GAD: Drug Treatment Validation of Functional Magnetic Resonance Imaging in Generalized Anxiety Disorder

• Sponsor: University of California, San Diego (Other)
• Overall Status: Completed
• CT.gov ID: NCT00662259
• Collaborator: Hoffmann-La Roche (Industry)
• Enrollment: 32
• Location: 1
• Arms: 2
• Duration (Months): 17
• Patients Per Site Per Month: 1.9

Study Details

Study Description

Brief Summary

The purpose of this study is to find out how an anti-anxiety drug or placebo affects the activity of your brain when you are at rest and when you are viewing emotional material, such as, emotional faces and pictures.

Condition or Disease	Intervention/Treatment	Phase
Generalized Anxiety Disorder	Drug: Alprazolam (Xanax); Drug: Placebo	Phase 4

Detailed Description

This is an exploratory study to evaluate the usefulness of fMRI as a biomarker to measure the response to a known, FDA approved marketed anxiolytic. As such, this is not a study testing safety and efficacy of an approved medicine; it is a study to evaluate the usefulness of fMRI (a non-significant risk device procedure) to correlate the clinical/behavioral effects of a marketed anxiolytic with brain activity assessed by magnetic resonance imaging. fMRI is a more direct measure of brain function than behavior, outcomes are quantitative and objective. As such, it may be more specific, i.e., may be more sensitive to drug effects or show them earlier than clinical endpoints and enable determination of efficacy in smaller or shorter studies than those required to show effects on clinical endpoints. Finally, imaging may allow differentiation of placebo responders from true drug responders.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized, Double-blind, Placebo-controlled Study of a Benzodiazepine vs Placebo on Functional Magnetic Resonance Imaging (fMRI) of the Brain, and on Behavioral/Clinical Measures in Patients With Generalized Anxiety Disorder
• Study Start Date: Apr 1, 2008
• Actual Primary Completion Date: Sep 1, 2009
• Actual Study Completion Date: Sep 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: alprazolam Alprazolam, an FDA-approved drug, will be administered to 24 patients with generalized anxiety disorder.	Drug: Alprazolam (Xanax); Drug dose will be fixed across patients: alprazolam 0.5 mg b.i.d escalating to 1.0 mg b.i.d. The treatment duration will be approximately 28 days (4 weeks).; Other Names: Xanax
Placebo Comparator: placebo A placebo comparator will be administered to 12 patients with generalized anxiety disorder	Drug: Placebo; Placebo, bid, p.o. for 28 +/- 2 days.

Outcome Measures

Primary Outcome Measures

1. Signal Change in Brain Activity in the Amygdala When Viewing Emotional Faces [0,1,28 days]

   Extent of activation a brain signal when matching emotional face expressions as a percentage of the brain signal when matching geometric designs. The brain signal is the blood oxygen level dependent signal measured by functional magnetic resonance imaging.

2. Signal Change in Brain Activity in the Insula When Anticipating the Viewing of Emotional Pictures. [0,1,28 days]

   Extent of activation of a brain signal when anticipating the viewing of an emotional picture as a percentage of brain signal when the viewing of an emotional signal is not anticipated. The brain signal is the blood oxygen level dependent signal as measured by functional magnetic resonance imaging.

Secondary Outcome Measures

1. Score on the Hamilton Anxiety Scale [0, 7, 28 days]

   Measured participant's general anxiety; range 0 - 56; higher scores worse

2. Score on the Penn State Worry Scale [0, 7, 28 days]

   Measured participant's extent of worry; range 16 - 80, higher scores worse

Other Outcome Measures

1. Score on Quick Inventory of Depressive Symptomatology [0, 7, 28 days]

   Measured the level of a participant's depression; 0 - 48; higher scores worse

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female between 18 - 65 years of age, inclusive

2. In good general health (as determined by medical history, physical examination, laboratory assessments and electrocardiogram (ECG)), especially no findings (including concomitant medications) that would constitute contraindications for treatment with alprazolam

3. Diagnostic and Statistical Manual-IV criteria for Generalized Anxiety Disorder (GAD) (exception: at least 3 months of symptoms)

4. Hamilton Anxiety Scale at screening >/= 20

5. Montgomery-Asberg Depression Rating Scale (MADRS) at screening < 25

6. Prior medications washout:

• 2-week medication washout prior to randomization for most psychotropic medications

• If prior history of fluoxetine use, this drug must have been discontinued at least 5 weeks before randomization

1. For females of non-childbearing potential: either postmenopausal for the past year (confirmed by an follicle stimulating hormone level greater than 40 mIU/mL unless the subject is receiving hormone replacement therapy), or surgically sterile (e.g., tubal ligation, hysterectomy)

2. Males and female subjects of child-bearing potential may be included if using appropriate contraceptive methods:

• must use abstinence or two methods of contraception throughout the trial:

• should include one primary (e.g., systemic hormonal contraception, vasectomy of the male partner) AND one secondary barrier method (e.g., latex condoms, spermicide) OR

• a double barrier method (e.g., latex condom plus spermicide (foam, suppository, gel, cream)) may be used

1. GAD should be the clinically predominant disorder, as judged by the investigator, considering relative severity and impact on functioning

Exclusion Criteria:

1. Axis I disorder other than stated above with the exception of the following permitted comorbidities:

• history of (within past 6 months) or current dysthymia

• current (within past 6 months) depressive episode with MADRS at baseline < 25

• history of major depression as long as no current depressive episode as defined above

1. Drug or alcohol dependence in the past 6 months

2. Positive urine toxicology (drugs of abuse as determined by clinician's assessment of positive urine test)

3. Active suicidal ideation (determined by clinician)

4. For females of childbearing potential: Pregnancy or intent to become pregnant or currently breastfeeding

5. Current use of beta-blockers or stimulants (e.g., Methylphenidate, d-Amphetamine, modafinil, and illicit drugs like cocaine or 3,4-methylenedioxy-N-methylamphetamine [MDMA])

6. Current regular use of antihistamines (except for inhalants which are permitted)

7. Current use of herbal medication for mood or anxiety disorders and unwillingness to discontinue use for the duration of the study

8. Current use of fluoxetine

9. Concomitant psychotropic medications including regular use of sleeping medications (also herbals)

• occasional use of sleeping medication, with the exception of benzodiazepines, is permitted as long as it is not taken the evening prior to a visit

1. Past intolerance (including allergic) to, or clear history of non-response to the study medication

2. Current smoker (> 10 cigarettes/day); habitual caffeine consumption of more than 400 mg/d (approximately 4 cups of coffee or equivalent)

3. Body mass index > 32.5 kg/m2

4. Contraindication to magnetic resonance imaging based on a standard fMRI screening forms

5. Concurrent participation in an institutional review board (IRB) approved investigational drug trial

6. Any other reason why, per clinician, the patient should not participate in this study (to be included in this assessment are all considerations, warnings, precautions as per current FDA-approved drug label for Xanax®)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Diego	San Diego	California	United States	92093

Sponsors and Collaborators

• University of California, San Diego
• Hoffmann-La Roche

Investigators

• Principal Investigator: Martin P Paulus, MD, University of California, San Diego

Study Documents (Full-Text)

None provided.

More Information

Publications

• Baas JM, Grillon C, Böcker KB, Brack AA, Morgan CA 3rd, Kenemans JL, Verbaten MN. Benzodiazepines have no effect on fear-potentiated startle in humans. Psychopharmacology (Berl). 2002 May;161(3):233-47. Epub 2002 Mar 20.
• Grillon C, Baas JM, Pine DS, Lissek S, Lawley M, Ellis V, Levine J. The benzodiazepine alprazolam dissociates contextual fear from cued fear in humans as assessed by fear-potentiated startle. Biol Psychiatry. 2006 Oct 1;60(7):760-6. Epub 2006 Apr 21.
• Paulus MP, Feinstein JS, Castillo G, Simmons AN, Stein MB. Dose-dependent decrease of activation in bilateral amygdala and insula by lorazepam during emotion processing. Arch Gen Psychiatry. 2005 Mar;62(3):282-8.
• Salmeron BJ, Stein EA. Pharmacological applications of magnetic resonance imaging. Psychopharmacol Bull. 2002 Winter;36(1):102-29. Review.
• Simmons A, Strigo I, Matthews SC, Paulus MP, Stein MB. Anticipation of aversive visual stimuli is associated with increased insula activation in anxiety-prone subjects. Biol Psychiatry. 2006 Aug 15;60(4):402-9.

• Responsible Party: Gregory G. Brown, Professor, University of California, San Diego
• ClinicalTrials.gov Identifier: NCT00662259
• Other Study ID Numbers: WP21030
• First Posted: Apr 21, 2008
• Last Update Posted: Jul 25, 2019
• Last Verified: Jun 1, 2019

• Keywords provided by Gregory G. Brown, Professor, University of California, San Diego: Anxiety disorders; Generalized anxiety
• Additional relevant MeSH terms: Disease; Anxiety Disorders; Alprazolam

Study Results

Participant Flow

Arm/Group Title	Alprazolam	Placebo
Arm/Group Description	Alprazolam, an FDA-approved drug, will be administered to 24 patients with generalized anxiety disorder. Alprazolam (Xanax): Drug dose will be fixed across patients: alprazolam 0.5 mg b.i.d escalating to 1.0 mg b.i.d. The treatment duration will be approximately 28 days (4 weeks).	A placebo comparator will be administered to 12 patients with generalized anxiety disorder Placebo: Placebo, bid, p.o. for 28 +/- 2 days.
Period Title: Overall Study
STARTED	21	11
COMPLETED	19	11
NOT COMPLETED	2	0

Baseline Characteristics

Arm/Group Title	Alprazolam	Placebo	Total
Arm/Group Description	Alprazolam, an FDA-approved drug, will be administered to 24 patients with generalized anxiety disorder. Alprazolam (Xanax): Drug dose will be fixed across patients: alprazolam 0.5 mg b.i.d escalating to 1.0 mg b.i.d. The treatment duration will be approximately 28 days (4 weeks).	A placebo comparator will be administered to 12 patients with generalized anxiety disorder Placebo: Placebo, bid, p.o. for 28 +/- 2 days.	Total of all reporting groups
Overall Participants	21	11	32
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	38.63 (14.77)	36.27 (14.69)	37.8 (14.74)
Sex: Female, Male (Count of Participants)
Female	11 52.4%	9 81.8%	20 62.5%
Male	10 47.6%	2 18.2%	12 37.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 9.5%	1 9.1%	3 9.4%
Not Hispanic or Latino	19 90.5%	10 90.9%	29 90.6%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 4.8%	2 18.2%	3 9.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	20 95.2%	9 81.8%	29 90.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Signal Change in Brain Activity in the Amygdala When Viewing Emotional Faces
Description	Extent of activation a brain signal when matching emotional face expressions as a percentage of the brain signal when matching geometric designs. The brain signal is the blood oxygen level dependent signal measured by functional magnetic resonance imaging.
Time Frame	0,1,28 days

Outcome Measure Data

Analysis Population Description

19 out of 21 participants analyzed due to 2 withdrawing from adverse events.

Arm/Group Title	Alprazolam	Placebo
Arm/Group Description	Alprazolam, an FDA-approved drug, will be administered to 24 patients with generalized anxiety disorder. Alprazolam (Xanax): Drug dose will be fixed across patients: alprazolam 0.5 mg b.i.d escalating to 1.0 mg b.i.d. The treatment duration will be approximately 28 days (4 weeks).	A placebo comparator will be administered to 12 patients with generalized anxiety disorder Placebo: Placebo, bid, p.o. for 28 +/- 2 days.
Measure Participants	19	11
Day 0 (Baseline)	.1489 (.1529)	.1074 (.1123)
Day 1	.0119 (.1050)	.1404 (.0987)
Day 28	.1230 (.1366)	.1699 (.1058)

2. Primary Outcome

Title	Signal Change in Brain Activity in the Insula When Anticipating the Viewing of Emotional Pictures.
Description	Extent of activation of a brain signal when anticipating the viewing of an emotional picture as a percentage of brain signal when the viewing of an emotional signal is not anticipated. The brain signal is the blood oxygen level dependent signal as measured by functional magnetic resonance imaging.
Time Frame	0,1,28 days

Outcome Measure Data

Analysis Population Description

Nineteen of 21 alprazolam participants analyzed to two subjects withdrawing due to adverse events.

Arm/Group Title	Alprazolam	Placebo
Arm/Group Description	Alprazolam, an FDA-approved drug, will be administered to 24 patients with generalized anxiety disorder. Alprazolam (Xanax): Drug dose will be fixed across patients: alprazolam 0.5 mg b.i.d escalating to 1.0 mg b.i.d. The treatment duration will be approximately 28 days (4 weeks).	A placebo comparator will be administered to 12 patients with generalized anxiety disorder Placebo: Placebo, bid, p.o. for 28 +/- 2 days.
Measure Participants	19	11
Day 0 (Baseline)	.0707 (.0322)	.0724 (.0522)
Day 1	.0458 (.0274)	.0645 (.0310)
Day 28	.0596 (.0426)	.0461 (.0337)

3. Secondary Outcome

Title	Score on the Hamilton Anxiety Scale
Description	Measured participant's general anxiety; range 0 - 56; higher scores worse
Time Frame	0, 7, 28 days

Outcome Measure Data

Analysis Population Description

Nineteen of 21 participants analyzed due to two participants withdrawing due to adverse events.

Arm/Group Title	Alprazolam	Placebo
Arm/Group Description	Alprazolam, an FDA-approved drug, will be administered to 24 patients with generalized anxiety disorder. Alprazolam (Xanax): Drug dose will be fixed across patients: alprazolam 0.5 mg b.i.d escalating to 1.0 mg b.i.d. The treatment duration will be approximately 28 days (4 weeks).	A placebo comparator will be administered to 12 patients with generalized anxiety disorder Placebo: Placebo, bid, p.o. for 28 +/- 2 days.
Measure Participants	19	11
Day 0 (Baseline)	27.79 (5.99)	28.00 (5.42)
Day 7	13.58 (6.94)	22.18 (6.71)
Day 28	10.85 (6.01)	20.18 (8.74)

4. Secondary Outcome

Title	Score on the Penn State Worry Scale
Description	Measured participant's extent of worry; range 16 - 80, higher scores worse
Time Frame	0, 7, 28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alprazolam	Placebo
Arm/Group Description	Alprazolam, an FDA-approved drug, will be administered to 24 patients with generalized anxiety disorder. Alprazolam (Xanax): Drug dose will be fixed across patients: alprazolam 0.5 mg b.i.d escalating to 1.0 mg b.i.d. The treatment duration will be approximately 28 days (4 weeks).	A placebo comparator will be administered to 12 patients with generalized anxiety disorder Placebo: Placebo, bid, p.o. for 28 +/- 2 days.
Measure Participants	19	11
Day 0 (Baseline)	64.74 (8.31)	66.73 (7.76)
Day 7	50.26 (10.57)	62.45 (7.58)
Day 28	48.11 (12.28)	61.36 (10.33)

5. Other Pre-specified Outcome

Title	Score on Quick Inventory of Depressive Symptomatology
Description	Measured the level of a participant's depression; 0 - 48; higher scores worse
Time Frame	0, 7, 28 days

Outcome Measure Data

Analysis Population Description

Nineteen of 21 participants analyzed due to 2 participants withdrawal due to adverse events.

Arm/Group Title	Alprazolam	Placebo
Arm/Group Description	Alprazolam, an FDA-approved drug, will be administered to 24 patients with generalized anxiety disorder. Alprazolam (Xanax): Drug dose will be fixed across patients: alprazolam 0.5 mg b.i.d escalating to 1.0 mg b.i.d. The treatment duration will be approximately 28 days (4 weeks).	A placebo comparator will be administered to 12 patients with generalized anxiety disorder Placebo: Placebo, bid, p.o. for 28 +/- 2 days.
Measure Participants	19	11
Day 0 (Baseline)	12.42 (4.90)	12.09 (4.35)
Day 7	8.05 (4.96)	10.09 (3.83)
Day 28	6.42 (3.36)	9.09 (3.30)

Adverse Events

Time Frame	From day 0 (baseline) to day 28.
Arm/Group Title	Alprazolam		Placebo
Arm/Group Description	Alprazolam, an FDA-approved drug, will be administered to 24 patients with generalized anxiety disorder. Alprazolam (Xanax): Drug dose will be fixed across patients: alprazolam 0.5 mg b.i.d escalating to 1.0 mg b.i.d. The treatment duration will be approximately 28 days (4 weeks).		A placebo comparator will be administered to 12 patients with generalized anxiety disorder Placebo: Placebo, bid, p.o. for 28 +/- 2 days.
All Cause Mortality
	Alprazolam		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Alprazolam		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/11 (0%)
Other (Not Including Serious) Adverse Events
	Alprazolam		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/21 (9.5%)		0/11 (0%)
Psychiatric disorders
Drowsiness	1/21 (4.8%)	1	0/11 (0%)	0
Claustrophobia	1/21 (4.8%)	1	0/11 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT 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.