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Rasagiline in the Treatment of Persistent Negative Symptoms of Schizophrenia

Primary Purpose

Schizophrenia

Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
rasagiline (Pharmacodynamics)
Placebo
Sponsored by
University of Maryland, Baltimore
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Schizophrenia focused on measuring Cognitive impairments, Negative symptoms

Eligibility Criteria

18 Years - 64 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Subjects will meet DSM-IV criteria for schizophrenia or schizoaffective disorder.
  • Current treatment with one or more second generation antipsychotics, except ziprasidone
  • On same second generation antipsychotic(s)for at least 56 days
  • On same dose of second generation antipsychotic(s)for at least 30 days
  • 22-item SANS: Total score (i.e.all items minus global items and poverty of content of speech)greater than 20 or global Rating of Affective Flattening greater than or equal to 3 or global Rating of alogia greater than or equal to 3
  • BPRS: Sum of the four positive symptom items less than or equal to 16 (items 4,11,12,15)
  • BPRS: Sum of the four Anxiety/Depression Factor items less than or equal to 14 (items 1,2,5,9)
  • Simpson-Angus Scale: Total score less than or equal to 8

Exclusion Criteria:

  • DSM-IV Major Depressive Disorder within last 6 months
  • Current treatment with ziprasidone
  • DSM-IV diagnosis of alcohol or substance dependence within the last 6 months
  • DSM-IV criteria for alcohol or substance abuse within the last month
  • evidence of illicit substance use, as identified with urine toxicology screen
  • History of an organic brain disorder, mental retardation,epilepsy, or a medical condition, whose pathology or treatment could alter the presentation or treatment of schizophrenia or significantly increase the risk associated with the proposed treatment protocol. See those listed below
  • Uncontrolled hypertension defined as BP exceeding 145/90 on 3 consecutive readings despite adequate treatment, pheochromocytoma, melanoma, hepatic insufficiency
  • Pregnancy or lactation in females
  • Pheochromocytoma
  • Melanoma
  • Hepatic insufficiency

Sites / Locations

  • Baltimore VA Medical Center
  • Keypoint Mental health Center
  • Maryland Psychiatric REsearch Center
  • Mosaic Community Mental health Center
  • Keypoint Mental health Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Rasagiline

Inactive pill

Arm Description

Treatment with Rasagiline

Treatment with Placebo

Outcomes

Primary Outcome Measures

Change in Negative Symptoms
The Scale for the Assessment of Negative Symptoms (SANS) rating scale was used to assess the negative symptoms of schizophrenia. Scores on the subscales are combined (summed) to compute a total score. There are a total of 17 subscales. Each subscale ranges from 0="Not at all" to 5="Severe". Every 4 weeks the summed subscale scores provide a total score for that week (0-85). Higher scores indicate more severe negative symptoms.
Cognitive Testing - Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score
The RBANS is a brief, individually administered test designed to evaluate neuropsychological status of adults, ages 20-89. The 12 subtests measure attention, language, visuospatial/constructional abilities, and immediate and delayed memory. The raw scores from the subtests are scaled together to create index scores, and these are summed for conversion to a total scale score. Higher score equals a better outcome. The total index score range for the RBANS is 40-160.
Cognitive Testing - N-Back Neurocognitive Task
The N-Back task is a sequential letter working memory task. D-prime was used to measure accuracy on the 0-back, 1-back, and 2-back conditions. D-prime scores range from 0 to 8.6. Higher scores are better. As memory load increases from 0 to 1, from 1 to 2, D-prime scores are expected to be lower.
Cognitive Testing - Probabilistic Learning Task
To assess reward learning, participants used performance feedback to choose the most frequently rewarded item in each of three pairs of stimuli (one pair had reward probabilities: 80% vs 20%; one pair had reward probabilities of 70% vs 30%; one pair had the probabilities of 60% vs 40 %) (PL; Frank et al, 2004). A total of 240 trials were administered so each pair was seen 80 times. Higher scores represent more frequent choices of the optimal stimulus in each pair. The frequencies with which participants repeated an item choice that was rewarded on the previous presentation (win-stay) is also presented as a percentage. Similarly, the lose-shift score is the percentage of times that participants changed their choice for unrewarded items (lose-shift). The win-stay score serves as a measure of the impact of positive feedback on subsequent choices while the lost-shift score serves as a measure of the impact of negative feedback on subsequent choices.
Cognitive Testing - Delayed Discounting
The monetary choice questionnaire for hypothetical monetary rewards was used to assess delayed discounting (Kirby et al, 1999). The measure includes 27 items in which participants choose between a smaller, immediate reward (SIR) and a larger, delayed reward (LDR). There are three LDR sizes: small ($25-35), medium ($50-60) and large ($75-85). By examining the pattern of choices that participants make across the set of 27 items it is possible to calculate their delay discounting rate, termed K. The discount rate determines the steepness of the reduction in the present value of a reward with increases in the delay to the possible receipt of that reward. Thus, higher values in K represent greater discounting of the value of future rewards. With this measure K values can range between a low of 0.00016 to a high of 0.25. Higher K values have been linked to measures of impulsivity. Shown in the table are the K values observed when the future rewards were small, medium, or large.

Secondary Outcome Measures

Extrapyramidal Symptoms
The Simpson Angus Scale (SAS; Simpson and Angus, 1970) was used to assess extrapyramidal symptoms (EPS). The assessment consists of 11 items, each rating the severity of potential symptoms of movement disorders. Total scores are calculated by summing the scores of each of the 11 items for a potential total score of 0-44, with higher scores indicating more severe EPS.
Number of Participants With Akathisia
The Barnes Akathisia Scale (BAS; Barnes, 1989) was used to assess akathisia, a type of extrapyramidal symptom. The global clinical assessment of akathisia score is rated on a scale from 0=Absent to 5=Severe Akathisia.
Change in Persistent Positive Symptoms
The Brief Psychiatric Rating Scale (BPRS) positive symptom item total score was used to assess positive symptom change. The BPRS positive symptom items are: conceptual disorganization, hallucinatory behavior, unusual thought content, and suspiciousness. The total score is calculated by adding the scores for each item. Each scale ranges from "1=Not Present" to "7=Very Severe". The minimum score is 4 and the maximum score is 28. A higher score indicates a more severe positive symptom rating.
Depressive Symptoms
The Calgary Depression Scale (CDS; Addington et al, 1997) total score was used to assess depressive symptoms over the course of the study. Total scores were calculated by summing the scores of each of the 9 items. Total scores can range from 0-27, with higher scores indicating more severe depressive symptoms.
Global Change in Illness Severity
The Clinical Global Impression (CGI) severity of illness item was used to assess global changes. Scores on this item range from 1="Normal, not at all ill" to 7="Among the most extremely ill".
Number of Participants Exhibiting Side Effects
The Side Effect Checklist (SEC) was used to assess side effects. The SEC is comprised of 22 common side effects, which are rated on a 1 (none)-4 (severe) scale. Side effects are determined to be clinically significant if there is a two or more point increase in severity from baseline, or any side effect that receives a severity rating of "4" (severe) at any point in the treatment phase of the study.

Full Information

First Posted
June 26, 2007
Last Updated
September 23, 2019
Sponsor
University of Maryland, Baltimore
Collaborators
Stanley Medical Research Institute
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1. Study Identification

Unique Protocol Identification Number
NCT00492336
Brief Title
Rasagiline in the Treatment of Persistent Negative Symptoms of Schizophrenia
Official Title
Rasagiline in the Treatment of Persistent Negative Symptoms of Schizophrenia
Study Type
Interventional

2. Study Status

Record Verification Date
June 2013
Overall Recruitment Status
Completed
Study Start Date
January 2007 (undefined)
Primary Completion Date
February 2012 (Actual)
Study Completion Date
February 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Maryland, Baltimore
Collaborators
Stanley Medical Research Institute

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a study of a new medication for the treatment of cognitive impairments (thinking difficulties) and negative symptoms in people with schizophrenia. The new medication is rasagiline. Rasagiline is a drug which has been approved by the Food and Drug Administration for the treatment of Parkinson's disease. It is used to treat cognitive problems.
Detailed Description
The study will consist of two phases: a 4-week continued stability phase (lead-in phase) and a 12-week double-blind treatment phase. In the lead-in phase, subjects receiving antipsychotic medication, who manifest moderate to severe and persistent negative symptoms, will remain on their maintenance regimen for at least four weeks. The treatment phase will be a 12-week, parallel groups, double-blind, placebo-controlled trial of adjunctive rasagiline (1 mg/day), a selective MAO-B oxidase inhibitor.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Schizophrenia
Keywords
Cognitive impairments, Negative symptoms

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
84 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Rasagiline
Arm Type
Active Comparator
Arm Description
Treatment with Rasagiline
Arm Title
Inactive pill
Arm Type
Placebo Comparator
Arm Description
Treatment with Placebo
Intervention Type
Drug
Intervention Name(s)
rasagiline (Pharmacodynamics)
Intervention Description
Rasagiline 1 mg/day for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo 1 tablet each day
Primary Outcome Measure Information:
Title
Change in Negative Symptoms
Description
The Scale for the Assessment of Negative Symptoms (SANS) rating scale was used to assess the negative symptoms of schizophrenia. Scores on the subscales are combined (summed) to compute a total score. There are a total of 17 subscales. Each subscale ranges from 0="Not at all" to 5="Severe". Every 4 weeks the summed subscale scores provide a total score for that week (0-85). Higher scores indicate more severe negative symptoms.
Time Frame
Every 4 weeks over a 12 week period
Title
Cognitive Testing - Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score
Description
The RBANS is a brief, individually administered test designed to evaluate neuropsychological status of adults, ages 20-89. The 12 subtests measure attention, language, visuospatial/constructional abilities, and immediate and delayed memory. The raw scores from the subtests are scaled together to create index scores, and these are summed for conversion to a total scale score. Higher score equals a better outcome. The total index score range for the RBANS is 40-160.
Time Frame
Beginning of treatment phase (week 0) and end of treatment phase (week 12)
Title
Cognitive Testing - N-Back Neurocognitive Task
Description
The N-Back task is a sequential letter working memory task. D-prime was used to measure accuracy on the 0-back, 1-back, and 2-back conditions. D-prime scores range from 0 to 8.6. Higher scores are better. As memory load increases from 0 to 1, from 1 to 2, D-prime scores are expected to be lower.
Time Frame
Beginning of treatment phase (week 0) and end of treatment phase (week 12)
Title
Cognitive Testing - Probabilistic Learning Task
Description
To assess reward learning, participants used performance feedback to choose the most frequently rewarded item in each of three pairs of stimuli (one pair had reward probabilities: 80% vs 20%; one pair had reward probabilities of 70% vs 30%; one pair had the probabilities of 60% vs 40 %) (PL; Frank et al, 2004). A total of 240 trials were administered so each pair was seen 80 times. Higher scores represent more frequent choices of the optimal stimulus in each pair. The frequencies with which participants repeated an item choice that was rewarded on the previous presentation (win-stay) is also presented as a percentage. Similarly, the lose-shift score is the percentage of times that participants changed their choice for unrewarded items (lose-shift). The win-stay score serves as a measure of the impact of positive feedback on subsequent choices while the lost-shift score serves as a measure of the impact of negative feedback on subsequent choices.
Time Frame
Beginning of treatment phase (week 0) and end of treatment phase (week 12)
Title
Cognitive Testing - Delayed Discounting
Description
The monetary choice questionnaire for hypothetical monetary rewards was used to assess delayed discounting (Kirby et al, 1999). The measure includes 27 items in which participants choose between a smaller, immediate reward (SIR) and a larger, delayed reward (LDR). There are three LDR sizes: small ($25-35), medium ($50-60) and large ($75-85). By examining the pattern of choices that participants make across the set of 27 items it is possible to calculate their delay discounting rate, termed K. The discount rate determines the steepness of the reduction in the present value of a reward with increases in the delay to the possible receipt of that reward. Thus, higher values in K represent greater discounting of the value of future rewards. With this measure K values can range between a low of 0.00016 to a high of 0.25. Higher K values have been linked to measures of impulsivity. Shown in the table are the K values observed when the future rewards were small, medium, or large.
Time Frame
Beginning of treatment phase (week 0) and end of treatment phase (week 12)
Secondary Outcome Measure Information:
Title
Extrapyramidal Symptoms
Description
The Simpson Angus Scale (SAS; Simpson and Angus, 1970) was used to assess extrapyramidal symptoms (EPS). The assessment consists of 11 items, each rating the severity of potential symptoms of movement disorders. Total scores are calculated by summing the scores of each of the 11 items for a potential total score of 0-44, with higher scores indicating more severe EPS.
Time Frame
Baseline (Week 0) and End of Study (Week 12)
Title
Number of Participants With Akathisia
Description
The Barnes Akathisia Scale (BAS; Barnes, 1989) was used to assess akathisia, a type of extrapyramidal symptom. The global clinical assessment of akathisia score is rated on a scale from 0=Absent to 5=Severe Akathisia.
Time Frame
Baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks.
Title
Change in Persistent Positive Symptoms
Description
The Brief Psychiatric Rating Scale (BPRS) positive symptom item total score was used to assess positive symptom change. The BPRS positive symptom items are: conceptual disorganization, hallucinatory behavior, unusual thought content, and suspiciousness. The total score is calculated by adding the scores for each item. Each scale ranges from "1=Not Present" to "7=Very Severe". The minimum score is 4 and the maximum score is 28. A higher score indicates a more severe positive symptom rating.
Time Frame
Every 4 weeks for 12 weeks.
Title
Depressive Symptoms
Description
The Calgary Depression Scale (CDS; Addington et al, 1997) total score was used to assess depressive symptoms over the course of the study. Total scores were calculated by summing the scores of each of the 9 items. Total scores can range from 0-27, with higher scores indicating more severe depressive symptoms.
Time Frame
Every 4 weeks for 12 weeks.
Title
Global Change in Illness Severity
Description
The Clinical Global Impression (CGI) severity of illness item was used to assess global changes. Scores on this item range from 1="Normal, not at all ill" to 7="Among the most extremely ill".
Time Frame
Every 4 weeks for 12 weeks.
Title
Number of Participants Exhibiting Side Effects
Description
The Side Effect Checklist (SEC) was used to assess side effects. The SEC is comprised of 22 common side effects, which are rated on a 1 (none)-4 (severe) scale. Side effects are determined to be clinically significant if there is a two or more point increase in severity from baseline, or any side effect that receives a severity rating of "4" (severe) at any point in the treatment phase of the study.
Time Frame
Every week for 12 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
64 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Subjects will meet DSM-IV criteria for schizophrenia or schizoaffective disorder. Current treatment with one or more second generation antipsychotics, except ziprasidone On same second generation antipsychotic(s)for at least 56 days On same dose of second generation antipsychotic(s)for at least 30 days 22-item SANS: Total score (i.e.all items minus global items and poverty of content of speech)greater than 20 or global Rating of Affective Flattening greater than or equal to 3 or global Rating of alogia greater than or equal to 3 BPRS: Sum of the four positive symptom items less than or equal to 16 (items 4,11,12,15) BPRS: Sum of the four Anxiety/Depression Factor items less than or equal to 14 (items 1,2,5,9) Simpson-Angus Scale: Total score less than or equal to 8 Exclusion Criteria: DSM-IV Major Depressive Disorder within last 6 months Current treatment with ziprasidone DSM-IV diagnosis of alcohol or substance dependence within the last 6 months DSM-IV criteria for alcohol or substance abuse within the last month evidence of illicit substance use, as identified with urine toxicology screen History of an organic brain disorder, mental retardation,epilepsy, or a medical condition, whose pathology or treatment could alter the presentation or treatment of schizophrenia or significantly increase the risk associated with the proposed treatment protocol. See those listed below Uncontrolled hypertension defined as BP exceeding 145/90 on 3 consecutive readings despite adequate treatment, pheochromocytoma, melanoma, hepatic insufficiency Pregnancy or lactation in females Pheochromocytoma Melanoma Hepatic insufficiency
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Robert W Buchanan, M.D.
Organizational Affiliation
University of Maryland, College Park
Official's Role
Principal Investigator
Facility Information:
Facility Name
Baltimore VA Medical Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Facility Name
Keypoint Mental health Center
City
Catonsville
State/Province
Maryland
ZIP/Postal Code
21228
Country
United States
Facility Name
Maryland Psychiatric REsearch Center
City
Catonsville
State/Province
Maryland
ZIP/Postal Code
21228
Country
United States
Facility Name
Mosaic Community Mental health Center
City
Catonsville
State/Province
Maryland
ZIP/Postal Code
21228
Country
United States
Facility Name
Keypoint Mental health Center
City
Dundalk
State/Province
Maryland
ZIP/Postal Code
21222
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
25368372
Citation
Buchanan RW, Weiner E, Kelly DL, Gold JM, Keller WR, Waltz JA, McMahon RP, Gorelick DA. Rasagiline in the Treatment of the Persistent Negative Symptoms of Schizophrenia. Schizophr Bull. 2015 Jul;41(4):900-8. doi: 10.1093/schbul/sbu151. Epub 2014 Nov 2.
Results Reference
derived

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Rasagiline in the Treatment of Persistent Negative Symptoms of Schizophrenia

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