Cognitive Impairment Associated With Schizophrenia
Conditions
Brief summary
The primary objective of the study is to evaluate the efficacy of BIIB104 in participants with CIAS, using the Working Memory Domain of the MATRICS Consensus Cognitive Battery (MCCB). The secondary objectives of this study are to evaluate the safety and tolerability of BIIB104 in participants with CIAS, and to evaluate the efficacy of BIIB104 in participants with CIAS on measures of cognition, functioning, and psychiatric symptomology.
Interventions
DRUGBIIB104
Administered as specified in the treatment arm
OTHERPlacebo
Administered as specified in the treatment arm
Sponsors
Biogen
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 55 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Otherwise healthy participant with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), diagnosis of schizophrenia of at least 2 years' duration as confirmed by the mini-international neuropsychiatric interview (MINI) 7.0.2 for Psychotic Disorders. * Evidence of stable schizophrenia symptomatology ≥12 weeks (e.g., no hospitalizations for schizophrenia, no increase in level of psychiatric care due to worsening of schizophrenia symptoms). * Participants must be in ongoing maintenance atypical antipsychotic therapy (except clozapine), on a stable treatment regimen for ≥8 weeks prior to Baseline/Day 1, including concomitant psychotropic medication. Doses of background atypical antipsychotics should be within the recommended dose range listed in the approved product labeling of the country where the study is being conducted. * SCI-PANSS: No more than moderate-severe rating (score ≤5) on delusions, hallucinatory behavior, grandiosity, suspiciousness / persecution, and hostility (i.e. PANSS, positive symptom items P1, P3, P5, P6, P7); or unusual thought content (G9); and no more than a moderate rating (score ≤4) on conceptual disorganization (P2). Key
Exclusion criteria
* Participation in a trial using any component or version of the MATRICS Consensus Cognitive Battery (MCCB) or the University of California, San Diego (UCSD) Performance-Based Skills Assessment test within the previous 6 months. * Participation in cognitive remediation therapy within 6 months prior to randomization. * Screening MCCB Working Memory Domain T-score ≥60. * Current DSM-5 diagnosis of schizoaffective disorder on the MINI 7.0.2 for Psychotic Disorders. * Current DSM-5 diagnosis of major depressive episode, manic and hypomanic episode, panic disorder, agoraphobia, social anxiety disorder, obsessive-compulsive disorder, posttraumatic stress disorder, and/or generalized anxiety disorder on the MINI 7.0.2 for Psychotic Disorders. * Lifetime DSM-5 diagnosis of antisocial personality disorder, anorexia nervosa, bulimia nervosa, and/or binge-eating disorder on the MINI 7.0.2 for Psychotic Disorders. * Meets the DSM-5 diagnosis of moderate or severe substance use disorder (excluding nicotine dependence) within 12 months of screening on the MINI 7.0.2 for Psychotic Disorders interview. * DSM-5 diagnosis of Intellectual Disability (intellectual developmental disorder). NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Change From Baseline in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) Working Memory Domain Score at Week 12 | Baseline and Week 12 | The MCCB is a cognitive battery that assesses 7 domains recommended by the MATRICS initiative (i.e., Working Memory, Verbal Learning, Speed of Processing, Attention/Vigilance, Visual Learning, Social Cognition, and Reasoning and Problem Solving). MCCB was administered via laptop computer and paper-and-pencil assessments. T-scores for the individual tests were calculated according to the developer's recommended scoring algorithms. MCCB composite T scores are between 40 and 60 (normal range). Higher scores indicate better cognitive functioning. The working memory domain score of the MCCB is reported in this outcome measure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Total Score Assessed by Scale for the Assessment and Rating of Ataxia (SARA) | Baseline, Weeks 2, 6, 12 and safety follow-up (Week 14) | The SARA is a clinical scale that is based on a semiquantitative assessment of cerebellar ataxia on an impairment level and complements the brief neurological examination. The SARA scale is an eight-item clinical rating scale (gait, stance, sitting, speech, finger-chase test, nose-finger test, fast alternating movements, and heel-shin test) with a total score range of 0-40, where 0 is the best neurological status and 40 is the worst neurological status. |
| Number of Participants With at Least One Event of Suicidal Ideation and/or Suicidal Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score | Up to Week 14 | The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and suicidal behavior. Suicidal ideation is classified on a 5-item scale: 1 (wish to be dead), 2 (nonspecific active suicidal thoughts), 3 (active suicidal ideation with any methods \[not plan\] without intent to act), 4 (active suicidal ideation with some intent to act, without specific plan), and 5 (active suicidal ideation with specific plan and intent). Suicidal behavior is classified on a 6-item scale: 1 (actual attempt), 2 (interrupted attempt), 3 (aborted attempt), 4 (preparatory acts or behavior), 5 (suicidal behavior), and 6 (suicide). The data analyzed signifies the participants with at least one event of suicidal ideation and/or suicidal behavior. |
| Change From Baseline in University of California, San Diego Performance Based Skills Assessment-Brief International Version (UPSA-Bi) Assessment at Week 12 | Baseline and Week 12 | The UPSA-Bi, international version, an abbreviated version of the UPSA-Validation of Intermediate Measures, is a measure of functional capacity and assesses skills used in community tasks. This assessment measures 2 general skills that were previously identified as essential to functioning in the community: financial skills and communication skills. The UPSA-Bi assessment is scored from 0-100, higher scores indicating higher functional status. |
| Change From Baseline in Schizophrenia Cognition Rating Scale (SCoRS) Assessment Score at Week 12 | Baseline and Week 12 | The SCoRS is an interview-based assessment of cognition that involves interviews with participants and informants. The SCoRS includes 20 items designed to specifically assess aspects of cognitive functioning found in each of the seven MCCB cognitive domains including the following: Memory: 4 items; Learning: 2 items; Attention: 3 items; Working memory: 2 items; Problem solving: 3 items; Processing/motor speed: 2 items; Social cognition: 3 items; Language: 1 item. Total score range is 20-80, lower scores indicating higher functional status. The data reported in this outcome measure are for global rating score. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From first dose of study drug through end of the study (up to Week 14) | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that at any dose results in death, places the participant at immediate risk of death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or is a medically important event. |
| Change From Baseline in MCCB Individual Domain Scores (Excluding Working Memory Domain) at Week 12 | Baseline and Week 12 | The MCCB is a cognitive battery that assesses 7 domains recommended by the MATRICS initiative (i.e., working memory, verbal learning, speed of processing, attention/vigilance, visual learning, social cognition, and reasoning and problem solving). MCCB was administered via laptop computer and paper-and-pencil assessments. T-scores for the individual tests were calculated according to the developer's recommended scoring algorithms. MCCB composite T scores are between 40 and 60 (normal range). Higher scores indicate better cognitive functioning. All the domain scores of the MCCB are reported in this outcome measure with the exception of working memory domain. |
| Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score, Positive Subscale, and Negative Subscale Scores at Week 12 | Baseline and Week 12 | The PANSS includes 3 subscales and 30 items: 7 items that make up the Positive subscale (e.g., delusions, conceptual disorganization, hallucinatory behaviour); 7 items that make up the Negative subscale (e.g., blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal); and 16 items that make up the General Psychopathology subscale (e.g., somatic concern, anxiety, guilt feelings, mannerisms and posturing, motor retardation, uncooperativeness, disorientation, poor impulse control, preoccupation). Each item on the positive, negative and general psychopathology subscale is rated from 1 (absent) to 7 (extreme). The score range is 7-49 for positive and negative subscales, score range is 16-112 for the general psychopathology subscale. Total PANSS score (positive+ negative + general psychopathology subscale scores) range from 30 to 210. Higher scores represent more severity in symptoms. |
| Change From Baseline in Clinical Global Impression-Severity (CGI-S) Scores at Week 12 | Baseline and Week 12 | The CGI-S consists of a single 7-point rating score of illness severity. The following question: Considering your total clinical experience with this particular population, how mentally ill is your participant at this time? is rated with a score from 1 to 7- 1: Normal, not ill at all; 2: Borderline mentally ill; 3: Mildly ill; 4: Moderately ill; 5: Markedly ill; 6: Severely ill; or 7: Among the most severely ill participants. Lower scores indicate less severity of illness. |
| Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12 | Week 12 | The CGI-I consists of a single 7-point rating score total improvement, regardless of whether or not the change is due entirely to drug treatment. The following question: Compared to your participant's condition at the beginning of treatment, how much has your participant changed? is rated with a score from 1 to 7- 1: Very much improved; 2: Much improved; 3: Minimally improved; 4: No change; 5: Minimally worse; 6: Much worse; or 7: Very much worse. Lower scores indicate greater improvement. |
| Change From Baseline in MCCB Neurocognitive Composite Scores at Week 12 | Baseline and Week 12 | The MCCB is a cognitive battery that assesses 7 domains recommended by the MATRICS initiative (i.e., Working Memory, Verbal Learning, Speed of Processing, Attention/Vigilance, Visual Learning, Social Cognition, and Reasoning and Problem Solving). MCCB was administered via laptop computer and paper-and-pencil assessments. T-scores for the individual tests were calculated according to the developer's recommended scoring algorithms. MCCB composite T scores are between 40 and 60 (normal range). Higher scores indicate better cognitive functioning. The MCCB composite score contains all of the tests and domains of the MCCB. |
Countries
Germany, Japan, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 53 investigative sites in the United States, Japan, Spain, Germany, and the United Kingdom from 15 Nov 2018 to 07 April 2022.
Pre-assignment details
A total of 554 participants were screened out of which, 195 participants were randomized and dosed to receive BIIB104 or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received BIIB104 matching placebo capsules, BID, orally for 12 weeks. | 64 |
| BIIB104 0.15 mg Participants received 0.15 mg capsules of BIIB104, BID, orally for 12 weeks. | 66 |
| BIIB104 0.5 mg Participants received 0.5 mg capsules of BIIB104, BID, orally for 12 weeks. | 65 |
| Total | 195 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 3 | 2 |
| Overall Study | Lost to Follow-up | 2 | 0 | 3 |
| Overall Study | Non-Compliance with Study Drug | 4 | 3 | 0 |
| Overall Study | Physician decision unrelated to safety/efficacy | 0 | 0 | 4 |
| Overall Study | Reason not Specified | 2 | 4 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 4 | 4 |
Baseline characteristics
| Characteristic | Total | BIIB104 0.5 mg | BIIB104 0.15 mg | Placebo |
|---|---|---|---|---|
| Age, Continuous | 39.8 years STANDARD_DEVIATION 9.58 | 41.3 years STANDARD_DEVIATION 9.63 | 37.7 years STANDARD_DEVIATION 9.41 | 40.6 years STANDARD_DEVIATION 9.47 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 25 Participants | 6 Participants | 9 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 141 Participants | 49 Participants | 47 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 29 Participants | 10 Participants | 10 Participants | 9 Participants |
| MATRICS Consensus Cognitive Battery (MCCB) Working Memory Domain Score | 39.3 score on a scale | 39.8 score on a scale | 38.5 score on a scale | 39.6 score on a scale |
| Race/Ethnicity, Customized Asian | 31 Participants | 13 Participants | 8 Participants | 10 Participants |
| Race/Ethnicity, Customized Black or African American | 82 Participants | 26 Participants | 27 Participants | 29 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown | 29 Participants | 10 Participants | 10 Participants | 9 Participants |
| Race/Ethnicity, Customized White | 49 Participants | 15 Participants | 19 Participants | 15 Participants |
| Sex: Female, Male Female | 59 Participants | 18 Participants | 21 Participants | 20 Participants |
| Sex: Female, Male Male | 136 Participants | 47 Participants | 45 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 63 | 0 / 66 | 0 / 66 |
| other Total, other adverse events | 2 / 63 | 2 / 66 | 8 / 66 |
| serious Total, serious adverse events | 1 / 63 | 1 / 66 | 2 / 66 |
Outcome results
Primary
Change From Baseline in Change From Baseline in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) Working Memory Domain Score at Week 12
The MCCB is a cognitive battery that assesses 7 domains recommended by the MATRICS initiative (i.e., Working Memory, Verbal Learning, Speed of Processing, Attention/Vigilance, Visual Learning, Social Cognition, and Reasoning and Problem Solving). MCCB was administered via laptop computer and paper-and-pencil assessments. T-scores for the individual tests were calculated according to the developer's recommended scoring algorithms. MCCB composite T scores are between 40 and 60 (normal range). Higher scores indicate better cognitive functioning. The working memory domain score of the MCCB is reported in this outcome measure.
Time frame: Baseline and Week 12
Population: ITT population included all randomized participants who received at least one dose of study treatment (BIIB104 or placebo). Here, Overall Number of Participants Analyzed signifies the number of participants analyzed in this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Change From Baseline in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) Working Memory Domain Score at Week 12 | 1.17 score on a scale | Standard Error 0.939 |
| BIIB104 0.15 mg | Change From Baseline in Change From Baseline in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) Working Memory Domain Score at Week 12 | 0.91 score on a scale | Standard Error 0.936 |
| BIIB104 0.5 mg | Change From Baseline in Change From Baseline in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) Working Memory Domain Score at Week 12 | 0.84 score on a scale | Standard Error 0.934 |
Comparison: Mixed Model Repeated Measures(MMRM)model was used to analyze change from baseline of outcome measure(OM)using fixed effects of treatment group,region,study visit,study visit-by-treatment interaction,baseline value of OM,baseline-by-visit interaction.p-value: =0.847295% CI: [-2.88, 2.37]MMRM
Comparison: A MMRM model was used to analyze the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.p-value: =0.805395% CI: [-2.94, 2.29]MMRM
Secondary
Change From Baseline in Clinical Global Impression-Severity (CGI-S) Scores at Week 12
The CGI-S consists of a single 7-point rating score of illness severity. The following question: Considering your total clinical experience with this particular population, how mentally ill is your participant at this time? is rated with a score from 1 to 7- 1: Normal, not ill at all; 2: Borderline mentally ill; 3: Mildly ill; 4: Moderately ill; 5: Markedly ill; 6: Severely ill; or 7: Among the most severely ill participants. Lower scores indicate less severity of illness.
Time frame: Baseline and Week 12
Population: ITT population included all randomized participants who received at least one dose of study treatment (BIIB104 or placebo). Here, Overall Number of Participants Analyzed signifies the number of participants analyzed in this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Clinical Global Impression-Severity (CGI-S) Scores at Week 12 | -0.19 score on a scale | Standard Error 0.091 |
| BIIB104 0.15 mg | Change From Baseline in Clinical Global Impression-Severity (CGI-S) Scores at Week 12 | -0.16 score on a scale | Standard Error 0.091 |
| BIIB104 0.5 mg | Change From Baseline in Clinical Global Impression-Severity (CGI-S) Scores at Week 12 | -0.19 score on a scale | Standard Error 0.091 |
Comparison: A MMRM model was used to analyze the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.p-value: =0.851795% CI: [-0.23, 0.28]MMRM
Comparison: A MMRM model was used to analyze the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.p-value: =0.995295% CI: [-0.25, 0.25]MMRM
Secondary
Change From Baseline in MCCB Individual Domain Scores (Excluding Working Memory Domain) at Week 12
The MCCB is a cognitive battery that assesses 7 domains recommended by the MATRICS initiative (i.e., working memory, verbal learning, speed of processing, attention/vigilance, visual learning, social cognition, and reasoning and problem solving). MCCB was administered via laptop computer and paper-and-pencil assessments. T-scores for the individual tests were calculated according to the developer's recommended scoring algorithms. MCCB composite T scores are between 40 and 60 (normal range). Higher scores indicate better cognitive functioning. All the domain scores of the MCCB are reported in this outcome measure with the exception of working memory domain.
Time frame: Baseline and Week 12
Population: ITT population included all randomized participants who received at least one dose of study treatment (BIIB104 or placebo). Here, Overall Number of Participants Analyzed signifies the number of participants analyzed in this outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in MCCB Individual Domain Scores (Excluding Working Memory Domain) at Week 12 | Verbal Learning: Change at Week 12 | 0.95 score on a scale | Standard Error 0.951 |
| Placebo | Change From Baseline in MCCB Individual Domain Scores (Excluding Working Memory Domain) at Week 12 | Speed of Processing: Change at Week 12 | 4.42 score on a scale | Standard Error 0.824 |
| Placebo | Change From Baseline in MCCB Individual Domain Scores (Excluding Working Memory Domain) at Week 12 | Attention/Vigilance: Change at Week 12 | 0.62 score on a scale | Standard Error 0.852 |
| Placebo | Change From Baseline in MCCB Individual Domain Scores (Excluding Working Memory Domain) at Week 12 | Social Cognition: Change at Week 12 | -0.13 score on a scale | Standard Error 0.959 |
| Placebo | Change From Baseline in MCCB Individual Domain Scores (Excluding Working Memory Domain) at Week 12 | Reasoning and Problem Solving: Change at Week 12 | 2.81 score on a scale | Standard Error 1.019 |
| Placebo | Change From Baseline in MCCB Individual Domain Scores (Excluding Working Memory Domain) at Week 12 | Visual Learning: Change at Week 12 | 1.70 score on a scale | Standard Error 1.131 |
| BIIB104 0.15 mg | Change From Baseline in MCCB Individual Domain Scores (Excluding Working Memory Domain) at Week 12 | Attention/Vigilance: Change at Week 12 | 0.53 score on a scale | Standard Error 0.848 |
| BIIB104 0.15 mg | Change From Baseline in MCCB Individual Domain Scores (Excluding Working Memory Domain) at Week 12 | Verbal Learning: Change at Week 12 | 1.41 score on a scale | Standard Error 0.946 |
| BIIB104 0.15 mg | Change From Baseline in MCCB Individual Domain Scores (Excluding Working Memory Domain) at Week 12 | Social Cognition: Change at Week 12 | 1.06 score on a scale | Standard Error 0.953 |
| BIIB104 0.15 mg | Change From Baseline in MCCB Individual Domain Scores (Excluding Working Memory Domain) at Week 12 | Reasoning and Problem Solving: Change at Week 12 | 2.10 score on a scale | Standard Error 1.1014 |
| BIIB104 0.15 mg | Change From Baseline in MCCB Individual Domain Scores (Excluding Working Memory Domain) at Week 12 | Speed of Processing: Change at Week 12 | 2.28 score on a scale | Standard Error 0.819 |
| BIIB104 0.15 mg | Change From Baseline in MCCB Individual Domain Scores (Excluding Working Memory Domain) at Week 12 | Visual Learning: Change at Week 12 | 0.19 score on a scale | Standard Error 1.125 |
| BIIB104 0.5 mg | Change From Baseline in MCCB Individual Domain Scores (Excluding Working Memory Domain) at Week 12 | Speed of Processing: Change at Week 12 | 3.99 score on a scale | Standard Error 0.817 |
| BIIB104 0.5 mg | Change From Baseline in MCCB Individual Domain Scores (Excluding Working Memory Domain) at Week 12 | Attention/Vigilance: Change at Week 12 | 1.55 score on a scale | Standard Error 0.848 |
| BIIB104 0.5 mg | Change From Baseline in MCCB Individual Domain Scores (Excluding Working Memory Domain) at Week 12 | Social Cognition: Change at Week 12 | 0.95 score on a scale | Standard Error 0.955 |
| BIIB104 0.5 mg | Change From Baseline in MCCB Individual Domain Scores (Excluding Working Memory Domain) at Week 12 | Visual Learning: Change at Week 12 | 1.77 score on a scale | Standard Error 1.125 |
| BIIB104 0.5 mg | Change From Baseline in MCCB Individual Domain Scores (Excluding Working Memory Domain) at Week 12 | Verbal Learning: Change at Week 12 | 0.41 score on a scale | Standard Error 0.95 |
| BIIB104 0.5 mg | Change From Baseline in MCCB Individual Domain Scores (Excluding Working Memory Domain) at Week 12 | Reasoning and Problem Solving: Change at Week 12 | 4.40 score on a scale | Standard Error 1.011 |
Comparison: Verbal Learning: Change From Baseline at Week 12p-value: =0.737295% CI: [-2.21, 3.11]MMRM
Comparison: Verbal Learning: Change From Baseline at Week 12p-value: =0.689495% CI: [-3.2, 2.12]MMRM
Comparison: Speed of Processing: Change From Baseline at Week 12p-value: =0.067495% CI: [-4.44, 0.16]MMRM
Comparison: Speed of Processing: Change From Baseline at Week 12p-value: =0.713295% CI: [-2.72, 1.87]MMRM
Comparison: Attention/Vigilance: Change From Baseline at Week 12p-value: =0.942895% CI: [-2.46, 2.29]MMRM
Comparison: Attention/Vigilance: Change From Baseline at Week 12p-value: =0.442595% CI: [-1.45, 3.3]MMRM
Comparison: Visual Learning: Change From Baseline at Week 12p-value: =0.345595% CI: [-4.66, 1.64]MMRM
Comparison: Visual Learning: Change From Baseline at Week 12p-value: =0.968695% CI: [-3.09, 3.21]MMRM
Comparison: Social Cognition: Change From Baseline at Week 12p-value: =0.383295% CI: [-1.49, 3.85]MMRM
Comparison: Social Cognition: Change From Baseline at Week 12p-value: =0.429795% CI: [-1.61, 3.75]MMRM
Comparison: Reasoning and Problem Solving: Change From Baseline at Week 12p-value: =0.624595% CI: [-3.55, 2.14]MMRM
Comparison: Reasoning and Problem Solving: Change From Baseline at Week 12p-value: =0.269895% CI: [-1.25, 4.43]MMRM
Secondary
Change From Baseline in MCCB Neurocognitive Composite Scores at Week 12
The MCCB is a cognitive battery that assesses 7 domains recommended by the MATRICS initiative (i.e., Working Memory, Verbal Learning, Speed of Processing, Attention/Vigilance, Visual Learning, Social Cognition, and Reasoning and Problem Solving). MCCB was administered via laptop computer and paper-and-pencil assessments. T-scores for the individual tests were calculated according to the developer's recommended scoring algorithms. MCCB composite T scores are between 40 and 60 (normal range). Higher scores indicate better cognitive functioning. The MCCB composite score contains all of the tests and domains of the MCCB.
Time frame: Baseline and Week 12
Population: ITT population included all randomized participants who received at least one dose of study treatment (BIIB104 or placebo). Here, Overall Number of Participants Analyzed signifies the number of participants analyzed in this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in MCCB Neurocognitive Composite Scores at Week 12 | 2.90 score on a scale | Standard Error 0.733 |
| BIIB104 0.15 mg | Change From Baseline in MCCB Neurocognitive Composite Scores at Week 12 | 1.80 score on a scale | Standard Error 0.728 |
| BIIB104 0.5 mg | Change From Baseline in MCCB Neurocognitive Composite Scores at Week 12 | 3.39 score on a scale | Standard Error 0.727 |
Comparison: A MMRM model was used to analyze the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.p-value: =0.288695% CI: [-3.14, 0.94]MMRM
Comparison: A MMRM model was used to analyze the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.p-value: =0.634995% CI: [-1.55, 2.53]MMRM
Secondary
Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score, Positive Subscale, and Negative Subscale Scores at Week 12
The PANSS includes 3 subscales and 30 items: 7 items that make up the Positive subscale (e.g., delusions, conceptual disorganization, hallucinatory behaviour); 7 items that make up the Negative subscale (e.g., blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal); and 16 items that make up the General Psychopathology subscale (e.g., somatic concern, anxiety, guilt feelings, mannerisms and posturing, motor retardation, uncooperativeness, disorientation, poor impulse control, preoccupation). Each item on the positive, negative and general psychopathology subscale is rated from 1 (absent) to 7 (extreme). The score range is 7-49 for positive and negative subscales, score range is 16-112 for the general psychopathology subscale. Total PANSS score (positive+ negative + general psychopathology subscale scores) range from 30 to 210. Higher scores represent more severity in symptoms.
Time frame: Baseline and Week 12
Population: ITT population included all randomized participants who received at least one dose of study treatment (BIIB104 or placebo). Here, Overall Number of Participants Analyzed signifies the number of participants analyzed in this outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score, Positive Subscale, and Negative Subscale Scores at Week 12 | Positive Symptoms Subscale: Change From Baseline at Week 12 | -0.65 score on a scale | Standard Error 0.431 |
| Placebo | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score, Positive Subscale, and Negative Subscale Scores at Week 12 | Negative Symptoms Subscale: Change From Baseline at Week 12 | -0.90 score on a scale | Standard Error 0.461 |
| Placebo | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score, Positive Subscale, and Negative Subscale Scores at Week 12 | Total Score: Change From Baseline at Week 12 | -3.06 score on a scale | Standard Error 1.429 |
| BIIB104 0.15 mg | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score, Positive Subscale, and Negative Subscale Scores at Week 12 | Total Score: Change From Baseline at Week 12 | -4.26 score on a scale | Standard Error 1.421 |
| BIIB104 0.15 mg | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score, Positive Subscale, and Negative Subscale Scores at Week 12 | Negative Symptoms Subscale: Change From Baseline at Week 12 | -0.98 score on a scale | Standard Error 0.461 |
| BIIB104 0.15 mg | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score, Positive Subscale, and Negative Subscale Scores at Week 12 | Positive Symptoms Subscale: Change From Baseline at Week 12 | -1.09 score on a scale | Standard Error 0.43 |
| BIIB104 0.5 mg | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score, Positive Subscale, and Negative Subscale Scores at Week 12 | Total Score: Change From Baseline at Week 12 | -5.03 score on a scale | Standard Error 1.427 |
| BIIB104 0.5 mg | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score, Positive Subscale, and Negative Subscale Scores at Week 12 | Positive Symptoms Subscale: Change From Baseline at Week 12 | -0.98 score on a scale | Standard Error 0.429 |
| BIIB104 0.5 mg | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score, Positive Subscale, and Negative Subscale Scores at Week 12 | Negative Symptoms Subscale: Change From Baseline at Week 12 | -1.40 score on a scale | Standard Error 0.46 |
Comparison: Positive Symptoms Subscale: Change From Baseline at Week 12p-value: =0.465495% CI: [-1.65, 0.76]MMRM
Comparison: Positive Symptoms Subscale: Change From Baseline at Week 12p-value: =0.588695% CI: [-1.53, 0.87]MMRM
Comparison: Negative Symptoms Subscale: Change From Baseline at Week 12p-value: =0.907995% CI: [-1.37, 1.22]MMRM
Comparison: Negative Symptoms Subscale: Change From Baseline at Week 12p-value: =0.444195% CI: [-1.78, 0.79]MMRM
Comparison: Total Score: Change From Baseline at Week 12p-value: =0.553795% CI: [-5.18, 2.79]MMRM
Comparison: Total Score: Change From Baseline at Week 12p-value: =0.33295% CI: [-5.95, 2.02]MMRM
Secondary
Change From Baseline in Schizophrenia Cognition Rating Scale (SCoRS) Assessment Score at Week 12
The SCoRS is an interview-based assessment of cognition that involves interviews with participants and informants. The SCoRS includes 20 items designed to specifically assess aspects of cognitive functioning found in each of the seven MCCB cognitive domains including the following: Memory: 4 items; Learning: 2 items; Attention: 3 items; Working memory: 2 items; Problem solving: 3 items; Processing/motor speed: 2 items; Social cognition: 3 items; Language: 1 item. Total score range is 20-80, lower scores indicating higher functional status. The data reported in this outcome measure are for global rating score.
Time frame: Baseline and Week 12
Population: ITT population included all randomized participants who received at least one dose of study treatment (BIIB104 or placebo). Here, Overall Number of Participants Analyzed signifies the number of participants analyzed in this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Schizophrenia Cognition Rating Scale (SCoRS) Assessment Score at Week 12 | -0.51 score on a scale | Standard Error 0.146 |
| BIIB104 0.15 mg | Change From Baseline in Schizophrenia Cognition Rating Scale (SCoRS) Assessment Score at Week 12 | -0.42 score on a scale | Standard Error 0.148 |
| BIIB104 0.5 mg | Change From Baseline in Schizophrenia Cognition Rating Scale (SCoRS) Assessment Score at Week 12 | -0.41 score on a scale | Standard Error 0.145 |
Comparison: An ANCOVA model was applied adjusting for treatment group and baseline value of the OM.p-value: =0.665395% CI: [-0.32, 0.5]ANCOVA
Comparison: An ANCOVA model was applied adjusting for treatment group and baseline value of the OM.p-value: =0.61495% CI: [-0.3, 0.51]ANCOVA
Secondary
Change From Baseline in University of California, San Diego Performance Based Skills Assessment-Brief International Version (UPSA-Bi) Assessment at Week 12
The UPSA-Bi, international version, an abbreviated version of the UPSA-Validation of Intermediate Measures, is a measure of functional capacity and assesses skills used in community tasks. This assessment measures 2 general skills that were previously identified as essential to functioning in the community: financial skills and communication skills. The UPSA-Bi assessment is scored from 0-100, higher scores indicating higher functional status.
Time frame: Baseline and Week 12
Population: ITT population included all randomized participants who received at least one dose of study treatment (BIIB104 or placebo). Here, Overall Number of Participants Analyzed signifies the number of participants analyzed in this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in University of California, San Diego Performance Based Skills Assessment-Brief International Version (UPSA-Bi) Assessment at Week 12 | 2.07 score on a scale | Standard Error 1.303 |
| BIIB104 0.15 mg | Change From Baseline in University of California, San Diego Performance Based Skills Assessment-Brief International Version (UPSA-Bi) Assessment at Week 12 | 5.50 score on a scale | Standard Error 1.292 |
| BIIB104 0.5 mg | Change From Baseline in University of California, San Diego Performance Based Skills Assessment-Brief International Version (UPSA-Bi) Assessment at Week 12 | 5.49 score on a scale | Standard Error 1.305 |
Comparison: An analysis of covariance (ANCOVA) model was applied adjusting for treatment group and baseline value of the OM.p-value: =0.063795% CI: [-0.2, 7.06]ANCOVA
Comparison: An ANCOVA model was applied adjusting for treatment group and baseline value of the OM.p-value: =0.065995% CI: [-0.23, 7.06]ANCOVA
Secondary
Mean Total Score Assessed by Scale for the Assessment and Rating of Ataxia (SARA)
The SARA is a clinical scale that is based on a semiquantitative assessment of cerebellar ataxia on an impairment level and complements the brief neurological examination. The SARA scale is an eight-item clinical rating scale (gait, stance, sitting, speech, finger-chase test, nose-finger test, fast alternating movements, and heel-shin test) with a total score range of 0-40, where 0 is the best neurological status and 40 is the worst neurological status.
Time frame: Baseline, Weeks 2, 6, 12 and safety follow-up (Week 14)
Population: The safety population included all randomized participants who received at least 1 dose of study treatment (BIIB104 or placebo). Here, Overall number of participants analyzed signifies the number of participants analyzed in this outcome measure and number analyzed signifies the number of participants analyzed at specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Total Score Assessed by Scale for the Assessment and Rating of Ataxia (SARA) | Week 14 | 0.4 score on a scale | Standard Deviation 0.85 |
| Placebo | Mean Total Score Assessed by Scale for the Assessment and Rating of Ataxia (SARA) | Week 6 | 0.4 score on a scale | Standard Deviation 0.71 |
| Placebo | Mean Total Score Assessed by Scale for the Assessment and Rating of Ataxia (SARA) | Week 2 | 0.4 score on a scale | Standard Deviation 0.85 |
| Placebo | Mean Total Score Assessed by Scale for the Assessment and Rating of Ataxia (SARA) | Week 12 | 0.4 score on a scale | Standard Deviation 0.8 |
| Placebo | Mean Total Score Assessed by Scale for the Assessment and Rating of Ataxia (SARA) | Baseline | 0.5 score on a scale | Standard Deviation 1.03 |
| BIIB104 0.15 mg | Mean Total Score Assessed by Scale for the Assessment and Rating of Ataxia (SARA) | Week 14 | 0.3 score on a scale | Standard Deviation 0.91 |
| BIIB104 0.15 mg | Mean Total Score Assessed by Scale for the Assessment and Rating of Ataxia (SARA) | Baseline | 0.4 score on a scale | Standard Deviation 1.15 |
| BIIB104 0.15 mg | Mean Total Score Assessed by Scale for the Assessment and Rating of Ataxia (SARA) | Week 2 | 0.5 score on a scale | Standard Deviation 1.1 |
| BIIB104 0.15 mg | Mean Total Score Assessed by Scale for the Assessment and Rating of Ataxia (SARA) | Week 6 | 0.3 score on a scale | Standard Deviation 0.9 |
| BIIB104 0.15 mg | Mean Total Score Assessed by Scale for the Assessment and Rating of Ataxia (SARA) | Week 12 | 0.3 score on a scale | Standard Deviation 0.82 |
| BIIB104 0.5 mg | Mean Total Score Assessed by Scale for the Assessment and Rating of Ataxia (SARA) | Baseline | 0.3 score on a scale | Standard Deviation 0.92 |
| BIIB104 0.5 mg | Mean Total Score Assessed by Scale for the Assessment and Rating of Ataxia (SARA) | Week 12 | 0.2 score on a scale | Standard Deviation 0.72 |
| BIIB104 0.5 mg | Mean Total Score Assessed by Scale for the Assessment and Rating of Ataxia (SARA) | Week 14 | 0.2 score on a scale | Standard Deviation 0.69 |
| BIIB104 0.5 mg | Mean Total Score Assessed by Scale for the Assessment and Rating of Ataxia (SARA) | Week 2 | 0.3 score on a scale | Standard Deviation 0.68 |
| BIIB104 0.5 mg | Mean Total Score Assessed by Scale for the Assessment and Rating of Ataxia (SARA) | Week 6 | 0.2 score on a scale | Standard Deviation 0.58 |
Secondary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that at any dose results in death, places the participant at immediate risk of death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or is a medically important event.
Time frame: From first dose of study drug through end of the study (up to Week 14)
Population: The safety population included all randomized participants who received at least 1 dose of study treatment (BIIB104 or placebo).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 28 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| BIIB104 0.15 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 32 Participants |
| BIIB104 0.15 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| BIIB104 0.5 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 28 Participants |
| BIIB104 0.5 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 2 Participants |
Secondary
Number of Participants With at Least One Event of Suicidal Ideation and/or Suicidal Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score
The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and suicidal behavior. Suicidal ideation is classified on a 5-item scale: 1 (wish to be dead), 2 (nonspecific active suicidal thoughts), 3 (active suicidal ideation with any methods \[not plan\] without intent to act), 4 (active suicidal ideation with some intent to act, without specific plan), and 5 (active suicidal ideation with specific plan and intent). Suicidal behavior is classified on a 6-item scale: 1 (actual attempt), 2 (interrupted attempt), 3 (aborted attempt), 4 (preparatory acts or behavior), 5 (suicidal behavior), and 6 (suicide). The data analyzed signifies the participants with at least one event of suicidal ideation and/or suicidal behavior.
Time frame: Up to Week 14
Population: The safety population included all randomized participants who received at least 1 dose of study treatment (BIIB104 or placebo). Here, Overall Number of Participants Analyzed signifies the number of participants analyzed in this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With at Least One Event of Suicidal Ideation and/or Suicidal Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score | 3 Participants |
| BIIB104 0.15 mg | Number of Participants With at Least One Event of Suicidal Ideation and/or Suicidal Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score | 4 Participants |
| BIIB104 0.5 mg | Number of Participants With at Least One Event of Suicidal Ideation and/or Suicidal Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score | 0 Participants |
Secondary
Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12
The CGI-I consists of a single 7-point rating score total improvement, regardless of whether or not the change is due entirely to drug treatment. The following question: Compared to your participant's condition at the beginning of treatment, how much has your participant changed? is rated with a score from 1 to 7- 1: Very much improved; 2: Much improved; 3: Minimally improved; 4: No change; 5: Minimally worse; 6: Much worse; or 7: Very much worse. Lower scores indicate greater improvement.
Time frame: Week 12
Population: ITT population included all randomized participants who received at least one dose of study treatment (BIIB104 or placebo). Here, Overall Number of Participants Analyzed signifies the number of participants analyzed in this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12 | Much Worse | 2 Participants |
| Placebo | Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12 | Very Much Worse | 0 Participants |
| Placebo | Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12 | Minimally Improved | 13 Participants |
| Placebo | Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12 | Very Much Improved | 1 Participants |
| Placebo | Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12 | Much Improved | 11 Participants |
| Placebo | Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12 | No Change | 22 Participants |
| Placebo | Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12 | Minimally Worse | 2 Participants |
| BIIB104 0.15 mg | Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12 | Very Much Improved | 1 Participants |
| BIIB104 0.15 mg | Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12 | Much Worse | 0 Participants |
| BIIB104 0.15 mg | Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12 | Minimally Worse | 1 Participants |
| BIIB104 0.15 mg | Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12 | Very Much Worse | 0 Participants |
| BIIB104 0.15 mg | Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12 | No Change | 26 Participants |
| BIIB104 0.15 mg | Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12 | Minimally Improved | 18 Participants |
| BIIB104 0.15 mg | Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12 | Much Improved | 4 Participants |
| BIIB104 0.5 mg | Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12 | Much Worse | 0 Participants |
| BIIB104 0.5 mg | Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12 | Much Improved | 4 Participants |
| BIIB104 0.5 mg | Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12 | Minimally Improved | 18 Participants |
| BIIB104 0.5 mg | Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12 | No Change | 26 Participants |
| BIIB104 0.5 mg | Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12 | Minimally Worse | 2 Participants |
| BIIB104 0.5 mg | Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12 | Very Much Worse | 0 Participants |
| BIIB104 0.5 mg | Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12 | Very Much Improved | 0 Participants |