Schizophrenia
Conditions
Brief summary
The purpose of this study was to evaluate the efficacy and safety of elpipodect at a range of doses (8 mg, 16 mg, and 24 mg once daily \[QD\]) in adult participants who have an acute episode of schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5) criteria. The primary hypotheses were the following: (1) that elpipodect 24 mg is superior to placebo in reducing the Week 6 mean change from baseline in Positive and Negative Syndrome Scale (PANSS) total score, and (2) that elpipodect 16 mg is superior to placebo in reducing the Week 6 mean change from baseline in PANSS total score. With Amendment 4, enrollment was changed to approximately 500 participants with removal of the elpipodect 8 mg treatment arm. Participants enrolled before Amendment 4 who were assigned to elpipodect 8 mg QD remained on that dose regimen per protocol.
Interventions
DRUGElpipodect
MK-8189 administered QD at a dose of 8 mg, 16 mg, or 24 mg via oral tablet.
DRUGRisperidone
Risperidone administered QD at a dose of 6 mg via oral capsule.
MK-8189-matching placebo administered QD via oral tablet.
DRUGPlacebo to risperidone
Risperidone-matching placebo administered QD via oral capsule.
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
The main inclusion criteria include, but are not limited to the following: * Meet the diagnostic criteria for schizophrenia according to the DSM-5 * Have an illness duration for schizophrenia of at least 1 year * Be confirmed to be experiencing an acute episode of schizophrenia as evidenced by ALL of the following: (a) onset of the current acute episode is ≤6 weeks before screening (b) current symptoms represent a marked and substantial worsening compared with the participant's usual symptomatic state prior to the current acute episode, and are associated with diminished functional ability (c) in need of increased psychiatric attention to treat worsening acute episode symptoms * Have a CGI-S score of ≥4 (moderately ill) at screening and baseline * Have an identified responsible person referred to as the "external contact person" who has agreed to provide information about the participant's location if needed during outpatient portion of the study. The site personnel must consider this identified responsible person a reliable contact person, and the contact person must have regular contact with the participant (defined at screening as direct contact no fewer than 3 times per week), and with the expectation that this frequency of contact would continue (either in person or via other contact method), throughout duration of the study, including the follow-up period)
Exclusion criteria
The main
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 6 | Baseline and Week 6 | The PANSS assesses the severity of schizophrenia symptoms through a 30-item clinician-rated inventory organized into a positive subscale (7 items), a negative subscale (7 items) and a general psychopathology subscale (16 items). For each item, symptoms are rated on a 7-point scale from 1 (absent) to 7 (extreme). The PANSS total score for each participant was calculated as the sum of the rating assigned to each of the 30 PANSS items, and ranges from 30 (lowest total score) to 210 (highest total score). Higher and lower change scores reflect symptom worsening and improvement, respectively. Risperidone and placebo were active and inactive controls, respectively. |
| Number of Participants Who Experience One or More Adverse Events (AEs) | Up to Week 6 | An AE is any untoward medical occurrence in a clinical study participant, temporarily associated with the use of study intervention, whether or not considered related to the study intervention. Per protocol, events were assessed for the first 6 weeks of treatment. |
| Number of Participants Who Discontinued From Study Intervention Due to AE | Up to Week 6 | An AE is any untoward medical occurrence in a clinical study participant, temporarily associated with the use of study intervention, whether or not considered related to the study intervention. Per protocol, events were assessed for the first 6 weeks of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in PANSS Positive Subscale (PSS) Score at Week 6 | Baseline and Week 6 | The PANSS Positive Subscale (PSS) assesses the severity of schizophrenia symptoms. The PANSS PSS score was calculated as the sum of the rating assigned to each of the 7 PSS items and ranges from 7 (lowest total score) to 49 (highest total score). Higher and lower change scores reflect symptom worsening and improvement, respectively. Risperidone and placebo were active and inactive controls, respectively. |
| Change From Baseline in Clinical Global Impression-Severity of Illness (CGI-S) Score at Week 6 | Baseline and Week 6 | The CGI-S is a single item 7-point clinician rated scale for assessing the global severity of the participant's illness. CGI-S scores range from 1 (participant normal, not ill) to 7 (participant extremely ill); higher and lower change from baseline scores indicate symptom worsening and improvement, respectively. Risperidone and placebo were active and inactive controls, respectively. |
| Change From Baseline in Body Weight at Week 12 | Baseline and Week 12 | The change from baseline in body weigh was determined at Week 12. Negative and positive values represent body weight loss and gain from baseline, respectively. Weight was measured using a standardized scale. Risperidone and placebo were active and inactive controls, respectively. |
| Change From Baseline in Body Weight at Week 6 | Baseline and Week 6 | The change from baseline in body weigh was determined at Week 6. Negative and positive values represent body weight loss and gain from baseline, respectively. Weight was measured using a standardized scale. Risperidone and placebo were active and inactive controls, respectively. |
| Change From Baseline in Body Weight at Week 12: Model-based Analysis | Baseline and Week 12 | The change from baseline in body weigh was determined at Week 12. Negative and positive values represent body weight loss and gain from baseline, respectively. Weight was measured using a standardized scale. Risperidone and placebo were active and inactive controls, respectively. |
| Change From Baseline in Body Weight at Week 6: Model-based Analysis | Baseline and Week 6 | The change from baseline in body weigh was determined at Week 6. Negative and positive values represent body weight loss and gain from baseline, respectively. Weight was measured using a standardized scale. Risperidone and placebo were active and inactive controls, respectively. |
Countries
Bulgaria, Croatia, Japan, Latvia, Poland, Romania, Russia, Serbia, South Korea, Taiwan, Ukraine, United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Participant flow
Recruitment details
Participants were enrolled and randomized at 75 study sites in 11 countries.
Pre-assignment details
Randomization into the MK-8189 8 mg arm ceased as of Amendment 4.
Participants by arm
| Arm | Count |
|---|---|
| MK-8189 8 mg Participants received MK-8189 8 mg QD from Weeks 1 to 12, with 2 weeks of follow-up. | 41 |
| MK-8189 16 mg Participants received MK-8189 16 mg QD from Weeks 1 to 12, with 2 weeks of follow-up. | 132 |
| MK-8189 24 mg Participants received MK-8189 24 mg QD from Weeks 1 to 12, with 2 weeks of follow-up. | 132 |
| Risperidone 6 mg Participants received risperidone 6 mg QD from Weeks 1 to 12, with 2 weeks of follow-up. | 65 |
| Placebo and MK-8189 24 mg Participants received placebo QD from Weeks 1 to 6 and MK-8189 24 mg from Weeks 7 to 12, with 2 weeks of follow-up. | 129 |
| Total | 499 |
Baseline characteristics
| Characteristic | Total | MK-8189 8 mg | MK-8189 16 mg | MK-8189 24 mg | Risperidone 6 mg | Placebo and MK-8189 24 mg |
|---|---|---|---|---|---|---|
| Age, Continuous | 38.5 Years STANDARD_DEVIATION 9.3 | 35.7 Years STANDARD_DEVIATION 8.9 | 39.4 Years STANDARD_DEVIATION 9 | 36.9 Years STANDARD_DEVIATION 9.2 | 38.5 Years STANDARD_DEVIATION 9.6 | 40.2 Years STANDARD_DEVIATION 9.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 40 Participants | 1 Participants | 14 Participants | 10 Participants | 4 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 457 Participants | 40 Participants | 117 Participants | 121 Participants | 61 Participants | 118 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 12 Participants | 2 Participants | 3 Participants | 2 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 222 Participants | 18 Participants | 59 Participants | 59 Participants | 29 Participants | 57 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 258 Participants | 20 Participants | 68 Participants | 70 Participants | 34 Participants | 66 Participants |
| Sex: Female, Male Female | 167 Participants | 12 Participants | 46 Participants | 42 Participants | 25 Participants | 42 Participants |
| Sex: Female, Male Male | 332 Participants | 29 Participants | 86 Participants | 90 Participants | 40 Participants | 87 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 41 | 0 / 132 | 0 / 132 | 0 / 65 | 0 / 129 | 0 / 17 | 1 / 75 | 0 / 60 | 0 / 39 | 0 / 85 |
| other Total, other adverse events | 18 / 41 | 58 / 132 | 72 / 132 | 19 / 65 | 45 / 129 | 4 / 17 | 18 / 75 | 10 / 60 | 9 / 39 | 25 / 85 |
| serious Total, serious adverse events | 1 / 41 | 8 / 132 | 6 / 132 | 2 / 65 | 0 / 129 | 3 / 17 | 4 / 75 | 3 / 60 | 0 / 39 | 2 / 85 |
Outcome results
Primary
Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 6
The PANSS assesses the severity of schizophrenia symptoms through a 30-item clinician-rated inventory organized into a positive subscale (7 items), a negative subscale (7 items) and a general psychopathology subscale (16 items). For each item, symptoms are rated on a 7-point scale from 1 (absent) to 7 (extreme). The PANSS total score for each participant was calculated as the sum of the rating assigned to each of the 30 PANSS items, and ranges from 30 (lowest total score) to 210 (highest total score). Higher and lower change scores reflect symptom worsening and improvement, respectively. Risperidone and placebo were active and inactive controls, respectively.
Time frame: Baseline and Week 6
Population: All participants who receive ≥1 dose of MK-8189 (16 mg or 24 mg), risperidone, or placebo, and have both a baseline measurement and ≥1 valid post-baseline assessment, are included. Per protocol, the effect of the 8 mg dose was not assessed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-8189 16 mg | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 6 | -20.7 Score on a scale |
| MK-8189 24 mg | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 6 | -18.5 Score on a scale |
| Risperidone 6 mg | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 6 | -24.0 Score on a scale |
| Placebo and MK-8189 24 mg | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 6 | -17.8 Score on a scale |
p-value: 0.24197.5% CI: [-8.3, 2.6]ANCOVA
p-value: 0.78497.5% CI: [-6.3, 4.9]ANCOVA
Primary
Number of Participants Who Discontinued From Study Intervention Due to AE
An AE is any untoward medical occurrence in a clinical study participant, temporarily associated with the use of study intervention, whether or not considered related to the study intervention. Per protocol, events were assessed for the first 6 weeks of treatment.
Time frame: Up to Week 6
Population: All participants who received ≥1 dose of study intervention are included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-8189 8 mg | Number of Participants Who Discontinued From Study Intervention Due to AE | 8 Participants |
| MK-8189 16 mg | Number of Participants Who Discontinued From Study Intervention Due to AE | 17 Participants |
| MK-8189 24 mg | Number of Participants Who Discontinued From Study Intervention Due to AE | 33 Participants |
| Risperidone 6 mg | Number of Participants Who Discontinued From Study Intervention Due to AE | 8 Participants |
| Placebo and MK-8189 24 mg | Number of Participants Who Discontinued From Study Intervention Due to AE | 16 Participants |
Primary
Number of Participants Who Experience One or More Adverse Events (AEs)
An AE is any untoward medical occurrence in a clinical study participant, temporarily associated with the use of study intervention, whether or not considered related to the study intervention. Per protocol, events were assessed for the first 6 weeks of treatment.
Time frame: Up to Week 6
Population: All participants who received ≥1 dose of study intervention are included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-8189 8 mg | Number of Participants Who Experience One or More Adverse Events (AEs) | 29 Participants |
| MK-8189 16 mg | Number of Participants Who Experience One or More Adverse Events (AEs) | 85 Participants |
| MK-8189 24 mg | Number of Participants Who Experience One or More Adverse Events (AEs) | 94 Participants |
| Risperidone 6 mg | Number of Participants Who Experience One or More Adverse Events (AEs) | 31 Participants |
| Placebo and MK-8189 24 mg | Number of Participants Who Experience One or More Adverse Events (AEs) | 70 Participants |
Secondary
Change From Baseline in Body Weight at Week 12
The change from baseline in body weigh was determined at Week 12. Negative and positive values represent body weight loss and gain from baseline, respectively. Weight was measured using a standardized scale. Risperidone and placebo were active and inactive controls, respectively.
Time frame: Baseline and Week 12
Population: All participants who received ≥1 dose of MK-8189, risperidone, or placebo, and have both a baseline measurement and ≥1 valid post-baseline assessment, are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-8189 8 mg | Change From Baseline in Body Weight at Week 12 | -3.2 Kilograms | Standard Deviation 5.4 |
| MK-8189 16 mg | Change From Baseline in Body Weight at Week 12 | -5.0 Kilograms | Standard Deviation 5.6 |
| MK-8189 24 mg | Change From Baseline in Body Weight at Week 12 | -2.9 Kilograms | Standard Deviation 5.1 |
| Risperidone 6 mg | Change From Baseline in Body Weight at Week 12 | 2.7 Kilograms | Standard Deviation 3.8 |
| Placebo and MK-8189 24 mg | Change From Baseline in Body Weight at Week 12 | -2.0 Kilograms | Standard Deviation 3.9 |
Secondary
Change From Baseline in Body Weight at Week 12: Model-based Analysis
The change from baseline in body weigh was determined at Week 12. Negative and positive values represent body weight loss and gain from baseline, respectively. Weight was measured using a standardized scale. Risperidone and placebo were active and inactive controls, respectively.
Time frame: Baseline and Week 12
Population: All participants who received ≥1 dose of MK-8189 (16 or 24 mg), risperidone, or placebo, and have both a baseline measurement and ≥1 valid post-baseline assessment, are included. Per protocol, the 8 mg arm was excluded from analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-8189 16 mg | Change From Baseline in Body Weight at Week 12: Model-based Analysis | -5.4 Kilograms |
| MK-8189 24 mg | Change From Baseline in Body Weight at Week 12: Model-based Analysis | -4.3 Kilograms |
| Risperidone 6 mg | Change From Baseline in Body Weight at Week 12: Model-based Analysis | 3.0 Kilograms |
| Placebo and MK-8189 24 mg | Change From Baseline in Body Weight at Week 12: Model-based Analysis | -2.3 Kilograms |
p-value: <0.00197.5% CI: [-10.4, -6.5]ANCOVA
p-value: <0.00197.5% CI: [-9.3, -5.2]ANCOVA
Secondary
Change From Baseline in Body Weight at Week 6
The change from baseline in body weigh was determined at Week 6. Negative and positive values represent body weight loss and gain from baseline, respectively. Weight was measured using a standardized scale. Risperidone and placebo were active and inactive controls, respectively.
Time frame: Baseline and Week 6
Population: All participants who received ≥1 dose of MK-8189, risperidone, or placebo, and have both a baseline measurement and ≥1 valid post-baseline assessment, are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-8189 8 mg | Change From Baseline in Body Weight at Week 6 | -1.1 Kilograms | Standard Deviation 3 |
| MK-8189 16 mg | Change From Baseline in Body Weight at Week 6 | -3.2 Kilograms | Standard Deviation 4.1 |
| MK-8189 24 mg | Change From Baseline in Body Weight at Week 6 | -2.4 Kilograms | Standard Deviation 3.8 |
| Risperidone 6 mg | Change From Baseline in Body Weight at Week 6 | 2.6 Kilograms | Standard Deviation 3.4 |
| Placebo and MK-8189 24 mg | Change From Baseline in Body Weight at Week 6 | 0.5 Kilograms | Standard Deviation 3.5 |
Secondary
Change From Baseline in Body Weight at Week 6: Model-based Analysis
The change from baseline in body weigh was determined at Week 6. Negative and positive values represent body weight loss and gain from baseline, respectively. Weight was measured using a standardized scale. Risperidone and placebo were active and inactive controls, respectively.
Time frame: Baseline and Week 6
Population: All participants who received ≥1 dose of MK-8189 (16 or 24 mg), risperidone, or placebo, and have both a baseline measurement and ≥1 valid post-baseline assessment, are included. Per protocol, the 8 mg arm was excluded from analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-8189 16 mg | Change From Baseline in Body Weight at Week 6: Model-based Analysis | -3.2 Kilograms |
| MK-8189 24 mg | Change From Baseline in Body Weight at Week 6: Model-based Analysis | -2.8 Kilograms |
| Risperidone 6 mg | Change From Baseline in Body Weight at Week 6: Model-based Analysis | 2.8 Kilograms |
| Placebo and MK-8189 24 mg | Change From Baseline in Body Weight at Week 6: Model-based Analysis | 0.5 Kilograms |
p-value: <0.00197.5% CI: [-7.4, -4.6]ANCOVA
p-value: <0.00197.5% CI: [-7, -4.2]ANCOVA
Secondary
Change From Baseline in Clinical Global Impression-Severity of Illness (CGI-S) Score at Week 6
The CGI-S is a single item 7-point clinician rated scale for assessing the global severity of the participant's illness. CGI-S scores range from 1 (participant normal, not ill) to 7 (participant extremely ill); higher and lower change from baseline scores indicate symptom worsening and improvement, respectively. Risperidone and placebo were active and inactive controls, respectively.
Time frame: Baseline and Week 6
Population: All participants who received ≥1 dose of MK-8189 (16 mg or 24 mg), risperidone, or placebo, and have both a baseline measurement and ≥1 valid post-baseline assessment, are included. Per protocol, the effect of the 8 mg dose was not assessed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-8189 16 mg | Change From Baseline in Clinical Global Impression-Severity of Illness (CGI-S) Score at Week 6 | -1.1 Score on a scale |
| MK-8189 24 mg | Change From Baseline in Clinical Global Impression-Severity of Illness (CGI-S) Score at Week 6 | -1.0 Score on a scale |
| Risperidone 6 mg | Change From Baseline in Clinical Global Impression-Severity of Illness (CGI-S) Score at Week 6 | -1.3 Score on a scale |
| Placebo and MK-8189 24 mg | Change From Baseline in Clinical Global Impression-Severity of Illness (CGI-S) Score at Week 6 | -1.0 Score on a scale |
p-value: 0.25497.5% CI: [-0.5, 0.1]ANCOVA
p-value: 0.95997.5% CI: [-0.3, 0.3]ANCOVA
Secondary
Change From Baseline in PANSS Positive Subscale (PSS) Score at Week 6
The PANSS Positive Subscale (PSS) assesses the severity of schizophrenia symptoms. The PANSS PSS score was calculated as the sum of the rating assigned to each of the 7 PSS items and ranges from 7 (lowest total score) to 49 (highest total score). Higher and lower change scores reflect symptom worsening and improvement, respectively. Risperidone and placebo were active and inactive controls, respectively.
Time frame: Baseline and Week 6
Population: All participants who received ≥1 dose of MK-8189 (16 mg or 24 mg), risperidone, or placebo, and have both a baseline measurement and ≥1 valid post-baseline assessment, are included. Per protocol, the effect of the 8 mg dose was not assessed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-8189 16 mg | Change From Baseline in PANSS Positive Subscale (PSS) Score at Week 6 | -7.1 Score on a scale |
| MK-8189 24 mg | Change From Baseline in PANSS Positive Subscale (PSS) Score at Week 6 | -7.2 Score on a scale |
| Risperidone 6 mg | Change From Baseline in PANSS Positive Subscale (PSS) Score at Week 6 | -7.7 Score on a scale |
| Placebo and MK-8189 24 mg | Change From Baseline in PANSS Positive Subscale (PSS) Score at Week 6 | -5.8 Score on a scale |
p-value: 0.09697.5% CI: [-3.1, 0.5]ANCOVA
p-value: 0.09497.5% CI: [-3.2, 0.5]ANCOVA