Trial Outcomes & Findings for Efficacy and Safety of Pregabalin vs Placebo for Generalized Anxiety Disorder (GAD) Symptoms in Subjects Discontinuing Benzodiazepine Treatment and Remaining 6 Weeks on Study Medication, Free From Benzodiazepine Use. (NCT NCT00368745)
NCT ID: NCT00368745
Last Updated: 2021-02-09
Results Overview
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).
Recruitment status
COMPLETED
Study phase
PHASE3
Target enrollment
108 participants
Primary outcome timeframe
Endpoint (Post Alprazolam Free Week 6 or LOCF Post Alprazolam Free Week 1)
Results posted on
2021-02-09
Participant Flow
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).
Participant milestones
| Measure |
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.
|
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.
|
|---|---|---|
|
Randomized to Double-blind Treatment
STARTED
|
57
|
51
|
|
Randomized to Double-blind Treatment
COMPLETED
|
56
|
50
|
|
Randomized to Double-blind Treatment
NOT COMPLETED
|
1
|
1
|
|
Double-blind Treatment Period
STARTED
|
56
|
50
|
|
Double-blind Treatment Period
COMPLETED
|
30
|
19
|
|
Double-blind Treatment Period
NOT COMPLETED
|
26
|
31
|
Reasons for withdrawal
| Measure |
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.
|
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.
|
|---|---|---|
|
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
Withdrawal by Subject
|
5
|
3
|
|
Double-blind Treatment Period
Other
|
7
|
6
|
Baseline Characteristics
Efficacy and Safety of Pregabalin vs Placebo for Generalized Anxiety Disorder (GAD) Symptoms in Subjects Discontinuing Benzodiazepine Treatment and Remaining 6 Weeks on Study Medication, Free From Benzodiazepine Use.
Baseline characteristics by cohort
| Measure |
Pregabalin 75 mg to 300 mg PO BID
n=56 Participants
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.
|
Placebo 75 mg to 300 mg PO BID
n=50 Participants
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.
|
Total
n=106 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
|
40.1 years
STANDARD_DEVIATION 10.6 • n=5 Participants
|
43.5 years
STANDARD_DEVIATION 11.3 • n=7 Participants
|
41.7 years
STANDARD_DEVIATION 11.0 • n=5 Participants
|
|
Sex: Female, Male
Female
|
42 Participants
n=5 Participants
|
34 Participants
n=7 Participants
|
76 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
14 Participants
n=5 Participants
|
16 Participants
n=7 Participants
|
30 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: 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.
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).
Outcome measures
| Measure |
Pregabalin 75 mg to 300 mg PO BID
n=37 Participants
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.
|
Placebo 75 mg to 300 mg PO BID
n=27 Participants
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.
|
|---|---|---|
|
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
|
10 participants
|
SECONDARY outcome
Timeframe: 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.
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.
Outcome measures
| Measure |
Pregabalin 75 mg to 300 mg PO BID
n=46 Participants
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.
|
Placebo 75 mg to 300 mg PO BID
n=41 Participants
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.
|
|---|---|---|
|
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
|
-1.14 scores on scale
Standard Error 1.19
|
|
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
|
-2.47 scores on scale
Standard Error 1.14
|
|
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
|
-4.77 scores on scale
Standard Error 1.05
|
|
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
|
2.77 scores on scale
Standard Error 1.36
|
|
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
|
2.17 scores on scale
Standard Error 1.15
|
|
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
|
-0.21 scores on scale
Standard Error 1.32
|
|
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 0.90
|
2.40 scores on scale
Standard Error 1.15
|
|
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
|
-3.58 scores on scale
Standard Error 1.14
|
|
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
|
-3.34 scores on scale
Standard Error 1.18
|
|
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
|
0.67 scores on scale
Standard Error 0.81
|
|
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
|
1.91 scores on scale
Standard Error 1.82
|
|
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
|
2.86 scores on scale
Standard Error 2.97
|
|
Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores
AT Week 6 (n=17, 9)
|
-1.26 scores on scale
Standard Error 1.40
|
2.41 scores on scale
Standard Error 2.11
|
SECONDARY outcome
Timeframe: Baseline, Alprazolam Free Weeks 1 through 6, Endpoint (AF Week 6)Population: ITT; data not analyzed: PWC not measured at baseline.
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.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: Baseline, Alprazolam Free Weeks 1 through 6, Endpoint (AF Week 6)Population: ITT; data not analyzed: PWC not measured at baseline.
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.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: 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.
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.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: 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.
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.
Outcome measures
| Measure |
Pregabalin 75 mg to 300 mg PO BID
n=45 Participants
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.
|
Placebo 75 mg to 300 mg PO BID
n=41 Participants
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.
|
|---|---|---|
|
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
|
0.22 scores on scale
Standard Error 0.15
|
|
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 0.20
|
-0.10 scores on scale
Standard Error 0.26
|
|
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
|
-0.05 scores on scale
Standard Error 0.40
|
|
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
|
0.08 scores on scale
Standard Error 0.43
|
|
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
|
0.23 scores on scale
Standard Error 0.21
|
|
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
|
-0.32 scores on scale
Standard Error 0.27
|
|
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
|
-0.84 scores on scale
Standard Error 0.25
|
|
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
|
-0.75 scores on scale
Standard Error 0.26
|
|
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 0.20
|
-1.02 scores on scale
Standard Error 0.25
|
|
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
|
0.31 scores on scale
Standard Error 0.24
|
|
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
|
0.41 scores on scale
Standard Error 0.19
|
|
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
|
-0.04 scores on scale
Standard Error 0.32
|
|
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 0.20
|
-0.48 scores on scale
Standard Error 0.26
|
SECONDARY outcome
Timeframe: 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.
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.
Outcome measures
| Measure |
Pregabalin 75 mg to 300 mg PO BID
n=46 Participants
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.
|
Placebo 75 mg to 300 mg PO BID
n=41 Participants
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.
|
|---|---|---|
|
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 0.20
|
3.90 scores on scale
Standard Error 0.24
|
|
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
|
3.98 scores on scale
Standard Error 0.31
|
|
Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale
AT Week 5 (n=8, 5)
|
2.63 scores on scale
Standard Error 0.30
|
3.44 scores on scale
Standard Error 0.47
|
|
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
|
3.86 scores on scale
Standard Error 0.46
|
|
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
|
3.90 scores on scale
Standard Error 0.36
|
|
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
|
3.27 scores on scale
Standard Error 0.35
|
|
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
|
2.93 scores on scale
Standard Error 0.35
|
|
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
|
2.46 scores on scale
Standard Error 0.39
|
|
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
|
3.47 scores on scale
Standard Error 0.39
|
|
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
|
3.01 scores on scale
Standard Error 0.54
|
|
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
|
2.77 scores on scale
Standard Error 0.42
|
|
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
|
2.18 scores on scale
Standard Error 0.34
|
|
Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale
Endpoint [LOCF] (n= 46, 41)
|
2.57 scores on scale
Standard Error 0.30
|
3.52 scores on scale
Standard Error 0.35
|
SECONDARY outcome
Timeframe: 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.
PGI-I: subject rated 7-point scale measures change in overall status; range 1 (very much improved) to 7 (very much worse).
Outcome measures
| Measure |
Pregabalin 75 mg to 300 mg PO BID
n=46 Participants
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.
|
Placebo 75 mg to 300 mg PO BID
n=41 Participants
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.
|
|---|---|---|
|
Mean Scores for Patient Global Impression-Improvement (PGI-I)
AT Week 2 (n= 45, 37)
|
3.13 scores on scale
Standard Error 0.32
|
4.03 scores on scale
Standard Error 0.36
|
|
Mean Scores for Patient Global Impression-Improvement (PGI-I)
AT Week 4 (n=18, 11)
|
3.12 scores on scale
Standard Error 0.34
|
2.98 scores on scale
Standard Error 0.52
|
|
Mean Scores for Patient Global Impression-Improvement (PGI-I)
AT Week 5 (n=8, 5)
|
2.91 scores on scale
Standard Error 0.37
|
3.75 scores on scale
Standard Error 0.58
|
|
Mean Scores for Patient Global Impression-Improvement (PGI-I)
AT Week 6 (n=17, 9)
|
2.93 scores on scale
Standard Error 0.42
|
3.38 scores on scale
Standard Error 0.63
|
|
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
|
3.45 scores on scale
Standard Error 0.33
|
|
Mean Scores for Patient Global Impression-Improvement (PGI-I)
AF Week 2 (n=35, 24)
|
2.34 scores on scale
Standard Error 0.27
|
2.94 scores on scale
Standard Error 0.34
|
|
Mean Scores for Patient Global Impression-Improvement (PGI-I)
AF Week 4 (n=30, 19)
|
2.43 scores on scale
Standard Error 0.29
|
2.73 scores on scale
Standard Error 0.38
|
|
Mean Scores for Patient Global Impression-Improvement (PGI-I)
AF Week 5 (n=27, 18)
|
2.32 scores on scale
Standard Error 0.31
|
2.70 scores on scale
Standard Error 0.41
|
|
Mean Scores for Patient Global Impression-Improvement (PGI-I)
AF Week 6 (n=22, 14)
|
1.53 scores on scale
Standard Error 0.27
|
2.48 scores on scale
Standard Error 0.35
|
|
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
|
3.82 scores on scale
Standard Error 0.27
|
|
Mean Scores for Patient Global Impression-Improvement (PGI-I)
AT Week 3 (n=33, 26)
|
2.93 scores on scale
Standard Error 0.28
|
3.31 scores on scale
Standard Error 0.35
|
|
Mean Scores for Patient Global Impression-Improvement (PGI-I)
AF Week 3 (n=31, 26)
|
2.28 scores on scale
Standard Error 0.28
|
2.92 scores on scale
Standard Error 0.35
|
|
Mean Scores for Patient Global Impression-Improvement (PGI-I)
Endpoint [LOCF] (n=46, 41)
|
2.71 scores on scale
Standard Error 0.32
|
3.74 scores on scale
Standard Error 0.38
|
SECONDARY outcome
Timeframe: Baseline, Endpoint (AF Week 6 )Population: ITT; subject has baseline and endpoint (final visit) measurement; endpoint = AF Week 6 or LOCF.
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.
Outcome measures
| Measure |
Pregabalin 75 mg to 300 mg PO BID
n=33 Participants
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.
|
Placebo 75 mg to 300 mg PO BID
n=29 Participants
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.
|
|---|---|---|
|
Mean Change From Baseline in Digit Symbol Substitution Test (DSST) Scores
|
13.10 scores on scale
Standard Error 2.64
|
13.47 scores on scale
Standard Error 2.95
|
SECONDARY outcome
Timeframe: Baseline, Week 13 (Final Visit/Early Termination)Population: ITT; Week 13 (Final Visit/Early Termination) or LOCF.
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.
Outcome measures
| Measure |
Pregabalin 75 mg to 300 mg PO BID
n=19 Participants
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.
|
Placebo 75 mg to 300 mg PO BID
n=24 Participants
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.
|
|---|---|---|
|
Time to Discontinuation
|
51 days
|
33 days
|
SECONDARY outcome
Timeframe: Baseline, Week 13 (Final Visit/Early Termination)Population: ITT; Week 13 (Final Visit/Early Termination) or LOCF
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.
Outcome measures
| Measure |
Pregabalin 75 mg to 300 mg PO BID
n=11 Participants
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.
|
Placebo 75 mg to 300 mg PO BID
n=17 Participants
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.
|
|---|---|---|
|
Time to First Use of Rescue Medication
|
63 days
|
30 days
|
SECONDARY outcome
Timeframe: Alprazolam Free Week 6Population: ITT; endpoint = AF Week 6 or LOCF.
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.
Outcome measures
| Measure |
Pregabalin 75 mg to 300 mg PO BID
n=22 Participants
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.
|
Placebo 75 mg to 300 mg PO BID
n=15 Participants
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.
|
|---|---|---|
|
Number of Subjects in Relapse Free State at 6-week Benzodiazepine-free Endpoint (Alprazolam Free Week 6)
|
21 participants
|
12 participants
|
POST_HOC outcome
Timeframe: 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.
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.
Outcome measures
| Measure |
Pregabalin 75 mg to 300 mg PO BID
n=46 Participants
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.
|
Placebo 75 mg to 300 mg PO BID
n=41 Participants
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.
|
|---|---|---|
|
Mean Scores Physician's Withdrawal Checklist (PWC)
Alprazolam Taper (AT) Week 1 (n=43, 40)
|
6.32 scores on scale
Standard Error 1.40
|
8.50 scores on scale
Standard Error 1.45
|
|
Mean Scores Physician's Withdrawal Checklist (PWC)
AT Week 2 (n=44,37)
|
6.37 scores on scale
Standard Error 1.18
|
10.00 scores on scale
Standard Error 1.34
|
|
Mean Scores Physician's Withdrawal Checklist (PWC)
AT Week 6 (n=17, 9)
|
6.82 scores on scale
Standard Error 1.39
|
12.55 scores on scale
Standard Error 2.07
|
|
Mean Scores Physician's Withdrawal Checklist (PWC)
Alprazolam Free (AF) Week 1 (n=39, 28)
|
6.78 scores on scale
Standard Error 1.15
|
10.70 scores on scale
Standard Error 1.45
|
|
Mean Scores Physician's Withdrawal Checklist (PWC)
AF Week 4 (n=30, 19)
|
7.43 scores on scale
Standard Error 0.89
|
6.99 scores on scale
Standard Error 1.17
|
|
Mean Scores Physician's Withdrawal Checklist (PWC)
AF Week 6 (n=22, 15)
|
2.40 scores on scale
Standard Error 0.94
|
5.51 scores on scale
Standard Error 1.16
|
|
Mean Scores Physician's Withdrawal Checklist (PWC)
Endpoint [LOCF] (n=46, 41)
|
6.48 scores on scale
Standard Error 1.23
|
10.28 scores on scale
Standard Error 1.44
|
|
Mean Scores Physician's Withdrawal Checklist (PWC)
AT Week 3 (n=33, 26)
|
6.56 scores on scale
Standard Error 1.40
|
9.41 scores on scale
Standard Error 1.76
|
|
Mean Scores Physician's Withdrawal Checklist (PWC)
AT Week 4 (n=18, 11)
|
5.63 scores on scale
Standard Error 0.89
|
9.04 scores on scale
Standard Error 1.37
|
|
Mean Scores Physician's Withdrawal Checklist (PWC)
AT Week 5 (n=7, 5)
|
7.30 scores on scale
Standard Error 1.52
|
9.58 scores on scale
Standard Error 2.32
|
|
Mean Scores Physician's Withdrawal Checklist (PWC)
AF Week 2 (n=33, 24)
|
4.71 scores on scale
Standard Error 0.93
|
6.43 scores on scale
Standard Error 1.19
|
|
Mean Scores Physician's Withdrawal Checklist (PWC)
AF Week 3 (n=30, 26)
|
6.86 scores on scale
Standard Error 0.85
|
7.16 scores on scale
Standard Error 1.05
|
|
Mean Scores Physician's Withdrawal Checklist (PWC)
AF Week 5 (n=27, 18)
|
7.87 scores on scale
Standard Error 0.76
|
8.25 scores on scale
Standard Error 1.00
|
Adverse Events
Pregabalin 75 mg to 300 mg PO BID
Serious events: 0 serious events
Other events: 33 other events
Deaths: 0 deaths
Placebo 75 mg to 300 mg PO BID
Serious events: 0 serious events
Other events: 29 other events
Deaths: 0 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Pregabalin 75 mg to 300 mg PO BID
n=56 participants at risk
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.
|
Placebo 75 mg to 300 mg PO BID
n=50 participants at risk
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.
|
|---|---|---|
|
Ear and labyrinth disorders
Hyperacusis
|
5.4%
3/56
|
2.0%
1/50
|
|
Eye disorders
Vision blurred
|
8.9%
5/56
|
4.0%
2/50
|
|
Gastrointestinal disorders
Diarrhoea
|
5.4%
3/56
|
10.0%
5/50
|
|
Gastrointestinal disorders
Nausea
|
8.9%
5/56
|
14.0%
7/50
|
|
Gastrointestinal disorders
Vomiting
|
5.4%
3/56
|
0.00%
0/50
|
|
General disorders
Asthenia
|
5.4%
3/56
|
10.0%
5/50
|
|
General disorders
Fatigue
|
3.6%
2/56
|
6.0%
3/50
|
|
General disorders
Irritability
|
0.00%
0/56
|
8.0%
4/50
|
|
General disorders
Oedema peripheral
|
8.9%
5/56
|
0.00%
0/50
|
|
Musculoskeletal and connective tissue disorders
Pain in extremity
|
5.4%
3/56
|
0.00%
0/50
|
|
Nervous system disorders
Dizziness
|
21.4%
12/56
|
6.0%
3/50
|
|
Nervous system disorders
Headache
|
12.5%
7/56
|
26.0%
13/50
|
|
Nervous system disorders
Paraesthesia
|
10.7%
6/56
|
0.00%
0/50
|
|
Nervous system disorders
Somnolence
|
5.4%
3/56
|
4.0%
2/50
|
|
Nervous system disorders
Tremor
|
3.6%
2/56
|
8.0%
4/50
|
|
Psychiatric disorders
Anxiety
|
19.6%
11/56
|
20.0%
10/50
|
|
Psychiatric disorders
Insomnia
|
7.1%
4/56
|
14.0%
7/50
|
|
Skin and subcutaneous tissue disorders
Hyperhidrosis
|
5.4%
3/56
|
0.00%
0/50
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of \< 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), \< 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
- Publication restrictions are in place
Restriction type: OTHER