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. (GAD)

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of Pregabalin in Subjects With Generalized Anxiety Disorder (GAD) Switching From Benzodiazepine Therapy.

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.

Study Overview

• Status: Completed
• Conditions: Generalized Anxiety Disorder
• Intervention / Treatment: Drug: Pregabalin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 108
• Phase: Phase 3

Contacts and Locations

Study Locations

• Costa Rica
  • San José
    • San Pedro De Montes De Oca, San José, Costa Rica, 00
      • Pfizer Investigational Site
• Czechia
  • Plzen, Czechia, 301 00
    • Pfizer Investigational Site
  • Praha 10, Czechia, 100 00
    • Pfizer Investigational Site
  • Praha 6, Czechia, 163 00
    • Pfizer Investigational Site
  • Praha 7, Czechia, 170 00
    • Pfizer Investigational Site
  • Praha-Bubenec, Czechia, 170 00
    • Pfizer Investigational Site
• France
  • Arcachon, France, 33120
    • Pfizer Investigational Site
  • Caen, France, 14000
    • Pfizer Investigational Site
  • Elancourt, France, 78990
    • Pfizer Investigational Site
  • Nantes-Orvault, France, 44700
    • Pfizer Investigational Site
  • Cedex 12
    • Paris, Cedex 12, France, 75571
      • Pfizer Investigational Site
• Guatemala
  • Guatemala, Guatemala
    • Pfizer Investigational Site
• Italy
  • L'Aquila, Italy, 67100
    • Pfizer Investigational Site
  • Milan, Italy, 20157
    • Pfizer Investigational Site
• Mexico
  • Mexico D.F., Mexico, 03740
    • Pfizer Investigational Site
  • San Luis Potosi, Mexico, 78216
    • Pfizer Investigational Site
  • Nayarit
    • Tepic, Nayarit, Mexico, 63000
      • Pfizer Investigational Site
• Spain
  • Barcelona, Spain, 08036
    • Pfizer Investigational Site
  • Barcelona, Spain, 08025
    • Pfizer Investigational Site
  • Zamora, Spain, 49021
    • Pfizer Investigational Site
  • Asturias
    • Langreo, Asturias, Spain, 33900
      • Pfizer Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Pregabalin; Pregabalin treatment for GAD during 6 week taper/discontinuation from alprazolam treatment; followed by 6 weeks pregabalin treatment 'alprazolam free'.	Drug: Pregabalin; 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.; Other Names: Lyrica
Placebo Comparator: Placebo; Placebo treatment of GAD during 6 week taper/discontinuation of alprazolam treatment followed by 6 weeks continuation of placebo treatment 'alprazolam free'.	Drug: Placebo; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Endpoint (Post Alprazolam Free Week 6 or LOCF Post Alprazolam Free Week 1)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, Alprazolam Taper Weeks 1 through 6, Alprazolam Free Weeks 1 through 6, and Endpoint (Alprazolam Free [AF] Week 6)
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.	Baseline, Alprazolam Free Weeks 1 through 6, Endpoint (AF Week 6)
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.	Baseline, Alprazolam Free Weeks 1 through 6, Endpoint (AF Week 6)
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.	Baseline, Alprazolam Taper Weeks 1 through 6, Alprazolam Free Weeks 1 through 6, Endpoint (AF Week 6)
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.	Baseline, Alprazolam Taper Weeks 1 through 6, Alprazolam Free Weeks 1 through 6, and Endpoint (AF Week 6 )
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.	Alprazolam Taper Weeks 1 through 6, Alprazolam Free Weeks 1 through 6, and Endpoint (AF Week 6 )
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).	Alprazolam Taper Weeks 1 through 6, Alprazolam Free Weeks 1 through 6, and Endpoint (AF Week 6 )
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.	Baseline, Endpoint (AF Week 6 )
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.	Baseline, Week 13 (Final Visit/Early Termination)
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.	Baseline, Week 13 (Final Visit/Early Termination)
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.	Alprazolam Free Week 6

Collaborators and Investigators

• Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: September 1, 2006
• Primary Completion (Actual): August 1, 2008
• Study Completion (Actual): August 1, 2008

Study Registration Dates

• First Submitted: August 23, 2006
• First Submitted That Met QC Criteria: August 23, 2006
• First Posted (Estimate): August 25, 2006

Study Record Updates

• Last Update Posted (Actual): February 9, 2021
• Last Update Submitted That Met QC Criteria: January 21, 2021
• Last Verified: November 1, 2009

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Anxiety Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; Anti-Anxiety Agents; Anticonvulsants; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Pregabalin
• Other Study ID Numbers: A0081092