Trial Outcomes & Findings for A Physical Dependence Study in Schizophrenia (NCT NCT01452919)
NCT ID: NCT01452919
Last Updated: 2022-09-14
Results Overview
The checklist is a 30-item, participant-rated scale that asks whether participants experience symptoms such as nausea, vomiting, loss of appetite, anxiety, irritability, or craving for study drug during the previous day to assess potential symptoms of drug withdrawal. Each item is rated on a 0 (not at all) to 3 (severe). Total scores range from 0-90. Higher scores indicate greater severity of symptoms. The 3-day MA was calculated starting the third day until the last day of double-blind, randomized period. The 3-day MA was the average of scores from that day and previous 2 days. If scores from any of the days during the 3-day was missing, the average was based on the non-missing days. If there was no total scores for any day of the 3-day, the average was considered to be missing. An analysis of covariance (ANCOVA) was used to calculate Least Squares (LS) mean and standard error. LS mean values are controlled for baseline total score, treatment, pooled investigative site and gender.
COMPLETED
PHASE3
123 participants
Randomization up to Week 2 of randomization treatment
2022-09-14
Participant Flow
This study consisted of a 4-week open-label treatment period and a 2-week double-blind randomized withdrawal treatment period.
Participant milestones
| Measure |
LY2140023 (Open-Label )
40 milligram (mg) or 80 mg LY2140023 administered orally, twice daily for 4 weeks during open-label treatment period.
|
Placebo (Randomization)
Placebo administered orally, twice daily for 2 weeks during double-blind, randomized withdrawal treatment period.
|
LY2140023 (Randomization)
40 mg or 80 mg LY2140023 administered orally, twice daily for 2 weeks during double-blind, randomized withdrawal treatment period.
|
|---|---|---|---|
|
Open-Label Treatment
STARTED
|
123
|
0
|
0
|
|
Open-Label Treatment
Received at Least 1 Dose of Study Drug
|
123
|
0
|
0
|
|
Open-Label Treatment
COMPLETED
|
103
|
0
|
0
|
|
Open-Label Treatment
NOT COMPLETED
|
20
|
0
|
0
|
|
Randomization Treatment
STARTED
|
0
|
50
|
53
|
|
Randomization Treatment
Received at Least 1 Dose of Study Drug
|
0
|
50
|
53
|
|
Randomization Treatment
COMPLETED
|
0
|
47
|
51
|
|
Randomization Treatment
NOT COMPLETED
|
0
|
3
|
2
|
Reasons for withdrawal
| Measure |
LY2140023 (Open-Label )
40 milligram (mg) or 80 mg LY2140023 administered orally, twice daily for 4 weeks during open-label treatment period.
|
Placebo (Randomization)
Placebo administered orally, twice daily for 2 weeks during double-blind, randomized withdrawal treatment period.
|
LY2140023 (Randomization)
40 mg or 80 mg LY2140023 administered orally, twice daily for 2 weeks during double-blind, randomized withdrawal treatment period.
|
|---|---|---|---|
|
Open-Label Treatment
Adverse Event
|
5
|
0
|
0
|
|
Open-Label Treatment
Lost to Follow-up
|
4
|
0
|
0
|
|
Open-Label Treatment
Perceived lack of efficacy
|
3
|
0
|
0
|
|
Open-Label Treatment
Protocol Violation
|
4
|
0
|
0
|
|
Open-Label Treatment
Sponsor Decision
|
1
|
0
|
0
|
|
Open-Label Treatment
Withdrawal by Subject
|
2
|
0
|
0
|
|
Open-Label Treatment
Subject is moving or has moved
|
1
|
0
|
0
|
|
Randomization Treatment
Adverse Event
|
0
|
0
|
2
|
|
Randomization Treatment
Sponsor Decision
|
0
|
1
|
0
|
|
Randomization Treatment
Withdrawal by Subject
|
0
|
1
|
0
|
|
Randomization Treatment
Subject is moving or has moved
|
0
|
1
|
0
|
Baseline Characteristics
A Physical Dependence Study in Schizophrenia
Baseline characteristics by cohort
| Measure |
All Participants
n=123 Participants
40 milligram (mg) or 80 mg LY2140023 administered orally, twice daily for 4 weeks during open-label treatment period.
Placebo, or 40 mg or 80 mg LY2140023 administered orally, twice daily for 2 weeks during double-blind, randomized withdrawal treatment period.
|
|---|---|
|
Age, Continuous
|
42.86 years
STANDARD_DEVIATION 11.45 • n=5 Participants
|
|
Sex: Female, Male
Female
|
30 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
93 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
5 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
118 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
3 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Asian
|
1 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
1 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Black or African American
|
82 Participants
n=5 Participants
|
|
Race (NIH/OMB)
White
|
35 Participants
n=5 Participants
|
|
Race (NIH/OMB)
More than one race
|
1 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
|
Region of Enrollment
United States
|
107 participants
n=5 Participants
|
|
Region of Enrollment
Greece
|
16 participants
n=5 Participants
|
PRIMARY outcome
Timeframe: Randomization up to Week 2 of randomization treatmentPopulation: All randomized participants who received at least one dose of study drug and had Discontinuation Symptom Checklist-Modified Rickels total score measurement.
The checklist is a 30-item, participant-rated scale that asks whether participants experience symptoms such as nausea, vomiting, loss of appetite, anxiety, irritability, or craving for study drug during the previous day to assess potential symptoms of drug withdrawal. Each item is rated on a 0 (not at all) to 3 (severe). Total scores range from 0-90. Higher scores indicate greater severity of symptoms. The 3-day MA was calculated starting the third day until the last day of double-blind, randomized period. The 3-day MA was the average of scores from that day and previous 2 days. If scores from any of the days during the 3-day was missing, the average was based on the non-missing days. If there was no total scores for any day of the 3-day, the average was considered to be missing. An analysis of covariance (ANCOVA) was used to calculate Least Squares (LS) mean and standard error. LS mean values are controlled for baseline total score, treatment, pooled investigative site and gender.
Outcome measures
| Measure |
Placebo (Randomization)
n=50 Participants
Placebo administered orally, twice daily for 2 weeks during double-blind, randomized withdrawal treatment period.
|
LY2140023 (Randomization)
n=52 Participants
40 mg or 80 mg LY2140023 administered orally, twice daily for 2 weeks during double-blind, randomized withdrawal treatment period.
|
|---|---|---|
|
Maximum 3-Day Moving Average (MA) of the Discontinuation Symptom Checklist-Modified Rickels Total Score
|
13.23 units on a scale
Standard Error 0.96
|
11.50 units on a scale
Standard Error 0.99
|
SECONDARY outcome
Timeframe: Randomization, randomization treatment Weeks 0.5 and 1 and 1.5 and 2Population: All randomized participants who received at least one dose of study drug and had CIWA-Ar measurements at randomization and specified post-randomization visits.
The CIWA-Ar is a 10-item scale that was used to monitor for symptoms of drug withdrawal. The scale includes the following domains/criteria: nausea, vomiting; anxiety; paroxysmal sweats; tactile disturbances; visual disturbances; tremors; agitation; orientation and clouding of sensorium; auditory disturbances; and headache. Items 1-9 have possible scores of 0 (no symptom)-7 (severe symptom), and item 10 has possible scores of 0 (no symptom)-4 (severe symptom). Total scores range from 0-67. Higher scores indicate greater severity of symptom. The Mixed Model Repeated Measure (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values are controlled for baseline CIWA-Ar total score, treatment, gender, pooled investigative site, visit, baseline CIWA-Ar total score\*visit and treatment\*visit.
Outcome measures
| Measure |
Placebo (Randomization)
n=50 Participants
Placebo administered orally, twice daily for 2 weeks during double-blind, randomized withdrawal treatment period.
|
LY2140023 (Randomization)
n=53 Participants
40 mg or 80 mg LY2140023 administered orally, twice daily for 2 weeks during double-blind, randomized withdrawal treatment period.
|
|---|---|---|
|
Change From Randomization up to Week 2 in the Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA-Ar) Total Score
Week 0.5
|
-0.7 units on a scale
Standard Error 0.3
|
0.0 units on a scale
Standard Error 0.3
|
|
Change From Randomization up to Week 2 in the Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA-Ar) Total Score
Week 1
|
-0.9 units on a scale
Standard Error 0.3
|
-0.5 units on a scale
Standard Error 0.3
|
|
Change From Randomization up to Week 2 in the Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA-Ar) Total Score
Week 1.5
|
-0.8 units on a scale
Standard Error 0.3
|
-0.6 units on a scale
Standard Error 0.3
|
|
Change From Randomization up to Week 2 in the Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA-Ar) Total Score
Week 2
|
-0.4 units on a scale
Standard Error 0.3
|
-0.5 units on a scale
Standard Error 0.3
|
SECONDARY outcome
Timeframe: Randomization, randomization treatment Week 2Population: All randomized participants who received at least one dose of study drug and had BAS global score measurement at randomization and at least one post-randomization BAS global score.
The BAS is a 4-item instrument that evaluates akathisia associated with use of antipsychotic medications. Item 4 is the Global Clinical Assessment (Global Score) and is rated 0 to 5 (0 = absent, 5 = severe). The Mixed Model Repeated Measure (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values are controlled for baseline BAS global score, treatment, gender, pooled investigative site, visit, baseline BAS global score\*visit and treatment\*visit.
Outcome measures
| Measure |
Placebo (Randomization)
n=50 Participants
Placebo administered orally, twice daily for 2 weeks during double-blind, randomized withdrawal treatment period.
|
LY2140023 (Randomization)
n=53 Participants
40 mg or 80 mg LY2140023 administered orally, twice daily for 2 weeks during double-blind, randomized withdrawal treatment period.
|
|---|---|---|
|
Change From Randomization to Week 2 in Barnes Akathisia Scale (BAS) Global Score
|
-0.0 units on a scale
Standard Error 0.0
|
-0.0 units on a scale
Standard Error 0.0
|
SECONDARY outcome
Timeframe: Randomization, randomization treatment Week 2Population: All randomized participants who received at least one dose of study drug and had SAS total score measurement at randomization and at least one post-randomization SAS total score.
The SAS is used to measure parkinsonian-type symptoms in participants exposed to antipsychotics. SAS consists of 10 items; each rated on a 5-point scale, with 0 meaning complete absence of the condition and 4 meaning the presence of the condition in extreme form. The total score is obtained by adding the ten items, and ranges from 0 to 40. Higher scores indicate greater severity of illness. The Mixed Model Repeated Measure (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values are controlled for baseline SAS total score, treatment, gender, pooled investigative site, visit, baseline SAS total score\*visit and treatment\*visit.
Outcome measures
| Measure |
Placebo (Randomization)
n=50 Participants
Placebo administered orally, twice daily for 2 weeks during double-blind, randomized withdrawal treatment period.
|
LY2140023 (Randomization)
n=53 Participants
40 mg or 80 mg LY2140023 administered orally, twice daily for 2 weeks during double-blind, randomized withdrawal treatment period.
|
|---|---|---|
|
Change From Randomization to Week 2 in Simpson-Angus Scale (SAS) Total Score
|
-0.0 units on a scale
Standard Error 0.0
|
0.0 units on a scale
Standard Error 0.0
|
SECONDARY outcome
Timeframe: Randomization, randomization treatment Week 2Population: All randomized participants who received at least one dose of study drug and had AIMS total score measurement at randomization and at least one post-randomization AIMS total score.
The AIMS is a 12-item scale designed to record the occurrence of dyskinetic movements. Items 1 to 10 are rated on a 5- point scale, with 0 being no dyskinetic movements and 4 being severe dyskinetic movements. Items 11 and 12 are yes/no questions regarding the dental condition of a subject. The AIMS 1-7 total score is the total of items 1 through 7 of the AIMS, and ranges from 0 to 28. Higher scores indicate greater severity of illness. The Mixed Model Repeated Measure (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values are controlled for baseline AIMS 1-7 total score, treatment, gender, pooled investigative site, visit, baseline AIMS 1-7 total score\*visit and treatment\*visit.
Outcome measures
| Measure |
Placebo (Randomization)
n=50 Participants
Placebo administered orally, twice daily for 2 weeks during double-blind, randomized withdrawal treatment period.
|
LY2140023 (Randomization)
n=53 Participants
40 mg or 80 mg LY2140023 administered orally, twice daily for 2 weeks during double-blind, randomized withdrawal treatment period.
|
|---|---|---|
|
Change From Randomization to Week 2 in Abnormal Involuntary Movement Scale (AIMS) Total Score
|
0.0 units a scale
Standard Error 0.1
|
-0.0 units a scale
Standard Error 0.1
|
SECONDARY outcome
Timeframe: Baseline up to Week 4 of open-label treatmentPopulation: All enrolled participants who received at least one dose of study drug and had a baseline (before open-label treatment) and at least one post-baseline (during open-label treatment) C-SSRS measurement.
Columbia Suicide Rating Scale (C-SSRS) captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal ideation: a "yes" answer to any one of 5 suicidal ideation questions: wish to be dead, and 4 different categories of active suicidal ideation. Suicidal behavior: a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. The percentage of participants with treatment-emergent suicidal ideation or behavior during open-label treatment period (with a change from baseline in C-SSRS) was calculated as the number of participants with an increase in suicidal behavior or ideation over baseline (before open-label treatment), divided by the total number of participants multiplied by 100.
Outcome measures
| Measure |
Placebo (Randomization)
n=122 Participants
Placebo administered orally, twice daily for 2 weeks during double-blind, randomized withdrawal treatment period.
|
LY2140023 (Randomization)
40 mg or 80 mg LY2140023 administered orally, twice daily for 2 weeks during double-blind, randomized withdrawal treatment period.
|
|---|---|---|
|
Percentage of Participants With Suicidal Behaviors and Ideations Measured Using the Columbia Suicide Severity Rating Scale (C-SSRS) During Open-Label Treatment Period
Treatment-Emergent Suicidal Ideation
|
1.6 percentage of participants
|
—
|
|
Percentage of Participants With Suicidal Behaviors and Ideations Measured Using the Columbia Suicide Severity Rating Scale (C-SSRS) During Open-Label Treatment Period
Treatment-Emergent Suicidal Behavior
|
0.0 percentage of participants
|
—
|
SECONDARY outcome
Timeframe: Randomization up to Week 2 of randomization treatmentPopulation: All participants who received at least one dose of study drug and had C-SSRS measurement at randomization and at least one post-randomization C-SSRS measurement.
Columbia Suicide Rating Scale (C-SSRS) captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal ideation: a "yes" answer to any one of 5 suicidal ideation questions: wish to be dead, and 4 different categories of active suicidal ideation. Suicidal behavior: a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. The percentage of participants with treatment-emergent suicidal ideation or behavior during double-blind randomized treatment period (with a change from baseline in C-SSRS) was calculated as the number of participants with an increase in suicidal behavior or ideation over baseline (randomization), divided by the total number of participants multiplied by 100.
Outcome measures
| Measure |
Placebo (Randomization)
n=50 Participants
Placebo administered orally, twice daily for 2 weeks during double-blind, randomized withdrawal treatment period.
|
LY2140023 (Randomization)
n=53 Participants
40 mg or 80 mg LY2140023 administered orally, twice daily for 2 weeks during double-blind, randomized withdrawal treatment period.
|
|---|---|---|
|
Percentage of Participants With Suicidal Behaviors and Ideations Measured Using the Columbia Suicide Severity Rating Scale (C-SSRS) During Double-Blind Randomized Treatment Period
Treatment-Emergent Suicidal Ideation
|
0.0 percentage of participants
|
0.0 percentage of participants
|
|
Percentage of Participants With Suicidal Behaviors and Ideations Measured Using the Columbia Suicide Severity Rating Scale (C-SSRS) During Double-Blind Randomized Treatment Period
Treatment-Emergent Suicidal Behavior
|
0.0 percentage of participants
|
0.0 percentage of participants
|
SECONDARY outcome
Timeframe: Randomization, randomization treatment Week 2Population: All randomized participants who received at least one dose of study drug and had CGI-S measurement at randomization and at least one post-randomization CGI-S measurement.
The CGI-S instrument is used to record the severity of mental illness at the time of assessment. The score ranges from 1 (normal, not at all ill) to 7 (among the most extremely ill). Higher scores indicate greater severity of illness. The Mixed Model Repeated Measure (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values are controlled for baseline CGI-S score, treatment, gender, pooled investigative site, visit, baseline CGI-S score\*visit and treatment\*visit.
Outcome measures
| Measure |
Placebo (Randomization)
n=50 Participants
Placebo administered orally, twice daily for 2 weeks during double-blind, randomized withdrawal treatment period.
|
LY2140023 (Randomization)
n=53 Participants
40 mg or 80 mg LY2140023 administered orally, twice daily for 2 weeks during double-blind, randomized withdrawal treatment period.
|
|---|---|---|
|
Change From Randomization to Week 2 in Clinical Global Impression-Severity Scale (CGI-S)
|
-0.2 units on a scale
Standard Error 0.1
|
-0.0 units on a scale
Standard Error 0.1
|
SECONDARY outcome
Timeframe: Randomization, randomization treatment Week 2Population: All randomized participants who received at least one dose of study drug and had BPRS total score measurement at randomization and at least one post-randomization BPRS total score.
BPRS is an 18-item clinician-administered scale used to assess the degree of severity of a participant's general psychopathological symptoms. Item scores range from 1 (not present) to 7 (extremely severe). Total Scores range from 18 to 126. Higher scores indicate greater severity of illness. The Mixed Model Repeated Measure (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values are controlled for baseline BPRS total score, treatment, gender, pooled investigative site, visit, baseline BPRS total score\*visit and treatment\*visit.
Outcome measures
| Measure |
Placebo (Randomization)
n=49 Participants
Placebo administered orally, twice daily for 2 weeks during double-blind, randomized withdrawal treatment period.
|
LY2140023 (Randomization)
n=52 Participants
40 mg or 80 mg LY2140023 administered orally, twice daily for 2 weeks during double-blind, randomized withdrawal treatment period.
|
|---|---|---|
|
Change From Randomization to Week 2 in Brief Psychiatric Rating Scale (BPRS) Total Scores
|
-2.20 units on a scale
Standard Error 0.55
|
-1.28 units on a scale
Standard Error 0.54
|
Adverse Events
LY2140023 (Open-Label )
Placebo (Randomization)
LY2140023 (Randomization)
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
LY2140023 (Open-Label )
n=123 participants at risk
40 milligram (mg) or 80 mg LY2140023 administered orally, twice daily for 4 weeks during open-label treatment period.
|
Placebo (Randomization)
n=50 participants at risk
Placebo administered orally, twice daily for 2 weeks during double-blind randomized withdrawal treatment period.
|
LY2140023 (Randomization)
n=53 participants at risk
40 mg or 80 mg LY2140023 administered orally, twice daily for 2 weeks during double-blind randomized withdrawal treatment period.
|
|---|---|---|---|
|
Ear and labyrinth disorders
Hearing impaired
|
2.4%
3/123 • Number of events 3
|
4.0%
2/50 • Number of events 2
|
0.00%
0/53
|
|
Eye disorders
Visual impairment
|
1.6%
2/123 • Number of events 2
|
4.0%
2/50 • Number of events 2
|
1.9%
1/53 • Number of events 1
|
|
Gastrointestinal disorders
Constipation
|
4.9%
6/123 • Number of events 6
|
2.0%
1/50 • Number of events 1
|
1.9%
1/53 • Number of events 1
|
|
Gastrointestinal disorders
Diarrhoea
|
4.1%
5/123 • Number of events 7
|
2.0%
1/50 • Number of events 1
|
0.00%
0/53
|
|
Gastrointestinal disorders
Nausea
|
28.5%
35/123 • Number of events 39
|
2.0%
1/50 • Number of events 1
|
5.7%
3/53 • Number of events 3
|
|
Gastrointestinal disorders
Vomiting
|
8.1%
10/123 • Number of events 17
|
0.00%
0/50
|
3.8%
2/53 • Number of events 2
|
|
Investigations
Blood creatine phosphokinase increased
|
7.3%
9/123 • Number of events 9
|
0.00%
0/50
|
5.7%
3/53 • Number of events 3
|
|
Nervous system disorders
Dizziness
|
4.9%
6/123 • Number of events 6
|
0.00%
0/50
|
0.00%
0/53
|
|
Nervous system disorders
Headache
|
15.4%
19/123 • Number of events 20
|
8.0%
4/50 • Number of events 4
|
1.9%
1/53 • Number of events 2
|
|
Nervous system disorders
Somnolence
|
5.7%
7/123 • Number of events 7
|
0.00%
0/50
|
0.00%
0/53
|
|
Nervous system disorders
Tremor
|
8.1%
10/123 • Number of events 12
|
2.0%
1/50 • Number of events 1
|
3.8%
2/53 • Number of events 2
|
|
Psychiatric disorders
Agitation
|
6.5%
8/123 • Number of events 9
|
2.0%
1/50 • Number of events 1
|
7.5%
4/53 • Number of events 4
|
|
Psychiatric disorders
Anxiety
|
8.1%
10/123 • Number of events 11
|
8.0%
4/50 • Number of events 4
|
7.5%
4/53 • Number of events 4
|
|
Psychiatric disorders
Insomnia
|
4.9%
6/123 • Number of events 6
|
0.00%
0/50
|
0.00%
0/53
|
|
Skin and subcutaneous tissue disorders
Hyperhidrosis
|
5.7%
7/123 • Number of events 7
|
0.00%
0/50
|
3.8%
2/53 • Number of events 2
|
Additional Information
Chief Medical Officer
Eli Lilly and Company
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place
Restriction type: GT60