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.

This study has been completed.

Sponsor:

Information provided by:

Pfizer

ClinicalTrials.gov Identifier:

NCT00368745

First received: August 23, 2006

Last updated: November 9, 2009

Last verified: November 2009

History of Changes

Results First Received: August 10, 2009

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition:	Generalized Anxiety Disorder
Interventions:	Drug: Pregabalin Drug: Placebo

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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).

Reporting Groups

Description

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.

Participant Flow for 2 periods

Period 1: Randomized to Double-blind Treatment

	Pregabalin 75 mg to 300 mg PO BID	Placebo 75 mg to 300 mg PO BID
STARTED	57	51
COMPLETED	56 ^[1]	50 ^[2]
NOT COMPLETED	1	1

[1]	One subject did not return following randomization; study drug not dispensed.
[2]	One subject did not want to participate in study.

Period 2: Double-blind Treatment Period

	Pregabalin 75 mg to 300 mg PO BID	Placebo 75 mg to 300 mg PO BID
STARTED	56	50
COMPLETED	30	19
NOT COMPLETED	26	31
Adverse Event	6	6
Lack of Efficacy	7	16
Lost to Follow-up	1	0
Withdrawal by Subject	5	3
Unknown	7	6

Baseline Characteristics

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Reporting Groups

	Description
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.
Total	Total of all reporting groups

Baseline Measures

	Pregabalin 75 mg to 300 mg PO BID	Placebo 75 mg to 300 mg PO BID	Total
Number of Participants [units: participants]	56	50	106
Age [units: years] Mean ± Standard Deviation	40.1 ± 10.6	43.5 ± 11.3	41.7 ± 11.0
Gender [units: participants]
Female	42	34	76
Male	14	16	30

Outcome Measures

Show All Outcome Measures

1. 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 [ Time Frame: Endpoint (Post Alprazolam Free Week 6 or LOCF Post Alprazolam Free Week 1) ]

Show Outcome Measure 1

2. Secondary:

Mean Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores [ Time Frame: Baseline, Alprazolam Taper Weeks 1 through 6, Alprazolam Free Weeks 1 through 6, and Endpoint (Alprazolam Free [AF] Week 6) ]

Show Outcome Measure 2

3. Secondary:

Number of Subjects With > = 6 Point Increase in Physician's Withdrawal Checklist (PWC) Scores [ Time Frame: Baseline, Alprazolam Free Weeks 1 through 6, Endpoint (AF Week 6) ]

Show Outcome Measure 3

4. Secondary:

Number of Subjects With > = 5 New PWC Symptoms [ Time Frame: Baseline, Alprazolam Free Weeks 1 through 6, Endpoint (AF Week 6) ]

Show Outcome Measure 4

5. Secondary:

Mean Change From Baseline in Physician's Withdrawal Checklist (PWC) Scores [ Time Frame: Baseline, Alprazolam Taper Weeks 1 through 6, Alprazolam Free Weeks 1 through 6, Endpoint (AF Week 6) ]

Show Outcome Measure 5

6. Secondary:

Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. [ Time Frame: Baseline, Alprazolam Taper Weeks 1 through 6, Alprazolam Free Weeks 1 through 6, and Endpoint (AF Week 6 ) ]

Hide Outcome Measure 6

Measure Type	Secondary
Measure Title	Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores.
Measure Description	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 )
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

Description

Pregabalin 75 mg to 300 mg PO BID

Placebo 75 mg to 300 mg PO BID

Measured Values

	Pregabalin 75 mg to 300 mg PO BID	Placebo 75 mg to 300 mg PO BID
Number of Participants Analyzed [units: participants]	45	41
Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores. [units: scores on scale] Least Squares Mean ± Standard Error
Alprazolam Taper (AT) Week 1 (n=45, 40)	-0.23 ± 0.13	0.22 ± 0.15
AT Week 2 (n=44, 37)	-0.33 ± 0.17	0.41 ± 0.19
AT Week 3 (n=32, 27)	-0.60 ± 0.20	-0.10 ± 0.26
AT Week 4 (n=17, 11)	-0.41 ± 0.21	-0.04 ± 0.32
AT Week 5 (n=7, 5)	-0.77 ± 0.27	-0.05 ± 0.40
AT Week 6 (n=16, 9)	-0.63 ± 0.32	0.08 ± 0.43
Alprazolam Free (AF) Week 1 (n=38, 28)	-0.46 ± 0.17	0.23 ± 0.21
AF Week 2 (n=34, 24)	-0.98 ± 0.20	-0.48 ± 0.26
AF Week 3 (n=30, 26)	-0.88 ± 0.22	-0.32 ± 0.27
AF Week 4 (n=30, 19)	-0.87 ± 0.18	-0.84 ± 0.25
AF Week 5 (n=26, 18)	-0.82 ± 0.19	-0.75 ± 0.26
AF Week 6 (n=21, 15)	-1.33 ± 0.20	-1.02 ± 0.25
Endpoint [LOCF] (n=45, 41)	-0.45 ± 0.21	0.31 ± 0.24

Statistical Analysis 1 for Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores.

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.0052
Mean Difference (Final Values) ^[4]	-0.45
Standard Error of the mean	± 0.16
95% Confidence Interval	( -0.76 to -0.14 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Alprazolam Taper (AT) Week 1
[2]	Other relevant information, such as adjustments or degrees of freedom:
	LS Means from the ANCOVA model with treatment as the main effect and country and baseline as covariate
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	contrasts performed using Dunnett's Test
[4]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores.

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.0001
Mean Difference (Final Values) ^[4]	-0.74
Standard Error of the mean	± 0.18
95% Confidence Interval	( -1.11 to -0.38 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	AT Week 2
[2]	Other relevant information, such as adjustments or degrees of freedom:
	LS Means from the ANCOVA model with treatment as the main effect and country and baseline as covariate
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	contrasts performed using Dunnett's Test
[4]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores.

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.0528
Mean Difference (Final Values) ^[4]	-0.50
Standard Error of the mean	± 0.25
95% Confidence Interval	( -1.00 to 0.01 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	AT Week 3
[2]	Other relevant information, such as adjustments or degrees of freedom:
	LS Means from the ANCOVA model with treatment as the main effect and country and baseline as covariate
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	contrasts performed using Dunnett's Test
[4]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores.

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.3085
Mean Difference (Final Values) ^[4]	-0.37
Standard Error of the mean	± 0.35
95% Confidence Interval	( -1.11 to 0.37 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	AT Week 4
[2]	Other relevant information, such as adjustments or degrees of freedom:
	LS Means from the ANCOVA model with treatment as the main effect and country and baseline as covariate
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	contrasts performed using Dunnett's Test
[4]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores.

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.1807
Mean Difference (Final Values) ^[4]	-0.72
Standard Error of the mean	± 0.47
95% Confidence Interval	( -1.92 to 0.47 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	AT Week 5
[2]	Other relevant information, such as adjustments or degrees of freedom:
	LS Means from the ANCOVA model with treatment as the main effect and country and baseline as covariate
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	contrasts performed using Dunnett's Test
[4]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores.

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.1074
Mean Difference (Final Values) ^[4]	-0.71
Standard Error of the mean	± 0.42
95% Confidence Interval	( -1.58 to 0.17 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	AT Week 6
[2]	Other relevant information, such as adjustments or degrees of freedom:
	LS Means from the ANCOVA model with treatment as the main effect and country and baseline as covariate
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	contrasts performed using Dunnett's Test
[4]	Other relevant estimation information:
	No text entered.

Statistical Analysis 7 for Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores.

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.0013
Mean Difference (Final Values) ^[4]	-0.69
Standard Error of the mean	± 0.20
95% Confidence Interval	( -1.10 to -0.28 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Alprazolam Free (AF) Week 1
[2]	Other relevant information, such as adjustments or degrees of freedom:
	LS Means from the ANCOVA model with treatment as the main effect and country and baseline as covariate
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	contrasts performed using Dunnett's Test
[4]	Other relevant estimation information:
	No text entered.

Statistical Analysis 8 for Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores.

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.0503
Mean Difference (Final Values) ^[4]	-0.50
Standard Error of the mean	± 0.25
95% Confidence Interval	( -0.99 to 0.00 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	AF Week 2
[2]	Other relevant information, such as adjustments or degrees of freedom:
	LS Means from the ANCOVA model with treatment as the main effect and country and baseline as covariate
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	contrasts performed using Dunnett's Test
[4]	Other relevant estimation information:
	No text entered.

Statistical Analysis 9 for Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores.

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.0364
Mean Difference (Final Values) ^[4]	-0.56
Standard Error of the mean	± 0.26
95% Confidence Interval	( -1.09 to -0.04 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	AF Week 3
[2]	Other relevant information, such as adjustments or degrees of freedom:
	LS Means from the ANCOVA model with treatment as the main effect and country and baseline as covariate
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	contrasts performed using Dunnett's Test
[4]	Other relevant estimation information:
	No text entered.

Statistical Analysis 10 for Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores.

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.9140
Mean Difference (Final Values) ^[4]	-0.03
Standard Error of the mean	± 0.24
95% Confidence Interval	( -0.51 to 0.46 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	AF Week 4
[2]	Other relevant information, such as adjustments or degrees of freedom:
	LS Means from the ANCOVA model with treatment as the main effect and country and baseline as covariate
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	contrasts performed using Dunnett's Test
[4]	Other relevant estimation information:
	No text entered.

Statistical Analysis 11 for Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores.

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.7789
Mean Difference (Final Values) ^[4]	-0.08
Standard Error of the mean	± 0.27
95% Confidence Interval	( -0.62 to 0.47 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	AF Week 5
[2]	Other relevant information, such as adjustments or degrees of freedom:
	LS Means from the ANCOVA model with treatment as the main effect and country and baseline as covariate
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	contrasts performed using Dunnett's Test
[4]	Other relevant estimation information:
	No text entered.

Statistical Analysis 12 for Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores.

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.3189
Mean Difference (Final Values) ^[4]	-0.32
Standard Error of the mean	± 0.31
95% Confidence Interval	( -0.95 to 0.32 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	AF Week 6
[2]	Other relevant information, such as adjustments or degrees of freedom:
	LS Means from the ANCOVA model with treatment as the main effect and country and baseline as covariate
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	contrasts performed using Dunnett's Test
[4]	Other relevant estimation information:
	No text entered.

Statistical Analysis 13 for Mean Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Scores.

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.0031
Mean Difference (Final Values) ^[4]	-0.76
Standard Error of the mean	± 0.25
95% Confidence Interval	( -1.26 to -0.27 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Endpoint [LOCF]
[2]	Other relevant information, such as adjustments or degrees of freedom:
	LS Means from the ANCOVA model with treatment as the main effect and country and baseline as covariate
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	contrasts performed using Dunnett's Test
[4]	Other relevant estimation information:
	No text entered.

7. Secondary:

Mean Scores for Clinical Global Impression-Improvement (CGI-I) Scale [ Time Frame: Alprazolam Taper Weeks 1 through 6, Alprazolam Free Weeks 1 through 6, and Endpoint (AF Week 6 ) ]

Show Outcome Measure 7

8. Secondary:

Mean Scores for Patient Global Impression-Improvement (PGI-I) [ Time Frame: Alprazolam Taper Weeks 1 through 6, Alprazolam Free Weeks 1 through 6, and Endpoint (AF Week 6 ) ]

Show Outcome Measure 8

9. Secondary:

Mean Change From Baseline in Digit Symbol Substitution Test (DSST) Scores [ Time Frame: Baseline, Endpoint (AF Week 6 ) ]

Show Outcome Measure 9

10. Secondary:

Time to Discontinuation [ Time Frame: Baseline, Week 13 (Final Visit/Early Termination) ]

Show Outcome Measure 10

11. Secondary:

Time to First Use of Rescue Medication [ Time Frame: Baseline, Week 13 (Final Visit/Early Termination) ]

Show Outcome Measure 11

12. Secondary:

Number of Subjects in Relapse Free State at 6-week Benzodiazepine-free Endpoint (Alprazolam Free Week 6) [ Time Frame: Alprazolam Free Week 6 ]

Show Outcome Measure 12

13. Post-Hoc:

Mean Scores Physician's Withdrawal Checklist (PWC) [ Time Frame: Baseline, Alprazolam Taper Weeks 1 through 6, Alprazolam Free Weeks 1 through 6, Endpoint (AF Week 6 ) ]

Show Outcome Measure 13

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: 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.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact:

Name/Title: Pfizer ClinicalTrials.gov Call Center
Organization: Pfizer, Inc.
phone: 1-800-718-1021
e-mail: ClinicalTrials.govCallCenter@pfizer.com

No publications provided

Responsible Party:	Director, Clinical Trial Disclosure Group, Pfizer, Inc.
ClinicalTrials.gov Identifier:	NCT00368745 History of Changes
Other Study ID Numbers:	A0081092
Study First Received:	August 23, 2006
Results First Received:	August 10, 2009
Last Updated:	November 9, 2009
Health Authority:	Mexico: Secretaria de Salud de Mexico

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