61 research outputs found
sj-pdf-1-tpp-10.1177_20451253231200258 – Supplemental material for Comparative effectiveness study of paliperidone palmitate 6-month with a real-world external comparator arm of paliperidone palmitate 1-month or 3-month in patients with schizophrenia
No full textSupplemental material, sj-pdf-1-tpp-10.1177_20451253231200258 for Comparative effectiveness study of paliperidone palmitate 6-month with a real-world external comparator arm of paliperidone palmitate 1-month or 3-month in patients with schizophrenia by Ibrahim Turkoz, Joshua Wong, Benjamin Chee, Uzma Siddiqui, R. Karl Knight, Ute Richarz and Christoph U. Correll in Therapeutic Advances in Psychopharmacology</p
Direct and indirect effects of paliperidone extended-release tablets on negative symptoms of schizophrenia
No full textIbrahim Turkoz, Cynthia A Bossie, Bryan Dirks, Carla M CanusoOrtho-McNeil Janssen Scientific Affairs, LLC, Titusville, NJ, USAAbstract: Direct and indirect effects of the new psychotropic paliperidone extended-release (paliperidone ER) tablets on negative symptom improvement in schizophrenia were investigated using path analysis. A post hoc analysis of pooled data from three 6-week, double-blind, placebo-controlled studies of paliperidone ER in patients experiencing acute exacerbation was conducted. Regression analysis explored relationships between baseline/study characteristics and negative symptoms. Change in Positive and Negative Syndrome Scale (PANSS) negative factor score at endpoint was the dependent variable; explanatory variables included demographic and clinical characteristics. Path analysis determined direct and indirect effects of treatment on negative symptom change. Indirect mediators of negative symptom change in the model included changes in positive symptoms, anxiety/depression symptoms and movement disorders. Path analysis indicated that up to 33% of negative symptom improvement was a direct treatment effect. Indirect effects on negative symptoms were mediated through changes in positive symptoms (51%) and anxiety/depression symptoms (18%), whereas changes in movement disorders had a 2.1% inverse effect. Path analysis indicated that paliperidone ER has a direct effect on negative symptoms. Negative symptom improvement also was indirectly mediated via changes in positive and depressive symptoms.Keywords: antipsychotic, paliperidone ER, path analysis, psychotropic, schizophreni
Predictors of achieving remission in schizophrenia patients treated with paliperidone palmitate 3-month formulation
No full textAbigail I Nash,1 Ibrahim Turkoz,2 Adam J Savitz,2 Maju Mathews,2 Edward Kim1 1Janssen Scientific Affairs, LLC, Titusville, NJ 08560, USA; 2Janssen Research and Development, LLC, Titusville, NJ 08560, USA Purpose: Long-acting injectable (LAI) antipsychotic paliperidone palmitate 3-month formulation (PP3M) is indicated in the United States for the treatment of schizophrenia only after adequate treatment with paliperidone palmitate 1-month formulation (PP1M) for ≥4 months. This analysis aimed to identify patient and disease characteristics during PP1M treatment associated with greater likelihood of achieving remission after transition to PP3M.Methods: A post hoc analysis of a randomized, Phase III, double-blind, noninferiority trial of PP3M vs PP1M (ClinicalTrials.gov identifier: NCT01515423) was conducted in adult patients with schizophrenia. Patients achieving clinical stability after 17 weeks of open-label PP1M were randomized to 48 weeks of double-blind treatment with PP3M or PP1M. The primary objective of this exploratory post hoc analysis was to identify demographic and/or clinical variables associated with persistent remission after treatment with PP3M. Multiple logistic regression analysis identified the following significant predictors of remission: Positive and Negative Syndrome Scale (PANSS) Marder negative symptom factor score, Clinical Global Impression-Severity (CGI-S) total score, and Personal and Social Performance (PSP) total score.Results: At double-blind baseline, a 1-point reduction in Marder negative symptom factor score was associated with a 20% increase in the odds of achieving remission after PP3M treatment; 1-point reduction in CGI-S was associated with a doubling in remission odds; and 7- and 10-point improvements in PSP scores, respectively, were associated with 42% and 65% increases in remission odds.Conclusion: Patients with early clinically meaningful improvements in disease symptoms and severity while establishing stable PP1M dosage are more likely to achieve remission after transition to PP3M. Keywords: long-acting injectable, symptomatic remission, double-blind treatmen
Efficacy and safety of once-monthly injection of paliperidone palmitate in hospitalized Asian patients with acute exacerbated schizophrenia: an open-label, prospective, noncomparative study
No full textHuaFang Li,1 Ibrahim Turkoz,2 Fan Zhang3 1Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Janssen Research & Development, LLC, Titusville, NJ, USA; 3Xi’an Janssen Pharmaceutical Ltd., Beijing, People’s Republic of China Introduction: This single-group, open-label, prospective, noncomparative, multicenter, Phase IV study explored the efficacy and tolerability of paliperidone palmitate (PP) in hospitalized patients with acute exacerbation of schizophrenia.Methods: Asian patients of either sex, between 18 and 65 years of age, diagnosed with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) with acute exacerbations within the previous 4 weeks, were enrolled. Intramuscular PP was initiated at doses of 150 milligram equivalent (mg eq) (day 1) and 100 mg eq (day 8), followed by a monthly maintenance dose between 75 mg eq and 150 mg eq (days 36 and 64). Primary efficacy endpoint was the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score (last-observation-carried-forward) at week 13.Results: Of the 212 enrolled patients, 152 (71.7%) completed the 13-week treatment; withdrawal of consent (24 [11.3%] patients) was the most common reason for study discontinuation. Mean (standard deviation) PANSS total score from baseline (90.0 [17.41]) improved significantly at day 4 (-6.1 [9.27]; 95% confidence interval: -7.38, -4.85; P<0.001) and week 13 endpoint (-23.9 [23.24]; 95% confidence interval: -27.10, -20.78; P<0.001). Similarly, the secondary endpoints (Clinical Global Impression-Severity, Physical and Social Performance, each PANSS subscale, and Marder factor scores) improved significantly from baseline to week 13 endpoint (P<0.001 for all). At week 13, 112/210 (53.3%) patients had a 40% improvement in the PANSS total score (responder rate), and 133/212 (62.7%) patients were ready for hospital discharge. Overall, 139 (65.6%) patients experienced at least one treatment-emergent adverse event (TEAE). Most common (>5%) TEAEs were hyperprolactinemia, constipation, nasopharyngitis, insomnia, increased weight, and tremor. Worsening of schizophrenia (3.3%) and sinus bradycardia (2.0%) were serious TEAEs; no deaths were reported.Conclusion: PP was generally tolerable and efficacious in a hospital setting for the treatment of acute exacerbated schizophrenia with significant improvements in psychotic symptoms, social functioning, and severity of illness. Keywords: paliperidone palmitate, exacerbation, Asian, hospital, acute schizophreni
BLINDED EVALUATIONS OF EFFECT SIZES IN CLINICAL TRIALS: COMPARISONS BETWEEN BAYESIAN AND EM ANALYSES
No full textClinical trials are major and costly undertakings for researchers. Planning a clinical trial involves careful selection of the primary and secondary efficacy endpoints. The 2010 draft FDA guidance on adaptive designs acknowledges possible study design modifications, such as selection and/or order of secondary endpoints, in addition to sample size re-estimation. It is essential for the integrity of a double-blind clinical trial that individual treatment allocation of patients remains unknown. Methods have been proposed for re-estimating the sample size of clinical trials, without unblinding treatment arms, for both categorical and continuous outcomes. Procedures that allow a blinded estimation of the treatment effect, using knowledge of trial operational characteristics, have been suggested in the literature. Clinical trials are designed to evaluate effects of one or more treatments on multiple primary and secondary endpoints. The multiplicity issues when there is more than one endpoint require careful consideration for controlling the Type I error rate. A wide variety of multiplicity approaches are available to ensure that the probability of making a Type I error is controlled within acceptable pre-specified bounds. The widely used fixed sequence gate-keeping procedures require prospective ordering of null hypotheses for secondary endpoints. This prospective ordering is often based on a number of untested assumptions about expected treatment differences, the assumed population variance, and estimated dropout rates. We wish to update the ordering of the null hypotheses based on estimating standardized treatment effects. We show how to do so while the study is ongoing, without unblinding the treatments, without losing the validity of the testing procedure, and with maintaining the integrity of the trial. Our simulations show that we can reliably order the standardized treatment effect also known as signal-to-noise ratio, even though we are unable to estimate the unstandardized treatment effect. In order to estimate treatment difference in a blinded setting, we must define a latent variable substituting for the unknown treatment assignment. Approaches that employ the EM algorithm to estimate treatment differences in blinded settings do not provide reliable conclusions about ordering the null hypotheses. We developed Bayesian approaches that enable us to order secondary null hypotheses. These approaches are based on posterior estimation of signal-to-noise ratios. We demonstrate with simulation studies that our Bayesian algorithms perform better than existing EM algorithm counterparts for ordering effect sizes. Introducing informative priors for the latent variables, in settings where the EM algorithm has been used, typically improves the accuracy of parameter estimation in effect size ordering. We illustrate our method with a secondary analysis of a longitudinal study of depression.Statistic
Long-term tolerability of once-monthly injectable paliperidone palmitate in subjects with recently diagnosed schizophrenia
No full textJennifer Kern Sliwa,1 Cynthia A Bossie,1 Dong-Jing Fu,1 Ibrahim Turkoz,2 Larry Alphs11Janssen Scientific Affairs LLC, 2Janssen Research and Development, LLC, Titusville, NJ, USABackground: A post hoc analysis from a multiphase trial with open-label transition and maintenance phases, a double-blind relapse prevention phase, and an optional open-label extension examined the long-term tolerability with continuous once-monthly injectable paliperidone palmitate 39, 78, 117, or 156 mg (25, 50, 75, or 100 mg equivalents [mg eq] of paliperidone) in subjects with recently diagnosed (&le;5 years; n = 216) versus chronic illness (&gt;5 years; n = 429) schizophrenia.Methods: Adverse events reported at a &ge;2% margin between subgroups were identified. Relative risks (in the recently diagnosed compared with the chronically ill) and 95% confidence intervals (CI) were determined, and CI not including 1 were considered potentially significant.Results: In both subgroups, the mean monthly dose was 109 mg (69.9 mg eq). Continuous mean exposures were 333.9 &plusmn; 271.9 and 308.7 &plusmn; 278.3 days in the recently diagnosed and chronic illness subgroups, respectively. Using the criteria outlined in the methods, nasopharyngitis was a potentially significant event reported in more chronically ill than recently diagnosed subjects at months 6, 9, 12, and endpoint (7.2% versus 2.8%; relative risk 0.384; 95% CI 0.163&ndash;0.907). Influenza (2.8% versus 0.7%; relative risk 3.9; 95% CI 1.003&ndash;15.730) and amenorrhea (3.2% versus 0.9%; relative risk 3.476; 95% CI 1.029&ndash;11.744) at endpoint were potentially significant events in more recently diagnosed than chronically ill subjects. Mean weight changes, sedation/somnolence, any extrapyramidal symptom-related or glucose-related events were generally similar between the groups. The mean prolactin level increased in both sexes in both subgroups (changes from baseline of +41.8 ng/mL and +26.5 ng/mL in recently diagnosed and chronic illness females and +12.3 ng/mL and +15.1 ng/mL in recently diagnosed and chronic illness males, respectively), and were higher in females with recently diagnosed illness than in females who were chronically ill (P = 0.0002 at endpoint). Prolactin-related events were reported by 7.9% of recently diagnosed subjects with schizophrenia and 3.5% of those who were chronically ill.Conclusion: The long-term tolerability of paliperidone palmitate was generally similar in recently diagnosed schizophrenia subjects and those with more chronic illness, with the exception of some prolactin-related measures.Keywords: paliperidone palmitate, long-acting antipsychotic, recently diagnosed, early illness, schizophreni
Impact of time of initiation of once-monthly paliperidone palmitate in hospitalized Asian patients with acute exacerbation of schizophrenia: a post hoc analysis from the PREVAIL study
No full textHuafang Li,1,2 Yan Li,1,2 Yu Feng,3 Jianmin Zhuo,4 Ibrahim Turkoz,5 Maju Mathews,5 Wilson Tan3 1Shanghai Mental Health Centre, Shanghai Jiao Tong University School of Medicine, Shanghai, China; 2Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China; 3Janssen Pharmaceutical Companies of Johnson and Johnson, Singapore; 4Janssen China Research and Development, Shanghai, China; 5Janssen Research & Development LLC, Titusville, NJ, USA Purpose: To evaluate the differences in efficacy and safety outcomes in acute exacerbating schizophrenia patients between 2 subgroups (≤1 week and >1 week), differing in time interval from hospitalization to time of initiation of once-monthly paliperidone palmitate. Patients and methods: PREVAIL was a multicenter, single-arm, open-label, prospective Phase IV study in hospitalized Asian patients (either sex, aged 18–65 years) diagnosed with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition). Change from baseline to week 13 in primary (Positive and Negative Syndrome Scale [PANSS] total score), secondary endpoints (PANSS responder rate, PANSS subscale, PANSS Marder factor, Clinical Global Impression-Severity, and Personal and Social Performance scale scores, readiness for hospital discharge questionnaire) and safety were assessed in this post hoc analysis. Results: Significant mean reduction from baseline to week 13 in the PANSS total score, 30% PANSS responder rates (P≤0.01), PANSS subscales (positive and general psychopathology; all P≤0.01), PANSS Marder factor (positive symptoms, uncontrolled hostility, and excitement and anxiety/depression; all P≤0.01), Personal and Social Performance scale scores (P≤0.05) and Clinical Global Impression-Severity categorical summary (P≤0.05) were significantly greater in the ≤1 week subgroup versus >1 week subgroup (P≤0.05). The readiness for hospital discharge questionnaire improved over time for the overall study population, but remained similar between subgroups at all-time points. Treatment-emergent adverse events were similar between the subgroups. Conclusion: Early initiation of once-monthly paliperidone palmitate in hospitalized patients with acute exacerbation of schizophrenia led to greater improvements in psychotic symptoms with comparable safety than treatment initiation following 1 week of hospitalization. Keywords: early treatment initiation, hospital setting, long acting injectable, Asian, hospital discharge, efficacy, safety, positive and negative syndrome scale total scor
Harnessing Knowledge on Very Important Pharmacogenes CYP2C9 and CYP2C19 Variation for Precision Medicine in Resource-Limited Global Conflict Zones
No full textPharmacogenomics harnesses the utility of a patient's genome (n=1) in decisions on which therapeutic drugs and in what amounts should be administered. Often, patients with shared ancestry present with comparable genetic profiles that predict drug response. However, populations are not static, thus, often, population mobility through migration, especially enmasse as is seen for refugees, changes the pharmacogenetic profiles of resultant populations and therefore observed responses to commonly used therapeutic drugs. For example, in the aftermath of the Syrian civil war since 2011, millions have fled their homes to neighboring countries in the Middle East. The growing permanence of refugees and mass migrations is a call to shift our focus in the life sciences community from old models of pharmaceutical innovation. These seismic social changes demand faster decisions for population-to-population bridging, whereby novel drugs developed in or for particular regions/countries can meet with rational regulatory decisions/approval in world regions impacted by migrant/refugee populations whose profiles are dynamic, such as in the Eastern Mediterranean region at present. Thus, it is important to characterize and report on the prevalence of pharmacogenes that affect commonly used medications and predict if population changes may call for attention to particular differences that may impact health of patients. Thus, we report here on four single-nucleotide polymorphism (SNP) variations in CYP2C9 and CYP2C19 genes among Mersin-Turkish healthy volunteers in the Mersin Province in the Eastern Mediterranean region that is currently hosting a vast number of migrant populations from Syria. Both CYP2C9 and CYP2C19 are very important pharmacogene molecular targets. We compare and report here on the observed SNP genetic variation in our sample with data on 12 world populations from dbSNP and discuss the feasibility of forecasting the pharmacokinetics of drugs utilized by migrant communities in Mersin and the Eastern Mediterranean region. This study can serve as a catalyst to invest in research in Syrian populations currently living in the Eastern Mediterranean. The findings have salience for rapid and rational regulatory decision-making for worldwide precision medicine and, specifically, pharmacogenovigilance-guided bridging of pharmacokinetics across world populations in the current era of planetary scale migration
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