Primary Fibromyalgia
Conditions
Keywords
pain, sleep
Brief summary
TNX-102 capsules \[formerly known as very low dose (VLD) cyclobenzaprine\] at bedtime have shown promise as a treatment of fibromyalgia, but the drug required new formulation technology for bedtime use. The present trial was designed to assess the safety and efficacy of TNX-102 SL 2.8 mg tablets, taken daily at bedtime over 12 weeks to treat fibromyalgia.
Interventions
DRUGTNX-102 SL 2.8mg
Patients will take 1 tablet of randomly assigned study drug sublingually each day at bedtime starting on Day 0 for 12 weeks.
DRUGPlacebo
Patients will take 1 tablet of randomly assigned study drug sublingually each day at bedtime starting on Day 0 for 12 weeks.
Sponsors
Tonix Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of primary Fibromyalgia (ACR criteria) * Male or female 18-65 years old * For patients with major depressive disorders only: clinically stable, no suicidal risk and stable anti-depressent therapy * Willing and able to withdraw specific therapies (ask PI) * Medically acceptable form of contraception (female only) * Signed informed consent
Exclusion criteria
* Arthritis, lupus and other systemic auto-immune diseases * Regional or persistent pain that could interfere with assessment of fibromyalgia pain * Bipolar and psychotic disorders * Increased risk of suicide * Significant clinical (cardiac, systemic infection, systemic corticosteroid requirement, drug/alcohol abuse) or laboratory abnormalities. * Inability to wash-off specific medications (ask PI) * Known hypersensitivity to cyclobenzaprine * Others: seizure disorders, sleep apnea, continuous positive airway pressure (CPAP) use, BMI\>40
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Weekly Average of Daily Pain Scores at Week 12 | Baseline, Week 12 | Daily pain scores were assessed using a 24-hour recall response provided by each patient via an interactive voice response system (IVRS) daily telephone diary. Average daily pain was measured using an 11-point (0-10) numerical rating scale (NRS), with higher scores representing worse pain. Jump to control was used to replace missing data in each treatment arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 30% Responder Analysis of IVRS NRS Pain Assessments at Week 12 | Baseline, Week 12 | The weekly averages of daily pain scores were calculated using the daily, 24-hour-recall, IVRS NRS pain assessments. Patients who had at least a 30% improvement from baseline to week 12 in weekly average of daily pain scores were considered responders. |
| Change From Baseline to Week 12 in PROMIS T-score for Sleep Disturbance | Baseline, Week 12 | The Patient-Reported Outcome Measurement Information System (PROMIS) sleep disturbance instrument consists of 8 items in which responses are scored 1 to 5 for each item. A higher score on 5 of the 8 items reflects a worse outcome, whereas a higher score on 3 items reflects an improved outcome; therefore, the directionality of the 8 item scores are first synchronized prior to calculation of the total raw score. PROMIS scores are presented as T-scores in which the raw score has been rescaled into a standardized score with a mean of 50 and a standard deviation of 10. Higher T-scores represent more of the concept being measured (in this case, sleep disturbance). |
| Patient Global Impression of Change (PGIC) Responder Status (Very Much Improved or Much Improved vs All Other Categories) at Week 12 | Week 12 | The PGIC is a 7-point scale (1=very much improved; 7=very much worse) that assesses the patient's perception of the overall change in his/her fibromyalgia symptoms since entering the study. Scores of 1 and 2 were considered responders. |
| Change From Baseline to Week 12 in FIQ-R Total Score | Baseline, Week 12 | The Fibromyalgia Impact Questionnaire (revised) FIQ-R is made up of 3 domains: functional (9 questions), overall (2 questions) and symptoms (10 questions). All questions are based on an 11-point numerical rating scale (NRS) of 0-10, with 10 being worst. Total FIQ-R scores can range from 0-100, with higher scores reflecting worsening status. The patient's total score on the FIQ-R was assessed at Visits 2, 3, 4, 5, and 6 (Week 12). Jump to control was used to replace missing data in each treatment arm. |
Countries
United States
Participant flow
Recruitment details
A total of 205 patients were randomized to either TNX-102 SL or placebo; however, one patient was randomized in error (to the placebo group) and was not dispensed any study drug. Therefore, all disposition and safety tables are based on the safety population of 204 patients. Of these, 174 patients completed the study.
Pre-assignment details
Screening for eligibility and washout of restricted medications.
Participants by arm
| Arm | Count |
|---|---|
| TNX-102 SL 2.8 mg Tablets 1 x TNX-102 SL 2.8mg Tablet taken sublingually each day at bedtime for 12 weeks.
TNX-102 SL 2.8mg Tablets: Patients will take 1 tablet of randomly assigned study drug sublingually each day at bedtime starting on Day 0 for 12 weeks. | 103 |
| Placebo 1 x Placebo Tablet taken sublingually each day at bedtime for 12 weeks.
Placebo: Patients will take 1 tablet of randomly assigned study drug sublingually each day at bedtime starting on Day 0 for 12 weeks. (One patient randomized in error never received study drug and therefore is not included in this table.) | 101 |
| Total | 204 |
Baseline characteristics
| Characteristic | TNX-102 SL 2.8 mg Tablets | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 5 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 103 Participants | 96 Participants | 199 Participants |
| Age, Continuous | 50.7 years | 49.7 years | 50.2 years |
| Gender Female | 96 Participants | 98 Participants | 194 Participants |
| Gender Male | 7 Participants | 3 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 65 / 103 | 14 / 101 |
| serious Total, serious adverse events | 0 / 103 | 1 / 101 |
Outcome results
Primary
Mean Change From Baseline in Weekly Average of Daily Pain Scores at Week 12
Daily pain scores were assessed using a 24-hour recall response provided by each patient via an interactive voice response system (IVRS) daily telephone diary. Average daily pain was measured using an 11-point (0-10) numerical rating scale (NRS), with higher scores representing worse pain. Jump to control was used to replace missing data in each treatment arm.
Time frame: Baseline, Week 12
Population: Patients in the Intention-to-treat (ITT) population: all randomized patients
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TNX-102 SL 2.8 mg Tablets | Mean Change From Baseline in Weekly Average of Daily Pain Scores at Week 12 | -1.39 units on a scale | Standard Error 0.253 |
| Placebo | Mean Change From Baseline in Weekly Average of Daily Pain Scores at Week 12 | -0.95 units on a scale | Standard Error 0.271 |
Secondary
30% Responder Analysis of IVRS NRS Pain Assessments at Week 12
The weekly averages of daily pain scores were calculated using the daily, 24-hour-recall, IVRS NRS pain assessments. Patients who had at least a 30% improvement from baseline to week 12 in weekly average of daily pain scores were considered responders.
Time frame: Baseline, Week 12
Population: Patients in the Intention-to-treat (ITT) population: all randomized patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TNX-102 SL 2.8 mg Tablets | 30% Responder Analysis of IVRS NRS Pain Assessments at Week 12 | 34 percentage of participants |
| Placebo | 30% Responder Analysis of IVRS NRS Pain Assessments at Week 12 | 20.6 percentage of participants |
Secondary
Change From Baseline to Week 12 in FIQ-R Total Score
The Fibromyalgia Impact Questionnaire (revised) FIQ-R is made up of 3 domains: functional (9 questions), overall (2 questions) and symptoms (10 questions). All questions are based on an 11-point numerical rating scale (NRS) of 0-10, with 10 being worst. Total FIQ-R scores can range from 0-100, with higher scores reflecting worsening status. The patient's total score on the FIQ-R was assessed at Visits 2, 3, 4, 5, and 6 (Week 12). Jump to control was used to replace missing data in each treatment arm.
Time frame: Baseline, Week 12
Population: Patients in the Intention-to-treat (ITT) population: all randomized patients
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TNX-102 SL 2.8 mg Tablets | Change From Baseline to Week 12 in FIQ-R Total Score | -15.59 units on a scale | Standard Error 2.079 |
| Placebo | Change From Baseline to Week 12 in FIQ-R Total Score | -8.54 units on a scale | Standard Error 2.133 |
Secondary
Change From Baseline to Week 12 in PROMIS T-score for Sleep Disturbance
The Patient-Reported Outcome Measurement Information System (PROMIS) sleep disturbance instrument consists of 8 items in which responses are scored 1 to 5 for each item. A higher score on 5 of the 8 items reflects a worse outcome, whereas a higher score on 3 items reflects an improved outcome; therefore, the directionality of the 8 item scores are first synchronized prior to calculation of the total raw score. PROMIS scores are presented as T-scores in which the raw score has been rescaled into a standardized score with a mean of 50 and a standard deviation of 10. Higher T-scores represent more of the concept being measured (in this case, sleep disturbance).
Time frame: Baseline, Week 12
Population: Patients in the Intention-to-treat (ITT) population: all randomized patients
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TNX-102 SL 2.8 mg Tablets | Change From Baseline to Week 12 in PROMIS T-score for Sleep Disturbance | -8.96 units on a scale | Standard Error 0.993 |
| Placebo | Change From Baseline to Week 12 in PROMIS T-score for Sleep Disturbance | -5.13 units on a scale | Standard Error 1.029 |
Secondary
Patient Global Impression of Change (PGIC) Responder Status (Very Much Improved or Much Improved vs All Other Categories) at Week 12
The PGIC is a 7-point scale (1=very much improved; 7=very much worse) that assesses the patient's perception of the overall change in his/her fibromyalgia symptoms since entering the study. Scores of 1 and 2 were considered responders.
Time frame: Week 12
Population: Patients in the Intention-to-treat (ITT) population: all randomized patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TNX-102 SL 2.8 mg Tablets | Patient Global Impression of Change (PGIC) Responder Status (Very Much Improved or Much Improved vs All Other Categories) at Week 12 | 30.1 percentage of participants |
| Placebo | Patient Global Impression of Change (PGIC) Responder Status (Very Much Improved or Much Improved vs All Other Categories) at Week 12 | 16.7 percentage of participants |