Generalized Anxiety Disorder
Conditions
Brief summary
GAD subjects maintained on a stable dose of alprazolam for at least four weeks who meet eligibility criteria will be randomized to receive pregabalin vs matching placebo while simultaneously tapering off of alprazolam over 6 weeks. Subjects return weekly for assessment of safety/tolerability of pregabalin vs placebo as well as for assessment of anxiety and benzodiazepine withdrawal symptoms. Subjects successfully able to discontinue alprazolam, will continue 6 weeks of treatment with pregabalin vs placebo (free of benzodiazepine use). The efficacy and safety of pregabalin vs placebo for anxiety symptoms and ability to discontinue/remain free of alprazolam will be compared among pregabalin and placebo treated groups. Hypothesis is that a greater proportion of subjects will be successful in discontinuing and remaining free from benzodiazepines who were treated with pregabalin as compared to subjects treated with placebo.
Interventions
DRUGPregabalin
GAD subjects on stable dose of alprazolam will be randomized to double-blind pregabalin at starting dose of 75mg twice daily. Weekly assessments of tolerability, need for rescue medication, anxiety/withdrawal symptoms will guide flexible dose titration of pregabalin at dose range between 75 and 300mg twice daily. Subjects successful in discontinuation of alprazolam while treated with pregabalin will continue to be maintained on pregabalin for 6 weeks and assessed weekly for ability to remain in the study.
DRUGPlacebo
GAD subjects on stable dose of alprazolam will be randomized to double-blind placebo matching assessments and study medication titration as detailed under the pregabalin arm description. Subjects successful in discontinuation of alprazolam while treated with placebo will continue to be maintained on placebo for 6 weeks and assessed weekly for ability to remain in the study.
Sponsors
Pfizer's Upjohn has merged with Mylan to form Viatris 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
* Provide written informed consent * 18-65 years old * male and female * A primary lifetime diagnosis of DSM-IV-TR (2000) GAD (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition)
Exclusion criteria
* Pregnant or lactating women * History of non-response to alprazolam, other benzodiazepines, gabapentin or pregabalin given for the treatment of anxiety as indicated by a (screening or baseline) Hamilton Anxiety Scale (HAM-A) score \> 18
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects at Endpoint (Post Alprazolam Free Week 6 or Last Observation Carried Forward [LOCF] Post Alprazolam Free Week 1) Who Are Benzodiazepine Free | Endpoint (Post Alprazolam Free Week 6 or LOCF Post Alprazolam Free Week 1) | Number of subjects benzodiazepine free: \< 2 doses rescue medication; negative urine benzodiazepine psychoactive toxicology assay (each visit Alprazolam Free phase); negative serum benzodiazepine alcohol assay (endpoint or LOCF). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | Baseline, Alprazolam Taper Weeks 1 through 6, Alprazolam Free Weeks 1 through 6, and Endpoint (Alprazolam Free [AF] Week 6) | HAM-A measures treatment-related changes in generalized anxiety symptoms; 14 item questionnaire scored 0 (not present) to 4 (very severe); lower score indicates less affected. Change from baseline: mean at observation minus mean at baseline. |
| Number of Subjects With > = 6 Point Increase in Physician's Withdrawal Checklist (PWC) Scores | Baseline, Alprazolam Free Weeks 1 through 6, Endpoint (AF Week 6) | PWC: 20 item physician rated interview (0 = not present; 3 = severe; score range: 0 to 60) measuring: signs of anxiolytic drug withdrawal and gastrointestinal (GI), mood, sleep, motor, somatic, perception and cognition symptoms. Data not analyzed: PWC not measured at baseline. |
| Number of Subjects With > = 5 New PWC Symptoms | Baseline, Alprazolam Free Weeks 1 through 6, Endpoint (AF Week 6) | PWC: 20 item physician rated interview (0 = not present; 3 = severe; score range: 0 to 60) measuring: signs of anxiolytic drug withdrawal and gastrointestinal (GI), mood, sleep, motor, somatic, perception and cognition symptoms. Data not analyzed: PWC not measured at baseline. |
| Mean Change From Baseline in Physician's Withdrawal Checklist (PWC) Scores | Baseline, Alprazolam Taper Weeks 1 through 6, Alprazolam Free Weeks 1 through 6, Endpoint (AF Week 6) | PWC: 20 item physician rated interview (0 = not present; 3 = severe; score range: 0 to 60) measuring: signs of anxiolytic drug withdrawal and gastrointestinal (GI), mood, sleep, motor, somatic, perception and cognition symptoms. Change from baseline not analyzed as PWC was not measured at baseline. Mean PWS scores presented in Post-hoc outcome measure Mean PWS scores. |
| Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | Baseline, Alprazolam Taper Weeks 1 through 6, Alprazolam Free Weeks 1 through 6, and Endpoint (AF Week 6 ) | CGI-S: 7-point scale to assess global change in subject condition compared to baseline; range 1 (no evidence of illness) to 7 (among the most severely ill); higher score = more affected. Change from baseline: mean at observation minus mean at baseline. |
| Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | Alprazolam Taper Weeks 1 through 6, Alprazolam Free Weeks 1 through 6, and Endpoint (AF Week 6 ) | CGI-I: 7-point scale to assess global change in subject condition compared to baseline; range 1 (very much improved) to 7 (very much worse); higher score = more affected. |
| Mean Change From Baseline in Digit Symbol Substitution Test (DSST) Scores | Baseline, Endpoint (AF Week 6 ) | DSST: subject-rated; evaluates aspects of cognition (includes attending to directions, processing speed, sustained attention, visual-motor integration, learning and psychomotor speed). Subject matches symbol (1 to 9) with corresponding number key (1 to 9); number of correct symbol-number pairs completed by subject over a 90-second test period determines DSST score. Change: mean at observation minus mean at baseline. Data summarized as change from baseline to endpoint. |
| Time to Discontinuation | Baseline, Week 13 (Final Visit/Early Termination) | The 25th percentile estimate of time until discontinuation is based on Kaplan-Meier estimates. Event day is the study day when the subject discontinued from study. |
| Time to First Use of Rescue Medication | Baseline, Week 13 (Final Visit/Early Termination) | The 25th percentile estimate of time until first use of rescue medication is based on Kaplan-Meier estimates. Event day is the study day when the subject first used rescue medication. Rescue medication: packet with 2 doses alprazolam to take only in the event subject experiences severe symptoms of benzodiazepine withdrawal or rebound anxiety. |
| Number of Subjects in Relapse Free State at 6-week Benzodiazepine-free Endpoint (Alprazolam Free Week 6) | Alprazolam Free Week 6 | Number of subjects benzodiazepine free: \< 2 doses rescue medication; negative urine toxicology assay (each visit Alprazolam Free phase), negative urine alcohol assay (Alprazolam Free Week 6 = endpoint or LOCF). Relapse: \> = 2 intakes rescue medication, positive urine and /or alcohol assays, unable to tolerate alprazolam taper, or discontinuation. |
| Mean Scores for Patient Global Impression-Improvement (PGI-I) | Alprazolam Taper Weeks 1 through 6, Alprazolam Free Weeks 1 through 6, and Endpoint (AF Week 6 ) | PGI-I: subject rated 7-point scale measures change in overall status; range 1 (very much improved) to 7 (very much worse). |
Countries
Costa Rica, Czechia, France, Guatemala, Italy, Mexico, Spain
Participant flow
Pre-assignment details
Prior to randomization, subjects were stabilized on a therapeutic dose of open-label alprazolam (minimum of 2 weeks) if they entered the study on a stable alprazolam dose or for up to 4 weeks if entered on a different benzodiazepine. Alprazolam dose range during 2-4 week stabilization phase was 1-4 milligrams (mg) by mouth (PO) twice a day (BID).
Participants by arm
| Arm | Count |
|---|---|
| Pregabalin 75 mg to 300 mg PO BID Pregabalin treatment following randomization to double-blind treatment: Baseline to Week 1: Pregabalin 75 mg PO BID (150 mg/day); Week 2: Pregabalin 150 mg PO BID (300 mg/day); Week 3 to Week 6 Pregabalin PO dosing ranged from 150 to 600 mg/day, given BID; during double-blind the alprazolam dose was tapered with a 25% reduction each week from baseline up to 6 weeks depending on the starting dose of alprazolam and toleration of dose reduction. Subjects successfully discontinued from alprazolam, continued for an additional 6 weeks of double-blind treatment with pregabalin at the same dose as during the double-blind taper. | 56 |
| Placebo 75 mg to 300 mg PO BID Placebo treatment following randomization to double-blind treatment: Baseline to Week 1: placebo 75 mg PO BID (150 mg/day); Week 2: placebo 150 mg PO BID (300 mg/day); Week 3 to Week 6 placebo PO dosing ranged from 150 to 600 mg/day, given BID; during double-blind the alprazolam dose was tapered with a 25% reduction each week from baseline up to 6 weeks depending on the starting dose of alprazolam and toleration of dose reduction. Subjects successfully discontinued from alprazolam, continued for an additional 6 weeks of double-blind treatment with placebo at the same dose as during the double-blind taper. | 50 |
| Total | 106 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-blind Treatment Period | Adverse Event | 6 | 6 |
| Double-blind Treatment Period | Lack of Efficacy | 7 | 16 |
| Double-blind Treatment Period | Lost to Follow-up | 1 | 0 |
| Double-blind Treatment Period | Other | 7 | 6 |
| Double-blind Treatment Period | Withdrawal by Subject | 5 | 3 |
Baseline characteristics
| Characteristic | Pregabalin 75 mg to 300 mg PO BID | Placebo 75 mg to 300 mg PO BID | Total |
|---|---|---|---|
| Age, Continuous | 40.1 years STANDARD_DEVIATION 10.6 | 43.5 years STANDARD_DEVIATION 11.3 | 41.7 years STANDARD_DEVIATION 11 |
| Sex: Female, Male Female | 42 Participants | 34 Participants | 76 Participants |
| Sex: Female, Male Male | 14 Participants | 16 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 33 / 56 | 29 / 50 |
| serious Total, serious adverse events | 0 / 56 | 0 / 50 |
Outcome results
Primary
Number of Subjects at Endpoint (Post Alprazolam Free Week 6 or Last Observation Carried Forward [LOCF] Post Alprazolam Free Week 1) Who Are Benzodiazepine Free
Number of subjects benzodiazepine free: \< 2 doses rescue medication; negative urine benzodiazepine psychoactive toxicology assay (each visit Alprazolam Free phase); negative serum benzodiazepine alcohol assay (endpoint or LOCF).
Time frame: Endpoint (Post Alprazolam Free Week 6 or LOCF Post Alprazolam Free Week 1)
Population: Intent to Treat (ITT) population: received at least 1 dose pregabalin or placebo. Primary outcome ITT = all treated subjects in alprazolam free phase. Endpoint = Post Alprazolam Free Week 6 or LOCF Post Alprazolam Free Week 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pregabalin 75 mg to 300 mg PO BID | Number of Subjects at Endpoint (Post Alprazolam Free Week 6 or Last Observation Carried Forward [LOCF] Post Alprazolam Free Week 1) Who Are Benzodiazepine Free | 20 participants |
| Placebo 75 mg to 300 mg PO BID | Number of Subjects at Endpoint (Post Alprazolam Free Week 6 or Last Observation Carried Forward [LOCF] Post Alprazolam Free Week 1) Who Are Benzodiazepine Free | 10 participants |
Comparison: Primary objective: evaluate the efficacy of pregabalin in maintaining the benzodiazepine free state in subjects with prior stable alprazolam use.p-value: 0.2838Cochran-Mantel-Haenszel
Secondary
Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores.
CGI-S: 7-point scale to assess global change in subject condition compared to baseline; range 1 (no evidence of illness) to 7 (among the most severely ill); higher score = more affected. Change from baseline: mean at observation minus mean at baseline.
Time frame: Baseline, Alprazolam Taper Weeks 1 through 6, Alprazolam Free Weeks 1 through 6, and Endpoint (AF Week 6 )
Population: ITT; subject has a baseline and at least 1 post-baseline endpoint measurement; endpoint = AF Week 6 or LOCF; (n) = number of subjects with data for analysis for pregabalin and placebo, respectively.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | AT Week 3 (n=32, 27) | -0.60 scores on scale | Standard Error 0.2 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | AF Week 2 (n=34, 24) | -0.98 scores on scale | Standard Error 0.2 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | AT Week 5 (n=7, 5) | -0.77 scores on scale | Standard Error 0.27 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | AF Week 3 (n=30, 26) | -0.88 scores on scale | Standard Error 0.22 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | AT Week 2 (n=44, 37) | -0.33 scores on scale | Standard Error 0.17 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | AF Week 4 (n=30, 19) | -0.87 scores on scale | Standard Error 0.18 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | AT Week 6 (n=16, 9) | -0.63 scores on scale | Standard Error 0.32 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | AF Week 5 (n=26, 18) | -0.82 scores on scale | Standard Error 0.19 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | AT Week 4 (n=17, 11) | -0.41 scores on scale | Standard Error 0.21 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | AF Week 6 (n=21, 15) | -1.33 scores on scale | Standard Error 0.2 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | Alprazolam Free (AF) Week 1 (n=38, 28) | -0.46 scores on scale | Standard Error 0.17 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | Endpoint [LOCF] (n=45, 41) | -0.45 scores on scale | Standard Error 0.21 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | Alprazolam Taper (AT) Week 1 (n=45, 40) | -0.23 scores on scale | Standard Error 0.13 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | Endpoint [LOCF] (n=45, 41) | 0.31 scores on scale | Standard Error 0.24 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | Alprazolam Taper (AT) Week 1 (n=45, 40) | 0.22 scores on scale | Standard Error 0.15 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | AT Week 2 (n=44, 37) | 0.41 scores on scale | Standard Error 0.19 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | AT Week 3 (n=32, 27) | -0.10 scores on scale | Standard Error 0.26 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | AT Week 4 (n=17, 11) | -0.04 scores on scale | Standard Error 0.32 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | AT Week 5 (n=7, 5) | -0.05 scores on scale | Standard Error 0.4 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | AT Week 6 (n=16, 9) | 0.08 scores on scale | Standard Error 0.43 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | Alprazolam Free (AF) Week 1 (n=38, 28) | 0.23 scores on scale | Standard Error 0.21 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | AF Week 2 (n=34, 24) | -0.48 scores on scale | Standard Error 0.26 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | AF Week 3 (n=30, 26) | -0.32 scores on scale | Standard Error 0.27 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | AF Week 4 (n=30, 19) | -0.84 scores on scale | Standard Error 0.25 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | AF Week 5 (n=26, 18) | -0.75 scores on scale | Standard Error 0.26 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. | AF Week 6 (n=21, 15) | -1.02 scores on scale | Standard Error 0.25 |
Comparison: Alprazolam Taper (AT) Week 1p-value: 0.005295% CI: [-0.76, -0.14]ANCOVA
Comparison: AT Week 2p-value: 0.000195% CI: [-1.11, -0.38]ANCOVA
Comparison: AT Week 3p-value: 0.052895% CI: [-1, 0.01]ANCOVA
Comparison: AT Week 4p-value: 0.308595% CI: [-1.11, 0.37]ANCOVA
Comparison: AT Week 5p-value: 0.180795% CI: [-1.92, 0.47]ANCOVA
Comparison: AT Week 6p-value: 0.107495% CI: [-1.58, 0.17]ANCOVA
Comparison: Alprazolam Free (AF) Week 1p-value: 0.001395% CI: [-1.1, -0.28]ANCOVA
Comparison: AF Week 2p-value: 0.050395% CI: [-0.99, 0]ANCOVA
Comparison: AF Week 3p-value: 0.036495% CI: [-1.09, -0.04]ANCOVA
Comparison: AF Week 4p-value: 0.91495% CI: [-0.51, 0.46]ANCOVA
Comparison: AF Week 5p-value: 0.778995% CI: [-0.62, 0.47]ANCOVA
Comparison: AF Week 6p-value: 0.318995% CI: [-0.95, 0.32]ANCOVA
Comparison: Endpoint \[LOCF\]p-value: 0.003195% CI: [-1.26, -0.27]ANCOVA
Secondary
Mean Change From Baseline in Digit Symbol Substitution Test (DSST) Scores
DSST: subject-rated; evaluates aspects of cognition (includes attending to directions, processing speed, sustained attention, visual-motor integration, learning and psychomotor speed). Subject matches symbol (1 to 9) with corresponding number key (1 to 9); number of correct symbol-number pairs completed by subject over a 90-second test period determines DSST score. Change: mean at observation minus mean at baseline. Data summarized as change from baseline to endpoint.
Time frame: Baseline, Endpoint (AF Week 6 )
Population: ITT; subject has baseline and endpoint (final visit) measurement; endpoint = AF Week 6 or LOCF.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Digit Symbol Substitution Test (DSST) Scores | 13.10 scores on scale | Standard Error 2.64 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Digit Symbol Substitution Test (DSST) Scores | 13.47 scores on scale | Standard Error 2.95 |
p-value: 0.889795% CI: [-5.74, 4.99]ANCOVA
Secondary
Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores
HAM-A measures treatment-related changes in generalized anxiety symptoms; 14 item questionnaire scored 0 (not present) to 4 (very severe); lower score indicates less affected. Change from baseline: mean at observation minus mean at baseline.
Time frame: Baseline, Alprazolam Taper Weeks 1 through 6, Alprazolam Free Weeks 1 through 6, and Endpoint (Alprazolam Free [AF] Week 6)
Population: ITT; subject has a baseline and at least 1 post-baseline measurement before week 13; endpoint = AF Week 6 or LOCF; (n) = number of subjects with data for analysis for pregabalin and placebo, respectively.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | Alprazolam Taper (AT) Week 1 (n=46, 40) | -0.82 scores on scale | Standard Error 0.66 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | AT Week 2 (n=45, 37) | -1.72 scores on scale | Standard Error 0.98 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | AT Week 4 (n=18, 11) | -1.47 scores on scale | Standard Error 1.11 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | AT Week 5 (n=8, 5) | -2.36 scores on scale | Standard Error 2.19 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | AT Week 6 (n=17, 9) | -1.26 scores on scale | Standard Error 1.4 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | Alprazolam Free (AF) Week 1 (n=39, 28) | -0.43 scores on scale | Standard Error 0.9 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | AF Week 2 (n=35, 24) | -2.15 scores on scale | Standard Error 0.91 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | AF Week 3 (n=31, 26) | -3.46 scores on scale | Standard Error 0.92 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | AF Week 4 (n=31, 19) | -3.58 scores on scale | Standard Error 0.84 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | AF Week 5 (n=27, 18) | -3.85 scores on scale | Standard Error 0.87 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | AT Week 3 (n=33, 26) | -2.59 scores on scale | Standard Error 0.99 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | AF Week 6 (n=22, 15) | -5.62 scores on scale | Standard Error 0.84 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | Endpoint [LOCF] (n=46, 41) | -2.01 scores on scale | Standard Error 1.13 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | Endpoint [LOCF] (n=46, 41) | 2.77 scores on scale | Standard Error 1.36 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | Alprazolam Taper (AT) Week 1 (n=46, 40) | 0.67 scores on scale | Standard Error 0.81 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | AF Week 2 (n=35, 24) | -1.14 scores on scale | Standard Error 1.19 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | AT Week 2 (n=45, 37) | 2.17 scores on scale | Standard Error 1.15 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | AT Week 3 (n=33, 26) | -0.21 scores on scale | Standard Error 1.32 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | AF Week 6 (n=22, 15) | -4.77 scores on scale | Standard Error 1.05 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | AT Week 4 (n=18, 11) | 1.91 scores on scale | Standard Error 1.82 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | AF Week 3 (n=31, 26) | -2.47 scores on scale | Standard Error 1.14 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | AT Week 5 (n=8, 5) | 2.86 scores on scale | Standard Error 2.97 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | AF Week 5 (n=27, 18) | -3.34 scores on scale | Standard Error 1.18 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | AT Week 6 (n=17, 9) | 2.41 scores on scale | Standard Error 2.11 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | AF Week 4 (n=31, 19) | -3.58 scores on scale | Standard Error 1.14 |
| Placebo 75 mg to 300 mg PO BID | Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores | Alprazolam Free (AF) Week 1 (n=39, 28) | 2.40 scores on scale | Standard Error 1.15 |
Comparison: Alprazolam Taper (AT) Week 1p-value: 0.070995% CI: [-3.1, 0.13]ANCOVA
Comparison: AT Week 2p-value: 0.000695% CI: [-6.04, -1.74]ANCOVA
Comparison: AT Week 3p-value: 0.071895% CI: [-4.98, 0.22]ANCOVA
Comparison: AT Week 4p-value: 0.09295% CI: [-7.37, 0.6]ANCOVA
Comparison: AT week 5p-value: 0.137195% CI: [-12.67, 2.23]ANCOVA
Comparison: AT Week 6p-value: 0.088295% CI: [-7.96, 0.61]ANCOVA
Comparison: Alprazolam Free (AF) Week 1p-value: 0.013595% CI: [-5.05, -0.61]ANCOVA
Comparison: AF Week 2p-value: 0.392495% CI: [-3.38, 1.35]ANCOVA
Comparison: AF Week 3p-value: 0.386895% CI: [-3.29, 1.3]ANCOVA
Comparison: AF Week 4p-value: 0.996695% CI: [-2.31, 2.32]ANCOVA
Comparison: AF Week 5p-value: 0.687395% CI: [-3.07, 2.05]ANCOVA
Comparison: AF Week 6p-value: 0.533795% CI: [-3.62, 1.91]ANCOVA
Comparison: Endpoint \[LOCF\]p-value: 0.000895% CI: [-7.51, -2.07]ANCOVA
Secondary
Mean Change From Baseline in Physician's Withdrawal Checklist (PWC) Scores
PWC: 20 item physician rated interview (0 = not present; 3 = severe; score range: 0 to 60) measuring: signs of anxiolytic drug withdrawal and gastrointestinal (GI), mood, sleep, motor, somatic, perception and cognition symptoms. Change from baseline not analyzed as PWC was not measured at baseline. Mean PWS scores presented in Post-hoc outcome measure Mean PWS scores.
Time frame: Baseline, Alprazolam Taper Weeks 1 through 6, Alprazolam Free Weeks 1 through 6, Endpoint (AF Week 6)
Population: ITT; Change from baseline not analyzed as PWC was not measured at baseline. Mean PWS scores presented in Post-hoc outcome measure Mean PWS scores.
Secondary
Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale
CGI-I: 7-point scale to assess global change in subject condition compared to baseline; range 1 (very much improved) to 7 (very much worse); higher score = more affected.
Time frame: Alprazolam Taper Weeks 1 through 6, Alprazolam Free Weeks 1 through 6, and Endpoint (AF Week 6 )
Population: ITT; subject has a baseline and endpoint measurement; endpoint = AF Week 6 or LOCF; (n) = number of subjects with data for analysis for pregabalin and placebo, respectively.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | AT Week 4 (n=18, 11) | 3.09 scores on scale | Standard Error 0.35 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | AT Week 6 (n=17, 9) | 3.00 scores on scale | Standard Error 0.31 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | AT Week 3 (n=33, 27) | 2.88 scores on scale | Standard Error 0.31 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | AF Week 2 (n=35, 24) | 2.39 scores on scale | Standard Error 0.28 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | Alprazolam Free (AF) Week 1 (n=39, 28) | 2.93 scores on scale | Standard Error 0.28 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | AF Week 3 (n=30, 26) | 2.15 scores on scale | Standard Error 0.28 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | Endpoint [LOCF] (n= 46, 41) | 2.57 scores on scale | Standard Error 0.3 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | AF Week 4 (n=31, 19) | 2.20 scores on scale | Standard Error 0.29 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | AT Week 5 (n=8, 5) | 2.63 scores on scale | Standard Error 0.3 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | AF Week 5 (n=27, 18) | 2.29 scores on scale | Standard Error 0.32 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | Alprazolam Taper (AT) Week 1 (n=46, 39) | 3.52 scores on scale | Standard Error 0.2 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | AF Week 6 (n=22, 15) | 1.52 scores on scale | Standard Error 0.28 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | AT Week 2 (n=45, 37) | 3.17 scores on scale | Standard Error 0.27 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | AF Week 6 (n=22, 15) | 2.18 scores on scale | Standard Error 0.34 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | AT Week 2 (n=45, 37) | 3.98 scores on scale | Standard Error 0.31 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | AT Week 4 (n=18, 11) | 3.01 scores on scale | Standard Error 0.54 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | AT Week 5 (n=8, 5) | 3.44 scores on scale | Standard Error 0.47 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | AT Week 6 (n=17, 9) | 3.86 scores on scale | Standard Error 0.46 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | Endpoint [LOCF] (n= 46, 41) | 3.52 scores on scale | Standard Error 0.35 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | Alprazolam Taper (AT) Week 1 (n=46, 39) | 3.90 scores on scale | Standard Error 0.24 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | AT Week 3 (n=33, 27) | 3.47 scores on scale | Standard Error 0.39 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | Alprazolam Free (AF) Week 1 (n=39, 28) | 3.90 scores on scale | Standard Error 0.36 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | AF Week 2 (n=35, 24) | 3.27 scores on scale | Standard Error 0.35 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | AF Week 3 (n=30, 26) | 2.93 scores on scale | Standard Error 0.35 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | AF Week 4 (n=31, 19) | 2.46 scores on scale | Standard Error 0.39 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale | AF Week 5 (n=27, 18) | 2.77 scores on scale | Standard Error 0.42 |
Comparison: AF Week 2p-value: 0.01495% CI: [-1.56, -0.18]ANCOVA
Comparison: Alprazolam Free (AF) Week 1p-value: 0.006395% CI: [-1.67, -0.29]ANCOVA
Comparison: Alprazolam Taper (AT) Week 1p-value: 0.12695% CI: [-0.86, 0.11]ANCOVA
Comparison: AT Week 2p-value: 0.007495% CI: [-1.4, -0.22]ANCOVA
Comparison: AT Week 3p-value: 0.12595% CI: [-1.35, 0.17]ANCOVA
Comparison: AT Week 4p-value: 0.899195% CI: [-1.17, 1.32]ANCOVA
Comparison: AT Week 5p-value: 0.174795% CI: [-2.07, 0.46]ANCOVA
Comparison: AT Week 6p-value: 0.074495% CI: [-1.79, 0.09]ANCOVA
Comparison: AF Week 3p-value: 0.026795% CI: [-1.46, -0.09]ANCOVA
Comparison: AF Week 4p-value: 0.510495% CI: [-1.03, 0.52]ANCOVA
Comparison: AF Week 5p-value: 0.270295% CI: [-1.35, 0.39]ANCOVA
Comparison: AF Week 6p-value: 0.124195% CI: [-1.52, 0.19]ANCOVA
Comparison: Endpoint \[LOCF\]p-value: 0.010995% CI: [-1.67, -0.22]ANCOVA
Secondary
Mean Scores for Patient Global Impression-Improvement (PGI-I)
PGI-I: subject rated 7-point scale measures change in overall status; range 1 (very much improved) to 7 (very much worse).
Time frame: Alprazolam Taper Weeks 1 through 6, Alprazolam Free Weeks 1 through 6, and Endpoint (AF Week 6 )
Population: ITT; endpoint = AF Week 6 or LOCF; (n) = number of subjects with data for analysis for pregabalin and placebo, respectively.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | Alprazolam Taper (AT) Week 1 (n=46, 40) | 3.16 scores on scale | Standard Error 0.23 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | AT Week 2 (n= 45, 37) | 3.13 scores on scale | Standard Error 0.32 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | AT Week 3 (n=33, 26) | 2.93 scores on scale | Standard Error 0.28 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | AT Week 4 (n=18, 11) | 3.12 scores on scale | Standard Error 0.34 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | AT Week 5 (n=8, 5) | 2.91 scores on scale | Standard Error 0.37 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | AT Week 6 (n=17, 9) | 2.93 scores on scale | Standard Error 0.42 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | AF Week 2 (n=35, 24) | 2.34 scores on scale | Standard Error 0.27 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | Alprazolam Free (AF) Week 1 (n=39, 28) | 2.95 scores on scale | Standard Error 0.26 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | AF Week 3 (n=31, 26) | 2.28 scores on scale | Standard Error 0.28 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | AF Week 4 (n=30, 19) | 2.43 scores on scale | Standard Error 0.29 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | AF Week 5 (n=27, 18) | 2.32 scores on scale | Standard Error 0.31 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | AF Week 6 (n=22, 14) | 1.53 scores on scale | Standard Error 0.27 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | Endpoint [LOCF] (n=46, 41) | 2.71 scores on scale | Standard Error 0.32 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | AF Week 4 (n=30, 19) | 2.73 scores on scale | Standard Error 0.38 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | Alprazolam Taper (AT) Week 1 (n=46, 40) | 3.82 scores on scale | Standard Error 0.27 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | AF Week 2 (n=35, 24) | 2.94 scores on scale | Standard Error 0.34 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | AT Week 2 (n= 45, 37) | 4.03 scores on scale | Standard Error 0.36 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | AF Week 6 (n=22, 14) | 2.48 scores on scale | Standard Error 0.35 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | AT Week 3 (n=33, 26) | 3.31 scores on scale | Standard Error 0.35 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | AF Week 5 (n=27, 18) | 2.70 scores on scale | Standard Error 0.41 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | AT Week 4 (n=18, 11) | 2.98 scores on scale | Standard Error 0.52 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | AF Week 3 (n=31, 26) | 2.92 scores on scale | Standard Error 0.35 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | AT Week 5 (n=8, 5) | 3.75 scores on scale | Standard Error 0.58 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | Endpoint [LOCF] (n=46, 41) | 3.74 scores on scale | Standard Error 0.38 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | AT Week 6 (n=17, 9) | 3.38 scores on scale | Standard Error 0.63 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores for Patient Global Impression-Improvement (PGI-I) | Alprazolam Free (AF) Week 1 (n=39, 28) | 3.45 scores on scale | Standard Error 0.33 |
Comparison: Alprazolam Taper (AT) Week 1p-value: 0.022695% CI: [-1.22, -0.09]ANCOVA
Comparison: AT Week 2p-value: 0.009995% CI: [-1.58, -0.22]ANCOVA
Comparison: AT Week 3p-value: 0.282795% CI: [-1.07, 0.32]ANCOVA
Comparison: AT Week 4p-value: 0.823295% CI: [-1.07, 1.34]ANCOVA
Comparison: AT Week 5p-value: 0.240995% CI: [-2.41, 0.72]ANCOVA
Comparison: AT Week 6p-value: 0.47695% CI: [-1.73, 0.84]ANCOVA
Comparison: Alprazolam Free (AF) Week 1p-value: 0.125295% CI: [-1.14, 0.14]ANCOVA
Comparison: AF Week 2p-value: 0.071795% CI: [-1.26, 0.06]ANCOVA
Comparison: AF Week 3p-value: 0.070795% CI: [-1.33, 0.06]ANCOVA
Comparison: AF Week 4p-value: 0.434195% CI: [-1.08, 0.47]ANCOVA
Comparison: AF Week 5p-value: 0.3795% CI: [-1.23, 0.47]ANCOVA
Comparison: AF Week 6p-value: 0.032895% CI: [-1.83, -0.08]ANCOVA
Comparison: Endpoint \[LOCF\]p-value: 0.009695% CI: [-1.8, -0.26]ANCOVA
Secondary
Number of Subjects in Relapse Free State at 6-week Benzodiazepine-free Endpoint (Alprazolam Free Week 6)
Number of subjects benzodiazepine free: \< 2 doses rescue medication; negative urine toxicology assay (each visit Alprazolam Free phase), negative urine alcohol assay (Alprazolam Free Week 6 = endpoint or LOCF). Relapse: \> = 2 intakes rescue medication, positive urine and /or alcohol assays, unable to tolerate alprazolam taper, or discontinuation.
Time frame: Alprazolam Free Week 6
Population: ITT; endpoint = AF Week 6 or LOCF.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pregabalin 75 mg to 300 mg PO BID | Number of Subjects in Relapse Free State at 6-week Benzodiazepine-free Endpoint (Alprazolam Free Week 6) | 21 participants |
| Placebo 75 mg to 300 mg PO BID | Number of Subjects in Relapse Free State at 6-week Benzodiazepine-free Endpoint (Alprazolam Free Week 6) | 12 participants |
p-value: 0.1159Cochran-Mantel-Haenszel
Secondary
Number of Subjects With > = 5 New PWC Symptoms
PWC: 20 item physician rated interview (0 = not present; 3 = severe; score range: 0 to 60) measuring: signs of anxiolytic drug withdrawal and gastrointestinal (GI), mood, sleep, motor, somatic, perception and cognition symptoms. Data not analyzed: PWC not measured at baseline.
Time frame: Baseline, Alprazolam Free Weeks 1 through 6, Endpoint (AF Week 6)
Population: ITT; data not analyzed: PWC not measured at baseline.
Secondary
Number of Subjects With > = 6 Point Increase in Physician's Withdrawal Checklist (PWC) Scores
PWC: 20 item physician rated interview (0 = not present; 3 = severe; score range: 0 to 60) measuring: signs of anxiolytic drug withdrawal and gastrointestinal (GI), mood, sleep, motor, somatic, perception and cognition symptoms. Data not analyzed: PWC not measured at baseline.
Time frame: Baseline, Alprazolam Free Weeks 1 through 6, Endpoint (AF Week 6)
Population: ITT; data not analyzed: PWC not measured at baseline.
Secondary
Time to Discontinuation
The 25th percentile estimate of time until discontinuation is based on Kaplan-Meier estimates. Event day is the study day when the subject discontinued from study.
Time frame: Baseline, Week 13 (Final Visit/Early Termination)
Population: ITT; Week 13 (Final Visit/Early Termination) or LOCF.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pregabalin 75 mg to 300 mg PO BID | Time to Discontinuation | 51 days |
| Placebo 75 mg to 300 mg PO BID | Time to Discontinuation | 33 days |
p-value: 0.0626Log Rank
Secondary
Time to First Use of Rescue Medication
The 25th percentile estimate of time until first use of rescue medication is based on Kaplan-Meier estimates. Event day is the study day when the subject first used rescue medication. Rescue medication: packet with 2 doses alprazolam to take only in the event subject experiences severe symptoms of benzodiazepine withdrawal or rebound anxiety.
Time frame: Baseline, Week 13 (Final Visit/Early Termination)
Population: ITT; Week 13 (Final Visit/Early Termination) or LOCF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pregabalin 75 mg to 300 mg PO BID | Time to First Use of Rescue Medication | 63 days |
| Placebo 75 mg to 300 mg PO BID | Time to First Use of Rescue Medication | 30 days |
p-value: 0.0148Log Rank
Post Hoc
Mean Scores Physician's Withdrawal Checklist (PWC)
Mean scores at each visit for PWC: 20-item physician-rated interview measures presence of anxiolytic drug withdrawal-related signs and symptoms (gastrointestinal, mood, sleep, motor, somatic, perception, and cognition); range 0 (not present) to 3 (severe). Total score: 0 to 60; higher score = more affected. Mean scores entered as post-hoc analysis as Mean change from baseline in PWS scores not analyzed: PWS not measured at baseline.
Time frame: Baseline, Alprazolam Taper Weeks 1 through 6, Alprazolam Free Weeks 1 through 6, Endpoint (AF Week 6 )
Population: ITT; (n) = number of subjects with data for analysis for pregabalin and placebo, respectively. Endpoint = AF Week 6 or LOCF. Refer to measure Mean Change From Baseline in Physician's Withdrawal Checklist (PWC) Scores.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | AF Week 2 (n=33, 24) | 4.71 scores on scale | Standard Error 0.93 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | Endpoint [LOCF] (n=46, 41) | 6.48 scores on scale | Standard Error 1.23 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | AF Week 4 (n=30, 19) | 7.43 scores on scale | Standard Error 0.89 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | Alprazolam Taper (AT) Week 1 (n=43, 40) | 6.32 scores on scale | Standard Error 1.4 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | Alprazolam Free (AF) Week 1 (n=39, 28) | 6.78 scores on scale | Standard Error 1.15 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | AT Week 2 (n=44,37) | 6.37 scores on scale | Standard Error 1.18 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | AF Week 5 (n=27, 18) | 7.87 scores on scale | Standard Error 0.76 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | AT Week 3 (n=33, 26) | 6.56 scores on scale | Standard Error 1.4 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | AF Week 3 (n=30, 26) | 6.86 scores on scale | Standard Error 0.85 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | AT Week 4 (n=18, 11) | 5.63 scores on scale | Standard Error 0.89 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | AF Week 6 (n=22, 15) | 2.40 scores on scale | Standard Error 0.94 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | AT Week 5 (n=7, 5) | 7.30 scores on scale | Standard Error 1.52 |
| Pregabalin 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | AT Week 6 (n=17, 9) | 6.82 scores on scale | Standard Error 1.39 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | AT Week 5 (n=7, 5) | 9.58 scores on scale | Standard Error 2.32 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | AT Week 6 (n=17, 9) | 12.55 scores on scale | Standard Error 2.07 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | Alprazolam Free (AF) Week 1 (n=39, 28) | 10.70 scores on scale | Standard Error 1.45 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | AF Week 2 (n=33, 24) | 6.43 scores on scale | Standard Error 1.19 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | AF Week 3 (n=30, 26) | 7.16 scores on scale | Standard Error 1.05 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | AF Week 4 (n=30, 19) | 6.99 scores on scale | Standard Error 1.17 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | AF Week 5 (n=27, 18) | 8.25 scores on scale | Standard Error 1 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | AF Week 6 (n=22, 15) | 5.51 scores on scale | Standard Error 1.16 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | Endpoint [LOCF] (n=46, 41) | 10.28 scores on scale | Standard Error 1.44 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | Alprazolam Taper (AT) Week 1 (n=43, 40) | 8.50 scores on scale | Standard Error 1.45 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | AT Week 2 (n=44,37) | 10.00 scores on scale | Standard Error 1.34 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | AT Week 3 (n=33, 26) | 9.41 scores on scale | Standard Error 1.76 |
| Placebo 75 mg to 300 mg PO BID | Mean Scores Physician's Withdrawal Checklist (PWC) | AT Week 4 (n=18, 11) | 9.04 scores on scale | Standard Error 1.37 |
Comparison: Alprazolam Taper (AT) Week 1p-value: 0.12295% CI: [-4.97, 0.6]ANCOVA
Comparison: AT Week 2p-value: 0.005395% CI: [-6.15, -1.11]ANCOVA
Comparison: AT Week 3p-value: 0.104895% CI: [-6.32, 0.62]ANCOVA
Comparison: AT Week 4p-value: 0.035795% CI: [-6.57, -0.25]ANCOVA
Comparison: AT Week 5p-value: 0.426395% CI: [-8.82, 4.26]ANCOVA
Comparison: AT Week 6p-value: 0.010495% CI: [-9.96, -1.51]ANCOVA
Comparison: Alprazolam Free (AF) Week 1p-value: 0.006995% CI: [-6.73, -1.12]ANCOVA
Comparison: AF Week 2p-value: 0.218595% CI: [-4.47, 1.05]ANCOVA
Comparison: AF Week 3p-value: 0.783295% CI: [-2.41, 1.83]ANCOVA
Comparison: AF Week 4p-value: 0.706295% CI: [-1.9, 2.79]ANCOVA
Comparison: AF Week 5p-value: 0.716195% CI: [-2.49, 1.73]ANCOVA
Comparison: AF Week 6p-value: 0.037695% CI: [-6.03, -0.19]ANCOVA
Comparison: Endpoint \[LOCF\]p-value: 0.012295% CI: [-6.74, -0.85]ANCOVA