- Email: [email protected]
305 – A comparative analysis of paliperidone ER and quetiapine in patients with a recent, acute exacerbation of schizophrenia
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ABSTRACTS / Schizophrenia Research 98 (2008) 3–199
Background: Extended release quetiapine fumarate (quetiapine XR) is a new, once-daily formulation developed to enable rapid increases (2 days) to the effective dose range (400–800 mg/day) in schizophrenia. The tolerability of quetiapine XR was analyzed during rapid dose escalation. Methods: A post-hoc analysis of pooled data from two 6-week, double-blind, double-dummy, randomized, placebo-controlled trials in acute schizophrenia (D1444C00132, D1444C00133). Both studies included twice-daily quetiapine immediate release (IR) arms. Target doses were reached by Days 2 (400, 600 mg/day) and 3 (800 mg/day) in the quetiapine XR groups and by Days 5 and 7 in the quetiapine IR 400 mg/day and 800 mg/day groups, respectively. Adverse event (AE) data from the first week of the studies are reported here. Results: The incidence of AEs during the first 7 days of treatment with quetiapine XR (n = 679) and IR (n = 238) was similar (43% and 42%, respectively), compared with 32% for placebo (n = 235). Serious AEs were experienced by 1.2%, 1.3% and 0.4% of patients receiving quetiapine XR, quetiapine IR and placebo, respectively. Rates of patient discontinuation due to AEs during the first 7 days of treatment were 1.5%, 0.8% and 0.9% for quetiapine XR, quetiapine IR and placebo, respectively. The most common treatment-related AEs with quetiapine XR, quetiapine IR and placebo were somnolence (8.4%, 8.8%, 1.3%), sedation (7.1%, 9.2%, 3.0%), dry mouth (6.0%, 5.9%, 0.9%) and dizziness (4.7%, 3.8%, 2.6%). No relationship between dose and incidence of these AEs was seen with quetiapine XR or IR. Conclusions: Rapid dose escalation of quetiapine XR is well-tolerated in patients with acute schizophrenia. Acknowledgement: These studies were sponsored by AstraZeneca. doi:10.1016/j.schres.2007.12.370
from 0.25 mg on day 1 and approximately doubled daily to target dosage. Primary inclusion criteria: schizophrenia diagnosis for ≥2 years; antipsychotic treatment unchanged for 1-month pre-screening; PANSS TS ≥ 60; CGI-S ≥ 4; PANSS single-item P7 (hostility) or G8 (uncooperativeness) ≤4; residual symptoms or insufficient tolerance to current antipsychotic treatment. Primary efficacy assessment: time to deterioration (TTD) from randomization; secondary assessments included baseline-to-endpoint change in PANSS TS. Results: Bifeprunox patients experienced significantly longer TTD than placebo (20 mg: P= 0.008; 30 mg: P =0.006). With bifeprunox, PANSS TS decreased from baseline to week 9 then remained stable to month 6; with placebo it decreased at week 2 then steadily increased to above baseline by month 6. Adjusted mean changes from baseline in PANSS TS were significantly different for both bifeprunox groups versus placebo at week 6 and all subsequent time-points, to month 6. Most common adverse events (≥5%, ≥2× placebo) included nausea, vomiting, anorexia, dizziness, akathisia, dyskinesia and asthenia. Conclusions: Bifeprunox 20 and 30 mg treatment of stable patients with schizophrenia initially decreased then stabilized PANSS TS, indicating long-term treatment viability in post-acute maintenancephase patients. doi:10.1016/j.schres.2007.12.371
305 – A COMPARATIVE ANALYSIS OF PALIPERIDONE ER AND QUETIAPINE IN PATIENTS WITH A RECENT, ACUTE EXACERBATION OF SCHIZOPHRENIA C. Canuso 1, B. Dirks 1, J. Carothers 1, Y. Zhu 1, C. Kosik-Gonzalez 1. 1
304 – EFFICACY OF BIFEPRUNOX IN PATIENTS IN THE POST-ACUTE, MAINTENANCE PHASE OF SCHIZOPHRENIA: FINDINGS FROM A 6-MONTH STUDY M. Bourin 1, M. Debelle 2, J. Heisterberg 2, M. Krog Josiassen 3, J. Buch Østergaard 2, E. Sands 4. 1
Department of Neurobiology of Anxiety and Depression, University of Nantes, Nantes, France 2 International Clinical Research – Psychosis, H. Lundbeck A/S, Copenhagen, Denmark 3 International Clinical Research – Biostatistics, H. Lundbeck A/S, Copenhagen, Denmark 4 Research and Development, Solvay Pharmaceuticals, Inc., Marietta, United States Presenting Author details: [email protected] rue Gaston Veil, 53508 Nantes, France, Tel.: +33 2 40412852. Background: Evaluate the efficacy of the investigational partial dopamine agonist bifeprunox over 6 months in post-acute, maintenance-phase schizophrenia. This presentation examines the secondary efficacy measure, change in PANSS total score (TS), to support the study's positive primary efficacy finding. Methods: A total of 497 stable patients with schizophrenia were randomly assigned, double-blind, to once-daily bifeprunox 20 mg (n = 159), 30 mg (n = 172), or placebo (n = 166). Bifeprunox was titrated
Ortho-McNeil Janssen Scientific Affairs, L.L.C., Titusville, USA
Presenting Author details: [email protected] 1125 Trenton-Harbourton Road, 08560 Titusville, United States, Tel.: +609 730 7732. Background: An ongoing double-blind, placebo-controlled study comparing the effects of paliperidone extended-release (ER) and quetiapine and polypharmacy use in patients with a recent acute exacerbation of schizophrenia requiring hospitalization. Methods: This is an international 6-week, double-blind study of recently and acutely exacerbated inpatients with schizophrenia randomized to paliperidone ER, quetiapine or placebo in a 2:2:1 ratio. The study consists of a 2-week monotherapy phase (primary endpoint) followed by a 4-week additive therapy phase. Target doses are 9 or 12 mg/day of paliperidone ER and 600 or 800 mg/day of quetiapine. Outcome measures include the Positive and Negative Syndrome Scale (PANSS), Composite Treatment Response (PANSS total score reduction ≥ 30% and Clinical Global Impressions – Change score ≤2), Readiness for Discharge Questionnaire, Medication Satisfaction Questionnaire, adverse events and use of additional psychotropic medications. Results: A total of 395 patients have been randomized. Preliminary blinded baseline data are available on 150 patients, of whom 69.3% (n = 104) completed the 6-week, double-blind study. In this subsample, the mean (SD) age is 37.5 (11.2) and 73.6% are male. The mean (SD) body mass index is 26.8 kg/m2 (6.7). The mean (SD) baseline PANSS and Clinical Global Impressions – Severity scores are 100.2 (13.4) and 5.1(0.4), respectively.
ABSTRACTS / Schizophrenia Research 98 (2008) 3–199 Conclusions: Preliminary baseline data suggest that, on average, subjects included are markedly symptomatic, reflective of recent and acute illness. Results from the full 395-subject sample will be presented and will provide direct comparative data on paliperidone ER and quetiapine in schizophrenia patients who require hospitalization due to a recent exacerbation. Acknowledgement: Supported by funding from Ortho-McNeil Janssen Scientific Affairs, L.L.C. doi:10.1016/j.schres.2007.12.372
306 – PHARMACODYNAMICS OF PALIPERIDONE EXTENDED-RELEASE TABLETS AND IMMEDIATE-RELEASE RISPERIDONE IN SCHIZOPHRENIA S. Rossenu 1, A. Cleton 1, K. Talluri 1, I. Francetic 2, C. Canuso 3, B. Remmerie 1, L. Janssens 1, M. Eerdekens 1, S. Boom 1. 1
Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium 2 Institute of Clinical Pharmacology, Clinical Hospital Centre, Zagreb, Croatia 3 Johnson & Johnson Pharmaceutical Research and Development, Titusville, NJ, USA Presenting Author details: [email protected] 1125 Trenton-Harbourton Road, 08560 Titusville, United States, Tel.: +609 730 7732. Background: Orthostatic tolerability and prolactin levels associated with paliperidone extended-release tablets (ER) and immediate-release (IR) risperidone treatment were investigated. Methods: A double-blind, placebo and active-controlled, parallelgroup study randomized schizophrenia patients (n = 113) to: placebo (Day 1) and paliperidone ER 12 mg (Days 2–6) (PBO/PAL); paliperidone ER 12 mg (Days 1–6) (PAL); or IR risperidone 2 mg (Day 1) and 4 mg (Days 2–6) (RIS). Day 1 changes from baseline in mean 2- and 22-h orthostatic supine blood pressure (SBP) (predicted tmax for IR risperidone and paliperidone ER, respectively) were analyzed. Noninferiority of paliperidone ER 12 mg to IR risperidone 2 mg was confirmed for initial orthostatic tolerability if the lower limit 95% confidence interval (CI) for difference between groups was above − 10.0 mmHg. Serum prolactin levels were also assessed. Results: Mean difference on Day 1 between paliperidone ER and IR risperidone in average orthostatic 1-min SBP changes from baseline to 2- and 22-h post dose = − 1.02 mmHg (95%CI − 4.07, 2.02). Maximal mean prolactin concentrations for PAL and RIS on Day 1 = 71.8 ng/mL (6.5 h post dose) and 89.7 ng/mL (2.6 h post dose), respectively. On Day 6, maximum prolactin concentrations were comparable across groups; peak/trough variation was considerably lower in paliperidone ER groups. Conclusions: Paliperidone ER 12 mg was noninferior to IR risperidone 2 mg for initial orthostatic tolerability in schizophrenia patients; treatment can be initiated at ≤12 mg, with no dose titration needed to mitigate orthostatic hypotension. Absolute increases in prolactin levels were similar between groups, although a reduced magnitude in peak/ trough variation was observed with paliperidone ER. Acknowledgement: Data previously presented at Pharmaceutical Sciences World Congress, 2007. Supported by funding from Johnson
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& Johnson Pharmaceutical Services, LLC, and Johnson & Johnson Pharmaceutical Research & Development. doi:10.1016/j.schres.2007.12.373
307 – METABOLIC MONITORING OF SECOND-GENERATION ANTIPSYCHOTIC PRESCRIPTION: GAP BETWEEN INTERNATIONAL RECOMMENDATIONS AND CLINICAL PRACTICE H. Verdoux 1,2,3, S. Boulon 3, A. Cougnard 1,2. 1
INSERM U 657, 146 rue Léo Saignat, 33076 Bordeaux, France University Victor Segalen Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux France 3 Centre Hospitalier Charles Perrens, Bordeaux, France 2
Presenting Author details: [email protected] 146 rue Léo Saignat, 33076 BORDEAUX, France, Tel.: +33 557 574 655; fax: +33 557 574 660. Background: To explore whether international recommendations for metabolic monitoring of patients receiving second-generation antipsychotics are respected by prescribers in clinical practice. Methods: Survey questionnaires were mailed to all state hospital psychiatrists practicing in South-Western France (n = 219). Psychiatrists were asked to give information on the metabolic monitoring of (i) the last seen patient with first initiation of a second-generation antipsychotic (ii) the last seen patient treated by the same secondgeneration antipsychotic for at least 1 year. Results: The response rate was 24.7%. Information was obtained on 43 patients with an incident prescription of a second-generation antipsychotic. Only 2 patients had a complete assessment of baseline metabolic risk according to international recommendations, and none of the markers of metabolic risk was controlled for more than one out of four patients. For example, BMI were not assessed before prescription for 80% of patients. Adequate assessment was less frequent in women, but was not influenced by other patient's or prescriber's characteristics. Information obtained on 36 patients with a continuous prescription of the same second-generation antipsychotic showed that only 16.7% of patients had over the prior year a metabolic monitoring in conformity with international recommendations. For example, BMI was never monitored for 39% patients. The adequacy of metabolic monitoring was not associated with patient's and prescriber's characteristics. Conclusions: This study highlights the gap between international recommendations and clinical practice. Due to a potential selection bias of responders favoring those with updated knowledge of international recommendations, the percentages of adequate monitoring might even be lower in the whole population of prescribers concerned by the survey. Prescribers are yet insufficiently aware of the fact that subjects prescribed antipsychotics are exposed to potentially severe metabolic side-effects and efforts have to be made in initial training, as well as in continuing medical education, to improve level of knowledge about these risks.
doi:10.1016/j.schres.2007.12.374
ABSTRACTS / Schizophrenia Research 98 (2008) 3–199
Background: Extended release quetiapine fumarate (quetiapine XR) is a new, once-daily formulation developed to enable rapid increases (2 days) to the effective dose range (400–800 mg/day) in schizophrenia. The tolerability of quetiapine XR was analyzed during rapid dose escalation. Methods: A post-hoc analysis of pooled data from two 6-week, double-blind, double-dummy, randomized, placebo-controlled trials in acute schizophrenia (D1444C00132, D1444C00133). Both studies included twice-daily quetiapine immediate release (IR) arms. Target doses were reached by Days 2 (400, 600 mg/day) and 3 (800 mg/day) in the quetiapine XR groups and by Days 5 and 7 in the quetiapine IR 400 mg/day and 800 mg/day groups, respectively. Adverse event (AE) data from the first week of the studies are reported here. Results: The incidence of AEs during the first 7 days of treatment with quetiapine XR (n = 679) and IR (n = 238) was similar (43% and 42%, respectively), compared with 32% for placebo (n = 235). Serious AEs were experienced by 1.2%, 1.3% and 0.4% of patients receiving quetiapine XR, quetiapine IR and placebo, respectively. Rates of patient discontinuation due to AEs during the first 7 days of treatment were 1.5%, 0.8% and 0.9% for quetiapine XR, quetiapine IR and placebo, respectively. The most common treatment-related AEs with quetiapine XR, quetiapine IR and placebo were somnolence (8.4%, 8.8%, 1.3%), sedation (7.1%, 9.2%, 3.0%), dry mouth (6.0%, 5.9%, 0.9%) and dizziness (4.7%, 3.8%, 2.6%). No relationship between dose and incidence of these AEs was seen with quetiapine XR or IR. Conclusions: Rapid dose escalation of quetiapine XR is well-tolerated in patients with acute schizophrenia. Acknowledgement: These studies were sponsored by AstraZeneca. doi:10.1016/j.schres.2007.12.370
from 0.25 mg on day 1 and approximately doubled daily to target dosage. Primary inclusion criteria: schizophrenia diagnosis for ≥2 years; antipsychotic treatment unchanged for 1-month pre-screening; PANSS TS ≥ 60; CGI-S ≥ 4; PANSS single-item P7 (hostility) or G8 (uncooperativeness) ≤4; residual symptoms or insufficient tolerance to current antipsychotic treatment. Primary efficacy assessment: time to deterioration (TTD) from randomization; secondary assessments included baseline-to-endpoint change in PANSS TS. Results: Bifeprunox patients experienced significantly longer TTD than placebo (20 mg: P= 0.008; 30 mg: P =0.006). With bifeprunox, PANSS TS decreased from baseline to week 9 then remained stable to month 6; with placebo it decreased at week 2 then steadily increased to above baseline by month 6. Adjusted mean changes from baseline in PANSS TS were significantly different for both bifeprunox groups versus placebo at week 6 and all subsequent time-points, to month 6. Most common adverse events (≥5%, ≥2× placebo) included nausea, vomiting, anorexia, dizziness, akathisia, dyskinesia and asthenia. Conclusions: Bifeprunox 20 and 30 mg treatment of stable patients with schizophrenia initially decreased then stabilized PANSS TS, indicating long-term treatment viability in post-acute maintenancephase patients. doi:10.1016/j.schres.2007.12.371
305 – A COMPARATIVE ANALYSIS OF PALIPERIDONE ER AND QUETIAPINE IN PATIENTS WITH A RECENT, ACUTE EXACERBATION OF SCHIZOPHRENIA C. Canuso 1, B. Dirks 1, J. Carothers 1, Y. Zhu 1, C. Kosik-Gonzalez 1. 1
304 – EFFICACY OF BIFEPRUNOX IN PATIENTS IN THE POST-ACUTE, MAINTENANCE PHASE OF SCHIZOPHRENIA: FINDINGS FROM A 6-MONTH STUDY M. Bourin 1, M. Debelle 2, J. Heisterberg 2, M. Krog Josiassen 3, J. Buch Østergaard 2, E. Sands 4. 1
Department of Neurobiology of Anxiety and Depression, University of Nantes, Nantes, France 2 International Clinical Research – Psychosis, H. Lundbeck A/S, Copenhagen, Denmark 3 International Clinical Research – Biostatistics, H. Lundbeck A/S, Copenhagen, Denmark 4 Research and Development, Solvay Pharmaceuticals, Inc., Marietta, United States Presenting Author details: [email protected] rue Gaston Veil, 53508 Nantes, France, Tel.: +33 2 40412852. Background: Evaluate the efficacy of the investigational partial dopamine agonist bifeprunox over 6 months in post-acute, maintenance-phase schizophrenia. This presentation examines the secondary efficacy measure, change in PANSS total score (TS), to support the study's positive primary efficacy finding. Methods: A total of 497 stable patients with schizophrenia were randomly assigned, double-blind, to once-daily bifeprunox 20 mg (n = 159), 30 mg (n = 172), or placebo (n = 166). Bifeprunox was titrated
Ortho-McNeil Janssen Scientific Affairs, L.L.C., Titusville, USA
Presenting Author details: [email protected] 1125 Trenton-Harbourton Road, 08560 Titusville, United States, Tel.: +609 730 7732. Background: An ongoing double-blind, placebo-controlled study comparing the effects of paliperidone extended-release (ER) and quetiapine and polypharmacy use in patients with a recent acute exacerbation of schizophrenia requiring hospitalization. Methods: This is an international 6-week, double-blind study of recently and acutely exacerbated inpatients with schizophrenia randomized to paliperidone ER, quetiapine or placebo in a 2:2:1 ratio. The study consists of a 2-week monotherapy phase (primary endpoint) followed by a 4-week additive therapy phase. Target doses are 9 or 12 mg/day of paliperidone ER and 600 or 800 mg/day of quetiapine. Outcome measures include the Positive and Negative Syndrome Scale (PANSS), Composite Treatment Response (PANSS total score reduction ≥ 30% and Clinical Global Impressions – Change score ≤2), Readiness for Discharge Questionnaire, Medication Satisfaction Questionnaire, adverse events and use of additional psychotropic medications. Results: A total of 395 patients have been randomized. Preliminary blinded baseline data are available on 150 patients, of whom 69.3% (n = 104) completed the 6-week, double-blind study. In this subsample, the mean (SD) age is 37.5 (11.2) and 73.6% are male. The mean (SD) body mass index is 26.8 kg/m2 (6.7). The mean (SD) baseline PANSS and Clinical Global Impressions – Severity scores are 100.2 (13.4) and 5.1(0.4), respectively.
ABSTRACTS / Schizophrenia Research 98 (2008) 3–199 Conclusions: Preliminary baseline data suggest that, on average, subjects included are markedly symptomatic, reflective of recent and acute illness. Results from the full 395-subject sample will be presented and will provide direct comparative data on paliperidone ER and quetiapine in schizophrenia patients who require hospitalization due to a recent exacerbation. Acknowledgement: Supported by funding from Ortho-McNeil Janssen Scientific Affairs, L.L.C. doi:10.1016/j.schres.2007.12.372
306 – PHARMACODYNAMICS OF PALIPERIDONE EXTENDED-RELEASE TABLETS AND IMMEDIATE-RELEASE RISPERIDONE IN SCHIZOPHRENIA S. Rossenu 1, A. Cleton 1, K. Talluri 1, I. Francetic 2, C. Canuso 3, B. Remmerie 1, L. Janssens 1, M. Eerdekens 1, S. Boom 1. 1
Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium 2 Institute of Clinical Pharmacology, Clinical Hospital Centre, Zagreb, Croatia 3 Johnson & Johnson Pharmaceutical Research and Development, Titusville, NJ, USA Presenting Author details: [email protected] 1125 Trenton-Harbourton Road, 08560 Titusville, United States, Tel.: +609 730 7732. Background: Orthostatic tolerability and prolactin levels associated with paliperidone extended-release tablets (ER) and immediate-release (IR) risperidone treatment were investigated. Methods: A double-blind, placebo and active-controlled, parallelgroup study randomized schizophrenia patients (n = 113) to: placebo (Day 1) and paliperidone ER 12 mg (Days 2–6) (PBO/PAL); paliperidone ER 12 mg (Days 1–6) (PAL); or IR risperidone 2 mg (Day 1) and 4 mg (Days 2–6) (RIS). Day 1 changes from baseline in mean 2- and 22-h orthostatic supine blood pressure (SBP) (predicted tmax for IR risperidone and paliperidone ER, respectively) were analyzed. Noninferiority of paliperidone ER 12 mg to IR risperidone 2 mg was confirmed for initial orthostatic tolerability if the lower limit 95% confidence interval (CI) for difference between groups was above − 10.0 mmHg. Serum prolactin levels were also assessed. Results: Mean difference on Day 1 between paliperidone ER and IR risperidone in average orthostatic 1-min SBP changes from baseline to 2- and 22-h post dose = − 1.02 mmHg (95%CI − 4.07, 2.02). Maximal mean prolactin concentrations for PAL and RIS on Day 1 = 71.8 ng/mL (6.5 h post dose) and 89.7 ng/mL (2.6 h post dose), respectively. On Day 6, maximum prolactin concentrations were comparable across groups; peak/trough variation was considerably lower in paliperidone ER groups. Conclusions: Paliperidone ER 12 mg was noninferior to IR risperidone 2 mg for initial orthostatic tolerability in schizophrenia patients; treatment can be initiated at ≤12 mg, with no dose titration needed to mitigate orthostatic hypotension. Absolute increases in prolactin levels were similar between groups, although a reduced magnitude in peak/ trough variation was observed with paliperidone ER. Acknowledgement: Data previously presented at Pharmaceutical Sciences World Congress, 2007. Supported by funding from Johnson
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& Johnson Pharmaceutical Services, LLC, and Johnson & Johnson Pharmaceutical Research & Development. doi:10.1016/j.schres.2007.12.373
307 – METABOLIC MONITORING OF SECOND-GENERATION ANTIPSYCHOTIC PRESCRIPTION: GAP BETWEEN INTERNATIONAL RECOMMENDATIONS AND CLINICAL PRACTICE H. Verdoux 1,2,3, S. Boulon 3, A. Cougnard 1,2. 1
INSERM U 657, 146 rue Léo Saignat, 33076 Bordeaux, France University Victor Segalen Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux France 3 Centre Hospitalier Charles Perrens, Bordeaux, France 2
Presenting Author details: [email protected] 146 rue Léo Saignat, 33076 BORDEAUX, France, Tel.: +33 557 574 655; fax: +33 557 574 660. Background: To explore whether international recommendations for metabolic monitoring of patients receiving second-generation antipsychotics are respected by prescribers in clinical practice. Methods: Survey questionnaires were mailed to all state hospital psychiatrists practicing in South-Western France (n = 219). Psychiatrists were asked to give information on the metabolic monitoring of (i) the last seen patient with first initiation of a second-generation antipsychotic (ii) the last seen patient treated by the same secondgeneration antipsychotic for at least 1 year. Results: The response rate was 24.7%. Information was obtained on 43 patients with an incident prescription of a second-generation antipsychotic. Only 2 patients had a complete assessment of baseline metabolic risk according to international recommendations, and none of the markers of metabolic risk was controlled for more than one out of four patients. For example, BMI were not assessed before prescription for 80% of patients. Adequate assessment was less frequent in women, but was not influenced by other patient's or prescriber's characteristics. Information obtained on 36 patients with a continuous prescription of the same second-generation antipsychotic showed that only 16.7% of patients had over the prior year a metabolic monitoring in conformity with international recommendations. For example, BMI was never monitored for 39% patients. The adequacy of metabolic monitoring was not associated with patient's and prescriber's characteristics. Conclusions: This study highlights the gap between international recommendations and clinical practice. Due to a potential selection bias of responders favoring those with updated knowledge of international recommendations, the percentages of adequate monitoring might even be lower in the whole population of prescribers concerned by the survey. Prescribers are yet insufficiently aware of the fact that subjects prescribed antipsychotics are exposed to potentially severe metabolic side-effects and efforts have to be made in initial training, as well as in continuing medical education, to improve level of knowledge about these risks.
doi:10.1016/j.schres.2007.12.374