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.
To evaluate the relationship between clinical improvement in Myasthenia Gravis-Activities of Daily Living (MG-ADL) scores and the pharmacodynamic effects of IgG autoantibody lowering induced by nipocalimab in the Vivacity MG Phase 2 study.
Background
Nipocalimab is a fully human, aglycosylated, effectorless IgG1 anti-FcRn monoclonal antibody that targets the neonatal Fc receptor (FcRn) with high affinity, thereby lowering IgG pathogenic antibodies in autoimmune disease.
Design/Methods
The relationship between the reduction in acetylcholine-receptor (AChR)- and Muscle-Specific-Tyrosine-Kinase (MuSK)- autoantibodies with improvement in MG-ADL scores were explored across the four nipocalimab dose arms in the Vivacity MG Phase 2 Study in generalized myasthenia gravis (gMG) patients.
Results
Of the 68 patients enrolled, 54 were randomized to one of the four nipocalimab dosing arms. 51 (94%) were seropositive for anti-AChR, 3 (6%) for anti-MuSK. Nipocalimab was well-tolerated and achieved substantial, dose-dependent and rapid reductions in serum total IgG, including all IgG subtypes and anti-AChR autoantibodies. These reductions were associated with dose-dependent, durable and rapid MG-ADL responses in all nipocalimab-treated groups. A similar trend in IgG4 reduction was noted, though the sample size of MuSK positive patients was small.
Conclusions
The results support the rapid, dose-dependent and predictable effect of nipocalimab in lowering pathogenic autoantibodies and inducing clinical improvement in patients with gMG. In addition, the close correlation between serum IgG, anti-AChR and clinical response suggest the potential of using serial serum IgG levels as a biomarker in management of gMG patients treated with nipocalimab; this will be tested in the ongoing Phase 3 gMG trial.
The authors assessed the efficacy and safety of the first long-acting atypical antipsychotic (long-acting injectable risperidone) in patients with schizophrenia.In a 12-week, multicenter, double-blind, randomized study, patients received intramuscular injections every 2 weeks of placebo or long-acting risperidone (25 mg, 50 mg, or 75 mg). The primary measure of efficacy was the change in total score on the Positive and Negative Syndrome Scale.Of the 554 patients who were enrolled, 400 entered the double-blind study, and 370 received at least one postbaseline assessment. Mean changes in score of -6.2, -8.5, and -7.4 on the Positive and Negative Syndrome Scale were seen at endpoint for the 25-, 50-, and 75-mg risperidone groups, respectively; all three change scores were significantly different from that seen with placebo (+2.6). Improvements in positive and negative symptoms were also significantly greater in patients receiving risperidone. Long-acting risperidone was well tolerated. Adverse events related to extrapyramidal symptoms were spontaneously reported by 13% of patients receiving placebo and 10% of patients in the 25-mg risperidone group, with higher rates in the 50-mg and 75-mg groups. Severity of extrapyramidal symptoms was mild at baseline and throughout the trial in each treatment group. Mean weight changes were small in the 25-, 50-, and 75-mg risperidone groups (0.5 kg, 1.2 kg, and 1.9 kg, respectively). Injection site pain was rated as low by the patients, consistent with the investigators' pain ratings.Long-acting injectable risperidone was efficacious and well tolerated and provides both clinicians and patients with a new mode of treatment that can improve the outcome of long-term therapy.
The primary objective of this 9-week open-label extension trial was to assess the effects of risperidone monotherapy in patients with acute bipolar I disorder who completed treatment in two preceding 3-week double-blind trials. Patients with DSM-IV bipolar I disorder, experiencing an acute manic episode, received a flexible dose of risperidone (1-6 mg/day) or placebo in two independent double-blind, randomized, 3-week monotherapy trials. Completers who required ongoing treatment were eligible to enter this open-label 9-week extension trial during which all patients received risperidone. The primary efficacy measure was the mean change in the Young Mania Rating Scale (YMRS) total score. Secondary efficacy measures included the Clinical Global Impressions-Severity Scale, Montgomery-Asberg Depression Rating Scale, Positive and Negative Syndrome Scale and Global Assessment Scale. Safety assessments included adverse event reports, laboratory tests, and the Extrapyramidal Symptom Rating Scale (ESRS). Of the 283 patients who entered the extension study, 160 had previously received risperidone (RIS/RIS) in the acute treatment trial and 123 had received placebo (PLA/RIS). This study was completed by 71% of these patients. The mean+/-SE modal dose of risperidone was 4.6+/-1.5 mg/day. Patients in both the RIS/RIS and PLA/RIS groups improved significantly at the endpoint of the 9-week open-label study compared to their open-label baseline scores (-5.2+/-0.69, P<0.001 and -9.12+/-1.44, P<0.001, respectively) on the YMRS. Furthermore, changes from double-blind baseline to open-label endpoint were -29.4+/-1.0 in the RIS/RIS group and -23.9+/-1.4 in the PLA/RIS group. Significant improvements from both double-blind and open-label baseline were seen at week 1 of the open-label trial (P<0.001) and at each subsequent timepoint. A similar pattern was observed on the secondary measures of efficacy. Most frequent adverse events were extrapyramidal disorder (18%) and somnolence (12%). Most adverse events were mild or moderate in severity. The mean score for the Parkinsonism subscale of the ESRS was 1.1 at open-label baseline, and decreased by 0.1 at endpoint. Mean increase in body weight from open-label baseline was 0.6 kg in patients treated with placebo in the preceding double-blind trial and 1.2 kg in patients previously treated with risperidone. Risperidone treatment was well tolerated and resulted in further improvement during the 9-week extension, beyond the 3 weeks of acute treatment. Patients switched from placebo to risperidone improved markedly. Risperidone treatment did not induce depression.
Uniform treatment based on the therapeutic approach of the 1st and 2nd US National Wilms' Tumor Study was decided on in March 1976 by paediatricians, surgeons, urologists and radiotherapists in Austria. Wilms' tumour was diagnosed in 34 children between 1 january 1976 an 29 february 1980 (stage I: n = 11, stage II: n = 8, stage III: n = 8, stage IV: n = 7). Parents of two children refused treatments; both children have since died of metastases. Of the remaining 32 children 29 (90.6%) are alive, 10 for more than 4, 15 for more than 3 and 19 for more than 2 years after diagnosis. 21 children are without need of treatment. Three children have died, one due to postoperative complications, one due to haemorrhagic chickenpox, but free of tumour, and one after insufficient treatment. Two of the five children with a recurrence between 2 1/4 to 15 months after diagnosis had been treated inadequately in the initial phase. The tumour free survival rate in 74.2%. Two children with early occurring or recurrent lung metastases have survived for 53 1/2 and 54 months up to now.
Atabecestat (JNJ-54861911), a beta-secretase inhibitor for slowing cognitive decline in cognitively unimpaired participants with preclinical Alzheimer's disease (AD) (elevated brain amyloid), was evaluated in phase 2b/3 EARLY trial. Study drug dosing was stopped early due to hepatic-related adverse events (AEs). Preliminary analyses suggested worsening of cognition and increased neuropsychiatric AEs in treated groups. Here we report final efficacy, safety and biomarker findings. This multicenter, double-blind, parallel-group study (NCT02569398) enrolled asymptomatic participants aged 60–85 years at risk for developing AD dementia. Participants were randomized (1:1:1) to receive atabecestat 5-mg, 25-mg or placebo. Cognitive endpoints analyzed by mixed-effects model for repeated measures (MMRM) included Preclinical Alzheimer's Cognitive Composite (PACC) and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Functional endpoints included AD Cooperative Study-Activities of Daily Living-Prevention Instrument (ADCS-ADL-PI). Changes in brain volumes were measured on vMRI by automated longitudinal LEAP (learning by embedded atlas propagation) algorithm. 557 participants were randomized to receive 5-mg (189), 25-mg (183) or placebo (185) before enrollment was stopped (Table 1). Atabecestat 25-mg group showed significant cognitive worsening versus placebo at 6 and 12 months on PACC and 3 months on RBANS (Table 2). Functional assessment on ADCS-ADL-PI did not show treatment differences (Table 3). Brain volume measurements showed small decreases in whole brain volume with 5-mg and 25-mg groups versus placebo at 6 and 12 months (Table 4). Follow-up cognitive testing, of variable time intervals on a subset of participants after drug discontinuation, suggested possible reversibility of drug-induced worsening in the 5-mg and 25-mg atabecestat groups (Figure 1). Incidence of neuropsychiatric AEs including cognition, depression, sleep/dream, and anxiety-related AEs were higher in atabecestat groups versus placebo (Table 5). No new safety signals were identified after drug discontinuation. Additional biomarker and outcome data will be presented. Final results of the EARLY trial confirm preliminary findings of a small, consistent worsening of cognitive performance, particularly in the 25-mg atabecestat group, evident as early as 3 months. Follow-up after drug discontinuation suggests possible reversibility of this cognitive worsening. Small reductions in whole brain volume and neuropsychiatric AEs were also observed.
