First-Line Trastuzumab Plus an Aromatase Inhibitor, With or Without Pertuzumab, in Human Epidermal Growth Factor Receptor 2-Positive and Hormone Receptor-Positive Metastatic or Locally Advanced Breast Cancer (PERTAIN): A Randomized, Open-Label Phase II Trial

To assess pertuzumab plus trastuzumab and an aromatase inhibitor (AI) in patients with human epidermal growth factor receptor 2 (HER2)-positive and hormone receptor-positive metastatic/locally advanced breast cancer (MBC/LABC)

Efficacy and Safety of Trastuzumab Emtansine Plus Capecitabine vs Trastuzumab Emtansine Alone in Patients With Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer A Phase 1 and Randomized Phase 2 Trial

Importance: ERBB2 (HER2)-targeted therapy provides benefits in metastatic breast cancer (mBC) and gastric cancer, but additional treatments are needed to maximize efficacy and quality of life. Objective: To determine maximum tolerated doses (MTDs) of trastuzumab emtansine (T-DM1) plus capecitabine in patients with previously treated ERBB2-positive mBC and locally advanced/metastatic gastric cancer (LA/mGC) (phase 1) and the efficacy and safety of this combination vs T-DM1 alone in patients with mBC (phase 2). Design, setting, and participants: The MTD in phase 1 was assessed using a 3 + 3 design with capecitabine dose modification. Phase 2 was an open-label, randomized, international multicenter study of patients with mBC treated with T-DM1 plus capecitabine or T-DM1 alone. Eligible patients had previously treated ERBB2-positive mBC or LA/mGC with no prior chemotherapy treatment for advanced disease. Interventions: Patients in the phase 1 mBC cohort received capecitabine (750 mg/m2, 700 mg/m2, or 650 mg/m2 twice daily, days 1-14 of a 3-week cycle) plus T-DM1 3.6 mg/kg every 3 weeks. Patients with LA/mGC received capecitabine at the mBC phase 1 MTD, de-escalating as needed, plus T-DM1 2.4 mg/kg weekly. In phase 2, patients with mBC were randomized (1:1) to receive capecitabine (at the phase 1 MTD) plus T-DM1 or T-DM1 alone. Main outcomes and measures: The phase 1 primary objective was to identify the MTD of capecitabine plus T-DM1. The phase 2 primary outcome was investigator-assessed overall response rate (ORR). Results: In phase 1, the median (range) age was 54.0 (37-71) and 57.5 (53-70) years for patients with mBC and patients with LA/mGC, respectively. The capecitabine MTD was identified as 700 mg/m2 in 11 patients with mBC and 6 patients with LA/mGC evaluable for dose-limiting toxic effects. In phase 2, between October 2014 and April 2016, patients with mBC (median [range] age, 52.0 [28-80] years) were randomized to receive combination therapy (n = 81) or T-DM1 (n = 80). The ORR was 44% (36 of 81 patients) and 36% (29 of 80 patients) in the combination and T-DM1 groups, respectively (difference, 8.2%; 90% CI, -4.5 to 20.9; P = .34; clinical cutoff, May 31, 2017). Adverse events (AEs) were reported in 78 of 82 patients (95%) in the combination group, with 36 (44%) experiencing grade 3-4 AEs, and 69 of 78 patients (88%) in the T-DM1 group, with 32 (41%) experiencing grade 3-4 AEs. No grade 5 AEs were reported. Conclusions and relevance: Adding capecitabine to T-DM1 did not statistically increase ORR associated with T-DM1 in patients with previously treated ERBB2-positive mBC. The combination group reported more AEs, but with no unexpected toxic effects

Psychopharmacology for children:From off label use to registration

Pharmacological treatment of children and adolescents is Largely based on evidence from adults' studies. There is, however, growing awareness that this evidence cannot simply be extrapolated to children. The Dutch Medicines Evaluation Board (MEB) in collaboration with the Child and Adolescent section of the Dutch Association of Psychiatry and the National Expertise Centre Child and Adolescent Psychiatry have organised a workshop to discuss the kind of evidence that would be necessary and the methods involved. There was consensus about the need to demonstrate efficacy in targeted disorders as well as symptoms within specific disorders and about the need for separate evidence for children and for adolescents. In addition, too little is known about safety, especially long-term safety, as consequences of treatment. Main issues are effects on growth, cognitive, motor, emotional, and sexual development, metabolic symptoms, cardiotoxicity, and dependence. Specific methodological issues were discussed, such as the role of different informants and the high rate of comorbidity. (C) 2009 Elsevier B.V. and ECNP. All rights reserved

The EU paediatric regulation:Effects on paediatric psychopharmacology in Europe

Child and adolescent psychiatry is a relatively young field and the recognition, classification, and treatment of disorders in children and adolescents lag behind those in adults. In recent years there is an increasing awareness of the differences between children and adults in psychopathology and of these measures on the field of paediatric psychopharmacology. The consequences of the paediatric and clinical practices. In the regulatory domain, the consequences include: new paediatric indications, inclusion of special (class) warnings, specification of dose regimens, and information on safety specific to children and adolescents, and development of new medicinal formulations. The paediatric regulation leads to timely development of paediatric friendly formulations and better quality of the clinical evidence. In clinical practices, an increased awareness of the uniqueness of paediatric clinical guidelines will have to be revised more frequently in order to integrate the recently acquired pharmacology. Related to this new paediatric regulations have been introduced. This article reviews the regulatory and legislative measures that were adopted in the EU in 2007 and the subsequent impact regulation in the EU are reflected in several domains: regulatory, research aimed at drug development pharmacology is emerging among medical professionals, and subsequent improvement of medical care (i.e. correct doses, appropriate formulation, monitoring for expected adverse events). In addition, knowledge. The new regulations stimulate transparency and discussions between academia, pharmaceutical industry, and regulators. The purpose is to optimize clinical research and obtain evidence for paediatric psychopharmacology, thereby providing adequate support for treatment. 2010 Elsevier B.V. and ECNP. All rights reserved

How real are patients in placebo-controlled studies of acute manic episode?

Objective: To determine whether the results from placebo-controlled studies conducted in patients with manic episode can be generalised to a routine population of hospitalised acute manic patients. Methods: A list of four most prevalent inclusion and the nine most prevalent exclusion criteria was constructed for participation in previous randomised-controlled trials (RCTs). On the basis of this list, a consecutive series of 68 patients with 74 episodes of acute mania who had been referred for routine treatment were retrospectively assessed to determine their eligibility for a hypothetical but representative randomised controlled trial. Results: Only 16% of the manic episodes would qualify for the hypothetical trial (male episodes 28%, female episodes 10%), whereas 37%, 20% and 27% of the manic episodes would have to be excluded because they did no fulfil one, two or at least three of the inclusion or exclusion criteria. The most common exclusion criterion was "no use of contraceptives". If this criterion was not taken into account, 28% of the male episodes and 33% of the female episodes would qualify for inclusion in the hypothetical study. Apart from the use of contraceptives, no significant differences between male and female episodes were observed in the reasons for exclusion: 11% suicidal ideation, 29% prior mood stabilising medication, 1% depot medication, 22% other axis I diagnosis, 27% internal disease somatic disease, 5% neurological disorder, 15% alcohol use disorder and 10% drug use disorder. Conclusion: Only a small percentage acute manic episodes in a routine mental hospital seem to qualify for a standard placebo-controlled RCT. It could be argued, however, that certain exclusion criteria (e.g. no use of contraceptives) are not very likely to reduce the external validity of a standard RCT. In contrast, some other exclusion criteria (e.g. comorbid alcohol and drug use disorders) may have resulted in an overestimation of the efficacy of anti-manic medications. These notions should be taken into account when evaluating the results of RCTs in bipolar patients with an acute manic episode. (C) 2003 Elsevier B.V./ECNP. All rights reserve

Antidepressants use in children and adolescents and the risk of suicide

Antidepressants use in paediatric patients has been linked with risk of suicidal behaviours. The aim of this paper, therefore, is to examine whether all antidepressants are associated with such risk. All 22 paediatric short-term placebo-controlled trials of SSRIs and NSRIs that were submitted to European registration authorities by pharmaceutical companies were identified and examined for events related to suicidality, which were defined as suicide, suicide attempts or suicidal thoughts. Random effect meta-analysis was used to combine the information from all trials. No completed suicides were reported. However, for each compound there was at least one study with an increased risk for events related to suicidality in the active compound group. The overall OR for these events in the depression studies was 1.67 (95% CI: 1.05-2.65) and for anxiety 1.33 (95% CI: 0.33-5.35). Caution is called for in the use of all SSRIs and NSRIs in the paediatric population. Furthermore, in the absence of contradictory information, caution in the use of other antidepressants in this population should be exercised as well (e.g. tricyclic antidepressants

Early Nonresponse in the Antipsychotic Treatment of Acute Mania: A Criterion for Reconsidering Treatment? Results From an Individual Patient Data Meta-Analysis

OBJECTIVE: To investigate whether early nonresponse to antipsychotic treatment of acute mania predicts treatment failure and, if so, to establish the best definition or criterion of an early nonresponse. DATA SOURCES: Short-term efficacy studies assessing antipsychotics that were submitted to the Dutch Medicines Evaluation Board during an 11-year period as part of the marketing authorization application for the indication of acute manic episode of bipolar disorder. Pharmaceutical companies provided their raw patient data, which enabled us to perform an individual patient data meta-analysis. STUDY SELECTION: All double-blind, randomized, placebo-controlled trials assessing the efficacy of antipsychotics for acute manic episode of bipolar disorder were included (10 trials). DATA EXTRACTION: All patients with data available for completer analysis (N = 1,243), symptom severity scores on the Young Mania Rating Scale (YMRS) at weeks 0, 1, and 2 and at study end point (week 3 or 4). RESULTS: The a priori chances of nonresponse and nonremission at study end point were 40.9% (95% CI, 38.2%-43.6%) and 65.3% (95% CI, 62.0%-68.6%), respectively. Early nonresponse in weeks 1 and 2, defined by cutoff scores ranging from a ≤ 10% to a ≤ 50% reduction in symptoms compared to baseline on the YMRS, significantly predicted nonresponse (≤ 0% symptom reduction) and nonremission (YMRS score higher than 8) in week 3. The predictive value of early nonresponse (PVnr_se) at week 1 for both nonresponse and nonremission at study end point declined linearly with increasing cutoff scores of early nonresponse; nonresponse: 76.0% (95% CI, 69.7%-82.3%) for a ≤ 10% response to 48.7% (95% CI, 45.5%-51.9%) for a ≤ 50% response; nonremission: 92.2% (95% CI, 88.3%-96.1%) for a ≤ 10% response to 76.8% (95% CI, 74.4%-79.5%) for a ≤ 50% response. A similar linear decline was observed for increasing cutoff scores of early nonresponse at week 2 for nonresponse, but not for nonremission at end point: nonresponse 90.3% (95% CI, 84.6%-96.0%) for a ≤ 10% response to 65.0% (95% CI, 61.4%-68.6%) for a ≤ 50% response; nonremission: 94.2% (95% CI, 89.7%-98.7%) for a ≤ 10% response and 93.2% (95% CI, 93.1%-95.1%) for a ≤ 50% response. Specific antipsychotic characteristics did not modify these findings at either time point (week 1: P = .127; week 2: P = .213). CONCLUSIONS: When patients fail to respond early (1-2 weeks) after the initiation of antipsychotic treatment for acute mania, clinicians should reconsider their treatment choice using a 2-stage strategy