Role of Proinflammatory Signaling in Alcohol Craving

• Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT01631630
• Collaborator: (none)
• Enrollment: 16
• Location: 1
• Arms: 2
• Duration (Months): 40
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Background:

• Drinking too much alcohol can injure cells in the body. Inflammation is the body s reaction to injured cells. Studies show that inflammation can cause cravings for alcohol. Researchers want to see if pioglitazone, a drug that decreases inflammation, can reduce alcohol craving. If so, it might help develop new ways to help alcoholics with craving.

Objectives:

• To see if pioglitazone can reduce alcohol craving.

Eligibility:

• Adults between 21 and 65 years of age who are alcoholic and have been drinking within the past month.

Design:

• Participants will be screened with a physical exam and medical history. Blood samples will also be collected.

• All participants will have inpatient treatment at the National Institutes of Health Clinical Center for the 5 weeks of the study. They will have standard treatment for alcoholism during their inpatient stay.

• Half of the people in this study will have pioglitazone. The other half will have a placebo.

• Participants will have different studies during their stay. These studies will include the following:

• Personalized audio recordings of stressful, alcohol-related, and neutral events to monitor mood

• Imaging studies to test alcohol cravings

• Questionnaires about mood and alcohol cravings

• Lumbar puncture to collect spinal fluid

• Inflammation test to see if the study drug can block alcohol cravings

• After the end of the 5-week study, all participants will be offered follow-up outpatient care through the Clinical Center, or referral to outside treatment.

Condition or Disease	Intervention/Treatment	Phase
Alcohol Dependence; Alcohol Drinking; Stress; Alcohol-Related Disorders	Drug: Pioglitazone; Drug: Placebo	Phase 2

Detailed Description

Objective: The objective of the present study is to evaluate the role of proinflammatory signaling in alcohol craving. The peroxisome proliferator-activated receptor y (PPARy) agonist pioglitazone, which modulates glial activity, will be used as an experimental treatment. Guided imagery auditory scripts will be used as an established set of stimuli to induce craving. Low dose lipopolysaccharide (LPS) administration which activates proinflammatory signaling will be used as a novel challenge, and evaluated for its ability to provoke alcohol craving. If LPS in fact induces alcohol craving, the present design will allow evaluation of whether pioglitazone can inhibit this response.

Study population: Up to 60 subjects will be recruited for a target accrual of 50 completers. Subjects will be aged 21-65 years, with alcohol dependence as their primary complaint, and without other serious medical or psychiatric conditions. They will be admitted to the NIAAA research inpatient unit at the NIH Clinical Research Center (CRC) through one of the screening protocols (05-AA-0121 Assessment and Treatment of People with Alcohol Drinking Problems ) or 14-AA-0181 "Unit and Clinic Evaluations, Screening, Assessment, and Management") which provides basic assessments and standard withdrawal treatment if needed.

Design: Following inclusion, subjects will undergo interviews for construction of guided imagery scripts, and these scripts will subsequently be used as stress-, alcohol- or neutral condition associated stimuli. Subjects will be randomized to pioglitazone (n=25; final dose: 45mg/daily) or identically looking placebo (n=25). Following at least two weeks of treatment, subjects will undergo three sessions of guided imagery, on separate days and in a counter-balanced order, exposing them to the personalized stress-, alcohol- or neutral condition associated auditory scripts, respectively. During the final week, subjects will undergo two challenge sessions, a minimum of five days apart, with lipopolysaccharide (LPS) or placebo, in counterbalanced order.

Outcome measures: Subjective ratings of mood, anxiety and craving will be obtained twice weekly throughout the study. During the challenge sessions that utilize psychological stimuli or LPS, subjective ratings of craving for alcohol, as well as ratings of negative emotions will be obtained. Lumbar puncture will be performed and cerebrospinal fluid (CSF) obtained to determine the effect of pioglitazone on levels of proinflammatory cytokines. Neuroendocrine, psychological and physiological measures will be collected for exploratory purposes. An fMRI scan will be obtained to evaluate the effect of pioglitazone on BOLD signal in response to emotionally salient visual cues.

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Role of Proinflammatory Signaling in Alcohol Craving
• Study Start Date: May 1, 2012
• Actual Primary Completion Date: Sep 1, 2015
• Actual Study Completion Date: Sep 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pioglitazone Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Drug: Pioglitazone; Pioglitazone is a thiazolidinedione antidiabetic. It works by lowering blood sugar by making the cells of the body more sensitive to the action of insulin.; Other Names: Actos
Placebo Comparator: Placebo Subjects received placebo on a similar dosing schedule, for a minimum total of 13 days	Drug: Placebo; Placebo is an inactive tablet design to look exactly like pioglitazone; Other Names: Sugar Pill

Outcome Measures

Primary Outcome Measures

1. Alcohol Craving in Response to the Alcohol Cue Script [15 minutes prior to the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period]

   Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

2. Alcohol Craving in Response to the Alcohol Cue Script [5 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period]

   Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

3. Alcohol Craving in Response to the Alcohol Cue Script [15 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period]

   Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

4. Alcohol Craving in Response to the Alcohol Cue Script [30 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period]

   Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

5. Alcohol Craving in Response to the Alcohol Cue Script [45 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period]

   Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

6. Alcohol Craving in Response to the Alcohol Cue Script [60 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period]

   Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

7. Alcohol Craving in Response to the Alcohol Cue Script [75 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period]

   Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

8. Alcohol Craving in Response to the Alcohol Cue Script [90 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period]

   Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

9. Alcohol Craving in Response to the Lipopolysaccharide Challenge [15 minutes prior to the subject receiving an intravenous bolus of lipopolysaccharide, which occurred on Day 25 or Day 32 of the treatment period]

   Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

10. Alcohol Craving in Response to the Lipopolysaccharide Challenge [1 hour after the subject received an intravenous bolus of lipopolysaccharide, which occurred on Day 25 or Day 32 of the treatment period]

    Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

11. Alcohol Craving in Response to the Lipopolysaccharide Challenge [2 hours after the subject received an intravenous bolus of lipopolysaccharide, which occurred on Day 25 or Day 32 of the treatment period]

    Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

12. Alcohol Craving in Response to the Lipopolysaccharide Challenge [3 hours after the subject received an intravenous bolus of lipopolysaccharide, which occurred on Day 25 or Day 32 of the treatment period]

    Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

13. Alcohol Craving in Response to the Lipopolysaccharide Challenge [4 hours after the subject received an intravenous bolus of lipopolysaccharide, which occurred on Day 25 or Day 32 of the treatment period]

    Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

14. Alcohol Craving in Response to the Lipopolysaccharide Challenge [5 hours after the subject received an intravenous bolus of lipopolysaccharide, which occurred on Day 25 or Day 32 of the treatment period]

    Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

15. Alcohol Craving in Response to the Lipopolysaccharide Challenge [6 hours after the subject received an intravenous bolus of lipopolysaccharide, which occurred on Day 25 or Day 32 of the treatment period]

    Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

16. Alcohol Craving in Response to the Stress Script [15 minutes prior to the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period]

    Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

17. Alcohol Craving in Response to the Stress Script [15 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period]

    Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

18. Alcohol Craving in Response to the Stress Script [5 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period]

    Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

19. Alcohol Craving in Response to the Stress Script [30 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period]

    Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

20. Alcohol Craving in Response to the Stress Script [45 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period]

    Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

21. Alcohol Craving in Response to the Stress Script [60 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period]

    Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

22. Alcohol Craving in Response to the Stress Script [75 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period]

    Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

23. Alcohol Craving in Response to the Stress Script [90 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period]

    Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

Secondary Outcome Measures

1. Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period [Day 1 of the treatment period]

   Anxiety symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).

2. Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period [Day 3 of the treatment period]

   Anxiety symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).

3. Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period [Day 7 of the treatment period]

   Anxiety symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).

4. Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period [Day 10 of the treatment period]

   Anxiety symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).

5. Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period [Day 14 of the treatment period]

   Anxiety symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).

6. Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period [Day 17 of the treatment period]

   Anxiety symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).

7. Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period [Day 21 of the treatment period]

   Anxiety symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).

8. Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period [Day 24 of the treatment period]

   Anxiety symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).

9. Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period [Day 28 of the treatment period]

   Anxiety symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).

10. Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period [Day 31 of the treatment period]

    Anxiety symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).

11. Depression Symptom Ratings Measured Bi-weekly During the Treatment Period [Day 1 of the treatment period]

    Depression symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).

12. Depression Symptom Ratings Measured Bi-weekly During the Treatment Period [Day 3 of the treatment period]

    Depression symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).

13. Depression Symptom Ratings Measured Bi-weekly During the Treatment Period [Day 7 of the treatment period]

    Depression symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).

14. Depression Symptom Ratings Measured Bi-weekly During the Treatment Period [Day 10 of the treatment period]

    Depression symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).

15. Depression Symptom Ratings Measured Bi-weekly During the Treatment Period [Day 14 of the treatment period]

    Depression symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).

16. Depression Symptom Ratings Measured Bi-weekly During the Treatment Period [Day 17 of the treatment period]

    Depression symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).

17. Depression Symptom Ratings Measured Bi-weekly During the Treatment Period [Day 21 of the treatment period]

    Depression symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).

18. Depression Symptom Ratings Measured Bi-weekly During the Treatment Period [Day 24 of the treatment period]

    Depression symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).

19. Depression Symptom Ratings Measured Bi-weekly During the Treatment Period [Day 28 of the treatment period]

    Depression symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).

20. Depression Symptom Ratings Measured Bi-weekly During the Treatment Period [Day 31 of the treatment period]

    Depression symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).

21. Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period [Day 1 of the treatment period]

    Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). The PACS is a five-item self-administered instrument for assessing alcohol craving over the course of the past week. The score ranges from 0 (lowest craving value) to 30 (highest craving value).

22. Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period [Day 3 of the treatment period]

    Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). The PACS is a five-item self-administered instrument for assessing alcohol craving over the course of the past week. The score ranges from 0 (lowest craving value) to 30 (highest craving value).

23. Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period [Day 7 of the treatment period]

    Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). The PACS is a five-item self-administered instrument for assessing alcohol craving over the course of the past week. The score ranges from 0 (lowest craving value) to 30 (highest craving value).

24. Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period [Day 10 of the treatment period]

    Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). The PACS is a five-item self-administered instrument for assessing alcohol craving over the course of the past week. The score ranges from 0 (lowest craving value) to 30 (highest craving value).

25. Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period [Day 14 of the treatment period]

    Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). The PACS is a five-item self-administered instrument for assessing alcohol craving over the course of the past week. The score ranges from 0 (lowest craving value) to 30 (highest craving value).

26. Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period [Day 17 of the treatment period]

    Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). The PACS is a five-item self-administered instrument for assessing alcohol craving over the course of the past week. The score ranges from 0 (lowest craving value) to 30 (highest craving value).

27. Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period [Day 21 of the treatment period]

    Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). The PACS is a five-item self-administered instrument for assessing alcohol craving over the course of the past week. The score ranges from 0 (lowest craving value) to 30 (highest craving value).

28. Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period [Day 24 of the treatment period]

    Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). The PACS is a five-item self-administered instrument for assessing alcohol craving over the course of the past week. The score ranges from 0 (lowest craving value) to 30 (highest craving value).

29. Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period [Day 28 of the treatment period]

    Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). The PACS is a five-item self-administered instrument for assessing alcohol craving over the course of the past week. The score ranges from 0 (lowest craving value) to 30 (highest craving value).

30. Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period [Day 31 of the treatment period]

    Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). The PACS is a five-item self-administered instrument for assessing alcohol craving over the course of the past week. The score ranges from 0 (lowest craving value) to 30 (highest craving value).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

1. Diagnostic and Statistical Manual (DSM)-IV diagnosis of alcohol dependence on Structured Clinical Interview for DSM Diagnosis (SCID) alcohol problems as primary complaint among substance use disorders, and alcohol use within the last month.

2. Age 21 65

3. Right handed

4. For women:

5. post-menopausal or surgically sterile (tubal ligation or hysterectomy); or

6. if sexually active with a male partner and able to get pregnant, documented agreement to use an effective form of birth control. Acceptable forms of contraception for this study include: hormonal contraceptives (birth-control pills, injectable hormones, vaginal-ring hormones); intrauterine device (IUD); diaphragm with spermicide; condom with spermicide.

EXCLUSION CRITERIA:

1. Any medical illness that in the view of the investigators would compromise participation in research, as determined by medical history, physical examination, laboratory tests (see details under Screening measures below), including, but not limited to:

2. Diabetes mellitus Type I or Type II

3. Past or current diagnosis of congestive heart failure

4. Signs and symptoms suggestive of congestive heart failure

5. Cardiovascular disease (e.g., history of congenital heart defect, heart disease, symptomatic coronary-artery disease, heart attack, clinically significant arrhythmia, etc.)

6. Cerebrovascular disease

7. Infection, autoimmune disease, or fever of unknown origin

8. Unexplained history of syncope

9. History of seizures, except for febrile seizures during childhood

10. History of head injury with loss of consciousness of more than 30 minutes or with postconcussive sequelae lasting more than two days, regardless of loss of consciousness

11. Chronic renal failure as estimated by glomerular filtration rate (GFR) <60 milliliters per minute 1.73 per Square

12. HIV infection

13. Active bladder cancer, history of bladder cancer, or persistent hematuria

14. Allergy, hypersensitivity, or intolerance to pioglitazone, other thiazolidinediones, or the metabolites of any of those drugs (determined by medical history)

15. Pregnancy or breastfeeding (urine pregnancy test; self-report)

16. Diabetes medications (e.g., sulfonylureas, metformin, insulin, etc.)

17. Contraindicated or strongly interacting medications: Gemfibrozil (inhibitor of CYP2C8) and rifampin (inducer of CYP2C8), atorvastatin, ketoconazole, nifedipine

18. Any ongoing, or regular use of central nervous system (CNS) active medications within the last week (fluoxetine: last 4 weeks), with the exception of withdrawal medication, obtained according to the NIAAA clinical guidelines if needed

19. Use of docosahexaenoic acid (DHA) dietary supplements, or consumption of oily fish >3 times per week (because of effects of DHA on inflammatory parameters)

20. History of Rhabdomyolysis

21. Psychiatric history:

22. Cognitive impairment severe enough to preclude informed consent or valid responses on questionnaires, as established by clinical exam, in questionable cases aided by a Mini Mental State Examination (with a score of <21, indicating more than mild cognitive impairment, being exclusionary)

23. Current diagnosis of schizophrenia or any other DSM-IV psychotic disorder, bipolar disorder, or major depressive disorder, in each case as established by clinical evaluation and SCID.

24. Substance use disorders:

25. Current alcohol intoxication on breathalyzer test or positive urine drug screen on enrollment

26. Current dependence on drugs other than alcohol or nicotine, as established by SCID interview

27. Inability or unwillingness to participate in an fMRI scan, including

28. Presence of ferromagnetic objects in the body that are contraindicated for MRI of the head (pacemakers or other implanted electrical devices, brain stimulators, some types of dental implants, aneurysm clips, metallic prostheses, permanent eyeliner, implanted delivery pump, or shrapnel fragments) or fear of enclosed spaces. Eligibility will be determined by a MRI Safety Screening Questionnaire and verified, if necessary, by a physician.

29. Subjects that cannot lie comfortably flat on their back for up to 2 hours in the MRI scanner.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Investigators

• Principal Investigator: Nancy Diazgranados, M.D., National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Capuron L, Miller AH. Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther. 2011 May;130(2):226-38. doi: 10.1016/j.pharmthera.2011.01.014. Epub 2011 Feb 17. Review.
• Crews FT, Zou J, Qin L. Induction of innate immune genes in brain create the neurobiology of addiction. Brain Behav Immun. 2011 Jun;25 Suppl 1:S4-S12. doi: 10.1016/j.bbi.2011.03.003. Epub 2011 Mar 21. Review.
• Dantzer R, Kelley KW. Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun. 2007 Feb;21(2):153-60. Epub 2006 Nov 7.

• Responsible Party: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• ClinicalTrials.gov Identifier: NCT01631630
• Other Study ID Numbers: 120143; 12-AA-0143
• First Posted: Jun 29, 2012
• Last Update Posted: Mar 9, 2017
• Last Verified: Jan 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by National Institute on Alcohol Abuse and Alcoholism (NIAAA): Alcohol; Alcohol Dependence; Alcohol Use; Nicotine Dependence; Nicotine
• Additional relevant MeSH terms: Alcoholism; Alcohol-Related Disorders; Alcohol Drinking; Pioglitazone

Study Results

Participant Flow

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Period Title: Overall Study
STARTED	8	8
COMPLETED	5	8
NOT COMPLETED	3	0

Baseline Characteristics

Arm/Group Title	Pioglitazone	Placebo	Total
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days	Total of all reporting groups
Overall Participants	8	8	16
Age (Count of Participants)
LTE18	0 0%	0 0%	0 0%
BTWN	8 100%	8 100%	16 100%
GTE65	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	0 0%	1 12.5%	1 6.3%
Male	8 100%	7 87.5%	15 93.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic	0 0%	0 0%	0 0%
Not Hispanic or Latino	8 100%	8 100%	16 100%
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	0 0%	1 12.5%	1 6.3%
Hawaiian	0 0%	0 0%	0 0%
Black	5 62.5%	4 50%	9 56.3%
White	2 25%	3 37.5%	5 31.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 12.5%	0 0%	1 6.3%

Outcome Measures

1. Primary Outcome

Title	Alcohol Craving in Response to the Alcohol Cue Script
Description	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Time Frame	15 minutes prior to the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed all three script types (neutral, alcohol, stress)

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	13.7505 (2.3136)	8.1871 (1.9853)

2. Primary Outcome

Title	Alcohol Craving in Response to the Alcohol Cue Script
Description	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Time Frame	5 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed all three script types (neutral, alcohol, stress)

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	20.5838 (2.3136)	9.6871 (1.9853)

3. Primary Outcome

Title	Alcohol Craving in Response to the Alcohol Cue Script
Description	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Time Frame	15 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed all three script types (neutral, alcohol, stress)

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	17.4172 (2.3136)	9.8121 (1.9853)

4. Primary Outcome

Title	Alcohol Craving in Response to the Alcohol Cue Script
Description	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Time Frame	30 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed all three script types (neutral, alcohol, stress)

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	19.0838 (2.3136)	10.5621 (1.9853)

5. Primary Outcome

Title	Alcohol Craving in Response to the Alcohol Cue Script
Description	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Time Frame	45 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed all three script types (neutral, alcohol, stress)

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	18.0838 (2.3136)	8.4371 (1.9853)

6. Primary Outcome

Title	Alcohol Craving in Response to the Alcohol Cue Script
Description	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Time Frame	60 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed all three script types (neutral, alcohol, stress)

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	16.4172 (2.3136)	8.9371 (1.9853)

7. Primary Outcome

Title	Alcohol Craving in Response to the Alcohol Cue Script
Description	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Time Frame	75 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed all three script types (neutral, alcohol, stress)

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	15.2505 (2.3136)	9.6871 (1.9853)

8. Primary Outcome

Title	Alcohol Craving in Response to the Alcohol Cue Script
Description	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Time Frame	90 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed all three script types (neutral, alcohol, stress)

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	19.2505 (2.3136)	8.9371 (1.9853)

9. Primary Outcome

Title	Alcohol Craving in Response to the Lipopolysaccharide Challenge
Description	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Time Frame	15 minutes prior to the subject receiving an intravenous bolus of lipopolysaccharide, which occurred on Day 25 or Day 32 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed both the lipopolysaccharide and placebo challenge sessions

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	5	8
Least Squares Mean (Standard Error) [Units on a scale]	11.1285 (1.5864)	10.7947 (1.2432)

10. Primary Outcome

Title	Alcohol Craving in Response to the Lipopolysaccharide Challenge
Description	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Time Frame	1 hour after the subject received an intravenous bolus of lipopolysaccharide, which occurred on Day 25 or Day 32 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed both the lipopolysaccharide and placebo challenge sessions

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	5	8
Least Squares Mean (Standard Error) [Units on a scale]	9.5285 (1.5864)	9.1697 (1.2432)

11. Primary Outcome

Title	Alcohol Craving in Response to the Lipopolysaccharide Challenge
Description	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Time Frame	2 hours after the subject received an intravenous bolus of lipopolysaccharide, which occurred on Day 25 or Day 32 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed both the lipopolysaccharide and placebo challenge sessions

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	5	8
Least Squares Mean (Standard Error) [Units on a scale]	11.9285 (1.5864)	9.0447 (1.2432)

12. Primary Outcome

Title	Alcohol Craving in Response to the Lipopolysaccharide Challenge
Description	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Time Frame	3 hours after the subject received an intravenous bolus of lipopolysaccharide, which occurred on Day 25 or Day 32 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed both the lipopolysaccharide and placebo challenge sessions

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	5	8
Least Squares Mean (Standard Error) [Units on a scale]	9.5285 (1.5864)	10.5447 (1.2432)

13. Primary Outcome

Title	Alcohol Craving in Response to the Lipopolysaccharide Challenge
Description	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Time Frame	4 hours after the subject received an intravenous bolus of lipopolysaccharide, which occurred on Day 25 or Day 32 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed both the lipopolysaccharide and placebo challenge sessions

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	5	8
Least Squares Mean (Standard Error) [Units on a scale]	12.1285 (1.5864)	10.5447 (1.2432)

14. Primary Outcome

Title	Alcohol Craving in Response to the Lipopolysaccharide Challenge
Description	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Time Frame	5 hours after the subject received an intravenous bolus of lipopolysaccharide, which occurred on Day 25 or Day 32 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed both the lipopolysaccharide and placebo challenge sessions

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	5	8
Least Squares Mean (Standard Error) [Units on a scale]	12.1285 (1.5864)	10.9197 (1.2432)

15. Primary Outcome

Title	Alcohol Craving in Response to the Lipopolysaccharide Challenge
Description	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Time Frame	6 hours after the subject received an intravenous bolus of lipopolysaccharide, which occurred on Day 25 or Day 32 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed both the lipopolysaccharide and placebo challenge sessions

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	5	8
Least Squares Mean (Standard Error) [Units on a scale]	9.9285 (1.5864)	9.6697 (1.2432)

16. Primary Outcome

Title	Alcohol Craving in Response to the Stress Script
Description	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Time Frame	15 minutes prior to the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed all three script types (neutral, alcohol, stress)

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	10 (1.779)	11.25 (1.5406)

17. Primary Outcome

Title	Alcohol Craving in Response to the Stress Script
Description	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Time Frame	15 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed all three script types (neutral, alcohol, stress)

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	10 (1.779)	12.125 (1.5406)

18. Primary Outcome

Title	Alcohol Craving in Response to the Stress Script
Description	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Time Frame	5 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed all three script types (neutral, alcohol, stress)

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	10.3333 (1.779)	11.875 (1.5406)

19. Primary Outcome

Title	Alcohol Craving in Response to the Stress Script
Description	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Time Frame	30 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed all three script types (neutral, alcohol, stress)

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	10 (1.779)	11.375 (1.5406)

20. Primary Outcome

Title	Alcohol Craving in Response to the Stress Script
Description	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Time Frame	45 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed all three script types (neutral, alcohol, stress)

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	10.1667 (1.779)	9.125 (1.5406)

21. Primary Outcome

Title	Alcohol Craving in Response to the Stress Script
Description	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Time Frame	60 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed all three script types (neutral, alcohol, stress)

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	10.1667 (1.779)	9.25 (1.5406)

22. Primary Outcome

Title	Alcohol Craving in Response to the Stress Script
Description	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Time Frame	75 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed all three script types (neutral, alcohol, stress)

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	10.1667 (1.779)	9.5 (1.5406)

23. Primary Outcome

Title	Alcohol Craving in Response to the Stress Script
Description	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Time Frame	90 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who completed all three script types (neutral, alcohol, stress)

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	10.6667 (1.779)	9.625 (1.5406)

24. Secondary Outcome

Title	Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period
Description	Anxiety symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).
Time Frame	Day 1 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline anxiety symptom rating taken 1 day after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	2.8502 (1.4379)	4.5791 (1.235)

25. Secondary Outcome

Title	Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period
Description	Anxiety symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).
Time Frame	Day 3 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline anxiety symptom rating taken 1 day after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	5.884 (1.3775)	0.5706 (1.1885)

26. Secondary Outcome

Title	Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period
Description	Anxiety symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).
Time Frame	Day 7 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline anxiety symptom rating taken 1 day after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	3.2897 (1.4413)	2.0706 (1.1885)

27. Secondary Outcome

Title	Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period
Description	Anxiety symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).
Time Frame	Day 10 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline anxiety symptom rating taken 1 day after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	3.3403 (1.4413)	1.1956 (1.1885)

28. Secondary Outcome

Title	Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period
Description	Anxiety symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).
Time Frame	Day 14 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline anxiety symptom rating taken 1 day after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	4.2173 (1.3775)	1.2136 (1.2176)

29. Secondary Outcome

Title	Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period
Description	Anxiety symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).
Time Frame	Day 17 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline anxiety symptom rating taken 1 day after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	5.0507 (1.3775)	1.0706 (1.1885)

30. Secondary Outcome

Title	Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period
Description	Anxiety symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).
Time Frame	Day 21 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline anxiety symptom rating taken 1 day after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	5.0507 (1.3775)	1.6956 (1.1885)

31. Secondary Outcome

Title	Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period
Description	Anxiety symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).
Time Frame	Day 24 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline anxiety symptom rating taken 1 day after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	3.884 (1.3775)	0.6956 (1.1885)

32. Secondary Outcome

Title	Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period
Description	Anxiety symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).
Time Frame	Day 28 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline anxiety symptom rating taken 1 day after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	4.884 (1.3775)	1.1125 (1.2543)

33. Secondary Outcome

Title	Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period
Description	Anxiety symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).
Time Frame	Day 31 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline anxiety symptom rating taken 1 day after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	7.2173 (1.3775)	1.8206 (1.1885)

34. Secondary Outcome

Title	Depression Symptom Ratings Measured Bi-weekly During the Treatment Period
Description	Depression symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).
Time Frame	Day 1 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline depression symptom rating taken 1 day after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	6.3661 (1.4855)	3.2956 (1.275)

35. Secondary Outcome

Title	Depression Symptom Ratings Measured Bi-weekly During the Treatment Period
Description	Depression symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).
Time Frame	Day 3 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline depression symptom rating taken 1 day after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	5.6366 (1.4174)	0.9937 (1.2232)

36. Secondary Outcome

Title	Depression Symptom Ratings Measured Bi-weekly During the Treatment Period
Description	Depression symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).
Time Frame	Day 7 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline depression symptom rating taken 1 day after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	4.9065 (1.4906)	0.9937 (1.2232)

37. Secondary Outcome

Title	Depression Symptom Ratings Measured Bi-weekly During the Treatment Period
Description	Depression symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).
Time Frame	Day 10 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline depression symptom rating taken 1 day after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	4.7167 (1.4906)	0.8687 (1.2232)

38. Secondary Outcome

Title	Depression Symptom Ratings Measured Bi-weekly During the Treatment Period
Description	Depression symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).
Time Frame	Day 14 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline depression symptom rating taken 1 day after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	4.6366 (1.4174)	0.5912 (1.2569)

39. Secondary Outcome

Title	Depression Symptom Ratings Measured Bi-weekly During the Treatment Period
Description	Depression symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).
Time Frame	Day 17 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline depression symptom rating taken 1 day after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	6.3032 (1.4174)	0.8687 (1.2232)

40. Secondary Outcome

Title	Depression Symptom Ratings Measured Bi-weekly During the Treatment Period
Description	Depression symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).
Time Frame	Day 21 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline depression symptom rating taken 1 day after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	5.1366 (1.4174)	1.4937 (1.2232)

41. Secondary Outcome

Title	Depression Symptom Ratings Measured Bi-weekly During the Treatment Period
Description	Depression symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).
Time Frame	Day 24 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline depression symptom rating taken 1 day after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	7.1366 (1.4174)	1.1187 (1.2232)

42. Secondary Outcome

Title	Depression Symptom Ratings Measured Bi-weekly During the Treatment Period
Description	Depression symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).
Time Frame	Day 28 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline depression symptom rating taken 1 day after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	6.4699 (1.4174)	1.1228 (1.299)

43. Secondary Outcome

Title	Depression Symptom Ratings Measured Bi-weekly During the Treatment Period
Description	Depression symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).
Time Frame	Day 31 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline depression symptom rating taken 1 day after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	8.6366 (1.4174)	0.8687 (1.2232)

44. Secondary Outcome

Title	Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period
Description	Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). The PACS is a five-item self-administered instrument for assessing alcohol craving over the course of the past week. The score ranges from 0 (lowest craving value) to 30 (highest craving value).
Time Frame	Day 1 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline craving measure taken 4 days after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	7.7503 (1.7317)	7.8122 (1.4976)

45. Secondary Outcome

Title	Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period
Description	Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). The PACS is a five-item self-administered instrument for assessing alcohol craving over the course of the past week. The score ranges from 0 (lowest craving value) to 30 (highest craving value).
Time Frame	Day 3 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline craving measure taken 4 days after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	8.417 (1.7317)	5.9372 (1.4976)

46. Secondary Outcome

Title	Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period
Description	Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). The PACS is a five-item self-administered instrument for assessing alcohol craving over the course of the past week. The score ranges from 0 (lowest craving value) to 30 (highest craving value).
Time Frame	Day 7 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline craving measure taken 4 days after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	7.0837 (1.7317)	4.1872 (1.4976)

47. Secondary Outcome

Title	Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period
Description	Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). The PACS is a five-item self-administered instrument for assessing alcohol craving over the course of the past week. The score ranges from 0 (lowest craving value) to 30 (highest craving value).
Time Frame	Day 10 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline craving measure taken 4 days after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	6.0837 (1.7317)	3.9372 (1.4976)

48. Secondary Outcome

Title	Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period
Description	Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). The PACS is a five-item self-administered instrument for assessing alcohol craving over the course of the past week. The score ranges from 0 (lowest craving value) to 30 (highest craving value).
Time Frame	Day 14 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline craving measure taken 4 days after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	4.7503 (1.7317)	4.1872 (1.4976)

49. Secondary Outcome

Title	Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period
Description	Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). The PACS is a five-item self-administered instrument for assessing alcohol craving over the course of the past week. The score ranges from 0 (lowest craving value) to 30 (highest craving value).
Time Frame	Day 17 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline craving measure taken 4 days after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	4.7503 (1.7317)	4.0622 (1.4976)

50. Secondary Outcome

Title	Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period
Description	Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). The PACS is a five-item self-administered instrument for assessing alcohol craving over the course of the past week. The score ranges from 0 (lowest craving value) to 30 (highest craving value).
Time Frame	Day 21 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline craving measure taken 4 days after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	4.417 (1.7317)	3.8122 (1.4976)

51. Secondary Outcome

Title	Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period
Description	Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). The PACS is a five-item self-administered instrument for assessing alcohol craving over the course of the past week. The score ranges from 0 (lowest craving value) to 30 (highest craving value).
Time Frame	Day 24 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline craving measure taken 4 days after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	5.917 (1.7317)	2.3122 (1.4976)

52. Secondary Outcome

Title	Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period
Description	Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). The PACS is a five-item self-administered instrument for assessing alcohol craving over the course of the past week. The score ranges from 0 (lowest craving value) to 30 (highest craving value).
Time Frame	Day 28 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline craving measure taken 4 days after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	6.417 (1.7317)	2.6872 (1.4976)

53. Secondary Outcome

Title	Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period
Description	Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). The PACS is a five-item self-administered instrument for assessing alcohol craving over the course of the past week. The score ranges from 0 (lowest craving value) to 30 (highest craving value).
Time Frame	Day 31 of the treatment period

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who had a baseline craving measure taken 4 days after inpatient admission (but prior to enrollment in this protocol), and who completed all 33 days of the treatment period

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days	Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
Measure Participants	6	8
Least Squares Mean (Standard Error) [Units on a scale]	4.5837 (1.7317)	2.8122 (1.4976)

Adverse Events

Time Frame	Adverse event data were collected throughout the 31 days of the inpatient stay for each subject
Arm/Group Title	Pioglitazone		Placebo
Arm/Group Description	Subjects received pioglitazone, 15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days		Subjects received placebo on a similar dosing schedule as pioglitazone, for a minimum total of 13 days
All Cause Mortality
	Pioglitazone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Pioglitazone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/8 (25%)		0/8 (0%)
Investigations
Abnormal glucose	1/8 (12.5%)		0/8 (0%)
Elevated Creatine Kinase	1/8 (12.5%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Pioglitazone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/8 (100%)		7/8 (87.5%)
Eye disorders
Blurred vision	0/8 (0%)		1/8 (12.5%)
Gastrointestinal disorders
Abdominal pain	0/8 (0%)		1/8 (12.5%)
Bloating	1/8 (12.5%)		0/8 (0%)
Blood in stool	0/8 (0%)		1/8 (12.5%)
Nausea	1/8 (12.5%)		2/8 (25%)
Stomach pain	1/8 (12.5%)		1/8 (12.5%)
Toothache	1/8 (12.5%)		3/8 (37.5%)
General disorders
Buzzed	1/8 (12.5%)		0/8 (0%)
Chills	0/8 (0%)		1/8 (12.5%)
Fatigue	0/8 (0%)		1/8 (12.5%)
Fever	1/8 (12.5%)		0/8 (0%)
Irritability	0/8 (0%)		1/8 (12.5%)
Loss of Appetite	2/8 (25%)		0/8 (0%)
Low RBC/HGB A1C	1/8 (12.5%)		0/8 (0%)
Pain	2/8 (25%)		0/8 (0%)
Sleepiness	1/8 (12.5%)		1/8 (12.5%)
Tiredness	5/8 (62.5%)		5/8 (62.5%)
Trouble Sleeping	1/8 (12.5%)		0/8 (0%)
Investigations
Abnormal platelet count	1/8 (12.5%)		0/8 (0%)
Aspartate aminotransferase increased	1/8 (12.5%)		0/8 (0%)
Elevated Creatine Kinase	4/8 (50%)		1/8 (12.5%)
Musculoskeletal and connective tissue disorders
Muscle aches	1/8 (12.5%)		3/8 (37.5%)
Muscle tightness	0/8 (0%)		1/8 (12.5%)
Neck pain	1/8 (12.5%)		0/8 (0%)
Pain in extremity	1/8 (12.5%)		0/8 (0%)
Nervous system disorders
Headache	2/8 (25%)		4/8 (50%)
Light headed	1/8 (12.5%)		1/8 (12.5%)
Sinus pain	0/8 (0%)		2/8 (25%)
Psychiatric disorders
Anxiety	0/8 (0%)		1/8 (12.5%)
Renal and urinary disorders
Dark Urine	0/8 (0%)		1/8 (12.5%)
Urinary frequency	0/8 (0%)		1/8 (12.5%)
Respiratory, thoracic and mediastinal disorders
Cold-like symptoms	0/8 (0%)		3/8 (37.5%)
Sore throat	2/8 (25%)		2/8 (25%)
Skin and subcutaneous tissue disorders
Acne	0/8 (0%)		1/8 (12.5%)
Itching	1/8 (12.5%)		1/8 (12.5%)
Vascular disorders
Phlebitis	0/8 (0%)		1/8 (12.5%)

Limitations/Caveats

This study was terminated early, so the number of subjects analyzed is small.

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.