Akathisia, Drug-Induced, Antipsychotic Agents, Movement Disorders
Conditions
Keywords
Antipsychotic Agents
Brief summary
This study is designed to evaluate the effectiveness of preladenant in the prevention (Part 1) or treatment (Part 2) of antipsychotic induced akathisia in participants with acute psychosis using the Barnes Akathisia Scale.
Interventions
DRUGPreladenant
Preladenant, one 25 mg capsule, administered orally every 12 hours
DRUGPlacebo
Matching placebo capsule administered orally every 12 hours
DRUGAnticholinergic agents or propanolol
Part 1 (as rescue therapy only): participants who develop akathisias may be treated with either anticholinergic agents or propranolol as a rescue medication at the discretion of the treating physician. Individual anticholinergic agents were not pre-specified per protocol. Part 2 (standard of care): anticholinergic agents or propanolol at a dose determined by the investigator according to the local standard of care. Individual anticholinergic agents were not pre-specified per protocol.
DRUGHaloperidol
Participants continued pre-study haloperidol, admistered orally, at a dose of at least 7.5 mg/day
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Participants or guardian must be willing to give written informed consent. * Part 1 Only: Participants with acute (not drug related) psychoses with a Positive and Negative Symptom Scale for Schizophrenia (PANSS) score of at least 60: schizophrenia, schizo-affective, schizo-manic, and acute mania with a history of previous treatment with neuroleptics. * Part 1 Only: Participants initiating haloperidol for the treatment of an acute psychotic episode at a dose of at least 7.5 mg per day. * Part 2 Only: Inpatient participants who have developed akathisia as a result of haloperidol at \>=5 mg per day for the treatment of acute psychosis. The enrollment of participants receiving other neuroleptics is allowed only after consultation and agreement by the sponsor. * Participants of either sex and of any race between the ages of 18 and 65 years, inclusive. * Participant's clinical laboratory tests (complete blood count \[CBC\], blood chemistry, and urinalysis) must be within normal limits or clinically acceptable to the investigator/sponsor. Participant's liver function test results (ie, aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\]) must not be elevated above the normal limits at Screening and on Day -1/1. * Participants must be free of any clinically significant disease other than psychosis that would interfere with the study evaluations. * Screening electrocardiogram (ECG) must be clinically acceptable to the investigator. * Female of childbearing potential must: * Have used a medically accepted method of contraception for 1 month (or abstained from sexual intercourse) prior to the screening period. An acceptable method of contraception includes one of the following: * condom (male or female) used with spermicide, * diaphragm or cervical cap used with spermicide and condom, * stable oral/transdermal/injectable hormonal contraceptive regimen without breakthrough uterine bleeding for 2 months prior to Screening visit and a condom used with spermicide, * intrauterine device (inserted at least 2 months prior to Screening visit) used with spermicide. Note: Vasectomy of the partner is not considered sufficient contraception and one of the 4 bulleted methods listed above must be used. * Agree to use one of the accepted methods of contraception (listed above) during the trial (including the screening period prior to receiving trial medication), and for 1 month after stopping the trial medication. * Participants enrolled in the placebo arm of Part 1 and who developed akathisia may be eligible for Part 2 in the standard of care arm.
Exclusion criteria
* Participants who have a positive screen for drugs with a high potential for abuse. Participants that screen positive for cannabis are permitted. * Participants who have previously received this compound. * Participants who are currently participating in another clinical study or have participated in a clinical study within 30 days (except participants enrolled in the Part 1 of the P05145 study). * Participants who are part of the study staff personnel or family members of the study staff personnel. * Participants with severe/uncontrolled hypertension will be excluded. Participants with hypertension well controlled on a stable dose of standard antihypertensive medication (excluding beta-blockers) will be eligible. * Participants with history of coronary artery disease including myocardial infarction (MI), or cerebrovascular disease (stroke, transient ischemic attack \[TIA\]), or peripheral arterial disease. * Participants with congestive heart failure or participants with ECGs consistent with ischemic heart disease, sick sinus syndrome or significant Q waves. * Participants who are found to be at immediate risk of suicide. * Female participants pregnant or nursing. * Participants treated by Clozapine will be excluded. A washout period of 6 months prior to dosing will be acceptable for study entry.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Number of Participants With Akathisia | Up to 13 days | Incidence of akathisia is reported as the number of participants who experienced akathisia. Akathisia is defined as a score of 3 on the Barnes akathisia scale (BAS) for 3 consecutive intervals or an akathisia score (BAS) of ≥4 for any single day, or the use of a rescue medication within 13 days of initiating treatment with haloperidol and preladenant. The BAS is scored as follows: objective akathisia, subjective awareness of restlessness and subjective distress related to restlessness are rated on a 4-point scale from 0 - 3 and are summed yielding a total score ranging from 0 (no akathisia) to 9 (severe akathisia). |
| Part 2: Number of Participants Who Were Treatment Failures | Up to 14 days | Incidence of treatment failure is reported as the number of participants who were treatment failures. A treatment failure is defined as the failure to achieve at least a 1 point reduction from baseline in BAS score at 24 to 26 hours following study treatment. The BAS is scored as follows: objective akathisia, subjective awareness of restlessness and subjective distress related to restlessness are rated on a 4-point scale from 0 - 3 and are summed yielding a total score ranging from 0 (no akathisia) to 9 (severe akathisia). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Mean Global Clinical Impression at Day 14 | Day 14 of Part 1 | Global clinical impression (GCI) was administered to assess whether any deterioration is due to akathisia or uncontrolled psychoses. Score on a scale +2 to -2 (+2 represents much improvement, +1 some improvement, 0 no change, -1 some worsening, and -2 much worsening). |
| Part 1: Mean Positive and Negative Symptom Scale for Schizophrenia (PANSS) Total Score at Day 14 | Day 14 of Part 1 | The PANSS is a 30-item clinician-rated instrument for assessing the symptoms of schizophrenia. It consists of 3 subscales: positive subscale (7 items), negative subscale (7 items), and general psychopathology subscale (16 items). Positive symptoms refer to an excess or distortion of normal mental status (e.g., delusions). Negative symptoms represent a diminution or loss of normal functions (e.g., emotional withdrawal). For each item, symptom severity was rated on a 7-point scale, from 0=absent to 6=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 ranged from 0 to 180 with a higher score indicating greater severity of symptoms. Although the PANSS is traditionally scored with a range of 30-210, with a score of absent = 1 (for each item), for this analysis the range was set from 0-180, with a score of absent = 0 (for each item). |
| Part 2: Mean GCI at Day 14 | Day 14 of Part 2 | The GCI was administered to assess whether any deterioration is due to akathisia or uncontrolled psychoses. Score on a scale +2 to -2 (+2 represents much improvement, +1 some improvement, 0 no change, -1 some worsening, and -2 much worsening). |
| Part 2: PANSS Total Score at Day 14 | Day 14 of Part 2 | The PANSS is a 30-item clinician-rated instrument for assessing the symptoms of schizophrenia. It consists of 3 subscales: positive subscale (7 items), negative subscale (7 items), and general psychopathology subscale (16 items). Positive symptoms refer to an excess or distortion of normal mental status (e.g., delusions). Negative symptoms represent a diminution or loss of normal functions (e.g., emotional withdrawal). For each item, symptom severity was rated on a 7-point scale, from 0=absent to 6=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 ranged from 0 to 180 with a higher score indicating greater severity of symptoms. Although the PANSS is traditionally scored with a range of 30-210, with a score of absent = 1 (for each item), for this analysis the range was set from 0-180, with a score of absent = 0 (for each item). |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Preladenant Preladenant 25 mg every 12 hours for 13 days | 19 |
| Part 1: Placebo Placebo every 12 hours for 13 days | 13 |
| Part 2: Preladenant Preladenant 25 mg every 12 hours for 13 days | 8 |
| Part 2: Standard of Care Anticholinergic agents or Propranolol as standard-of-care dosing regimen (supplied by the study site) | 6 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Part 1 | Adverse Event | 1 | 1 | 0 | 0 |
| Part 1 | Lost to Follow-up | 0 | 1 | 0 | 0 |
| Part 1 | Withdrew - reason unrelated to treatment | 5 | 2 | 0 | 0 |
| Part 2 | Adverse Event | 0 | 0 | 1 | 0 |
| Part 2 | Withdrew - reason unrelated to treatment | 0 | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Part 1: Preladenant | Part 1: Placebo | Part 2: Preladenant | Part 2: Standard of Care | Total |
|---|---|---|---|---|---|
| Age, Customized <18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Between 18 and <65 years | 19 Participants | 13 Participants | 8 Participants | 6 Participants | 46 Participants |
| Sex: Female, Male Female | 8 Participants | 1 Participants | 3 Participants | 2 Participants | 14 Participants |
| Sex: Female, Male Male | 11 Participants | 12 Participants | 5 Participants | 4 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 12 / 13 | 16 / 19 | 6 / 6 | 7 / 8 |
| serious Total, serious adverse events | 0 / 13 | 0 / 19 | 0 / 6 | 0 / 8 |
Outcome results
Primary
Part 1: Number of Participants With Akathisia
Incidence of akathisia is reported as the number of participants who experienced akathisia. Akathisia is defined as a score of 3 on the Barnes akathisia scale (BAS) for 3 consecutive intervals or an akathisia score (BAS) of ≥4 for any single day, or the use of a rescue medication within 13 days of initiating treatment with haloperidol and preladenant. The BAS is scored as follows: objective akathisia, subjective awareness of restlessness and subjective distress related to restlessness are rated on a 4-point scale from 0 - 3 and are summed yielding a total score ranging from 0 (no akathisia) to 9 (severe akathisia).
Time frame: Up to 13 days
Population: Efficacy analysis population was defined as participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Preladenant | Part 1: Number of Participants With Akathisia | 0 Participants |
| Part 1: Placebo | Part 1: Number of Participants With Akathisia | 0 Participants |
Primary
Part 2: Number of Participants Who Were Treatment Failures
Incidence of treatment failure is reported as the number of participants who were treatment failures. A treatment failure is defined as the failure to achieve at least a 1 point reduction from baseline in BAS score at 24 to 26 hours following study treatment. The BAS is scored as follows: objective akathisia, subjective awareness of restlessness and subjective distress related to restlessness are rated on a 4-point scale from 0 - 3 and are summed yielding a total score ranging from 0 (no akathisia) to 9 (severe akathisia).
Time frame: Up to 14 days
Population: Efficacy analysis population was defined as participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Preladenant | Part 2: Number of Participants Who Were Treatment Failures | 4 Participants |
| Part 1: Placebo | Part 2: Number of Participants Who Were Treatment Failures | 1 Participants |
Secondary
Part 1: Mean Global Clinical Impression at Day 14
Global clinical impression (GCI) was administered to assess whether any deterioration is due to akathisia or uncontrolled psychoses. Score on a scale +2 to -2 (+2 represents much improvement, +1 some improvement, 0 no change, -1 some worsening, and -2 much worsening).
Time frame: Day 14 of Part 1
Population: Efficacy analysis population was defined as participants who received at least one dose of study drug. The study was terminated early by the sponsor due to lack of enrollment. No formal statistical analysis was done due to the very small sample size in this study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Preladenant | Part 1: Mean Global Clinical Impression at Day 14 | 0.9231 Score on a scale | Standard Deviation 0.7596 |
| Part 1: Placebo | Part 1: Mean Global Clinical Impression at Day 14 | 1.7778 Score on a scale | Standard Deviation 0.441 |
Secondary
Part 1: Mean Positive and Negative Symptom Scale for Schizophrenia (PANSS) Total Score at Day 14
The PANSS is a 30-item clinician-rated instrument for assessing the symptoms of schizophrenia. It consists of 3 subscales: positive subscale (7 items), negative subscale (7 items), and general psychopathology subscale (16 items). Positive symptoms refer to an excess or distortion of normal mental status (e.g., delusions). Negative symptoms represent a diminution or loss of normal functions (e.g., emotional withdrawal). For each item, symptom severity was rated on a 7-point scale, from 0=absent to 6=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 ranged from 0 to 180 with a higher score indicating greater severity of symptoms. Although the PANSS is traditionally scored with a range of 30-210, with a score of absent = 1 (for each item), for this analysis the range was set from 0-180, with a score of absent = 0 (for each item).
Time frame: Day 14 of Part 1
Population: Efficacy analysis population was defined as participants who received at least one dose of study drug. The study was terminated early by the sponsor due to lack of enrollment. No formal statistical analysis was done due to the very small sample size in this study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Preladenant | Part 1: Mean Positive and Negative Symptom Scale for Schizophrenia (PANSS) Total Score at Day 14 | 38.4615 Score on a scale | Standard Deviation 19.4834 |
| Part 1: Placebo | Part 1: Mean Positive and Negative Symptom Scale for Schizophrenia (PANSS) Total Score at Day 14 | 36.3333 Score on a scale | Standard Deviation 17.0587 |
Secondary
Part 2: Mean GCI at Day 14
The GCI was administered to assess whether any deterioration is due to akathisia or uncontrolled psychoses. Score on a scale +2 to -2 (+2 represents much improvement, +1 some improvement, 0 no change, -1 some worsening, and -2 much worsening).
Time frame: Day 14 of Part 2
Population: Efficacy analysis population was defined as participants who received at least one dose of study drug. The study was terminated early by the sponsor due to lack of enrollment. No formal statistical analysis was done due to the very small sample size in this study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Preladenant | Part 2: Mean GCI at Day 14 | 0.6667 Score on a scale | Standard Deviation 1.0328 |
| Part 1: Placebo | Part 2: Mean GCI at Day 14 | 2.0000 Score on a scale | Standard Deviation 0 |
Secondary
Part 2: PANSS Total Score at Day 14
The PANSS is a 30-item clinician-rated instrument for assessing the symptoms of schizophrenia. It consists of 3 subscales: positive subscale (7 items), negative subscale (7 items), and general psychopathology subscale (16 items). Positive symptoms refer to an excess or distortion of normal mental status (e.g., delusions). Negative symptoms represent a diminution or loss of normal functions (e.g., emotional withdrawal). For each item, symptom severity was rated on a 7-point scale, from 0=absent to 6=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 ranged from 0 to 180 with a higher score indicating greater severity of symptoms. Although the PANSS is traditionally scored with a range of 30-210, with a score of absent = 1 (for each item), for this analysis the range was set from 0-180, with a score of absent = 0 (for each item).
Time frame: Day 14 of Part 2
Population: Efficacy analysis population was defined as participants who received at least one dose of study drug. The study was terminated early by the sponsor due to lack of enrollment. No formal statistical analysis was done due to the very small sample size in this study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Preladenant | Part 2: PANSS Total Score at Day 14 | 43.5000 Score on a scale | Standard Deviation 28.543 |
| Part 1: Placebo | Part 2: PANSS Total Score at Day 14 | 27.75 Score on a scale | Standard Deviation 11.2361 |