Different Safety Profile of Risperidone and Paliperidone Extended-release

This study has been completed.
Sponsor:
Collaborators:
AstraZeneca
Janssen Korea, Ltd., Korea
Korea Otsuka Pharmaceutical Co.,Ltd.
Sanofi-Synthelabo
Information provided by (Responsible Party):
Young Chul Chung, Chonbuk National University Hospital
ClinicalTrials.gov Identifier:
NCT01284959
First received: January 25, 2011
Last updated: September 21, 2012
Last verified: September 2012
  Purpose

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.


Condition Intervention Phase
Schizophrenia
Drug: risperidone
Drug: paliperidone ER
Drug: placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Official Title: Different Safety Profile of Risperidone and Paliperidone Extended-release: a Double-blind, Placebo-controlled Trial With Healthy Volunteers

Resource links provided by NLM:


Further study details as provided by Chonbuk National University Hospital:

Primary Outcome Measures:
  • Assessment of Negative Symptoms and Neuroleptic Induced Deficit Syndromes by Objective Rating Scales [ Time Frame: baseline and 2hr after third medication ] [ Designated as safety issue: No ]

    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.



Secondary Outcome Measures:
  • Assessment of Adverse Events by Objective Rating Scales and Self Report Scales [ Time Frame: baseline and 2hr after third medication ] [ Designated as safety issue: Yes ]

    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.


  • Assessment of Adverse Events by Objective Rating Scales and Self Report Scales [ Time Frame: baseline and 50hr after third medication ] [ Designated as safety issue: Yes ]
    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.

  • Assessment of Cognitive Functioning-1 [ Time Frame: baseline and 50hr after third medication ] [ Designated as safety issue: No ]

    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.


  • Symptoms Assessment by Objective Rating Scales [ Time Frame: baseline and 50hr after third medication ] [ Designated as safety issue: No ]
    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.

  • Assessment of Cognitive Functioning-2 [ Time Frame: baseline and 50hr after third medication ] [ Designated as safety issue: No ]

    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.


  • Assessment of Cognitive Functioning-3 [ Time Frame: baseline and 50hr after third medication ] [ Designated as safety issue: No ]

    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



Enrollment: 34
Study Start Date: June 2010
Study Completion Date: December 2010
Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: risperidone
Drug: risperidone 3mg, PO two times Groups: risperidone
Drug: risperidone
risperidone 3mg, PO, 3 times
Other Name: Rispedal
Placebo Comparator: placebo
drug: lactose, PO 3 times group: placebo
Drug: placebo
lactose PO, 3times
Other Name: placebo
Experimental: paliperidone ER
drug : Paliperidone ER 6mg PO, two times group: paliperidone ER
Drug: paliperidone ER
paliperidone ER 6mg, PO,3 times
Other Name: Invega

Detailed 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.

  Eligibility

Ages Eligible for Study:   18 Years to 38 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01284959

Locations
Korea, Republic of
Chonbuk national university hospital
Chonju, Korea, Republic of
Sponsors and Collaborators
Chonbuk National University Hospital
AstraZeneca
Janssen Korea, Ltd., Korea
Korea Otsuka Pharmaceutical Co.,Ltd.
Sanofi-Synthelabo
Investigators
Principal Investigator: Young-chul Chung, M.D., Ph.D. Chonbuk National University Hospital
  More Information

No publications provided

Responsible Party: Young Chul Chung, Professor of Psychiatry, Chonbuk National University Hospital
ClinicalTrials.gov Identifier: NCT01284959     History of Changes
Other Study ID Numbers: CBIRB1005-58
Study First Received: January 25, 2011
Results First Received: February 29, 2012
Last Updated: September 21, 2012
Health Authority: Korea: Institutional Review Board

Keywords provided by Chonbuk National University Hospital:
cognitive function
subjective experiences
neuroleptic-induced deficit syndrome
paliperidone extended-release
risperidone

Additional relevant MeSH terms:
Schizophrenia
Schizophrenia and Disorders with Psychotic Features
Mental Disorders
Risperidone
9-hydroxy-risperidone
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Central Nervous System Agents
Therapeutic Uses
Psychotropic Drugs
Dopamine Antagonists
Dopamine Agents

ClinicalTrials.gov processed this record on August 21, 2014