Schizophrenia
Conditions
Keywords
Acute Exacerbation of Schizophrenia
Brief summary
A study to evaluate the safety and efficacy of treatment with MK-8998 as compared to placebo and olanzapine for acutely psychotic patients with schizophrenia. The primary hypothesis is that in participants undergoing an acute psychotic episode of schizophrenia, MK-8998 6 to 8 mg twice daily is superior to placebo in the treatment of symptoms of schizophrenia as measured by the mean change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score at Week 4.
Interventions
DRUGMK-8998
MK-8998 6 mg capsules twice daily with food on Days 1 through 7. On Day 8, dosage will be increased to 8 mg capsules twice daily. Treatment period is 4 weeks. There will be a period of time when all participants will receive placebo.
DRUGComparator: Olanzapine
Olanzapine 5 mg tablets twice daily with food on Days 1 through 7. On Day 8, dosage will be increased to 5 mg tablets in the morning and 10 mg tablets in the evening. Treatment period is 4 weeks. There will be a period of time when all participants will receive placebo.
DRUGComparator: Placebo
Placebo tablets matching olanzapine tablets and MK-8998 capsules
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Patient's age is 18 to 55 * Patient meets DSM-IV/DSM-IV-TR criteria for a primary diagnosis of schizophrenia * The duration of the patients schizophrenia diagnosis must be greater than 1 year * Patient has an acute exacerbation of psychotic symptoms (of at least 3 days but no longer than 6 weeks) and marked deterioration of function
Exclusion criteria
* Patient currently has a clinically significant neurological, metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, and/or urological disorder that would pose a risk to the patient in the opinion of the investigator if they were to participate in the study or that might confound the results of the study * The patient has evidence of acute hepatitis, clinically significant chronic hepatitis, or impaired hepatic function * The patient has a chronic organic disease of the central nervous system (other than schizophrenia) such as, tumors, inflammation, active seizure disorder, vascular disorder, Parkinson's disease, Alzheimer's disease or other forms of dementia, myasthenia gravis, or other degenerative processes. In addition, patients must not have a history of mental retardation or persistent neurological symptoms attributable to serious head injury * Patient has a history of alcohol/drug dependence within 3 months or alcohol/drug abuse within 1 month of screening. Exceptions include caffeine and nicotine abuse/dependence * Patient has a history of hypersensitivity to olanzapine OR poor response to olanzapine in the last 2 years OR intolerable side effects due to olanzapine OR patients current psychotic relapse occurred while consistently taking a therapeutic dose (10 mg or more) of olanzapine OR olanzapine is medically contradicted * Patient is refractory to antipsychotic treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) at Week 4 | Baseline and Week 4 | PANSS is a medical scale used for measuring symptom severity of participants with schizophrenia. PANSS measure is composed of 3 scales: Positive scale, Negative scale, and General Psychopathology scale. Positive scale assesses hallucinations, delusions and related symptoms; Negative scale assesses emotional withdrawal, lack of motivation, and similar symptoms; and General Psychopathology scale addresses other symptoms such as anxiety, somatic concern and disorientation. The PANSS has 30 items in its 3 scales and an anchored Likert scale from 1 to 7 is used to score each item. Values of 2 and above indicate the presence of progressively more severe symptoms. The Positive scale has 7 items with a score from 7 to 49, the Negative scale has 7 items with a score from 7 to 49, and the General Psychopathology scale has 16 items with a score from 16 to 112. A total score is the sum of the 3 scores for the 3 scales. |
| Number of Participants Who Experienced at Least One Adverse Event | Up to 6 Weeks | An adverse event (AE) is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration whether or not considered related to the use of the study drug. |
| Number of Participants Who Discontinued Study Drug Due to an Adverse Event | Up to 4 Weeks | An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration whether or not considered related to the use of the study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Response at Week 4 | Week 4 | Responders were defined as participants who demonstrated ≥ 20% improvement from baseline on the PANSS total score. PANSS measure is composed of 3 scales: Positive scale, Negative scale, and General Psychopathology scale. Positive scale assesses hallucinations, delusions and related symptoms; Negative scale assesses emotional withdrawal, lack of motivation, and similar symptoms; and General Psychopathology scale addresses other symptoms such as anxiety, somatic concern and disorientation. The PANSS has 30 items in its 3 scales and an anchored Likert scale from 1 to 7 is used to score each item. Values of 2 and above indicate the presence of progressively more severe symptoms. The Positive scale has 7 items with a score from 7 to 49, the Negative scale has 7 items with a score from 7 to 49, and the General Psychopathology scale has 16 items with a score from 16 to 112. A total score is the sum of the 3 scores for the 3 scales. |
| Mean Change From Baseline in PANSS Negative Subscale at Week 4 | Baseline and Week 4 | PANSS Negative scale assesses emotional withdrawal, lack of motivation, and similar symptoms. The Negative scale has 7 items with an anchored Likert scale from 1 to 7 to score each item. Values of 2 and above indicate the presence of progressively more severe symptoms. A total score ranges from 7 to 49. |
| Mean Change From Baseline in Clinical Global Impression - Severity of Illness Scale (CGI-S) at Week 4 | Baseline and Week 4 | CGI-S is a commonly used measure of symptom severity in treatment studies of participants with mental disorders. CGI-S is a 7-point scale that requires the clinician to rate the severity of the participant's illness at the time of assessment, relative to the clinician's past experience with participants who have the same diagnosis. Considering total clinical experience, a participant is assessed on severity of mental illness at the time of rating 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; or 7 = extremely ill. |
| Mean Change From Baseline in PANSS Positive Subscale at Week 4 | Baseline and Week 4 | PANSS Positive scale assesses hallucinations, delusions and related symptoms. The Positive scale has 7 items with an anchored Likert scale from 1 to 7 to score each item. Values of 2 and above indicate the presence of progressively more severe symptoms. A total score ranges from 7 to 49. |
Participant flow
Recruitment details
Male and female inpatients who were experiencing an acute exacerbation of schizophrenia were randomized at 21 sites worldwide.
Pre-assignment details
Participants who met entry criteria were washed out of psychotropic medication and then entered a single-blind, in-patient, 3-day to 7-day, placebo lead-in period.
Participants by arm
| Arm | Count |
|---|---|
| MK-8998 MK-8998, 6 mg twice a day (BID) on Days 1 to 7, and 8 mg BID thereafter for a 4-week total treatment period | 86 |
| Olanzapine Olanzapine, 5 mg BID on Day 1 to 7, and 15 mg (5 mg in the morning and 10 mg in the evening) thereafter for a 4-week total treatment period | 47 |
| Placebo Comparator Placebo Comparator to MK-8998 or olanzapine | 83 |
| Total | 216 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 0 | 0 |
| Overall Study | Lack of Efficacy | 16 | 4 | 15 |
| Overall Study | Physician Decision | 1 | 0 | 0 |
| Overall Study | Pregnancy | 0 | 1 | 0 |
| Overall Study | Progressive Disease | 1 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 6 | 2 | 6 |
Baseline characteristics
| Characteristic | MK-8998 | Olanzapine | Placebo Comparator | Total |
|---|---|---|---|---|
| Age, Continuous | 37.4 years | 36.1 years | 36.4 years | 36.8 years |
| Sex: Female, Male Female | 37 Participants | 23 Participants | 30 Participants | 90 Participants |
| Sex: Female, Male Male | 49 Participants | 24 Participants | 53 Participants | 126 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 19 / 86 | 14 / 47 | 11 / 83 |
| serious Total, serious adverse events | 0 / 86 | 0 / 47 | 1 / 83 |
Outcome results
Primary
Mean Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) at Week 4
PANSS is a medical scale used for measuring symptom severity of participants with schizophrenia. PANSS measure is composed of 3 scales: Positive scale, Negative scale, and General Psychopathology scale. Positive scale assesses hallucinations, delusions and related symptoms; Negative scale assesses emotional withdrawal, lack of motivation, and similar symptoms; and General Psychopathology scale addresses other symptoms such as anxiety, somatic concern and disorientation. The PANSS has 30 items in its 3 scales and an anchored Likert scale from 1 to 7 is used to score each item. Values of 2 and above indicate the presence of progressively more severe symptoms. The Positive scale has 7 items with a score from 7 to 49, the Negative scale has 7 items with a score from 7 to 49, and the General Psychopathology scale has 16 items with a score from 16 to 112. A total score is the sum of the 3 scores for the 3 scales.
Time frame: Baseline and Week 4
Population: Randomized participants with any PANSS measurements between Baseline and Week 4.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-8998 | Mean Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) at Week 4 | -13.3 Units on a scale |
| Olanzapine | Mean Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) at Week 4 | -17.0 Units on a scale |
| Placebo Comparator | Mean Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) at Week 4 | -12.7 Units on a scale |
p-value: 0.85995% CI: [-7, 5.8]Difference in the Least Squares Mean
p-value: 0.253495% CI: [-11.7, 3.1]Difference in the Least Squares Mean
Primary
Number of Participants Who Discontinued Study Drug Due to an Adverse Event
An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration whether or not considered related to the use of the study drug.
Time frame: Up to 4 Weeks
Population: All participants included in the All Patients as Treated (APaT) population received at least one dose of study treatment and were evaluated for safety.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-8998 | Number of Participants Who Discontinued Study Drug Due to an Adverse Event | 9 Participants |
| Olanzapine | Number of Participants Who Discontinued Study Drug Due to an Adverse Event | 1 Participants |
| Placebo Comparator | Number of Participants Who Discontinued Study Drug Due to an Adverse Event | 1 Participants |
Primary
Number of Participants Who Experienced at Least One Adverse Event
An adverse event (AE) is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration whether or not considered related to the use of the study drug.
Time frame: Up to 6 Weeks
Population: All participants included in the All Patients as Treated (APaT) population received at least one dose of study treatment and were evaluated for safety.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-8998 | Number of Participants Who Experienced at Least One Adverse Event | 41 Participants |
| Olanzapine | Number of Participants Who Experienced at Least One Adverse Event | 23 Participants |
| Placebo Comparator | Number of Participants Who Experienced at Least One Adverse Event | 33 Participants |
Secondary
Mean Change From Baseline in Clinical Global Impression - Severity of Illness Scale (CGI-S) at Week 4
CGI-S is a commonly used measure of symptom severity in treatment studies of participants with mental disorders. CGI-S is a 7-point scale that requires the clinician to rate the severity of the participant's illness at the time of assessment, relative to the clinician's past experience with participants who have the same diagnosis. Considering total clinical experience, a participant is assessed on severity of mental illness at the time of rating 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; or 7 = extremely ill.
Time frame: Baseline and Week 4
Population: Randomized participants with any CGI-S measurements between baseline and Week 4.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-8998 | Mean Change From Baseline in Clinical Global Impression - Severity of Illness Scale (CGI-S) at Week 4 | -0.9 Units on a scale |
| Olanzapine | Mean Change From Baseline in Clinical Global Impression - Severity of Illness Scale (CGI-S) at Week 4 | -0.8 Units on a scale |
| Placebo Comparator | Mean Change From Baseline in Clinical Global Impression - Severity of Illness Scale (CGI-S) at Week 4 | -0.9 Units on a scale |
p-value: 0.819995% CI: [-0.4, 0.3]Constrained longitudinal data analysis
p-value: 0.948695% CI: [-0.4, 0.4]Constrained longitudinal data analysis
Secondary
Mean Change From Baseline in PANSS Negative Subscale at Week 4
PANSS Negative scale assesses emotional withdrawal, lack of motivation, and similar symptoms. The Negative scale has 7 items with an anchored Likert scale from 1 to 7 to score each item. Values of 2 and above indicate the presence of progressively more severe symptoms. A total score ranges from 7 to 49.
Time frame: Baseline and Week 4
Population: Randomized participants with any PANSS negative subscale measurements between baseline and Week 4.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-8998 | Mean Change From Baseline in PANSS Negative Subscale at Week 4 | -3.3 Units on a scale |
| Olanzapine | Mean Change From Baseline in PANSS Negative Subscale at Week 4 | -3.1 Units on a scale |
| Placebo Comparator | Mean Change From Baseline in PANSS Negative Subscale at Week 4 | -2.9 Units on a scale |
p-value: 0.595395% CI: [-2, 1.2]Constrained longitudinal data analysis
p-value: 0.856795% CI: [-2, 1.6]Constrained longitudinal data analysis
Secondary
Mean Change From Baseline in PANSS Positive Subscale at Week 4
PANSS Positive scale assesses hallucinations, delusions and related symptoms. The Positive scale has 7 items with an anchored Likert scale from 1 to 7 to score each item. Values of 2 and above indicate the presence of progressively more severe symptoms. A total score ranges from 7 to 49.
Time frame: Baseline and Week 4
Population: Randomized participants with any PANSS positive subscale measurements between baseline and Week 4.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-8998 | Mean Change From Baseline in PANSS Positive Subscale at Week 4 | -4.2 Units on a scale |
| Olanzapine | Mean Change From Baseline in PANSS Positive Subscale at Week 4 | -5.6 Units on a scale |
| Placebo Comparator | Mean Change From Baseline in PANSS Positive Subscale at Week 4 | -4.2 Units on a scale |
p-value: 0.993795% CI: [-2, 2]Constrained longitudinal data analysis
p-value: 0.240695% CI: [-3.6, 0.9]Constrained longitudinal data analysis
Secondary
Percentage of Participants With Response at Week 4
Responders were defined as participants who demonstrated ≥ 20% improvement from baseline on the PANSS total score. PANSS measure is composed of 3 scales: Positive scale, Negative scale, and General Psychopathology scale. Positive scale assesses hallucinations, delusions and related symptoms; Negative scale assesses emotional withdrawal, lack of motivation, and similar symptoms; and General Psychopathology scale addresses other symptoms such as anxiety, somatic concern and disorientation. The PANSS has 30 items in its 3 scales and an anchored Likert scale from 1 to 7 is used to score each item. Values of 2 and above indicate the presence of progressively more severe symptoms. The Positive scale has 7 items with a score from 7 to 49, the Negative scale has 7 items with a score from 7 to 49, and the General Psychopathology scale has 16 items with a score from 16 to 112. A total score is the sum of the 3 scores for the 3 scales.
Time frame: Week 4
Population: Randomized participants with a PANSS measurement at Week 4.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-8998 | Percentage of Participants With Response at Week 4 | 57.4 Percentage of participants |
| Olanzapine | Percentage of Participants With Response at Week 4 | 66.7 Percentage of participants |
| Placebo Comparator | Percentage of Participants With Response at Week 4 | 48.3 Percentage of participants |
p-value: 0.497695% CI: [0.62, 2.64]Generalized linear mixed analysis model
p-value: 0.065395% CI: [0.95, 5.09]Generalized linear mixed analysis model