Trial Outcomes & Findings for Rasagiline in the Treatment of Persistent Negative Symptoms of Schizophrenia (NCT NCT00492336)

Last Updated: 2019-09-25

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

84 participants

Primary outcome timeframe

Every 4 weeks over a 12 week period

Results posted on

2019-09-25

Participant Flow

Subjects were recruited between May 2007-October 2011 from mental health clinics throughout the community.

Participants were excluded before assignment to treatment groups if they met any of the exclusion criteria, if they became clinically unstable, or they decided that the demands of the study were too great. 84 participants were enrolled into active participation; 57 started study treatment.

Participant milestones

Participant milestones
Measure	Rasagiline Treatment with Rasagiline	Inactive Pill Treatment with Placebo
Overall Study STARTED	28	29
Overall Study COMPLETED	26	23
Overall Study NOT COMPLETED	2	6

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Rasagiline in the Treatment of Persistent Negative Symptoms of Schizophrenia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rasagiline n=28 Participants Treatment with Rasagiline	Inactive Pill n=29 Participants Treatment with Placebo	Total n=57 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	28 Participants n=5 Participants	29 Participants n=7 Participants	57 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	46.3 years STANDARD_DEVIATION 12.2 • n=5 Participants	45.9 years STANDARD_DEVIATION 11.1 • n=7 Participants	46.09 years STANDARD_DEVIATION 11.59 • n=5 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	7 Participants n=7 Participants	11 Participants n=5 Participants
Sex: Female, Male Male	24 Participants n=5 Participants	22 Participants n=7 Participants	46 Participants n=5 Participants
Region of Enrollment United States	28 participants n=5 Participants	29 participants n=7 Participants	57 participants n=5 Participants

PRIMARY outcome

Timeframe: Every 4 weeks over a 12 week period

Population: Number of participants available for symptom efficacy analyses.

Outcome measures

Outcome measures
Measure	Inactive Pill n=28 Participants Treatment with Placebo	Rasagiline n=26 Participants Treatment with Rasagiline
Change in Negative Symptoms Week 0	33.5 units on a scale Standard Deviation 7.8	32.7 units on a scale Standard Deviation 8.5
Change in Negative Symptoms Week 4	32.3 units on a scale Standard Deviation 8.2	31.2 units on a scale Standard Deviation 9.4
Change in Negative Symptoms Week 8	34.1 units on a scale Standard Deviation 8.6	31.1 units on a scale Standard Deviation 8.1
Change in Negative Symptoms Week 12	34.3 units on a scale Standard Deviation 8.6	29.9 units on a scale Standard Deviation 3.9

PRIMARY outcome

Timeframe: Beginning of treatment phase (week 0) and end of treatment phase (week 12)

Population: Subjects completing the cognitive testing at both time points.

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.

Outcome measures

Outcome measures
Measure	Inactive Pill n=23 Participants Treatment with Placebo	Rasagiline n=26 Participants Treatment with Rasagiline
Cognitive Testing - Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score Week 0	74.2 units on a scale Standard Deviation 13.7	76.8 units on a scale Standard Deviation 12.5
Cognitive Testing - Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score Week 12	75.3 units on a scale Standard Deviation 14.5	78.7 units on a scale Standard Deviation 14.1
Cognitive Testing - Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score Change	1.1 units on a scale Standard Deviation 7.5	1.9 units on a scale Standard Deviation 6.9

PRIMARY outcome

Timeframe: Beginning of treatment phase (week 0) and end of treatment phase (week 12)

Population: Subjects completing the cognitive testing at both time points.

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.

Outcome measures

Outcome measures
Measure	Inactive Pill n=23 Participants Treatment with Placebo	Rasagiline n=26 Participants Treatment with Rasagiline
Cognitive Testing - N-Back Neurocognitive Task 0-Back: Week 0	3.52 units on a scale Standard Deviation 0.70	3.47 units on a scale Standard Deviation 0.74
Cognitive Testing - N-Back Neurocognitive Task 0-Back: Week 12	3.66 units on a scale Standard Deviation 0.71	3.79 units on a scale Standard Deviation 0.61
Cognitive Testing - N-Back Neurocognitive Task 0-Back: Change	0.14 units on a scale Standard Deviation 0.75	0.32 units on a scale Standard Deviation 0.53
Cognitive Testing - N-Back Neurocognitive Task 1-Back: Week 0	2.63 units on a scale Standard Deviation 0.73	2.75 units on a scale Standard Deviation 0.73
Cognitive Testing - N-Back Neurocognitive Task 1-Back: Week 12	2.66 units on a scale Standard Deviation 0.91	2.96 units on a scale Standard Deviation 0.67
Cognitive Testing - N-Back Neurocognitive Task 1-Back: Change	0.03 units on a scale Standard Deviation 0.70	0.20 units on a scale Standard Deviation 0.73
Cognitive Testing - N-Back Neurocognitive Task 2-Back: Week 0	1.56 units on a scale Standard Deviation 0.87	1.75 units on a scale Standard Deviation 0.72
Cognitive Testing - N-Back Neurocognitive Task 2-Back: Week 12	1.57 units on a scale Standard Deviation 0.86	1.59 units on a scale Standard Deviation 0.88
Cognitive Testing - N-Back Neurocognitive Task 2-Back: Change	0.01 units on a scale Standard Deviation 0.62	-0.16 units on a scale Standard Deviation 0.68

PRIMARY outcome

Timeframe: Beginning of treatment phase (week 0) and end of treatment phase (week 12)

Population: Subjects completing the cognitive testing at both time points. Results for lose shifts are calculated for 24 Rasagiline and 22 Placebo participants, due to missing data created by participants who had zero losses (and hence no need to shift) during both the 3rd and 4th blocks of trials.

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.

Outcome measures

PRIMARY outcome

Timeframe: Beginning of treatment phase (week 0) and end of treatment phase (week 12)

Population: Subjects completing the cognitive testing at both time points.

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.

Outcome measures

Outcome measures
Measure	Inactive Pill n=23 Participants Treatment with Placebo	Rasagiline n=26 Participants Treatment with Rasagiline
Cognitive Testing - Delayed Discounting Large Reward: Week 0	0.018 units on a scale Interval 0.007 to 0.046	0.004 units on a scale Interval 0.001 to 0.01
Cognitive Testing - Delayed Discounting Large Reward: Week 12	0.010 units on a scale Interval 0.004 to 0.023	0.010 units on a scale Interval 0.004 to 0.025
Cognitive Testing - Delayed Discounting Medium Reward: Week 0	0.024 units on a scale Interval 0.009 to 0.061	0.003 units on a scale Interval 0.001 to 0.007
Cognitive Testing - Delayed Discounting Medium Reward: Week 12	0.011 units on a scale Interval 0.004 to 0.027	0.008 units on a scale Interval 0.003 to 0.019
Cognitive Testing - Delayed Discounting Small Reward: Week 0	0.023 units on a scale Interval 0.011 to 0.048	0.009 units on a scale Interval 0.003 to 0.022
Cognitive Testing - Delayed Discounting Small Reward: Week 12	0.014 units on a scale Interval 0.005 to 0.034	0.016 units on a scale Interval 0.006 to 0.043

SECONDARY outcome

Timeframe: Baseline (Week 0) and End of Study (Week 12)

Population: SAS scores were collected at baseline on 28 Rasagiline and 29 Placebo patients. End of study scores were collected on 27 Rasagiline and 27 Placebo patients, including 5 patients who withdrew before Week 12 (1 Rasagiline patient at Week 4, 1 Placebo participant each at Weeks 3 and 6, and two Placebo participants at Week 8).

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.

Outcome measures

Outcome measures
Measure	Inactive Pill n=29 Participants Treatment with Placebo	Rasagiline n=28 Participants Treatment with Rasagiline
Extrapyramidal Symptoms Week 0	1.93 units on a scale Standard Deviation 2.07	1.82 units on a scale Standard Deviation 2.30
Extrapyramidal Symptoms Week 12	1.89 units on a scale Standard Deviation 2.71	0.96 units on a scale Standard Deviation 1.34
Extrapyramidal Symptoms Change	-0.04 units on a scale Standard Deviation 2.24	-0.85 units on a scale Standard Deviation 1.94

SECONDARY outcome

Timeframe: Baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks.

Population: Barnes Akathisia Scales at baseline and end of study were collected for 26 participants each in the rasagiline and placebo groups. End of study ratings were collected at week 12, except for 4 placebo participants (1 participant each at weeks 3 and 6, and two at week 8).

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.

Outcome measures

Outcome measures
Measure	Inactive Pill n=26 Participants Treatment with Placebo	Rasagiline n=26 Participants Treatment with Rasagiline
Number of Participants With Akathisia Score 3=Moderate Akathisia : Baseline	0 Participants	1 Participants
Number of Participants With Akathisia Score 0=Absent : Baseline	21 Participants	20 Participants
Number of Participants With Akathisia Score 0=Absent : End of Study	21 Participants	20 Participants
Number of Participants With Akathisia Score 1=Questionable : Baseline	5 Participants	3 Participants
Number of Participants With Akathisia Score 1=Questionable : End of Study	5 Participants	2 Participants
Number of Participants With Akathisia Score 2=Mild Akathisia : Baseline	0 Participants	2 Participants
Number of Participants With Akathisia Score 2=Mild Akathisia : End of Study	0 Participants	3 Participants
Number of Participants With Akathisia Score 3=Moderate Akathisia : End of Study	0 Participants	1 Participants

SECONDARY outcome

Timeframe: Every 4 weeks for 12 weeks.

Population: Number of participants available for symptom efficacy analyses.

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.

Outcome measures

Outcome measures
Measure	Inactive Pill n=28 Participants Treatment with Placebo	Rasagiline n=26 Participants Treatment with Rasagiline
Change in Persistent Positive Symptoms Week 0	9.1 units on a scale Standard Deviation 4.0	8.8 units on a scale Standard Deviation 3.2
Change in Persistent Positive Symptoms Week 4	9.1 units on a scale Standard Deviation 3.9	9.2 units on a scale Standard Deviation 3.7
Change in Persistent Positive Symptoms Week 8	9.8 units on a scale Standard Deviation 4.2	9.2 units on a scale Standard Deviation 3.5
Change in Persistent Positive Symptoms Week 12	8.9 units on a scale Standard Deviation 3.7	8.3 units on a scale Standard Deviation 3.3

SECONDARY outcome

Timeframe: Every 4 weeks for 12 weeks.

Population: Number of participants available for symptom efficacy analyses.

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.

Outcome measures

Outcome measures
Measure	Inactive Pill n=28 Participants Treatment with Placebo	Rasagiline n=26 Participants Treatment with Rasagiline
Depressive Symptoms Week 0	2.02 units on a scale Standard Deviation 2.37	2.29 units on a scale Standard Deviation 2.08
Depressive Symptoms Week 4	1.96 units on a scale Standard Deviation 2.30	2.19 units on a scale Standard Deviation 2.08
Depressive Symptoms Week 8	1.52 units on a scale Standard Deviation 1.94	2.31 units on a scale Standard Deviation 1.93
Depressive Symptoms Week 12	1.52 units on a scale Standard Deviation 2.25	2.58 units on a scale Standard Deviation 2.63

SECONDARY outcome

Timeframe: Every 4 weeks for 12 weeks.

Population: Number of participants available for symptom efficacy analyses.

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".

Outcome measures

Outcome measures
Measure	Inactive Pill n=28 Participants Treatment with Placebo	Rasagiline n=26 Participants Treatment with Rasagiline
Global Change in Illness Severity Week 4	4.32 units on a scale Standard Deviation 0.48	4.08 units on a scale Standard Deviation 0.39
Global Change in Illness Severity Week 0	4.31 units on a scale Standard Deviation 0.49	4.05 units on a scale Standard Deviation 0.42
Global Change in Illness Severity Week 8	4.36 units on a scale Standard Deviation 0.49	1.00 units on a scale Standard Deviation 0.4
Global Change in Illness Severity Week 12	4.27 units on a scale Standard Deviation 0.46	1.08 units on a scale Standard Deviation 0.48

SECONDARY outcome

Timeframe: Every week for 12 weeks

Population: One placebo patient for whom a baseline side effects checklist was excluded from these analyses.

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.

Outcome measures

Outcome measures
Measure	Inactive Pill n=28 Participants Treatment with Placebo	Rasagiline n=28 Participants Treatment with Rasagiline
Number of Participants Exhibiting Side Effects Abdominal Pain	7 Participants	5 Participants
Number of Participants Exhibiting Side Effects Anorexia	10 Participants	7 Participants
Number of Participants Exhibiting Side Effects Bruising Easily	1 Participants	4 Participants
Number of Participants Exhibiting Side Effects Constipation	9 Participants	12 Participants
Number of Participants Exhibiting Side Effects Diarrhea	6 Participants	9 Participants
Number of Participants Exhibiting Side Effects Dizziness	7 Participants	5 Participants
Number of Participants Exhibiting Side Effects Dry Mouth	11 Participants	7 Participants
Number of Participants Exhibiting Side Effects Enuresis	3 Participants	4 Participants
Number of Participants Exhibiting Side Effects Fever	5 Participants	2 Participants
Number of Participants Exhibiting Side Effects Headache	8 Participants	7 Participants
Number of Participants Exhibiting Side Effects Hypersalivation	7 Participants	4 Participants
Number of Participants Exhibiting Side Effects Insomnia	7 Participants	2 Participants
Number of Participants Exhibiting Side Effects Malaise	14 Participants	8 Participants
Number of Participants Exhibiting Side Effects Mucosal Ulceration	1 Participants	1 Participants
Number of Participants Exhibiting Side Effects Nausea	2 Participants	6 Participants
Number of Participants Exhibiting Side Effects Rash	5 Participants	3 Participants
Number of Participants Exhibiting Side Effects Restlessness	7 Participants	4 Participants
Number of Participants Exhibiting Side Effects Sedation	8 Participants	8 Participants
Number of Participants Exhibiting Side Effects Sore Throat	5 Participants	3 Participants
Number of Participants Exhibiting Side Effects Stiffness	5 Participants	7 Participants
Number of Participants Exhibiting Side Effects Tremor	11 Participants	3 Participants
Number of Participants Exhibiting Side Effects Urticaria	5 Participants	3 Participants
Number of Participants Exhibiting Side Effects Vomiting	4 Participants	4 Participants
Number of Participants Exhibiting Side Effects Weight Loss	12 Participants	10 Participants

Adverse Events

Rasagiline

Serious events: 1 serious events

Other events: 1 other events

Deaths: 0 deaths

Inactive Pill

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Rasagiline n=28 participants at risk Treatment with Rasagiline	Inactive Pill n=29 participants at risk Treatment with Placebo
Psychiatric disorders Hospitalization	3.6% 1/28 • During the 12-week Treatment Phase of the study.	0.00% 0/29 • During the 12-week Treatment Phase of the study.

Other adverse events

Other adverse events
Measure	Rasagiline n=28 participants at risk Treatment with Rasagiline	Inactive Pill n=29 participants at risk Treatment with Placebo
Psychiatric disorders suicidal ideation	3.6% 1/28 • Number of events 1 • During the 12-week Treatment Phase of the study.	0.00% 0/29 • During the 12-week Treatment Phase of the study.
Renal and urinary disorders increased urinary frequency	0.00% 0/28 • During the 12-week Treatment Phase of the study.	3.4% 1/29 • Number of events 1 • During the 12-week Treatment Phase of the study.
Psychiatric disorders conceptual disorganization	0.00% 0/28 • During the 12-week Treatment Phase of the study.	3.4% 1/29 • Number of events 1 • During the 12-week Treatment Phase of the study.
General disorders tooth problems	0.00% 0/28 • During the 12-week Treatment Phase of the study.	3.4% 1/29 • Number of events 1 • During the 12-week Treatment Phase of the study.

Additional Information

Dr. Robert Buchanan, M.D.

Maryland Psychiatric Research Center

Phone: 410-402-7876

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Inactive Pill n=23 Participants Treatment with Placebo	Rasagiline n=26 Participants Treatment with Rasagiline
Cognitive Testing - Probabilistic Learning Task 80 vs 20: Week 0	69.1 percentage of optimal stimuli chosen Standard Deviation 25.1	70.8 percentage of optimal stimuli chosen Standard Deviation 23.7
Cognitive Testing - Probabilistic Learning Task 80 vs 20: Week 12	68.5 percentage of optimal stimuli chosen Standard Deviation 25.8	70.4 percentage of optimal stimuli chosen Standard Deviation 24.5
Cognitive Testing - Probabilistic Learning Task 80 vs 20: Change	-0.7 percentage of optimal stimuli chosen Standard Deviation 36.8	-0.4 percentage of optimal stimuli chosen Standard Deviation 33.8
Cognitive Testing - Probabilistic Learning Task 70 vs 30: Week 0	66.1 percentage of optimal stimuli chosen Standard Deviation 19.8	69.7 percentage of optimal stimuli chosen Standard Deviation 22.3
Cognitive Testing - Probabilistic Learning Task 70 vs 30: Week 12	65.9 percentage of optimal stimuli chosen Standard Deviation 18.8	64.4 percentage of optimal stimuli chosen Standard Deviation 23.4
Cognitive Testing - Probabilistic Learning Task 70 vs 30: Change	-0.2 percentage of optimal stimuli chosen Standard Deviation 25.6	-5.3 percentage of optimal stimuli chosen Standard Deviation 27.4
Cognitive Testing - Probabilistic Learning Task 60 vs 40: Week 0	57.9 percentage of optimal stimuli chosen Standard Deviation 24.9	53.9 percentage of optimal stimuli chosen Standard Deviation 26.9
Cognitive Testing - Probabilistic Learning Task 60 vs 40: Week 12	58.6 percentage of optimal stimuli chosen Standard Deviation 18.2	58.7 percentage of optimal stimuli chosen Standard Deviation 23.8
Cognitive Testing - Probabilistic Learning Task 60 vs 40: Change	0.7 percentage of optimal stimuli chosen Standard Deviation 29.8	4.7 percentage of optimal stimuli chosen Standard Deviation 43.0
Cognitive Testing - Probabilistic Learning Task Lose Shifts: Week 0	56.5 percentage of optimal stimuli chosen Standard Deviation 12.9	48.6 percentage of optimal stimuli chosen Standard Deviation 16.4
Cognitive Testing - Probabilistic Learning Task Lose Shifts: Week 12	54.8 percentage of optimal stimuli chosen Standard Deviation 12.0	50.1 percentage of optimal stimuli chosen Standard Deviation 16.9
Cognitive Testing - Probabilistic Learning Task Lose Shifts: Change	-1.2 percentage of optimal stimuli chosen Standard Deviation 14.9	2.9 percentage of optimal stimuli chosen Standard Deviation 17.2
Cognitive Testing - Probabilistic Learning Task Win Stays: Week 0	62.2 percentage of optimal stimuli chosen Standard Deviation 18.7	64.6 percentage of optimal stimuli chosen Standard Deviation 19.5
Cognitive Testing - Probabilistic Learning Task Win Stays: Week 12	64.4 percentage of optimal stimuli chosen Standard Deviation 15.2	62.9 percentage of optimal stimuli chosen Standard Deviation 20.5
Cognitive Testing - Probabilistic Learning Task Win Stays: Change	2.3 percentage of optimal stimuli chosen Standard Deviation 21.9	-1.7 percentage of optimal stimuli chosen Standard Deviation 27.7