Bipolar Disorder
Conditions
Keywords
Bipolar, Depression, Cognition, Cognitive
Brief summary
The goals of this study are to evaluate the efficacy of JNJ-18038683 in an 8 week trial to ameliorate the cognitive deficit and reduce residual depressive symptoms in 60 stable bipolar outpatients receiving treatment for depression. JNJ-18038683 will be studied and compared with placebo as adjunctive treatment to standard pharmacologic treatment for bipolar disorder.
Detailed description
Most, but not all, patients with bipolar disorder (BPD) have clinically significant cognitive impairment. Impairment is present in both the manic and depressed phases of BPD, as well as in euthymic periods. The percentage of BPD patients with cognitive impairment (CIBD) varies among studies, with 40-60% representing the best estimate. The weight of the evidence supports no overall difference in the type and severity of cognitive impairment in any phase of BPD, i.e. it is a stable trait feature of BPD, albeit variable from one patient to another. The most commonly affected cognitive domains are speed of processing, declarative memory, attention and working memory. Although CIBD is milder in severity than the cognitive impairment associated with schizophrenia (CIAS), on average, as in schizophrenia, CIBD has a major impact on function and quality of life in most patients, particularly because the greater preservation of function of BPD enables them to engage in activities which are more dependent on intact cognitive function. Thus, it is highly likely that improvement in CIBD will have valuable clinical benefit, especially with regard to quality of life measures. It is reasonable to predict that treatments effective to improve CIBD could also be beneficial for CIAS. Efficacy for cognitive impairment is likely to be greater in BPD than schizophrenia, because the baseline severity is milder in the former. Despite this strong rationale for targeting CIBD, there has been minimal focus on clinical trials to improve CIBD, perhaps because so many resources have been devoted to the effort to treat CIAS, but lack of appreciation of the severity of CIBD and its importance as a determinant of functional outcome in BPD may be the most important factors. In a recent study of CIBD, using the MATRICS Consensus Cognitive Battery (MCCB), impairment was found in both treatment resistant BP I and II depressed inpatients within all MCCB domains. The greatest impairment was evident in speed of processing, declarative memory and attention. The impairment was numerically greater in BP I than BP II patients but the difference was not significant. Compared to normal controls, the deficits, in BP 1 patients, in speed of processing was 1.2SD, in attention, 1.0 SD, and in verbal learning, 1.8 SD. The least affected domain was visual learning, with a mean deficit of 0.8SD compared to normal controls. The mean composite score deficit was 1.25 SD. Medication for BPD, particularly mood stabilizers, may adversely affect some domains of cognition in BPD. However, antidepressant medications have not been found to affect the severity of cognitive impairment in major depression or BPD. Based on the pre-clinical, pro-cognitive effects of 5-HT7 antagonism in our laboratory, along with the reported pre-clinical antidepressant effects of JNJ-18038683, we propose to conduct a randomized, placebo- controlled parallel, design study to assess the effects of JNJ-18038683 on multiple domains of cognition and mood symptoms. Since our preclinical studies show that 5-HT7 receptor blockade is highly effective in improving declarative memory in rodents, the declarative memory measures will be the primary outcome measures. Due to the effect of JNJ-18038683 on depressive symptoms in preclinical paradigms, we will investigate the following in the clinical trial the potential antidepressant effect of JNJ-18038683 on patients with baseline MADRS score between 8 and 20.
Interventions
DRUGJNJ-18038683
JNJ-18038683 10-20 mg/day tablet for 8 weeks
DRUGPlacebo
placebo tablet daily
Sponsors
Janssen Research & Development, LLC
Herbert Meltzer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
1. All participants must have signed an informed consent document indicating they understand the purpose of the study and the procedures required for the study and are willing to participate by complying with the study procedures and restrictions. 2. Male or female individuals of any race; between 18 to 60 years of age, inclusive. 3. Resides in a stable living situation, according to the investigator's judgment. 4. Diagnosis of bipolar disorder I or II for at least 1 year in duration, as established by the SCID-I, and verified with medical records and/or confirmation of diagnosis by treating clinician. Patients will be in a nonacute phase at the time of initial screening and have been so for at least 1 month. 5. No more than moderate clinical symptom burden severity, as defined by the following: Montgomery Asberg Depression Rating Scale \< 20 Young Mania Rating Scale \<12 6. Individuals medically stable enough to complete an 8 week clinical trial, in the judgment of the investigator 7. Women of childbearing potential must have a negative pregnancy serum test at screening, negative pregnancy urine test at baseline, and agree to use adequate protection (i.e. double barrier method) for birth control. 8. Antidepressant (AD) medications are allowed if the subject has been treated with a stable dose for at least 2 months before screening. 9. Individuals receiving a single mood stabilizer (e.g., lithium. valproate, or lamictal) are allowed if a stable dose has been maintained for at least 2 months prior to screening. 10. Individuals may be receiving one treatment of each the following groups: antidepressants, mood stabilizers, and atypical antipsychotics other than clozapine, but not more than one from each group. 11. Individuals taking ripseridone, lurasidone, or ziprasidone must be currently taking \< doses of 3mg, 40mg, and, 80mg, respectively. 12. Subjects may be treated with inclusionary antipsychotic drugs as long as they are on a stable dose of injectable medication for 2 months or a sable dose of an oral medication for 1 month. Exclusionary antipsychotic drugs are listed in Appendix 2 in the protocol. 13. Patients with a history of compliance with a drug treatment regimen for bipolar disorder, as noted in medical/psychiatric history. 14. CNS stimulants (e.g., Adderall, Ritalin) are permitted if the participant is stable on their dosage of medication for 1 month before screening and cannot change dosage throughout the study. 15. Able to complete cognition assessments in English 16. Individuals must demonstrate a substantive cognitive deficit, as measured by the Trails A, Hopkins Verbal Learning Test (HVLT), and the Letter Number Span, administered at the screening visit. Eligible individuals will have an established cognitive deficit as measured by one or more of these tests, scoring below the 75th percentile, using comparative norms according to age, gender, and education. 17. Able to understand and complete cognition assessments
Exclusion criteria
1. Failure to perform screening or baseline examinations 2. Hospitalization within 8 weeks before screening, or change in mood stabilizing or antidepressant medication or dose within 2 months prior to screening. 3. Individuals who have participated in another clinical study within the past 2 months. 4. Individuals with tardive dyskinesia. 5. Individuals with other DSM-V Axis I or Axis II primary diagnoses. 6. Diagnosis of alcohol or substance use disorder within the past 3 months. 7. Subject assessed to be at significant suicide risk based on responses to the Columbia Suicide Severity Rating Scale (C-SSRS). 8. History of myocardial infarction, unstable angina, uncontrolled hypotension or hypertension within 3 months before screening. 9. Clinically significant abnormality on screening ECG. 10. Alanine transaminase (ALT) or aspartate transaminase (AST) \> 2.5 times the upper limit of normal (ULN). 11. History of stroke, brain tumor, head trauma with loss of consciousness, or other clinically significant neurological condition within 12 months before screening. 12. Individuals with other uncontrolled medical conditions, in the opinion of the investigator. 13. Use of drugs known to be metabolized by CYP2D6.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The 8-week Evaluation of Verbal Fluency Performance After Randomization | Baseline and week 8 | Change in a score of Verbal Fluency from baseline to week 8 A higher amount of change represents a better outcome V.F., as a primary outcome measure, is one of the Cognitive battery tests used to evaluate neurocognitive functions, i.e., speed of processing, attention/vigilance, working memory, verbal learning, and visual learning. The way to calculate the score: the participant is asked to produce as many words as possible from a category in a given time and each correct word gets 1 score Min raw score:0 Max raw score:60 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Montgomery-Asberg Depression Rating Scale | Baseline to week 8 | Secondary outcome measures will include mean changes of the Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline to week 8. The MADRS will be utilized to assess a subject's level of depressive symptoms and must be administered using a structured interview guide. This scale consists of 10 items, each with seven defined grades of severity (zero to six), and min score of 0, and a max score of 60. Higher values represent a worse outcome. Notably, mean changes were not statistically significant in both groups. |
| Clinical Global Impression Severity of the Subject With Bipolar Disorder Scale( CGI-S in BP) Change From Baseline to Week 8 | Baseline to 8 weeks | We assessed the clinical global Impression severity (CGI-S) scores change in JNJ-18038683 and the placebo group as an additional endpoint. The scale rates the subject's Severity of Illness (CGI-BPSeverity: mania, depression, and overall bipolar illness). Using ANCOVA analysis to assess changes from baseline to week 8, based on the least-square means and standard errors was the method. CGI-S scores range from 0 to 7. Higher scores mean a worse outcome. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| JNJ-18038683 Subjects will be randomized to receive JNJ-18038683 or placebo after the completion of the baseline assessments. Subjects randomized to JNJ-18038683 will receive 10 mg for one week, then titrate to 20 mg for the duration of the trial, with the provision for a single, downward dose adjustment for intolerance, based upon investigator judgment.
JNJ-18038683: JNJ-18038683 10-20 mg/day for 8 weeks | 30 |
| Placebo Placebo treatment for 8 weeks.
JNJ-18038683: JNJ-18038683 10-20 mg/day for 8 weeks | 30 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 2 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | JNJ-18038683 | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants | 30 Participants | 60 Participants |
| Age, Continuous | 39.1 years STANDARD_DEVIATION 12.1 | 37.4 years STANDARD_DEVIATION 11 | 38.2 years STANDARD_DEVIATION 11.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 10 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 22 Participants | 19 Participants | 41 Participants |
| Region of Enrollment United States | 30 participants | 30 participants | 60 participants |
| Sex: Female, Male Female | 22 Participants | 16 Participants | 38 Participants |
| Sex: Female, Male Male | 8 Participants | 14 Participants | 22 Participants |
| Verbal Fluency | 35.87 units on a scale STANDARD_DEVIATION 2.12 | 40.07 units on a scale STANDARD_DEVIATION 2.16 | 38.82 units on a scale STANDARD_DEVIATION 2.14 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 30 |
| other Total, other adverse events | 6 / 30 | 6 / 30 |
| serious Total, serious adverse events | 3 / 30 | 1 / 30 |
Outcome results
Primary
The 8-week Evaluation of Verbal Fluency Performance After Randomization
Change in a score of Verbal Fluency from baseline to week 8 A higher amount of change represents a better outcome V.F., as a primary outcome measure, is one of the Cognitive battery tests used to evaluate neurocognitive functions, i.e., speed of processing, attention/vigilance, working memory, verbal learning, and visual learning. The way to calculate the score: the participant is asked to produce as many words as possible from a category in a given time and each correct word gets 1 score Min raw score:0 Max raw score:60
Time frame: Baseline and week 8
Population: Although the total number of participants in each group was 30, the analysis was only done for those who had completed all study visits.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| JNJ-18038683 | The 8-week Evaluation of Verbal Fluency Performance After Randomization | 39.44 score on a scale | Standard Error 1.31 |
| Placebo | The 8-week Evaluation of Verbal Fluency Performance After Randomization | 41.12 score on a scale | Standard Error 1.33 |
p-value: <0.05ANCOVA
Secondary
Clinical Global Impression Severity of the Subject With Bipolar Disorder Scale( CGI-S in BP) Change From Baseline to Week 8
We assessed the clinical global Impression severity (CGI-S) scores change in JNJ-18038683 and the placebo group as an additional endpoint. The scale rates the subject's Severity of Illness (CGI-BPSeverity: mania, depression, and overall bipolar illness). Using ANCOVA analysis to assess changes from baseline to week 8, based on the least-square means and standard errors was the method. CGI-S scores range from 0 to 7. Higher scores mean a worse outcome.
Time frame: Baseline to 8 weeks
Population: Although the total number of participants in each group was 30, the analysis was only done for those who had completed all study visits. Using ANCOVA analysis to assess changes from baseline to week 8, based on the least-square means and standard errors was the method.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| JNJ-18038683 | Clinical Global Impression Severity of the Subject With Bipolar Disorder Scale( CGI-S in BP) Change From Baseline to Week 8 | CGI-S baseline score | 2.78 score on a scale | Standard Error 0.19 |
| JNJ-18038683 | Clinical Global Impression Severity of the Subject With Bipolar Disorder Scale( CGI-S in BP) Change From Baseline to Week 8 | CGI-S week 8 score | 2.59 score on a scale | Standard Error 0.19 |
| Placebo | Clinical Global Impression Severity of the Subject With Bipolar Disorder Scale( CGI-S in BP) Change From Baseline to Week 8 | CGI-S week 8 score | 2.37 score on a scale | Standard Error 0.19 |
| Placebo | Clinical Global Impression Severity of the Subject With Bipolar Disorder Scale( CGI-S in BP) Change From Baseline to Week 8 | CGI-S baseline score | 2.63 score on a scale | Standard Error 0.19 |
Secondary
Montgomery-Asberg Depression Rating Scale
Secondary outcome measures will include mean changes of the Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline to week 8. The MADRS will be utilized to assess a subject's level of depressive symptoms and must be administered using a structured interview guide. This scale consists of 10 items, each with seven defined grades of severity (zero to six), and min score of 0, and a max score of 60. Higher values represent a worse outcome. Notably, mean changes were not statistically significant in both groups.
Time frame: Baseline to week 8
Population: Although the total number of each group was 30, only data of the participants who completed week eight were analyzed on MADRS.~ANCOVA analysis for comparing the result of the Montgomery Asberg Depression rating scale between JNJ-18038683 and the placebo group, based on the least-square means and standard errors, will be the statistical method. The Missing data will be imputed by MMRM.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| JNJ-18038683 | Montgomery-Asberg Depression Rating Scale | MADRS baseline score | 2.93 score on a scale | Standard Error 0.71 |
| JNJ-18038683 | Montgomery-Asberg Depression Rating Scale | MADRS week 8 score | 6.63 score on a scale | Standard Error 1.26 |
| Placebo | Montgomery-Asberg Depression Rating Scale | MADRS baseline score | 3.37 score on a scale | Standard Error 0.71 |
| Placebo | Montgomery-Asberg Depression Rating Scale | MADRS week 8 score | 5.89 score on a scale | Standard Error 1.26 |