Study Discontinuation Rates Research Articles

Assessing the impact of open-label designs in patient-reported outcomes: investigation in oncology clinical trials.

Knowledge of treatment assignment may affect patient-reported outcomes (PROs), which is of concern in oncology, where open-label trials are common. This study measured the magnitude of open-label bias by comparing PROs for similar patient groups in oncology trials with different degrees of concealment. Individual patient data from ipilimumab arms of 2 melanoma and docetaxel arms of 2 non-small cell lung cancer (NSCLC) trials were adjusted for differences using propensity score weighting. Patients were aware of treatment assignment in CA184-022 and CheckMate 057 (open-label) but not in MDX010-20 and VITAL (blinded). Overall survival (OS) and mean changes from baseline to week 12 in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (melanoma) and Lung Cancer Symptom Scale (NSCLC) scores were compared between open-label and blinded groups. After adjustment, baseline characteristics were balanced between blinded (melanoma, n = 125; NSCLC, n = 424) and open-label (melanoma, n = 69; NSCLC, n = 205) groups. Study discontinuation and PRO completion rates at week 12 and OS were similar. There was no clear direction in differences in change scores between groups. In the melanoma trials, role functioning (mean = -5.2, 95% confidence interval [CI] = -15.4 to 5.0), global health status (mean = -1.3, 95% CI = -8.7 to 6.1), and pain (mean = 6.2 , 95% CI = -1.8 to 14.2) favored the blinded, whereas emotional functioning (mean = 2.2, 95% CI = -5.8 to 10.2) and diarrhea (mean = -8.3, 95% CI = -17.3 to 0.7) favored the open-label group. In the NSCLC trials, changes in dyspnea (mean = 5.4, 95% CI = -0.7 to 11.5) favored the blinded and changes in appetite (mean = -1.2, 95% CI = -8.1 to 5.7) favored the open-label group. None were clinically or statistically significant. This study adds to the growing evidence demonstrating that concerns regarding open-label bias should not prohibit the interpretation of large and meaningful treatment effects on PROs.

Therapeutic effects of antidepressants for global improvement and subdomain symptoms of autism spectrum disorder: a systematic review and meta-analysis.

Background:No established pharmacological treatment is available for the core symptoms of autism spectrum disorder (ASD). This study aimed at investigating the efficacy of antidepressants for the core and associated symptoms of ASD.Methods:We searched PubMed, Embase, ClinicalKey, Cochrane CENTRAL, ScienceDirect, Web of Science and ClinicalTrials.gov using the keywords “ASD” and “antidepressants.” We searched from database inception to June 2021 for randomized controlled trials of antidepressant use in patients with ASD. We calculated pooled effect sizes based on a random-effects model.Results:Analysis of 16 studies with 899 participants showed improvements in restricted and repetitive behaviours (effect size = 0.27) and global symptoms (effect size = 1.0) in patients with ASD taking antidepressants versus those taking placebos (p ≤ 0.01). We found no differences between the 2 groups (p ≥ 0.36) in terms of dropout rate (odds ratio [OR] = 1.17) or rate of study discontinuation because of adverse events (OR = 1.05). We also noted improvements in irritability and hyperactivity in the antidepressant group (Hedges g = 0.33 and 0.22, respectively, both p < 0.03). Subgroup analyses showed significant effects of medication type (i.e., clomipramine was better than SSRIs) and age (antidepressants were more effective in adults than in children or adolescents) on both restricted and repetitive behaviours and global improvement (p < 0.05). Meta-regression demonstrated that better therapeutic effects were associated with lower symptom severity and older age.Limitations:The small effect sizes and variations in treatment response that we found warrant further study. Conclusion:Our results supported the effectiveness of antidepressants for global symptoms and symptom subdomains of ASD, with tolerable adverse effects. Low symptom severity and adulthood were associated with better outcomes.

Efficacy and Safety of Blonanserin Oral Tablet in Adolescents with Schizophrenia: A 6-Week, Randomized Placebo-Controlled Study.

Objectives: To evaluate the short-term efficacy and safety of blonanserin in adolescents with schizophrenia.Methods: This 6-week multicenter, double-blind, randomized, placebo-controlled study investigated fixed-dose blonanserin (8 or 16 mg/day) in patients 12–18 years of age diagnosed with schizophrenia, as indicated by a Positive and Negative Syndrome Scale (PANSS) total score of 60–120 and a Clinical Global Impressions-Severity score of ≥3. The primary endpoint was change from baseline to week 6 in the PANSS total score, using a mixed model for repeated measures analysis. Safety was assessed by the incidence and severity of adverse events (AEs).Results: Among 151 randomized patients, 150 were included in the primary analysis population. Demographic and clinical characteristics were similar across groups at baseline. The rate of study discontinuation was 14.9%, 23.5%, and 28.3% in patients administered with placebo, blonanserin 8 mg/day, and blonanserin 16 mg/day, respectively. The least-squares mean change (95% confidence interval [CI]) from baseline to week 6 in PANSS total score was −10.6 (−16.10 to −5.10), −15.3 (−20.80 to −9.86), and −20.5 (−25.89 to −15.16) in patients administered placebo, 8 mg/day blonanserin, and 16 mg/day blonanserin, respectively. The 16-mg/day blonanserin group showed significantly greater reduction in the PANSS total score than the placebo group (least-squares mean difference [95% CI]: −9.9 [−17.61 to −2.25], p = 0.012, effect size: 0.538), although the 8-mg/day group showed no significant difference. The incidence of AEs such as akathisia, somnolence, and hyperprolactinemia was higher in the blonanserin groups than in the placebo group. AEs associated with blonanserin were generally mild and were consistent with its known profile in adults with schizophrenia.Conclusions: Blonanserin achieved a sufficient efficacy in adolescent patients, and the safety profile was similar to that in adults, which suggests that blonanserin may be a safe treatment option for adolescents with schizophrenia.Study registration number: Japic CTI-111724.

Sarilumab reduces disease activity in rheumatoid arthritis patients with inadequate response to janus kinase inhibitors or tocilizumab in regular care in Germany.

ObjectivesThe aim was to evaluate the safety and effectiveness of sarilumab in RA patients after inadequate response (IR) to janus kinase inhibitors (JAKi) and tocilizumab.MethodsThe prospective, observational, 24-month single-arm PROSARA study (SARILL08661) is currently running in Germany at 96 sites. RA patients were prospectively selected at the physician’s discretion according to label. This interim analysis included 536 patients over a treatment course of ≤6 months. Patients were stratified in four groups according to pretreatment before the start of sarilumab therapy: last prior treatment JAKi (JAKi-IR); last prior treatment tocilizumab (tocilizumab-IR); any other biological DMARD (bDMARD) in treatment history (bDMARD TH); and patients who had not received any bDMARDs or targeted synthetic (ts) DMARDs (b/tsDMARD naive) before.ResultsFor this preplanned interim analysis, 536 patients were included in the baseline population, of whom 502 patients had at least one corresponding post-baseline effectiveness assessment documented (main analysis population). In all analysed cohorts, safety was consistent with the anticipated profile of sarilumab, without new safety signals. Six months of sarilumab treatment attenuated disease activity in JAKi-IR, tocilizumab-IR, bDMARD TH and b/tsDMARD-naive patients to a very similar extent. Physical function did not change substantially over the course of treatment. Rates of premature study discontinuation were comparable between cohorts.ConclusionSarilumab treatment was effective in patients with IR to JAKi and tocilizumab, with an expectable safety profile and drug retention over 6 months. Confirmation of these promising results should encourage further studies on this treatment sequence, which is of high practical relevance.Study registrationPaul-Ehrlich-Institut—Federal Institute for Vaccine and Biomedics, SARILL08661.

Bioavailability of once-daily tacrolimus formulations used in clinical practice in the management of De Novo kidney transplant recipients: the better study.

Multicenter, prospective, observational study to compare the relative bioavailability of once‐daily tacrolimus formulations in de novo kidney transplant recipients. De novo kidney transplant recipients who started a tacrolimus‐based regimen were included 14 days post‐transplant and followed up for 6 months. Data from 218 participants were evaluated: 129 in the LCPT group (Envarsus) and 89 in the PR‐Tac (Advagraf) group. Patients in the LCPT group exhibited higher relative bioavailability (Cmin /total daily dose [TDD]) vs. PR‐Tac (61% increase; P < .001) with similar Cmin and 30% lower TDD levels (P < .0001). The incidence of treatment failure was 3.9% in the LCPT group and 9.0% in the PR‐Tac group (P = .117). Study discontinuation rates were 6.2% in the LCPT group and 12.4% in the PR‐Tac group (P = .113). Adverse events, renal function and other complications were comparable between groups. The median accumulated dose of tacrolimus in the LCPT group from day 14 to month 6 was 889 mg. Compared to PR‐Tac, LCPT showed higher relative bioavailability, similar effectiveness at preventing allograft rejection, comparable effect on renal function, safety, adherence, treatment failure and premature discontinuation rates.

Being Present 2.0: Online Mindfulness-Based Program for Metastatic Gastrointestinal Cancer Patients and Caregivers.

PurposeA metastatic cancer diagnosis is associated with high levels of distress in patients and caregivers, which may be alleviated by mindfulness interventions. Research on scalable, tailored, online mindfulness training programs is needed. We sought to test the feasibility and acceptability of a remotely delivered 8-week mindfulness-based intervention, Being Present 2.0 (BP2.0).MethodsWe performed a single-arm feasibility study of BP2.0 among patients with any metastatic gastrointestinal cancer receiving chemotherapy, with or without an informal caregiver. Participants were instructed to practice mindfulness using pre-recorded guided meditations 5 times per week using a study-specific website and to attend a weekly live, interactive virtual meeting facilitated by a trained instructor. The web-based platform enabled direct measurement of adherence.ResultsThe study enrolled 46 of 74 (62%) patients contacted, together with 23 caregivers (69 participants total), from May to October 2018. Median patient age was 52 (range 20-70 years), 39% were male, 67% non-Hispanic white, 65% had colorectal cancer, and 78% lived outside of San Francisco. The top reasons cited for participation were to reduce stress/anxiety and learn how to meditate. Mean baseline National Comprehensive Cancer Network Distress Thermometer (NCCN DT) scores were 4.7 (patients) and 5.8 (caregivers). The study discontinuation rate was 20% (eight patients and six caregivers). Among the remaining 55 participants, 43 (78%) listened to at least one audio recording and/or attended at least one virtual meeting, although adherence data was incomplete. The retention rate was 71%, with 39 participants completing at least one follow-up assessment. In post-intervention qualitative interviews, 88% of respondents reported a positive experience. Compared to baseline, participants reported significantly reduced post-intervention NCCN DT scores (mean 3.1; P = .012).ConclusionThe BP2.0 online mindfulness-based program is feasible and acceptable for patients with metastatic gastrointestinal cancer and caregivers. These results will guide plans for a follow-up efficacy study. ClinicalTrials.gov Identifier: NCT03528863.

Sabatolimab (MBG453) Dose Selection and Dose-Response Analysis in Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML): Population Pharmacokinetics (PK) Modeling and Evaluation of Clinical Efficacy/Safety By Dose

Sabatolimab (MBG453) Dose Selection and Dose-Response Analysis in Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML): Population Pharmacokinetics (PK) Modeling and Evaluation of Clinical Efficacy/Safety By Dose

Chronic urticaria in the real‐life clinical practice setting in the UK: results from the noninterventional multicentre AWARE study

Chronic urticaria (CU) is a skin condition characterized by repeated occurrence of itchy weals and/or angio-oedema for >6weeks. To provide data demonstrating the real-life burden of CU in the UK. This UK subset of the worldwide, prospective, noninterventional AWARE study included patients aged 18-75years diagnosed with H1-antihistamine (H1-AH)-refractory chronic spontaneous urticaria (CSU) for >2months. Baseline characteristics, disease activity, treatments, comorbidities and healthcare resource use were documented. Quality of life (QoL), work productivity and activity impairment were assessed. Baseline analysis included 252 UK patients. Mean age and body mass index were 45.0years and 29.0kg/m2 , respectively. Most patients were female (77.8%) and had moderate/severe disease activity (mean Urticaria Activity Score over 7days was 18.4) and a 'spontaneous' component to their CU (73.4% CSU; 24.6% CSU and chronic inducible urticaria). Common comorbidities included depression/anxiety (24.6%), asthma (23.8%) and allergic rhinitis (12.7%). A previous treatment was recorded for 57.9% of patients. Mean Dermatology Life Quality Index score was 9.5, and patients reported impairments in work productivity and activity. Healthcare resource use was high. Severity of CSU was associated with female sex, obesity, anxiety and diagnosis. Only 28.5% of patients completed all nine study visits, limiting analysis of long-term treatment patterns and disease impact. Adult H1-AH-refractory patients with CU in the UK reported high rates of healthcare resource use and impairment in QoL, work productivity and activity at baseline. The differing structures of UK healthcare may explain the high study discontinuation rates versus other countries.

Randomized Clinical Trial on the Effect of Bardoxolone Methyl on GFR in Diabetic Kidney Disease Patients (TSUBAKI Study)

IntroductionBardoxolone methyl significantly increases estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease (CKD). However, the phase 3 study, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes Mellitus: the Occurrence of Renal Events (BEACON), was terminated prematurely because bardoxolone methyl increased the risk for early-onset fluid overload in patients with identifiable risk factors for heart failure (elevated baseline B-type natriuretic peptide levels >200 pg/ml and prior history of hospitalization for heart failure). The Phase 2 Study of Bardoxolone Methyl in Patients with Chronic Kidney Disease and Type 2 Diabetes (TSUBAKI) study aimed to determine if patients without risk factors can mitigate the risk for fluid overload and whether changes in eGFR with bardoxolone methyl reflect true increases in GFR.MethodsThis phase 2, randomized, multicenter, double-blind, placebo-controlled study enrolled patients with type 2 diabetes and stage 3–4 CKD. Patients were randomized 1:1 to bardoxolone methyl (n = 41) or placebo (n = 41) (cohort G3), or 2:1 to bardoxolone methyl (n = 24) or placebo (n = 14) (cohort G4), administered orally once daily for 16 weeks using a dose-titration scheme. The primary efficacy endpoint was change from baseline in GFR measured by inulin clearance at week 16 in the cohort G3.ResultsA total of 40 patients were evaluated for the prespecified primary efficacy analysis. Mean change (95% confidence interval [CI]) from baseline in GFR was 5.95 (2.29 to 9.60) and −0.69 (−3.83 to 2.45) ml/min per 1.73 m2 for patients randomized to bardoxolone methyl and placebo, respectively, with a significant intergroup difference of 6.64 ml/min per 1.73 m2 (P = 0.008). Increases in the albumin/creatinine ratio were observed in the bardoxolone methyl group vs the placebo group. The most common adverse events (≥15% in either group) were viral upper respiratory tract infection, increased alanine aminotransferase, increased aspartate aminotransferase, increased γ-glutamyltransferase, and constipation. Peripheral edema was reported by 4 patients receiving bardoxolone methyl and by 1 patient receiving placebo; all events were mild and self-limiting. No patient died or experienced heart failure. The study discontinuation rate was higher in the bardoxolone methyl group (cohort G3, n = 8; cohort G4, n = 7) than the placebo group (cohort G3, n = 1; cohort G4, n = 0).ConclusionBardoxolone methyl significantly increased measured GFR, and further investigation is ongoing to evaluate whether it provides clinical benefit without major safety concerns in selected patients with CKD.

159 Safety and Efficacy of Lurasidone in Children and Adolescents with Bipolar Depression: Results from a 2-Year Open-label Extension Study

Bipolar I disorder frequently has an early onset, with an estimated prevalence rate of 1.8% in pediatric populations. Early onset is associated with a high degree of chronicity; however, limited data are available on the long-term efficacy of drug therapies in pediatric populations. The aim of the current study was to evaluate the long-term safety and efficacy of lurasidone in children and adolescents with bipolar depression. Patients 10-17 years with bipolar I depression were randomized to 6 weeks of double-blind (DB) treatment with lurasidone or placebo. Patients who completed the study were eligible to enroll in a 2-year, open-label (OL) extension study in which patients were continued on flexibly-dosed lurasidone (20-80 mg/d; LUR-LUR) or switched from placebo to lurasidone (PBO-LUR). The primary efficacy measure was the Children's Depression Rating Scale, Revised (CDRS-R); response was defined as ≥50% reduction from DB baseline in the CDRS-R total score. A total of 306 patients completed the 6-week DB study and entered the extension study; 195 (63.7%) completed 52 weeks, and 168 (54.9%) completed 104 weeks of treatment. Mean CDRS-R total score at DB baseline was 59.4 in patients treated with lurasidone, and 58.7 in patients treated with placebo; and mean CDRS-R total score at OL baseline (after 6 weeks of DB treatment) was 36.6 in the LUR-LUR group and 41.9 in the PBO-LUR group. For the total sample of patients in the OL study, mean change (from OL baseline) in the CDRS-R score was -13.4 at week 52 and -16.4 at week 104; and responder rates were 51.0% at OL baseline (64.5% for LUR-LUR; 36.9% for PBO-LUR), 88.4% at week 52, and 91.1% at week 104. During OL treatment with lurasidone, 31 patients (10.1%) discontinued due to an adverse event. The most commonly reported events were headache (23.9%), nausea (16.4%), and somnolence (9.8%). OL treatment with lurasidone was associated with few effects on metabolic parameters or prolactin. Mean change from DB baseline in weight was +4.25 kg at week 52 (vs. an expected weight gain of 3.76 kg based on CDC normative data), and +6.75 kg at week 104 (vs. CDC expected weight gain of 6.67 kg). Two years of treatment with lurasidone in children and adolescents with bipolar depression was generally well-tolerated, with relatively low rates of study discontinuation. Lurasidone treatment was associated with few effects on weight, metabolic parameters, and prolactin. Patients also continued to experience improvement in depressive symptoms during long-term treatment with lurasidone.Clinicaltrials.gov identifier: NCT01914393. Supported by funding from Sunovion Pharmaceuticals Inc.

Efficacy and safety of lithium and lamotrigine for the maintenance treatment of clinically stable patients with bipolar disorder: A systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials with an enrichment design.

AimWhether patients with adult bipolar disorder (BD) who have been clinically stabilized with lithium or lamotrigine should continue this medication is not established fully. This systematic review and meta‐analysis evaluated the efficacy and safety of lithium and lamotrigine for maintenance treatment in clinically stable patients with adult BD.MethodsThis meta‐analysis included only double‐blind, randomized, placebo‐controlled trials with an enrichment design that selected patients who responded acutely to lithium or lamotrigine. Reports prior to November 15, 2018, were retrieved from the PubMed/Cochrane Library/Embase. The primary outcome was the relapse rate due to any mood episode at the study endpoint. Other outcomes were relapse rates due to a manic/hypomanic/mixed episode or depression at the study endpoint, discontinuation rate, death, and death by suicide. Risk ratios (RRs) (95% confidence intervals) were calculated. When the random‐effects model showed significant differences between groups, the number‐needed‐to‐treat (NNT) was estimated.ResultsThe search retrieved two studies regarding lithium (N = 218) and four evaluating lamotrigine (N = 706). Both drugs were superior to placebo for reducing the relapse rate due to any mood episode [lithium: RR = 0.52 (0.41‐0.66), P < 0.00001, I 2 = 0%, NNT = 2.3 (1.6‐4.2); lamotrigine: RR = 0.81 (0.70‐0.93), P = 0.004, I 2 = 0%, NNT = 8.3 (5.0‐25.0)] and all‐cause discontinuation. There were no significant differences in other outcomes between lithium or lamotrigine and the placebo groups.ConclusionBoth drugs showed benefit for preventing relapse in clinically stable patients with adult BD. However, the number of studies and patients in this analysis was small.

Randomized phase II trial of bevacizumab plus everolimus versus bevacizumab alone for recurrent or persistent ovarian, fallopian tube or peritoneal carcinoma: An NRG oncology/gynecologic oncology group study

PurposeBevacizumab (BV) monotherapy leads to compensatory upregulation of multiple signaling pathways, resulting in mTOR activation. We evaluated combining BV and everolimus (EV), an mTOR kinase inhibitor, to circumvent BV-resistance in women with recurrent or persistent ovarian, fallopian tube or primary peritoneal cancer (OC). Patients and methodsEligible OC patients had measurable (RECIST1.1) or detectable disease, 1–3 prior regimens, performance status (PS) 0–2, and no prior m-TOR inhibitor. All patients received BV 10 mg/kg IV every 2wks. Patients were randomized (1:1) to oral EV (10 mg daily) or placebo stratified by platinum-free interval (PFI), measurable disease and prior BV. Primary endpoint was progression-free survival (PFS); secondary endpoints included safety and response. Results150 patients were randomized to BV with (n = 75) and without (n = 75) EV. Arms were well-balanced for age (median 63: range 28–92), PS (0: 73%, 1–2: 27%), prior regimens (1: 37%, 2: 47%, 3: 16%), prior BV (11%), PFI (<6mos: 65%) and measurable disease (81%). The BV + EV vs BV median PFS was 5.9 vs 4.5 months (hazard ratio [HR] 0.95 (95% CI, 0.66–1.37, p = 0.39)). Median OS was 16.6 vs 17.3 months (HR 1.16 (95% CI, 0.72–1.87, p = 0.55). Objective measurable responses were higher with BV + EV (22% vs 12%). Study removal due to toxicity was higher with BV + EV (29% vs 12%). Toxicity (≥grade 3) from BV + EV were “other GI (mucositis)” (23 vs 1%) and “metabolic/nutrition” (19 vs. 7%); common ≥ grade 2 toxicities with BV + EV were cytopenia, nausea, fatigue and rash. ConclusionThe combination regimen (BV + EV) did not significantly reduce the hazard of progression or death relative to BV and was associated with higher rates of adverse events and study discontinuation when compared to BV alone.

Efficacy and Safety of Lurasidone in Adolescents with Schizophrenia: A 6-Week, Randomized Placebo-Controlled Study.

Objective: To evaluate the efficacy and safety of lurasidone in acutely symptomatic adolescent patients with schizophrenia.Methods: Patients aged 13–17 years were randomly assigned to 6 weeks of double-blind, fixed-dose lurasidone (40 or 80 mg/day) or placebo. Primary and key secondary efficacy measures were change from baseline to week 6 in the Positive and Negative Symptom Scale (PANSS) total score and Clinical Global Impressions-Severity (CGI-S) score, respectively, using mixed model for repeated measurement (MMRM) analysis. The proportion of patients achieving treatment response at endpoint, based on ≥20% reduction in PANSS total score, was analyzed using a logistic regression model.Results: Least-squares (LS) mean change in PANSS total score from baseline to week 6 was −18.6 with lurasidone 40 mg/day (N = 108; p < 0.001 vs. placebo; effect size = 0.51), −18.3 with lurasidone 80 mg/day (N = 106; p < 0.001 vs. placebo; effect size = 0.48), and −10.5 with placebo (N = 112). Similarly, LS mean change in CGI-S score from baseline to week 6 was significantly greater with lurasidone 40 mg/day (−1.0; p < 0.001; effect size = 0.49) and 80 mg/day (−0.9; p = 0.0015; effect size = 0.45) compared with placebo (−0.5). A significantly higher proportion of patients met responder criteria on lurasidone 40 and 80 mg/day versus placebo (63.9% and 65.1% vs. 42.0%; p < 0.001 for both comparisons). The rate of study discontinuation was 10.3% in lurasidone-treated and 17.7% in placebo-treated patients. The most common adverse events (incidence ≥5% in either lurasidone dose group and at least twice the rate of placebo) for lurasidone 40 mg/day, 80 mg/day, and placebo, respectively, were nausea (12.7%, 14.4%, and 2.7%), somnolence (9.1%, 11.5%, and 5.4%), akathisia (9.1%, 8.7%, and 1.8%), vomiting (8.2%, 6.7%, and 1.8%), and sedation (5.5%, 1.9%, and 1.8%). Treatment with lurasidone was not associated with clinically meaningful effects on body weight, lipids, measures of glycemic control, or prolactin.Conclusions: In this 6-week study, lurasidone at doses of 40 and 80 mg/day demonstrated statistically significant and clinically meaningful symptom improvement in adolescent patients with schizophrenia. Lurasidone was generally well tolerated with few effects on weight and metabolic parameters, consistent with findings in adult patients with schizophrenia.

Discontinuation and non-publication of clinical trials in cardiovascular medicine

BackgroundAppropriate dissemination of clinical data is crucial for minimising bias. Despite this, high rates of study discontinuation and non-publication have been reported among clinical trials. Cardiovascular medicine receives a substantial proportion of academic funding; however, predictors of non-publication among cardiovascular trials are not well-established. MethodsThe National Clinical Trials database was searched for cardiovascular trials completed between January 2010 and January 2014. Associated publications were identified in Medline or Embase. Relevant variables were extracted and subject to chi-squared and logistic regression to identify predictors of discontinuation and non-publication. ResultsAfter reviewing 2035 trials, 431 trials were included, of which 82.1% (n=354; 119,233 participants) were completed. Among completed trials, 70.3% (n=249; 99,095 participants) were published. Industry funding was associated with increased likelihood of non-publication (odds ratio [OR] 2.84; 95% confidence interval [CI] 1.47–5.51; P=0.002), while non-randomised studies were more likely to remain unpublished than randomised counterparts. Industry-funded studies were over three times more likely to be discontinued than those sponsored by academic institutions (OR 3.89; CI 1.54–9.83; P=0.004). Trials studying heart failure and atrial fibrillation were more likely to be discontinued compared to trials studying coronary artery disease (OR 2.83; CI 1.23–6.51; and OR 3.10; CI 1.21–7.96, respectively). Of the total 135,714 participants, 25,565 were recruited into unpublished studies. ConclusionsDiscontinuation and non-publication of cardiovascular trials are common, resulting in data from thousands of participants remaining unpublished. Funding source and randomisation are strong predictors of non-publication, while sponsor type, phase and blinding status are key predictors of discontinuation.

SA114. Lurasidone for the Treatment of Adolescent Patients With Schizophrenia: Effect on PANSS Subscales

Background: Lurasidone is an atypical antipsychotic agent that has demonstrated efficacy in the treatment of adults with schizophrenia in the dose range of 40–160 mg/d. The objective of this randomized, double-blind, placebo-controlled study was to evaluate the acute efficacy and safety of lurasidone in adolescent patients with schizophrenia. Methods: Adolescents (13–17 years old) diagnosed with schizophrenia were randomly assigned to 6 weeks of double-blind treatment with fixed-dose lurasidone 40 mg/d, 80 mg/d, or placebo. Changes from baseline to Week 6 in PANSS total and subscale (positive, negative, general psychopathology, excitability) scores were evaluated using mixed-model, repeated-measures analysis. Treatment response was defined as ≥20% reduction from baseline in PANSS total score at Week 6 and was analyzed using a logistic regression model with last observation carried forward (LOCF) approach. Results: A total of 326 patients (mean age, 15.4 years) were randomized and received lurasidone 40 mg/d (N = 108), 80 mg/d (N = 106), or placebo (N = 112). The PANSS total score at Week 6 demonstrated a placebo-adjusted, least-squares (LS) mean improvement of −8.0 (P < .001; effect size [ES] = 0.51) for the 40 mg/d group and −7.7 (P < .001; ES = 0.48) for the 80 mg/d group. Placebo-adjusted LS mean change for lurasidone 40 mg/d and 80 mg/d, respectively, was −3.2 (P < .001; ES = 0.62) and −3.2 (P < .001; ES = 0.60) on the PANSS positive subscale, −1.7 (P = .011; ES = 0.41) and −1.6 (P = .022; ES = 0.35) on the PANSS negative subscale, −2.8 (P = .012; ES = 0.38) and −2.8 (P = 0.011; ES = 0.37) on the PANSS general psychopathology subscale, and −1.1 (P = .016; ES = 0.36) and −1.8 (P < .001; ES = 0.53) on the PANSS excitability subscale. The proportion of treatment responders at Week 6 (LOCF) was 42.0% in the placebo group, 63.9% in the lurasidone 40 mg/d group (P < .001; NNT = 5), and 65.1% in the lurasidone 80 mg/d group (P < .001; NNT = 5). The most common adverse events (incidence ≥5% in either lurasidone group and at least twice the rate of placebo) for lurasidone 40 mg/d, 80 mg/d, and placebo, respectively, were nausea (12.7%, 14.4%, and 2.7%), somnolence (9.1%, 11.5%, and 5.4%), akathisia (9.1%, 8.7%, and 1.8%), vomiting (8.2%, 6.7%, and 1.8%), and sedation (5.5%, 1.9%, and 1.8%). The rate of study discontinuation due to adverse events was higher in placebo-treated versus lurasidone-treated patients (8.0% vs. 3.7%, respectively). Conclusion: In this double-blind, placebo-controlled study of adolescent patients with schizophrenia, lurasidone (40 mg/d and 80 mg/d) demonstrated statistically significant efficacy and clinically meaningful improvement across a range of symptoms associated with this disorder. Lurasidone treatment was generally safe and well tolerated in this study. Sponsored by Sunovion Pharmaceuticals Inc. ClinicalTrials.gov identifier: {type:clinical-trial,attrs:{text:NCT01911429,term_id:NCT01911429}}NCT01911429

Pregabalin for Neuropathic Pain: Why Benefits Could Be Expected for Multiple Pain Conditions.

Limited research exists to support the extrapolation of the analgesic efficacy of pregabalin from one neuropathic pain condition to another. This retrospective analysis evaluated similarities in the efficacy of pregabalin for treating neuropathic pain associated with post-herpetic neuralgia (PHN), diabetic peripheral neuropathy (DPN), and spinal cord injury (SCI) in a Japanese population, as a basis for considering the extrapolation of these data to other neuropathic pain conditions. Data were analysed across pregabalin doses within each pain condition, from three comparable 13- to 16-week, randomized, double-blind, placebo-controlled trials (RCTs) and the corresponding 52-week, open-label extension trials of pregabalin in Japanese patients with PHN, DPN or SCI. Efficacy outcomes in the RCTs included endpoint and weekly mean pain and sleep interference scores; endpoint proportions of responders in pain; Patient Global Impression of Change scores; and 36-Item Short Form Health Survey (SF-36) scores or Hospital Anxiety and Depression Scale (HADS) assessments. Study discontinuation rates were compared between treatment groups. The extension trials assessed pain intensity, using the Short-Form McGill Pain Questionnaire. In the RCTs for all pain conditions, significant improvements in comparison with placebo in mean pain and sleep interference scores were evident after 1 week with pregabalin and were sustained throughout the treatment periods (p < 0.05). At the study endpoint, in comparison with placebo, a significantly greater percentage of pregabalin-treated patients experienced a ≥30 % reduction in pain across the RCTs (p < 0.05), and pregabalin significantly improved six of 16 SF-36 subscale scores in the PHN and DPN trials (p < 0.05). In the SCI trial, pregabalin-treated patients had numerically better outcomes of HADS scores. In the extension trials, improvements in pain intensity were maintained over a 52-week period. Similarities in the pregabalin efficacy profiles, including time to onset and magnitude of response, were confirmed regardless of the neuropathic pain condition. These data support the potential for extrapolating analgesic efficacy to other neuropathic pain conditions. CLINICALTRIALS. NCT00394901, NCT00553475, NCT00407745, NCT00424372, NCT00553280, NCT01202227.

Low Incidence of Corticosteroid-associated Adverse Events on Long-term Exposure to Low-dose Prednisone Given with Abiraterone Acetate to Patients with Metastatic Castration-resistant Prostate Cancer

BackgroundAbiraterone acetate (AA) is the prodrug of abiraterone, which inhibits CYP17A1 and testosterone synthesis and prolongs the survival of patients with metastatic castration-resistant prostate cancer (mCRPC). AA plus prednisone (P) (AA+P) is approved for the treatment of patients with mCRPC. ObjectiveTo investigate whether long-term use of low-dose P with or without AA leads to corticosteroid-associated adverse events (CA-AEs) in mCRPC patients. Design, setting, and participantsThe study included 2267 patients in COU-AA-301 and COU-AA-302. We used an inclusive Standardized MedDRA Queries–oriented approach to identify 112 preferred terms for known CA-AEs, and assessed the incidence of CA-AEs during 3-mo exposure intervals and across all P exposure levels. InterventionAll 2267 patients received 5mg of P twice daily, and 1333/2267 received AA (1g) plus P. Results and limitationsThe CA-AE incidence after any P exposure was 25%, 26%, and 23% for any grade, and 5%, 5%, and 4% for grade ≥3 CA-AEs for all patients and the AA+P and P alone groups, respectively. The most common any-grade CA-AEs were hyperglycemia (7.4%, 7.8%, and 6.9% for all patients, AA+P, and P alone, respectively) and weight increase (4.3%, 3.9%, and 4.8%, respectively). When assessed by duration of exposure (3-mo intervals up to ≥30 mo), no discernable trend was observed for CA-AEs, including hyperglycemia and weight increase. The investigator-reported study discontinuation rate due to CA-AEs was 11/2267 (0.5%), and one patient had a CA-AE resulting in death. ConclusionsLow-dose P given with or without AA is associated with low overall incidence of CA-AEs. The frequency of CA-AEs remained low with increased duration of exposure to P. Patient summaryWe assessed adverse events in patients with metastatic castration-resistant prostate cancer during long-term treatment with a low dose of a corticosteroid. We found that long-term treatment with this low-dose corticosteroid is safe and tolerable.

Hormone receptor positive, HER2 negative metastatic breast cancer: A systematic review of the current treatment landscape.

Endocrine therapy for the treatment of hormone receptor positive, HER2 negative, metastatic breast cancer is continually evolving. We systematically reviewed phase 2 and 3 randomized controlled trials (RCTs) of agents used in this setting to assess the effectiveness and safety of these agents for postmenopausal women. Across the 32 studies in more than 10,000 patients, the greatest improvement in progression-free survival (PFS) was seen with the addition of a cyclin-dependent kinase (CDK)4/6 inhibitor to standard endocrine therapy. Treatment with a mammalian target of rapamycin (mTOR) inhibitor, phosphoinositol-3-kinase (Pi3K) inhibitor, vascular endothelial growth factor (VEGF) inhibitor and with a selective estrogen receptor degrader (SERD) also showed benefit in PFS for selected trials. Overall survival (OS) improved with the use of mTOR inhibitors and a SERD; however, studies were not powered for an OS endpoint. Encouraging results from early studies of histone deacetylase (HDAC) and B-cell lymphoma (BCL2) inhibitors are yet to be confirmed in phase III clinical trials. Study discontinuation rates and toxicity-related deaths were highest with VEGF inhibitors in combination with endocrine therapy, limiting their use in hormone receptor positive breast cancer. CDK4/6 inhibitors and mTOR inhibitors appeared to have activity in both first and second line settings, but required additional monitoring for common toxicities. The activity of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors was limited to the first-line setting and treatment discontinuation rates were higher than with mTOR inhibitors and SERDs. Overall, PFS benefit appears to be greatest when agents acting on CDK4/6, mTOR and Pi3K pathways, and SERDs are added to standard endocrine therapy. If these early results persist in further studies, these data are likely to change the way we treat hormone receptor positive, HER2 negative metastatic breast cancer. In the follow-up article to this review, we will consider the potential future treatment options for these patients.

Comparative benefits and harms of second generation antidepressants and cognitive behavioral therapies in initial treatment of major depressive disorder: systematic review and meta-analysis

Study question What are the benefits and harms of second generation antidepressants and cognitive behavioral therapies (CBTs) in the initial treatment of a current episode of major depressive disorder in...

Prefmab: Final Analysis of Patient Preference for Subcutaneous Versus Intravenous Rituximab in Previously Untreated CD20+ Diffuse Large B-Cell Lymphoma and Follicular Lymphoma

BackgroundRituximab in combination with chemotherapy is the standard of care for patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). To improve patient convenience and to reduce healthcare resource burden, a subcutaneous (SC) formulation of rituximab has been developed and has been shown to be clinically comparable to intravenous (IV) rituximab. The aim of this study was to evaluate patient preference for rituximab IV or SC administration.MethodsPrefmab (NCT01724021) is a randomized, open-label, crossover phase IIIb study. Eligible patients were aged ≥18 to ≤80 years with previously untreated CD20+ DLBCL (IPI 1-4 or 0 with bulky disease) or FL (FLIPI grade 1-3a), at least 1 bidimensionally measureable lesion ≥1.5cm at its largest dimension by computed tomography, and an ECOG performance status ≤3; all provided written informed consent. Patients received 8 cycles of rituximab according to 2 schedules: Arm A received 1 cycle of rituximab IV (375mg/m2) and 3 cycles of rituximab SC (1400mg) then 4 cycles of rituximab IV; Arm B received 4 cycles of rituximab IV (375mg/m2) then 4 cycles of rituximab SC (1400mg). Alongside rituximab, both arms received 6-8 cycles of chemotherapy (CHOP [cyclophosphamide, doxorubicin, oncovin, prednisone], CVP [cyclophosphamide, vincristine, prednisone], or bendamustine as per standard local practice). A Patient Preference Questionnaire (PPQ) was conducted post-rituximab therapy at cycles 6 and 8. The primary endpoint was overall preference for rituximab IV or SC. The strength of patient preference was also assessed (very strong, fairly strong, or not very strong). Adverse events (AEs), including administration-related reactions, were evaluated according to NCI-CTCAE version 4.0.ResultsAt the primary data cut-off (January 19, 2015), the intent-to-treat population comprised 743 patients (Arm A: n=372; Arm B: n=371). The majority of patients had DLBCL (63%). The median age was 60 years (range 18-80) and baseline characteristics were balanced between arms. One hundred and twenty patients discontinued immunochemotherapy treatment prematurely, primarily due to AEs (n=52), but entered follow-up. A further 108 patients (Arm A: n=48; Arm B: n=60) discontinued the study and did not complete follow-up, primarily due to death (53 patients [DLBCL: n=48; FL: n=5], 19 of whom died due to progressive disease [DLBCL: n=16; FL: n=3]), patient request/withdrawal of consent (n=23), or AEs (n=9). Rates of study discontinuation and treatment discontinuation were balanced between arms. The PPQ was completed by 620 patients at cycle 6 and 591 at cycle 8. At cycle 6, rituximab SC was preferred by 80% (n=495) of patients (Arm A: 79%; Arm B: 81%) and rituximab IV by 10% (n=62; Arm A: 11%; Arm B: 9%), while 10% (n=63) had no preference (Arm A: 10%; Arm B: 10%). At cycle 8, the respective values were 81% (n=477; Arm A: 77%; Arm B: 84%), 11% (n=66; Arm A: 13%; Arm B: 10%), and 8% (n=48; Arm A: 10%; Arm B: 6%). The strength of patient preference for rituximab SC or IV is shown in Figure 1. Of patients who preferred rituximab SC, the main reasons were 'less time in the clinic' (cycle 6: 68%; cycle 8: 69%) and 'feels more comfortable during administration' (cycle 6: 37%; cycle 8: 37%). The mean cumulative rituximab administration time (mean ± standard deviation) was 865 ± 401 min for rituximab IV compared with 37 ± 100 min for rituximab SC. AEs were generally balanced between rituximab IV and SC administration, with the exception of gastrointestinal disorders (IV: 55%; SC: 31%) in patients with FL, notably nausea (IV: 28%; SC: 11%), constipation (IV: 14%; SC: 6%), and vomiting (IV 12%; SC 2%). No new safety signals were detected.ConclusionsMost previously untreated patients with CD20+ DLBCL or FL preferred SC compared with IV administration of rituximab, mainly due to reduction in the duration and discomfort of administration. [Display omitted] DisclosuresRummel:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Plenteda:Roche: Other: Sub-investigator. Mendoza:Roche: Employment. Smith:Roche: Employment. Osborne:Roche: Employment. Grigg:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.