Study of Preladenant for the Treatment of Neuroleptic Induced Akathisia (Study P05145)

Study Overview
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Brief Summary
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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.

Official Title
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Efficacy of SCH 420814 to Reduce the Frequency or Severity of Neuroleptic Induced Akathisia

Conditions
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Akathisia, Drug-Induced, Antipsychotic Agents, Movement Disorders

Intervention / Treatment
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* Drug: Preladenant
* Drug: Placebo
* Drug: Anticholinergic agents or propanolol
* Drug: Haloperidol


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Preladenant<br>Preladenant 25 mg every 12 hours for 13 days | Drug: Preladenant<br>* Preladenant, one 25 mg capsule, administered orally every 12 hours<br>* Other names: SCH 420814;Drug: Anticholinergic agents or propanolol<br>* 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.<br>Drug: Haloperidol<br>* Participants continued pre-study haloperidol, admistered orally, at a dose of at least 7.5 mg/day<br>|
| Placebo Comparator: Part 1: Placebo<br>Placebo every 12 hours for 13 days | Drug: Placebo<br>* Matching placebo capsule administered orally every 12 hours<br>Drug: Anticholinergic agents or propanolol<br>* 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.<br>Drug: Haloperidol<br>* Participants continued pre-study haloperidol, admistered orally, at a dose of at least 7.5 mg/day<br>|
| Experimental: Part 2: Preladenant<br>Preladenant 25 mg every 12 hours for 13 days | Drug: Preladenant<br>* Preladenant, one 25 mg capsule, administered orally every 12 hours<br>* Other names: SCH 420814;Drug: Haloperidol<br>* Participants continued pre-study haloperidol, admistered orally, at a dose of at least 7.5 mg/day<br>|
| Active Comparator: Part 2: Standard of Care<br>Anticholinergic agents or Propranolol as standard-of-care dosing regimen (supplied by the study site) | Drug: Anticholinergic agents or propanolol<br>* 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.<br>Drug: Haloperidol<br>* Participants continued pre-study haloperidol, admistered orally, at a dose of at least 7.5 mg/day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Up to 13 days | 
| 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). | Up to 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Day 14 of Part 1 | 
| 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). | Day 14 of Part 1 | 
| 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). | Day 14 of Part 2 | 
| 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). | Day 14 of Part 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antipsychotic Agents