orlando	Florida	United States	32801
13	Tonix Clinical Site	Atlanta	Georgia	United States	30341
14	Tonix Clinical Site	Evansville	Indiana	United States	47714
15	Tonix Clinical Site	West Des Moines	Iowa	United States	50265
16	Tonix Clinical Site	Prairie Village	Kansas	United States	66208
17	Tonix Clinical Site	New Orleans	Louisiana	United States	70115
18	Tonix Clinical Site	Boston	Massachusetts	United States	02131
19	Tonix Clinical Site	North Dartmouth	Massachusetts	United States	02747
20	Tonix Clinical Site	Las Vegas	Nevada	United States	89102
21	Tonix Clinical Site	Williamsville	New York	United States	14221
22	Tonix Clinical Site	High Point	North Carolina	United States	27262
23	Tonix Clinical Site	Raleigh	North Carolina	United States	27612
24	Tonix Clinical Site	Fargo	North Dakota	United States	58104
25	Tonix Clinical Site	Cincinnati	Ohio	United States	45219
26	Tonix Clinical Site	Dayton	Ohio	United States	45417
27	Tonix Clinical Site	North Canton	Ohio	United States	44720
28	Tonix Clinical Site	Oklahoma City	Oklahoma	United States	73112
29	Tonix Clinical Site	Tulsa	Oklahoma	United States	74133
30	Tonix Clinical Site	Portland	Oregon	United States	97210
31	Tonix Clinical Site	Allentown	Pennsylvania	United States	18104
32	Tonix Clinical Site	Warwick	Rhode Island	United States	02886
33	Tonix Clinical Site	Chattanooga	Tennessee	United States	37421
34	Tonix Clinical Site	Memphis	Tennessee	United States	38119
35	Tonix Clinical Site	Austin	Texas	United States	78737
36	Tonix Clinical Site	Dallas	Texas	United States	75231
37	Tonix Clinical Site	Salt Lake City	Utah	United States	84102
38	Tonix Clinical Site	Charlottesville	Virginia	United States	22911
39	Tonix Clinical Site	Kenosha	Wisconsin	United States	53144

Sponsors and Collaborators

• Tonix Pharmaceuticals, Inc.

Investigators

• Study Director: Gregory Sullivan, MD, Tonix Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Mar 27, 2020
• Statistical Analysis Plan - Oct 16, 2020

More Information

Publications

None provided.

• Responsible Party: Tonix Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT04172831
• Other Study ID Numbers: TNX-CY-F304
• First Posted: Nov 21, 2019
• Last Update Posted: Aug 8, 2022
• Last Verified: Jul 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Tonix Pharmaceuticals, Inc.: Pain; Sleep; Fibromyalgia; FM
• Additional relevant MeSH terms: Fibromyalgia; Myofascial Pain Syndromes; Cyclobenzaprine

Study Results

Participant Flow

Arm/Group Title	TNX-102 SL Tablets, 5.6 mg	Placebo SL Tablet
Arm/Group Description	1 x TNX-102 SL 2.8 mg Tablet taken sublingually each day at bedtime for 2 weeks then 2 x TNX-102 SL 2.8 mg (5.6 mg) Tablet taken sublingually each day at bedtime for 12 weeks. TNX-102 SL: Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks.	1 x Placebo Tablet taken sublingually each day at bedtime for 2 weeks then 2 x Placebo Tablet taken sublingually each day at bedtime for 12 weeks. Placebo SL Tablet: Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks.
Period Title: Overall Study
STARTED	248	255
COMPLETED	204	213
NOT COMPLETED	44	42

Baseline Characteristics

Arm/Group Title	TNX-102 SL Tablets, 5.6 mg	Placebo SL Tablet	Total
Arm/Group Description	1 x TNX-102 SL 2.8 mg Tablet taken sublingually each day at bedtime for 2 weeks then 2 x TNX-102 SL 2.8 mg (5.6 mg) Tablet taken sublingually each day at bedtime for 12 weeks. TNX-102 SL: Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks.	1 x Placebo Tablet taken sublingually each day at bedtime for 2 weeks then 2 x Placebo Tablet taken sublingually each day at bedtime for 12 weeks. Placebo SL Tablet: Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks.	Total of all reporting groups
Overall Participants	248	255	503
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.0 (9.40)	49.3 (10.16)	49.6 (9.79)
Sex: Female, Male (Count of Participants)
Female	232 93.5%	247 96.9%	479 95.2%
Male	16 6.5%	8 3.1%	24 4.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.4%	2 0.8%	3 0.6%
Asian	2 0.8%	5 2%	7 1.4%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.4%	1 0.2%
Black or African American	19 7.7%	20 7.8%	39 7.8%
White	222 89.5%	216 84.7%	438 87.1%
More than one race	3 1.2%	9 3.5%	12 2.4%
Unknown or Not Reported	1 0.4%	2 0.8%	3 0.6%
Region of Enrollment (participants) [Number]
United States	248 100%	255 100%	503 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 14 in the Numerical Rating Scale (NRS) Weekly Average of Daily Self-reported Average Pain Severity Scores.
Description	Patients provide a daily numeric assessment of their average pain (24-hour recall), via an electronic diary, using an 11-point NRS. Scores range from 0 (no pain) to 10 (worst possible pain).
Time Frame	14 weeks

Outcome Measure Data

Analysis Population Description

Intent to Treat Population (all patient who were randomized). Multiple imputation for missing data.

Arm/Group Title	TNX-102 SL Tablets, 5.6 mg	Placebo SL Tablet
Arm/Group Description	1 x TNX-102 SL 2.8 mg Tablet taken sublingually each day at bedtime for 2 weeks then 2 x TNX-102 SL 2.8 mg (5.6 mg) Tablet taken sublingually each day at bedtime for 12 weeks. TNX-102 SL: Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks.	1 x Placebo Tablet taken sublingually each day at bedtime for 2 weeks then 2 x Placebo Tablet taken sublingually each day at bedtime for 12 weeks. Placebo SL Tablet: Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks.
Measure Participants	248	255
Least Squares Mean (95% Confidence Interval) [score on a scale]	-1.9	-1.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TNX-102 SL Tablets, 5.6 mg, Placebo SL Tablet
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -0.7 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.16
	Estimation Comments	Treatment Difference = TNX-102 - Placebo

2. Secondary Outcome

Title	Number of Patients With a Patient's Global Impression of Change (PGIC) Rating of "Very Much Improved" or "Much Improved"
Description	The PGIC is a fibromyalgia specific validated instrument on a scale of 1 to 7, where a score of 1 indicates the highest level of improvement and a score of 7 indicates a much worse outcome.
Time Frame	14 weeks

Outcome Measure Data

Analysis Population Description

Intent to Treat population (all patient who were randomized). Patients with missing data as non-responders.

Arm/Group Title	TNX-102 SL Tablets, 5.6 mg	Placebo SL Tablet
Arm/Group Description	1 x TNX-102 SL 2.8 mg Tablet taken sublingually each day at bedtime for 2 weeks then 2 x TNX-102 SL 2.8 mg (5.6 mg) Tablet taken sublingually each day at bedtime for 12 weeks. TNX-102 SL: Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks.	1 x Placebo Tablet taken sublingually each day at bedtime for 2 weeks then 2 x Placebo Tablet taken sublingually each day at bedtime for 12 weeks. Placebo SL Tablet: Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks.
Measure Participants	248	255
Count of Participants [Participants]	93 37.5%	75 29.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TNX-102 SL Tablets, 5.6 mg, Placebo SL Tablet
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.058
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.44
	Confidence Interval	(2-Sided) 95%; 0.99 to 2.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline to Week 14 in the Fibromyalgia Impact Questionnaire - Revised (FIQR) Symptoms Domain Score
Description	The FIQ-R is a validated questionnaire. Scores on the symptoms domain range from 0 to 100 where a higher score means worse outcome.
Time Frame	14 weeks

Outcome Measure Data

Analysis Population Description

Intent to Treat Population (all patients who were randomized). Multiple imputation for missing data.

Arm/Group Title	TNX-102 SL Tablets, 5.6 mg	Placebo SL Tablet
Arm/Group Description	1 x TNX-102 SL 2.8 mg Tablet taken sublingually each day at bedtime for 2 weeks then 2 x TNX-102 SL 2.8 mg (5.6 mg) Tablet taken sublingually each day at bedtime for 12 weeks. TNX-102 SL: Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks.	1 x Placebo Tablet taken sublingually each day at bedtime for 2 weeks then 2 x Placebo Tablet taken sublingually each day at bedtime for 12 weeks. Placebo SL Tablet: Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks.
Measure Participants	248	255
Least Squares Mean (95% Confidence Interval) [score on a scale]	-18.4	-14.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TNX-102 SL Tablets, 5.6 mg, Placebo SL Tablet
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-4.3
	Confidence Interval	(2-Sided) 95%; -7.5 to -1.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.60
	Estimation Comments	Treatment Difference = TNX-102 - Placebo

4. Secondary Outcome

Title	Change From Baseline to Week 14 in the FIQR Function Domain Score
Description	The FIQ-R is a validated questionnaire. Scores on the function domain range from 0 to 90 where a higher score means worse outcome.
Time Frame	14 weeks

Outcome Measure Data

Analysis Population Description

Intent to Treat Population (all patients who were randomized). Multiple imputation for missing data.

Arm/Group Title	TNX-102 SL Tablets, 5.6 mg	Placebo SL Tablet
Arm/Group Description	1 x TNX-102 SL 2.8 mg Tablet taken sublingually each day at bedtime for 2 weeks then 2 x TNX-102 SL 2.8 mg (5.6 mg) Tablet taken sublingually each day at bedtime for 12 weeks. TNX-102 SL: Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks.	1 x Placebo Tablet taken sublingually each day at bedtime for 2 weeks then 2 x Placebo Tablet taken sublingually each day at bedtime for 12 weeks. Placebo SL Tablet: Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks.
Measure Participants	248	255
Least Squares Mean (95% Confidence Interval) [score on a scale]	-13.6	-9.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TNX-102 SL Tablets, 5.6 mg, Placebo SL Tablet
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-4.4
	Confidence Interval	(2-Sided) 95%; -7.7 to -1.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.69
	Estimation Comments	Treatment Difference = TNX-102 - Placebo

5. Secondary Outcome

Title	Change From Baseline to Week 14 in the Patient Reported Outcomes Measurement Information System (PROMIS) Score for Sleep Disturbance
Description	The PROMIS Sleep disturbance short form 8a consists of 8 questions on a 5-point scale (1 to 5) where a higher score indicates a worse outcome. The total score is reported on a range of 8 to 40.
Time Frame	14 weeks

Outcome Measure Data

Analysis Population Description

Intent to Treat population (all patients who were randomized). Multiple imputation for missing data.

Arm/Group Title	TNX-102 SL Tablets, 5.6 mg	Placebo SL Tablet
Arm/Group Description	1 x TNX-102 SL 2.8 mg Tablet taken sublingually each day at bedtime for 2 weeks then 2 x TNX-102 SL 2.8 mg (5.6 mg) Tablet taken sublingually each day at bedtime for 12 weeks. TNX-102 SL: Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks.	1 x Placebo Tablet taken sublingually each day at bedtime for 2 weeks then 2 x Placebo Tablet taken sublingually each day at bedtime for 12 weeks. Placebo SL Tablet: Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks.
Measure Participants	248	255
Least Squares Mean (95% Confidence Interval) [score on a scale]	-9.5	-6.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TNX-102 SL Tablets, 5.6 mg, Placebo SL Tablet
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-2.9
	Confidence Interval	(2-Sided) 95%; -4.5 to -1.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.82
	Estimation Comments	Treatment Difference = TNX-102 - Placebo

6. Secondary Outcome

Title	Change From Baseline to Week 14 in the PROMIS Score for Fatigue
Description	The PROMIS fatigue short form 8a consists of 8 questions on a 5 point scale (1 to 5) where a higher score indicates a worse outcome. The total score is reported on a range of 8 to 40.
Time Frame	14 weeks

Outcome Measure Data

Analysis Population Description

Intent to Treat population (all patients who were randomized). Multiple imputation for missing data.

Arm/Group Title	TNX-102 SL Tablets, 5.6 mg	Placebo SL Tablet
Arm/Group Description	1 x TNX-102 SL 2.8 mg Tablet taken sublingually each day at bedtime for 2 weeks then 2 x TNX-102 SL 2.8 mg (5.6 mg) Tablet taken sublingually each day at bedtime for 12 weeks. TNX-102 SL: Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks.	1 x Placebo Tablet taken sublingually each day at bedtime for 2 weeks then 2 x Placebo Tablet taken sublingually each day at bedtime for 12 weeks. Placebo SL Tablet: Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks.
Measure Participants	248	255
Least Squares Mean (95% Confidence Interval) [score on a scale]	-8.0	-6.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TNX-102 SL Tablets, 5.6 mg, Placebo SL Tablet
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.018
	Comments
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.8
	Confidence Interval	(2-Sided) 95%; -3.3 to -0.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.76
	Estimation Comments	Treatment Difference = TNX-102 - Placebo

7. Secondary Outcome

Title	Change From Baseline to Week 14 in the Weekly Average of the Daily Diary Assessment of Sleep Quality
Description	Patients provide a daily numeric assessment of their sleep quality for the previous night, via an electronic diary, using an 11-point NRS. Scores range from 0 (best possible sleep) to 10 (worst possible sleep).
Time Frame	14 weeks

Outcome Measure Data

Analysis Population Description

Intent to Treat population (all patients who were randomized). Multiple imputation for missing data.

Arm/Group Title	TNX-102 SL Tablets, 5.6 mg	Placebo SL Tablet
Arm/Group Description	1 x TNX-102 SL 2.8 mg Tablet taken sublingually each day at bedtime for 2 weeks then 2 x TNX-102 SL 2.8 mg (5.6 mg) Tablet taken sublingually each day at bedtime for 12 weeks. TNX-102 SL: Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks.	1 x Placebo Tablet taken sublingually each day at bedtime for 2 weeks then 2 x Placebo Tablet taken sublingually each day at bedtime for 12 weeks. Placebo SL Tablet: Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks.
Measure Participants	248	255
Least Squares Mean (95% Confidence Interval) [score on a scale]	-2.0	-1.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TNX-102 SL Tablets, 5.6 mg, Placebo SL Tablet
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -0.9 to -0.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.17
	Estimation Comments	Treatment Difference = TNX-102 - Placebo

Adverse Events

Time Frame	14 weeks
Arm/Group Title	TNX-102 SL Tablets, 5.6 mg		Placebo SL Tablet
Arm/Group Description	1 x TNX-102 SL 2.8 mg Tablet taken sublingually each day at bedtime for 2 weeks then 2 x TNX-102 SL 2.8 mg (5.6 mg) Tablet taken sublingually each day at bedtime for 12 weeks. TNX-102 SL: Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks.		1 x Placebo Tablet taken sublingually each day at bedtime for 2 weeks then 2 x Placebo Tablet taken sublingually each day at bedtime for 12 weeks. Placebo SL Tablet: Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks.
All Cause Mortality
	TNX-102 SL Tablets, 5.6 mg		Placebo SL Tablet
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/248 (0%)		0/255 (0%)
Serious Adverse Events
	TNX-102 SL Tablets, 5.6 mg		Placebo SL Tablet
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/248 (0.8%)		5/255 (2%)
Gastrointestinal disorders
Coeliac artery compression syndrome	0/248 (0%)		1/255 (0.4%)
Colitis	0/248 (0%)		1/255 (0.4%)
Gastrointestinal hemorrhage	0/248 (0%)		1/255 (0.4%)
Infections and infestations
Pneumonia	1/248 (0.4%)		0/255 (0%)
Corona virus infection	0/248 (0%)		1/255 (0.4%)
Injury, poisoning and procedural complications
Spinal compression fracture	1/248 (0.4%)		0/255 (0%)
Femoral neck fracture	0/248 (0%)		1/255 (0.4%)
Thoracic vertebral fracture	1/248 (0.4%)		0/255 (0%)
Femur fracture	0/248 (0%)		1/255 (0.4%)
Foot fracture	0/248 (0%)		1/255 (0.4%)
Joint dislocation	0/248 (0%)		1/255 (0.4%)
Ulna fracture	0/248 (0%)		1/255 (0.4%)
Road traffic accident	0/248 (0%)		1/255 (0.4%)
Vascular disorders
Hypotention	0/248 (0%)		1/255 (0.4%)
Other (Not Including Serious) Adverse Events
	TNX-102 SL Tablets, 5.6 mg		Placebo SL Tablet
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	70/248 (28.2%)		3/255 (1.2%)
Gastrointestinal disorders
Hypoaesthesia oral	43/248 (17.3%)		1/255 (0.4%)
Paraesthesia oral	14/248 (5.6%)		1/255 (0.4%)
Nervous system disorders
Dysguesia	13/248 (5.2%)		1/255 (0.4%)

Limitations/Caveats

Recruitment during COVID-19 pandemic

More Information

Certain Agreements

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

An industry standard NDA is in place with all study investigators.