Efficacy and Safety of Paliperidone Palmitate 3-Month Formulation for Patients with Schizophrenia: A Randomized, Multicenter, Double-Blind, Noninferiority Study.

BACKGROUND: This double-blind, parallel-group, multicenter, phase-3 study was designed to test the noninferiority of paliperidone palmitate 3-month formulation (PP3M) to the currently marketed 1-month formulation (PP1M) in patients (age 18-70 years) with schizophrenia, previously stabilized on PP1M. METHODS: After screening (≤3 weeks) and a 17-week, flexible-dosed, open-label phase (PP1M: day 1 [150mg eq. deltoid], day 8 [100mg eq. deltoid.], weeks 5, 9, and 13 [50, 75, 100, or 150mg eq., deltoid/gluteal]), clinically stable patients were randomized (1:1) to PP3M (fixed-dose, 175, 263, 350, or 525mg eq. deltoid/gluteal) or PP1M (fixed-dose, 50, 75, 100, or 150mg eq. deltoid/gluteal) for a 48-week double-blind phase. RESULTS: Overall, 1016/1429 open-label patients entered the double-blind phase (PP3M: n=504; PP1M: n=512) and 842 completed it (including patients with relapse). PP3M was noninferior to PP1M: relapse rates were similar in both groups (PP3M: n=37, 8%; PP1M: n=45, 9%; difference in relapse-free rate: 1.2% [95% CI:-2.7%; 5.1%]) based on Kaplan-Meier estimates (primary efficacy). Secondary endpoint results (changes from double-blind baseline in positive and negative symptom score total and subscale scores, Clinical Global Impression-Severity, and Personal and Social Performance scores) were consistent with primary endpoint results. No clinically relevant differences were observed in pharmacokinetic exposures between PP3M and PP1M. Both groups had similar tolerability profiles; increased weight was the most common treatment-emergent adverse event (double-blind phase; 21% each). No new safety signals were detected. CONCLUSION: Taken together, PP3M with its 3-month dosing interval is a unique option for relapse prevention in schizophrenia.

Risk of cardiovascular morbidity with risperidone or paliperidone treatment: analysis of 64 randomized, double-blind trials.

A post hoc analysis of the risperidone (RIS)/paliperidone (Pali) clinical trials database comprising 64 studies was conducted. Risk of sudden death, cardiovascular (CV), and cerebrovascular events during RIS or Pali treatment was estimated. Treatment emergent CV adverse events were identified using 7 prespecified Standardised MedDRA Queries as follows: embolic/thrombotic events, cerebrovascular disorders, ischemic heart disease, cardiac arrhythmias, cardiac failure, torsades/QT prolongation, and convulsions. Risk in the RIS/Pali pooled group was significantly increased compared to placebo for the following adverse events: syncope, tachycardia, palpitations, edema peripheral, dysarthria, and transient ischemic attack. Incidence of death related to CV events was low and similar across groups. Consistent with the known pharmacologic profile and product information, this analysis of treatment emergent adverse event data from a large, randomized, controlled clinical trials database described increased risk versus placebo for several specific CV events. Apart from events described in existing product labeling, no new safety findings emerged.

An analysis of potentially prolactin-related adverse events and abnormal prolactin values in randomized clinical trials with paliperidone palmitate.

BACKGROUND: Paliperidone palmitate has been associated with serum prolactin elevations in some patients. However, few individuals with elevated prolactin levels (hyperprolactinemia) have symptomatic potentially prolactin-related adverse events (PPR-AEs). OBJECTIVE: To quantify rates of hyperprolactinemia in subjects treated with the newly marketed paliperidone palmitate long-acting injection (PP-LAI) in randomized clinical trials, summarize rates of PPR-AEs in those trials by sex and dose, and determine how many PPR-AEs required treatment. METHODS: Numbers and rates of investigator-reported hyperprolactinemia and PPR-AEs were obtained from the sponsor's clinical trial database and have been included in regulatory filings. Results were tabulated for males, females, and overall, and by dose administered, using descriptive statistics. Those requiring treatment were described as well. RESULTS: There were 3173 subjects (61.4% males) exposed to PP-LAI in 10 clinical trials; 2831 (89.2%) patients had recorded prolactin levels, including 1759 males (90.3% of exposed males) and 1072 females (87.5% of exposed females). Overall, at any time, prolactin levels were elevated for 38.8% of the subjects (39.5% for males and 37.7% for females; p = 0.354 between sexes). However, there was no significant correlation between monthly dose and proportion of subjects with elevated prolactin levels (p = 0.109). There were 115 PPR-AEs in 107 patients (3.4%); 51 (44.3% of PPR-AEs) cases represented asymptomatic hyperprolactinemia. The remaining 64 symptomatic PPR-AEs affected 2.0% of the total number of subjects. Fifteen events in 13 participants (0.41% of patients or 4.7 events/1000 patients) required treatment. CONCLUSIONS: Clinicians should periodically assess patients on paliperidone palmitate for any PPR-AEs and carefully assess the benefits and risks when managing these effects.

A one-year prospective study of the safety, tolerability and pharmacokinetics of the highest available dose of paliperidone palmitate in patients with schizophrenia.

BACKGROUND: There are no previous reports of paliperidone palmitate's (PP) long term tolerability or pharmacokinetics of the highest dose in patients with schizophrenia. This study evaluates safety and tolerability, as well as pharmacokinetics, of the highest marketed dose of PP (150 mg eq. [234 mg]) in stable patients with schizophrenia over a 1-year period. METHODS: In this 1-year prospective study, eligible patients (aged 18-65 years; Positive and Negative Syndrome Scale's total score ≤ 70) received an initial deltoid injection of PP 150 mg eq. The second injection one week later and subsequent once-monthly injections were deltoid or gluteal. All injections were to be PP 150 mg eq. Patients willing to participate in intensive pharmacokinetic sampling were classified as Treatment A. Patients unwilling to undergo intensive pharmacokinetic sampling or unable to tolerate the 150 mg eq. dose (consequently receiving flexible doses of 50, 100 or 150 mg eq.) were classified as Treatment B. RESULTS: Of the 212 patients (safety analysis set), 73% were men; 45% white; 20% black; 34% Asians; mean (SD) age 41 (10.2) years, and mean (SD) baseline Positive and Negative Syndrome Scale total score 54.9 (9.03). A total of 53% (n = 113) patients completed the study and 104 received PP 150 mg eq. throughout. Mean (SD) mode dose of PP was 144.8 (19.58) mg eq. The dosing initiation regimen resulted in rapidly achieved and maintained therapeutic paliperidone levels over the study (average concentrations during the dosing interval were 34.7, 40.0, and 47.8 ng/mL after the 2nd, 8th, and 14th injection respectively). Most frequent (≥ 10%) treatment-emergent adverse events were nasopharyngitis (n = 37), insomnia (n = 32), injection-site pain (n = 32), headache (n = 28), and tachycardia (n = 27). Akathisia (n = 19) and tremor (n = 11) were the most common extrapyramidal adverse events. 33 patients had an SAE and 27 discontinued due to treatment-emergent adverse events. No deaths were reported. Mean (SD) weight change from baseline was 2.5 (5.41) kg at endpoint. Patients' psychoses remained stable. CONCLUSIONS: Safety results after one-year therapy with the highest available dose of once-monthly paliperidone palmitate were consistent with results from previous studies, with no new concerns noted. Plasma concentrations were within the expected range. TRIAL REGISTRATION NO: ClinicalTrials.gov: NCT01150448.

Relapse and Treatment Adherence in Patients with Schizophrenia Switching from Paliperidone Palmitate Once-Monthly to Three-Monthly Formulation: A Retrospective Health Claims Database Analysis.

PURPOSE: Relapse and treatment adherence to paliperidone palmitate once-monthly (PP1M) and three-monthly (PP3M) formulations in patients with schizophrenia were evaluated and compared using health claims data. PATIENTS AND METHODS: Data (June 2015─June 2018) obtained from the MarketScan® Multi-State Medicaid Database were retrospectively analyzed. Patients aged ≥18 years with ≥1 claim for schizophrenia diagnosis prior to and/or at index date (i.e., date of first PP3M prescription record for PP3M patients and same month/year as the matched PP3M patients for PP1M patients) and continuous enrollment in the insurance plan for ≥12 months prior to index date (baseline) were included. PP1M cohort included patients who received ≥4 PP1M doses. PP3M patients were matched with PP1M patients (1:3) using propensity score matching and prevalent new user design. Outcome measures were relapse rate, time to relapse, proportion of days covered (PDC), and level of treatment adherence defined by PDC in five levels. Time to relapse was compared by Kaplan-Meier survival curves and log-rank test with the hazard ratio calculated using Cox proportion hazards model; PDC by t-test, and relapse rate and PDC categories by chi-square test. RESULTS: A total of 1564 patients (428 PP3M and 1136 PP1M) were included. Relapse rate was lower in PP3M cohort (10.5%) compared with PP1M cohort (15.7%). Incidence rate of relapse was 8.98/100 person-years (PY) in PP3M cohort and 13.81/100 PY in PP1M cohort. After a mean (SD) follow-up of 456.1 (240.28) days in PP3M cohort and 465.4 (237.95) days in PP1M cohort, PP3M patients had a significantly lower relapse risk (hazard ratio: 0.65, 95% CI: 0.47, 0.90) than PP1M patients. Treatment adherence was significantly (p<0.0001) higher in PP3M versus PP1M cohort. CONCLUSION: Risk of relapse was significantly lower, and treatment adherence was significantly higher in PP3M cohort compared with PP1M cohort. Higher treatment adherence was associated with lower relapse rate.

A randomized, placebo- and active-controlled study of paliperidone extended release for the treatment of acute manic and mixed episodes of bipolar I disorder.

OBJECTIVES: To evaluate the antimanic efficacy and safety of paliperidone extended-release (ER) tablets in patients with bipolar I disorder. METHODS: This study included a 3-week, double-blind, acute treatment phase (paliperidone ER versus placebo, with quetiapine as control), and a 9-week, double-blind, maintenance phase (paliperidone ER versus quetiapine). Patients [n = 493; Young Mania Rating Scale (YMRS) score >or= 20] were randomized (2:2:1) to flexibly dosed paliperidone ER (3-12 mg/day), quetiapine (400-800 mg/day), or placebo for the acute treatment phase. During the maintenance phase, patients assigned to placebo were switched to paliperidone ER but not included in analysis of efficacy. RESULTS: Paliperidone ER was superior to placebo at the 3-week endpoint {primary outcome; least-squares mean difference in change from baseline in YMRS scores [95% confidence interval (CI)]: -5.5 (-7.57; -3.35); p < 0.001} and noninferior to quetiapine at the 12-week endpoint [least-squares mean difference (95% CI): 1.7 (-0.47; 3.96)]. The median mode dose during the 12-week treatment period was 9 mg for paliperidone ER and 600 mg for quetiapine. The most common (>or= 10%) treatment-emergent adverse events during the 12-week period were: headache (16%), somnolence (10%), and akathisia (10%) for paliperidone ER; somnolence (21%), sedation and dry mouth (17% each), headache (14%), and dizziness (13%) for quetiapine. Body weight increase >or= 7% from baseline to 12-week endpoint was 8% with paliperidone ER and 17% with quetiapine. A higher percentage of paliperidone ER (13.9%) versus quetiapine patients (7.5%) 'switched to depression' at the12-week endpoint. CONCLUSIONS: Paliperidone ER (3-12 mg/day) was efficacious and tolerable in the treatment of acute mania.

Cognitive functioning in adolescents with schizophrenia treated with paliperidone extended-release: 6-Month exploratory analysis from an open-label, single-arm safety study.

OBJECTIVE: To assess cognitive functioning in adolescents (12-17 years old) with schizophrenia during open-label treatment with paliperidone extended-release (pali ER). METHODS: In this exploratory analysis, adolescents treated with pali ER (oral, flexibly dosed, 1.5-12 mg/day) underwent cognitive assessments at baseline and month 6 using a battery of cognitive tests validated in adolescents. Correlation analysis was used to explore the relationship between cognitive assessments and clinical symptoms (Positive and Negative Syndrome Scales [PANSS] and factors) and functionality (Children Global Assessment Scale [CGAS]) at baseline and at 6 months. RESULTS: A total of 324 of 393 patients had evaluable neurocognitive data. Changes in cognition function tests from baseline to endpoint were generally small to modest, with improvement noted for most cognitive domains (motor speed, attention/working memory, verbal learning and memory, social cognition, speed of processing, executive functioning). No improvement was noted for visual learning and memory. At baseline, there were modest negative correlations between disorganized thoughts and most cognitive domains; these correlations persisted at 6 months. Other significant negative correlations at 6 months were between speed of processing and PANSS total score, positive symptoms, negative symptoms and uncontrolled hostility (p < 0.05). At 6 months, higher CGAS scores (improved functioning) positively correlated with speed of processing and executive functioning, especially among pali ER responders. CONCLUSIONS: In this large sample of adolescents with schizophrenia, frank cognitive deficits across multiple domains were observed. Treatment with pali ER over 6 months did not worsen neurocognitive functioning and was possibly associated with positive improvement in certain domains.

Patients' Preference for Long-Acting Injectable versus Oral Antipsychotics in Schizophrenia: Results from the Patient-Reported Medication Preference Questionnaire.

INTRODUCTION: Understanding patients' preferences for long-acting injectable (LAI) or oral antipsychotics (pills) could help reduce potential barriers to LAI use in schizophrenia. METHODS: Post hoc analyses were conducted from a double-blind, randomized, non-inferiority study (NCT01515423) of 3-monthly vs 1-monthly paliperidone palmitate in patients with schizophrenia. Data from the Medication Preference Questionnaire, administered on day 1 (baseline; open-label stabilization phase), were analyzed. The questionnaire includes four sets of items: 1) reasons for general treatment preference based on goals/outcomes and preference for LAI vs pills based on 2) personal experience, 3) injection-site (deltoid vs gluteal), 4) dosing frequency (3-monthly vs 1-monthly). A logistic regression analysis was performed to assess the effect of baseline variables on preference (LAIs or pills). RESULTS: Data from 1402 patients were available for analysis. Patients who preferred LAIs recognized these outcomes as important: "I feel more healthy" (57%), "I can get back to my favorite activities" (56%), "I don't have to think about taking my medicines" (54%). Most common reasons for medication preference (LAI vs pills) were: "LAIs/pills are easier for me" (67% vs 18%), "more in control/don't have to think about taking medicine" (64% vs 14%), "less pain/sudden symptoms" (38% vs 18%) and "less embarrassed" (0% vs 46%). Majority of patients (59%) preferred deltoid over gluteal injections (reasons: faster administration [63%], easier [51%], less embarrassing [44%]). In total, 50% of patients preferred 3-monthly over 1-monthly (38%) or every day (3%) dosing citing reasons: fewer injections [96%], fewer injections are less painful [84%], and fewer doctor visits [80%]. From logistic regression analysis, 77% of patients preferred LAI over pills; culture and race appeared to play a role in this preference. CONCLUSION: Patients who preferred LAI antipsychotics prioritized self-empowerment and quality-of-life-related goals. When given the option, patients preferred less-frequent, quarterly injections over monthly injections and daily oral medications.

Comparison of Relapse Prevention with 3 Different Paliperidone Formulations in Patients with Schizophrenia Continuing versus Discontinuing Active Antipsychotic Treatment: A Post-Hoc Analysis of 3 Similarly Designed Randomized Studies.

BACKGROUND: Sudden discontinuation from antipsychotic treatment is a common occurrence in patients with schizophrenia. Lower rates of relapse could be expected for patients discontinuing treatment from longer-acting formulations vs their shorter-acting equivalents. OBJECTIVE: To compare relapse rates and time-to-relapse between the active (analogous to adherent patients) and placebo (analogous to non-adherent patients in the real-world) arms of three different formulations of paliperidone (oral paliperidone extended release [paliperidone ER], paliperidone palmitate once monthly [PP1M], and paliperidone palmitate three monthly [PP3M] long-acting injectables). METHODS: Data from three similarly designed, randomized relapse prevention studies in adult patients with schizophrenia were analyzed. RESULTS: In total, 922 patients were included (active treatment: 473, placebo: 449). Lowest percentage of patients experienced relapse with PP3M PP1M (172 days [134-222 days])> paliperidone ER (58 days [42-114 days]) and was "not-estimable" in the active treatment group due to low relapse rates. Hazard ratios (HR) of the three paliperidone formulations relative to their respective placebos were PP3M ([HR: 3.81; 95% CI: 2.08, 6.99; P< 0.0001]> PP1M [HR: 3.60; 95% CI: 2.45, 5.28; P<0.0001]> paliperidone ER [HR: 2.83; 95% CI: 1.73, 4.63; P<0.001]). CONCLUSION: The lower percentage of relapse during active treatment and longer time to relapse after discontinuing active treatment with longer-duration antipsychotic formulations suggests the benefit of longer-acting over shorter-acting formulations, especially in patients susceptible to poor adherence.Clinical trial registration: paliperidone ER (NCT00086320), PP1M (NCT00111189), and PP3M (NCT01529515).

A Dunnett-Bonferroni-based parallel gatekeeping procedure for dose-response clinical trials with multiple endpoints.

This paper proposes a Dunnett-Bonferroni-based parallel gatekeeping procedure in a setting of dose-response clinical trials with multiple endpoints. It follows the Dunnett-based parallel gatekeeping strategy of Dmitrienko et al. (Pharm. Stat. 2006; 5:19-28), but differs in the calculation of the critical values. The implementation of the Dunnett-based parallel gatekeeping procedure relies on assumptions difficult to justify in typical clinical trials, namely (a) that the joint distribution of the test statistics from different endpoints can be approximated by a multivariate-t distribution and (b) that the true correlation between multiple endpoints can be well estimated using observed data. The proposed Dunnett-Bonferroni-based parallel gatekeeping procedure relaxes the preceding assumptions by splitting type I error rate among families using the Bonferroni inequality. While it is potentially less powerful than a Dunnett-based procedure when both procedures are applicable, the power loss is very minimal. Our proposed method avoids assumptions that might be challenged by regulatory agencies and does so with virtually no cost. Moreover, in most cases this method is easier to implement compared with the Dunnett-based procedure.

Efficacy and safety of paliperidone palmitate 3-month formulation in Latin American patients with schizophrenia: A subgroup analysis of data from two large phase 3 randomized, double-blind studies.

OBJECTIVE: To analyze the efficacy and safety of paliperidone palmitate 3-monthly (PP3M) in Latin American patients with schizophrenia vs. rest-of-world (ROW). METHODS: We analyzed data from two multinational, double-blind (DB), randomized, controlled phase 3 studies including patients with schizophrenia (DSM-IV-TR) previously stabilized on PP1M/PP3M (open-label [OL] phase). Patients were randomized to PP3M or PP1M (noninferiority study A) and PP3M or placebo (study B) in DB phase. The subgroup analysis included Latin American (Argentina, Brazil, Colombia, Mexico) patients. Primary efficacy endpoints were relapse-free rates (study A) and time-to-relapse (study B). RESULTS: In study A, 63/71 (88.7%) and in study B 38/43 (88.4%) Latin American patients completed the DB phase. In study A, relapse-free percentage was similar in Latin America (PP3M: 97%, PP1M: 100%) and ROW (PP3M: 91%, PP1M: 89%). In study B, median time-to-relapse was not estimable in the Latin American subgroup for either placebo or PP3M groups, nor for the ROW PP3M group; the median time-to-relapse in the ROW placebo group was 395 days. Caregiver burden improved in patients switching from oral antipsychotics (OL baseline) to PP3M/PP1M in DB phase (Involvement Evaluation Questionnaire score mean ± SD change, -9.4±15.16; p < 0.001). Treatment emergent adverse events with PP3M during DB phase were similar in Latin America (study A: 24/34 [70.6%]; study B: 15/21 [71.4%]) and ROW (study A: 318/470 [67.7%]; study B: 84/139 [60.4%]) subgroups. CONCLUSION: PP3M was efficacious and showed no new safety concerns in patients with schizophrenia from Latin America, corroborating ROW findings. CLINICAL TRIAL REGISTRATION: NCT01515423, NCT01529515.

Clinical relevance of paliperidone palmitate 3-monthly in treating schizophrenia.

Antipsychotics are the mainstay in schizophrenia management, and long-acting injectable (LAI) antipsychotics contribute to the successful maintenance of treatment by improving non-adherence and preventing relapses. Paliperidone palmitate 3-monthly (PP3M) formulation is the only available LAI antipsychotic that offers an extended 3-month window of stable plasma drug concentration, enabling only four injections per year. This paper summarizes clinically relevant endpoints from available evidence for PP3M to bridge translational research gaps and provide measurable outcomes that can be interpreted in clinical practice. Low number-needed-to-treat (NNT) for relapse prevention (NNT [95% CI] 6-month estimate: 4.8 [3.2; 10.0]; 12-month estimate: 3.4 [2.2; 7.0]), and high number-needed-to-harm (NNH [95% CI] akathisia, 27.1 [12.3; -667.1]; tremor, 80.0 [22.5; 67.3]; dyskinesia, -132.6 [44.5; -23.2]; parkinsonism, 160.0 [28.9; -49.8]) quantify the relative benefits and low propensity for adverse events with PP3M. Symptom remission and reductions in positive and negative symptoms indicate treatment stability. Additionally, meaningful functional remission, reduced dosing frequency, and freedom from daily negotiations favorably impact patient preference and attenuate burdensome aspects of caregiving, representing important healthcare determinants that enhance prospects of treatment continuity in schizophrenia. This information can potentially improve clinicians' judgment of treatment choices, clinical response, and patient selection in routine care. Taken together, PP3M is a valuable antipsychotic treatment option, meriting consideration for a broader role in the long-term management of schizophrenia; its utility should not be limited to patients with poor adherence or when oral antipsychotics have failed.

Severe odontogenic infections: a 5-year review of a major referral hospital in Ghana.

INTRODUCTION: Odontogenic infections are fairly common in healthcare settings. However, late presentations such as Ludwig's angina, facial cellulitis, necrotizing cervical fasciitis (NCF), among others could lead to mortality. In view of suggestions that the occurrence of severe, near-fatal odontogenic infections is declining, this study set out to determine the incidence of such severe odontogenic infections over the past 5 years at the Korle-Bu Teaching Hospital, a major referral centre in Ghana. METHODS: A retrospective review was done, involving all patients with severe odontogenic infection, thereby requiring admission, per stated criteria at the Department of Oral and Maxillofacial Surgery (Dental clinic), Korle-Bu Teaching Hospital, in the period between July 2012 and July 2017. The cumulative incidence for the respective years were then computed for the years of review. RESULTS: A total of 243 patients were included in the study. This consisted of 121 males and 122 females, with an average age of 42.9 years (SD = 16.6), ranging from 18 months to 91 years. Incidence proportions for the years of the review were 8.2, 8.9, 17.7, 17.9 and 27.7 people per 1000 cases of tooth-related infections for the respective years. With a fatality rate of 5.8%, the incidence of odontogenic infections among patients attending the outpatient Dental clinic of the hospital is 40.3%, while that of dentoalveolar abscess is 6.2%. Ludwig's angina was the commonest (52%) form of presentation of spreading odontogenic infection. CONCLUSION: This study highlights the importance of persisting severe, near-fatal odontogenic infections in Ghana. Not only is there a need to assess the public, professional and institutional strategies to management, but for more evidence-based studies in our local setting to aid in management.

Efficacy and safety of paliperidone palmitate 3-month versus 1-month formulation in patients with schizophrenia: comparison between European and non-European population.

PURPOSE: This randomized, double-blind (DB), non-inferiority phase 3 study was conducted to assess the efficacy and safety of paliperidone palmitate 3-month (PP3M) vs 1-month formulation (PP1M) in European and non-European patients with schizophrenia. PATIENTS AND METHODS: In this randomized, DB, parallel-group study, adult patients (18-70 years) with schizophrenia (per DSM-IV-TR) having Positive and Negative Syndrome Scale (PANSS) total score between 70 and 120; previously stabilized on PP1M were enrolled. The study had 4 phases: screening (3 weeks), open-label (OL) stabilization (17 weeks), DB (48 weeks) and follow-up (4-12 weeks) phase. Patients were treated with fixed-dose PP3M (175-525 mg eq deltoid/gluteal) or PP1M (50-150 mg eq deltoid/gluteal) for 48 weeks in DB phase. RESULTS: In total, 487 European (PP3M, n=242; PP1M, n=245) and 508 non-European patients (PP3M, n=241; PP1M, n=267) entered DB phase (modified intent-to-treat (mITT) [DB] analysis set). Among the 508 non-European patients in mITT set, 67.7% were from Asia (n=344) and 32.3% were from rest of world (ROW, n=164). During the DB phase, similar percentage of Europeans (PP3M: 7%; PP1M: 8%) and non-Europeans (PP3M: 9%; PP1M: 10%) experienced relapse (Kaplan-Meier estimate PP3M-PP1M [95% CI] of percentage of relapse-free patients at the end of DB phase [primary endpoint]: European: 1.0% [-4.3%; 6.2%]; non-European: 1.4% [-4.4%; 7.1%]; Asian: 1.6% [-5.7%; 9.0%]; and ROW: 1.4% [-7.0%, 9.8%], per-protocol analysis set). Incidence of treatment-emergent adverse events (TEAEs) was lower in Europeans (PP3M: 56%, PP1M: 59%) than non-Europeans (PP3M: 80%, PP1M: 73%). The most commonly reported TEAE was weight gain. CONCLUSION: PP3M showed similar efficacy to PP1M in Europeans and non-Europeans, consistent with non-inferiority of PP3M to PP1M observed in overall population. Rates of AEs were higher in non-Europeans. However, weight gain was greater in non-Europeans, especially the Asian population.

A comparative study of the efficacy of intravenous benzylpenicillin and intravenous augmentin in the empirical management of Ludwig's angina.

Background: Ludwig's angina is a potentially life-threatening condition characterized by bilateral cellulitis of the submandibular, submental, and sublingual spaces. Intravenous (I.V) penicillin G or amoxicillin-clavulanate (Augmentin) has been recommended for use as empirical management before obtaining culture and sensitivity results. Aim: The aim of this study was to compare the therapeutic efficacies and clinical outcomes of I.V benzylpenicillin with I.V Augmentin in the empirical management of Ludwig's angina. Methods: This was a prospective randomized clinical study carried out to measure the rate of swelling reduction (using the lobar rate, Adam's rate, and interincisal distance) and other clinical parameters among the two drug groups (I.V penicillin G and Augmentin). Descriptive summaries of variables were generated, and Student's t-test was used to compare the mean outcomes of the two groups. Results: A total of 26 individuals participated in the study, consisting of 46% (12) males and 54% (14) females. The participants ranged from 13 to 61 years with mean and median of 34.4 (±12.7) and 35 years, respectively. Only 8% of the cases of Ludwig's angina were not attributable to odontogenic factors, compared to 92% resulting from odontogenic causes. There was no significant difference in the efficacy of the two antibiotics used in this study. Conclusion: The efficacies and the clinical outcomes of the two antibiotics were similar. Benzylpenicillin is probably a suitable empirical alternative where Augmentin cannot be afforded, to reduce the mortality associated with the condition.

RésuméContexte: L'angine de Ludwig est une condition potentiellement mortelle caractérisée par la cellulite bilatérale des espaces sousmandibulaires, sousmentaux et souslinguaux. On a recommandé la pénicilline (I.V) intraveineuse G ou l'amoxicilline-clavulanate (Augmentin) pour l'utilisation comme la gestion(direction) empirique avant l'obtention de résultats de sensibilité et la culture. Objectif: Le but de cette étude était de comparer les efficacités thérapeutiques et les résultats cliniques d'I.V benzylpenicillin avec I.V Augmentin dans la gestion(direction) empirique de l'angine de Ludwig. Procédés: C'était une étude clinique randomisée éventuelle a effectué mesurer le taux de réduction se gonflant (utilisant le taux de lobar, le taux d'Adam et la distance interincisal) et d'autres paramètres cliniques parmi les deux groupes de médicament (la pénicilline I.V G et Augmentin). Les résumés descriptifs de variables ont été produits et le t-test de l'Étudiant a été utilisé pour comparer les résultats moyens des deux groupes. Résultats: un total de 26 individus a participé à l'étude, consistant de 46 % (12) mâles et 54 % (14) femelles. Les participants se sont étendus de 13 à 61 ans avec moyen et médian de 34.4 (±12.7) et 35 ans, respectivement. Seulement 8 % des cas(affaires) de l'angine de Ludwig n'étaient pas attribuables aux facteurs odontogenic, comparés à 92 % résultant odontogenic des causes. Il n'y avait aucune différence significative dans l'efficacité des deux antibiotiques utilisés dans cette étude. Conclusion: Il n'y avait aucune différence significative dans les efficacités des deux antibiotiques dans le résultat clinique de traitement. Benzylpenicillin est probablement une alternative empirique appropriée où Augmentin ne peut pas avoir droit, réduire la mortalité associée à la condition.

Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition.

BACKGROUND: A substantial number of patients with rheumatoid arthritis have an inadequate or unsustained response to tumor necrosis factor alpha (TNF-alpha) inhibitors. We conducted a randomized, double-blind, phase 3 trial to evaluate the efficacy and safety of abatacept, a selective costimulation modulator, in patients with active rheumatoid arthritis and an inadequate response to at least three months of anti-TNF-alpha therapy. METHODS: Patients with active rheumatoid arthritis and an inadequate response to anti-TNF-alpha therapy were randomly assigned in a 2:1 ratio to receive abatacept or placebo on days 1, 15, and 29 and every 28 days thereafter for 6 months, in addition to at least one disease-modifying antirheumatic drug. Patients discontinued anti-TNF-alpha therapy before randomization. The rates of American College of Rheumatology (ACR) 20 responses (indicating a clinical improvement of 20 percent or greater) and improvement in functional disability, as reflected by scores for the Health Assessment Questionnaire (HAQ) disability index, were assessed. RESULTS: After six months, the rates of ACR 20 responses were 50.4 percent in the abatacept group and 19.5 percent in the placebo group (P<0.001); the respective rates of ACR 50 and ACR 70 responses were also significantly higher in the abatacept group than in the placebo group (20.3 percent vs. 3.8 percent, P<0.001; and 10.2 percent vs. 1.5 percent, P=0.003). At six months, significantly more patients in the abatacept group than in the placebo group had a clinically meaningful improvement in physical function, as reflected by an improvement from baseline of at least 0.3 in the HAQ disability index (47.3 percent vs. 23.3 percent, P<0.001). The incidence of adverse events and peri-infusional adverse events was 79.5 percent and 5.0 percent, respectively, in the abatacept group and 71.4 percent and 3.0 percent, respectively, in the placebo group. The incidence of serious infections was 2.3 percent in each group. CONCLUSIONS: Abatacept produced significant clinical and functional benefits in patients who had had an inadequate response to anti-TNF-alpha therapy.

Relapse After Antipsychotic Discontinuation in Schizophrenia as a Withdrawal Phenomenon vs Illness Recurrence: A Post Hoc Analysis of a Randomized Placebo-Controlled Study.

BACKGROUND: It has been proposed that relapse rates after antipsychotic discontinuation may be artificially inflated and that some of these symptom recurrences may be due to rebound or withdrawal phenomena rather than due to illness recurrence. METHODS: Post hoc analysis of data from a relapse-prevention study (conducted from March 2005 to February 2007) of paliperidone palmitate once-monthly (PP1M) versus placebo was conducted to compare the nature of operationally defined relapse events in schizophrenia patients (diagnosed by DSM-IV criteria) experiencing relapses after randomization to placebo (n = 97) with those in patients receiving maintenance PP1M treatment (n = 36). These 2 groups were compared for onset and severity of recurrence symptoms, symptom profiles at relapse, and postrelapse treatment response. Psychological and physiological signs of discontinuation and signs of antipsychotic tolerance, dyskinesia, and prolactin elevation that might indicate dopamine receptor supersensitivity were compared. RESULTS: Both groups were similar in terms of relapse symptom profiles, onset and severity of relapse symptoms, and postrelapse treatment response. The Positive and Negative Syndrome Scale total score (mean ± SD) for placebo versus maintenance treatment group at baseline was 54.5 ± 11.74 vs 54.1 ± 11.64 and at relapse was 75.6 ± 16.79 vs 75.2 ± 17.23 (P = .9). No elevated blood pressure or heart rate, dyskinesia, antipsychotic tolerance, or elevated prolactin in the patients relapsing after antipsychotic discontinuation was noted. CONCLUSIONS: Findings suggest that relapses after treatment discontinuation reflect recurrence of the underlying illness and may be consistent with a hypothesis of direct relationship between dopamine and psychosis. No evidence was obtained for withdrawal-related phenomena contributing to the high relapse rates after treatment discontinuation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00111189.

An assessment of injection site reaction and injection site pain of 1-month and 3-month long-acting injectable formulations of paliperidone palmitate.

PURPOSE: To evaluate injection site reactions and pain following paliperidone palmitate 1-month (PP1M) and 3-month (PP3M) administration using safety data of double-blind (DB), noninferiority study. METHODS: Patients (n = 1,429) with schizophrenia, treated with PP1M (50-150 mg-eq, 17-week open-label [OL] phase) were randomized to PP1M or PP3M in 48-week DB phase. FINDINGS: PP1M and PP3M injections were well tolerated. Incidence of induration, redness, and swelling were low in both phases (OL: 9-12%; DB: 7-13%), and were mostly mild in both groups. Mean (SD) visual analog scale scores decreased from OL-baseline (22.0 [21.6]) to DB-baseline (19.5 [20.6] vs. 18.4 [20.4]) and DB-endpoint (15.6 [17.9] vs. 15.5 [18.3]). PRACTICE IMPLICATIONS: Injection site reactions and pain were low and similar between both treatments, regardless of administration site and dose.

Paliperidone Palmitate 3-Monthly Versus 1-Monthly Injectable in Patients With Schizophrenia With or Without Prior Exposure to Oral Risperidone or Paliperidone: A Post Hoc, Subgroup Analysis.

BACKGROUND AND OBJECTIVE: Paliperidone palmitate 3-monthly (PP3M) injectable formulation offers an advantage of improved medication adherence and lower relapse risk in patients with schizophrenia. This post hoc analysis compared outcomes following PP3M versus paliperidone palmitate 1-monthly (PP1M) treatment in patients with schizophrenia treated/untreated with oral risperidone/paliperidone (RIS/PALI). METHODS: Patients were treated with PP1M (50, 75, 100, or 150 mg equivalent [eq.]) for 17 weeks during an open-label (OL) phase and randomized (1:1) to PP3M (175, 263, 350, or 525 mg eq.) or PP1M (50, 75, 100, or 150 mg eq.) during a 48-week double-blind phase. Efficacy outcomes were compared based on prior oral RIS/PALI exposure: recent (≥ 28 days of oral RIS/PALI exposure with last dose within 14 days before study entry); or no (no oral RIS/PALI exposure within 60 days before study entry). RESULTS: A total of 452 OL patients received recent oral RIS/PALI (n = 323 [71%], randomized to PP3M = 166; PP1M = 157), and 709 OL patients were without recent oral RIS/PALI (n = 506 [71%], randomized to PP3M = 254; PP1M = 252). Improvements in Positive and Negative Syndrome Scale (PANSS) scores (OL baseline-to-endpoint) were similar in recent-RIS/PALI (mean [standard deviation]:18.3 [17.96]) and no-RIS/PALI (- 21.1 [16.40]) subgroups. Relapse-free rates were comparable between recent-RIS/PALI (relapse-free rate [95% confidence interval for difference]: 2.6 [- 4.7 to 10.0]; PP3M: 90%; PP1M: 87%) and no-RIS/PALI subgroups (0.8 [- 4.5 to 6.0]; PP3M: 92%; PP1M: 91%). Weight gain was the most common (> 5% incidence) treatment-emergent adverse event in both subgroups irrespective of the prior treatment. CONCLUSION: Patients with schizophrenia, irrespective of prior treatment with RIS/PALI, had comparable treatment outcomes and tolerability following PP3M or PP1M treatment. REGISTRATION: This study is registered at the EU clinical trial registry (EudraCT Number: 2011-004889-15) and ClinicalTrials.gov (identifier: NCT01515423).

Time to onset and time to resolution of extrapyramidal symptoms in patients with exacerbated schizophrenia treated with 3-monthly vs once-monthly paliperidone palmitate.

OBJECTIVE: The aim of this study was to evaluate the safety of 3-monthly paliperidone palmitate (PP3M) vs once-monthly paliperidone palmitate (PP1M) treatment with regard to extrapyramidal symptom (EPS)-related treatment-emergent adverse events (TEAEs) in patients with schizophrenia, previously stabilized on PP1M treatment. PATIENTS AND METHODS: Data on overall incidence, time to onset (TTO), and time to resolution (TTR) of EPS-related TEAEs (overall, subclasses such as dyskinesia, dystonia, hyperkinesia, parkinsonism, and tremor) from a randomized double-blind (DB) non-inferiority study were compared between PP3M and PP1M. Subgroup analysis was performed by age (18-25, 26-50, and 50+ years) and final open-label (OL) dose (50/75, 100, and 150 mg eq.). RESULTS: Overall incidence of spontaneously reported EPS-related TEAEs decreased from 12.6% (PP1M) in OL phase to 8.3% (PP3M) and 7.4% (PP1M) in the DB phase; overall median TTO and TTR values were comparable between both groups. Among patients with reported EPS-related TEAEs, the median TTO for all EPS-related TEAEs was 17 days (PP1M) in OL phase and 115 days (PP3M) and 98.5 days (PP1M) in DB phase; median TTR was 36.5 days (PP1M) in OL phase and 91 days (PP3M) and 85.5 days (PP1M) in DB phase. No clear dose- or age-related differences in TTO and TTR of EPS-related TEAEs were noted. CONCLUSION: Despite differences in apparent half-life and pharmacokinetic profiles (peak plasma exposure of PP3M formulation is 70% higher than that of PP1M formulation), both PP3M and PP1M formulations exhibited comparable incidence of EPS-related TEAEs, TTO, and TTR in patients with schizophrenia.