Different Safety Profile of Risperidone and Paliperidone Extended-release

Schizophrenia Clinical Trial

Official title:

Different Safety Profile of Risperidone and Paliperidone Extended-release: a Double-blind, Placebo-controlled Trial With Healthy Volunteers

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01284959
• Other study ID #: CBIRB1005-58
• Status: Completed
• Phase: Phase 4
• First received: January 25, 2011
• Last updated: September 21, 2012
• Start date: June 2010
• Est. completion date: December 2010

Study information

• Verified date: September 2012
• Source: Chonbuk National University Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: Korea: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

The main objective of this study was to assess subjective experiences related to secondary negative symptoms and cognitive performance in healthy volunteers in response to multiple doses of paliperidone ER and risperidone in a double-blind, placebo-controlled trial. Adverse events caused by these drugs were also evaluated.

Description:

A new oral antipsychotic drug, paliperidone extended-release (ER), has recently been developed and might represent an innovative approach in the treatment of schizophrenia. Paliperidone is 9-hydroxyrisperidone, the chief active metabolite of risperidone. Although paliperidone possesses a pharmacological profile very similar to that of its parent compound, it has many different pharmacokinetic and pharmacodynamic characteristics compared with risperidone (Pani and Marchese, 2009). First, paliperidone ER utilizes an osmotic controlled-release oral delivery system (OROS), resulting in a more stable serum concentration and reduced likelihood of causing unexpected over- or under-dosages due to CYP2D6 genetic variability. Second, paliperidone does not undergo significant hepatic metabolism, and the drug is predominantly excreted by the kidney as an unchanged drug; whereas risperidone is extensively metabolized by the CYP2D6 hepatic enzyme. Third, the off-rate for dissociation from human cloned D2 receptors in tissue culture cells is faster for paliperidone (60 s) compared with risperidone (27 min) (Seeman, 2005). Due to its looser binding to D2 receptors, paliperidone should be associated with a reduced risk of extrapyramidal side effects compared with its parent drug. Fourth, ex vivo studies have indicated that paliperidone injections induce relatively smaller H1 occupancy levels in the brains of animals when compared with similar dosages of risperidone (Schotte, et al. 1995 and 1996). This may contribute to a reduced sedative effect and less weight gain secondary to paliperidone when compared with risperidone. Finally, paliperidone has no relevant affinity toward muscarinic receptors, resulting in the absence of anticholinergic side effects; this is another important benefit compared with risperidone (Schotte, et al. 1996). Therefore, paliperidone would be the drug of choice in young psychotic patients for whom preservation or improvement of cognitive function is critical. All of these properties might be associated with improved efficacy and better tolerability of paliperidone ER compared with risperidone. In support of this view, recent studies (Canuso, et al. 2008 and 2010) demonstrated that switching from risperidone to paliperidone ER resulted in improvements in medication satisfaction, Positive and Negative Syndrome Scale (PANSS) (Kay, et al. 1987) score, and abbreviated Extrapyramidal Symptoms Rating Scale (Chouinard and Margolese, 2005) score. However, to date, no clinical trials have investigated the relative superiority of paliperidone ER over risperidone in terms of effects on cognitive function. Recently, interest in the negative subjective experiences secondary to antipsychotic medications has been renewed, as these experiences are key factors in adherence and clinical outcomes (Awad, 1993; van Putten and May, 1978). Artaloytia et al. (2006) reported that risperidone induced negative symptoms in healthy volunteers, which might be termed secondary negative symptoms. Therefore, we hypothesized that paliperidone ER has a better safety profile in terms of subjective experiences and cognitive function compared with risperidone. Research on the effects of antipsychotic drugs on subjective experiences and cognitive function in patients with schizophrenia may be hampered by numerous confounding factors, such as pathological features of the illness, patient motivation, or concomitant medications. Investigating the effects of antipsychotic drugs in healthy subjects provides a method for controlling these variables. Therefore, the main objective of this study was to assess subjective experiences related to secondary negative symptoms and cognitive performance in healthy volunteers in response to multiple doses of paliperidone ER and risperidone in a double-blind, placebo-controlled trial. Adverse events caused by these drugs were also evaluated.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 34
• Est. completion date: December 2010
• Est. primary completion date: July 2010
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 38 Years

Eligibility

Inclusion Criteria:

• Aged 18-38 years and meet no DSM-IV diagnostic criteria as assessed by using the Structured Clinical Interview for DSM-IV, research version

Exclusion Criteria:

Anyone who:

• Participated in other clinical trials within 30 days from the start of this clinical trial or is currently participating in one

• Has progressive disease or in unstable medical condition unfit for the trial

• Has been diagnosed in psychiatric terms in the past, depends on psychotropic substance, or has overdosed or depended on the substance or alcohol (except for coffee or tobacco) within 1 month from the trial start

• Is suicidal or highly probable of suicides; OR

• Has test results considered clinically meaningful

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator)

Related Conditions & MeSH terms

• Schizophrenia

Intervention

Drug:
• risperidone
risperidone 3mg, PO, 3 times
• paliperidone ER
paliperidone ER 6mg, PO,3 times
• placebo
lactose PO, 3times

Locations

Country	Name	City	State
Korea, Republic of	Chonbuk national university hospital	Chonju

Sponsors (5)

Lead Sponsor	Collaborator
Chonbuk National University Hospital	AstraZeneca, Janssen Korea, Ltd., Korea, Korea Otsuka Pharmaceutical Co.,Ltd., Sanofi-Synthelabo

Country where clinical trial is conducted

Korea, Republic of, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Assessment of Negative Symptoms and Neuroleptic Induced Deficit Syndromes by Objective Rating Scales	SANS(Scale for the Assessment of Negative Symptoms), NIDSS(Neuroleptic induced Deficit Syndrome Scale) In NIDSS, the average of number 1 to 5 is blunted affect, the average of number 16 to 20 is avolition, the average of number 6 to 15 is cognition, the average of all score is total.; Minimum of NIDSS(avolition, blunted affect, cognition, total) is -3, maximum is +3.(subscale score and total) '+' is better outcome, '-' is worse outcome. Minimum of SANS-Global score for alogia and blunted affect is 0, Maximum of SANS-Global score for alogia and blunted affect is 5 The higher number is worse outcome. The zeros are measured and Calcuated value This outcome measure is reporting a change between baseline and 2hr after third medication.	baseline and 2hr after third medication	No
Secondary	Assessment of Adverse Events by Objective Rating Scales and Self Report Scales	DIEPSS(Drug-Induced Extrapyramidal Symptoms Scale), VAS(Visual analog scale);mental sedation (alert-drowsy, muzzy-clear headed, mentally slow-quick witted, attentive-dreamy), physical sedation (strong-feeble, well coordinated-clumsy, lethargic-energetic, incompetent-proficient), tranquilization (calm-excited, contented-discontented, troubled-tranquil, tense-relaxed), and other types of feelings (happy-sad, antagonistic-amicable, interested-bored, withdrawn-gregarious) Minimum of VAS(Mental sedation score,Physical sedation score,Total score) is 0, Maximum is 10.; VAS-total score is average of all subscale scores. Minimum of DIEPSS is 0, Maximum is 4. The higher number is worse outcome. The score ranges are for subscale score. This outcome measure is reporting a change between baseline and 2hr after third medication.	baseline and 2hr after third medication	Yes
Secondary	Assessment of Adverse Events by Objective Rating Scales and Self Report Scales	DIEPSS(Drug-Induced Extrapyramidal Symptoms Scale), VAS(Visual analog scale);mental sedation (alert-drowsy, muzzy-clear headed, mentally slow-quick witted, attentive-dreamy), physical sedation (strong-feeble, well coordinated-clumsy, lethargic-energetic, incompetent-proficient), tranquilization (calm-excited, contented-discontented, troubled-tranquil, tense-relaxed), and other types of feelings (happy-sad, antagonistic-amicable, interested-bored, withdrawn-gregarious) Minimum of VAS is 0, Maximum is 10 Minimum of DIEPSS is 0, Maximum is 4 The higher number is worse outcome. The score ranges are for subscale score. This outcome measure is reporting a change between baseline and 50hr after third medication.	baseline and 50hr after third medication	Yes
Secondary	Assessment of Cognitive Functioning-1	CNT(Computerized Neuro-Cognitive Function Test System); The tests included a word fluency test. All of the assessments except the CNT were conducted immediately prior to administration of the medication and at 2 (for risperidone and placebo) or 24 h (for paliperidone ER) after the first and third administrations of the study medications.; Minimum of Wisconsin card sorting test-Category completed is 0, Maximum is 6, the lower number is worse outcome.; Minimum of Wisconsin card sorting test-Perseverative response and Trials to complete is 0, Maximum is 128, the lower number is worse outcome.; Minimum of Wisconsin card sorting test-Perseverative error is 0, Maximum is 128, the higher number is worse outcome.; Minimum of Word-fluency test is 0 and no maximum value, the higher number is better outcome.; The score ranges are for subscale score. This outcome measure is reporting a change between baseline and 50hr after third medication.	baseline and 50hr after third medication	No
Secondary	Symptoms Assessment by Objective Rating Scales	SANS(Scale for the Assessment of Negative Symptoms), NIDSS(Neuroleptic induced Deficit Syndrome Scale) Minimum of NIDSS is -3, maximum of NIDSS is +3. '+' is better outcome, '-' is worse outcome. Minimum of SNAS-Global score is 0, Maximum of SNAS-Global score is 5 The higher number is worse outcome. The zeros are measured and Calcuated value. The score ranges are for subscale score. This outcome measure is reporting a change between baseline and 50hr after third medication.	baseline and 50hr after third medication	No
Secondary	Assessment of Cognitive Functioning-2	CNT(Computerized Neuro-Cognitive Function Test System); The tests included the Stroop test, Trail-Making Test B (TMT B). All of the assessments except the CNT were conducted immediately prior to administration of the medication and at 2 (for risperidone and placebo) or 24 h (for paliperidone ER) after the first and third administrations of the study medications Minimum of Stroop test is 0, no maximum limit, the higher number is worse outcome.; Minimum of Trail making test B is 0 and no maximum limit, the higher number is worse outcome.; The score ranges are for subscale score. This outcome measure is reporting a change between baseline and 50hr after third medication.	baseline and 50hr after third medication	No
Secondary	Assessment of Cognitive Functioning-3	CNT(Computerized Neuro-Cognitive Function Test System); The tests included Wisconsin Card-Sorting Test (WCST). All of the assessments except the CNT were conducted immediately prior to administration of the medication and at 2 (for risperidone and placebo) or 24 h (for paliperidone ER) after the first and third administrations of the study medications.; Minimum of Wisconsin card sorting test-Category completed is 0, Maximum is 6, the lower number is worse outcome.; Minimum of Wisconsin card sorting test-Perseverative response and Trials to complete is 0, Maximum is 128, the lower number is worse outcome.; Minimum of Wisconsin card sorting test-Trials to complete first category trials is 0, Maximum is 128 and minimum of Wisconsin card sorting test-Perseverative error is 0, Maximum is 128, the higher number is worse outcome.; The score ranges are for subscale score. This outcome measure is reporting a change between baseline and 50hr after th	baseline and 50hr after third medication	No