Estimands in CNS trials - A review of strategies for addressing intercurrent events.

Background: The estimands framework represents a significant innovation for the design, conduct, analysis, and interpretation of clinical trials. An aim of the framework is to increase precision and transparency on the handling of intercurrent events (IEs), defined as events occurring after treatment initiation and affecting the endpoint. While the experience in constructing and reporting estimands in the published literature is limited, developers performing confirmatory studies are already making use of the new paradigm, allowing to survey the strategies proposed by applicants and endorsed by regulators.

A Phase 1b Study to Evaluate the Safety and Efficacy of Durvalumab in Combination With Tremelimumab or Danvatirsen in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

Background: Despite recent advances, outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) remain poor. Immune checkpoint inhibitors have shown limited efficacy in this setting, but combinations with novel agents may enhance benefit. Combination therapy with durvalumab, an anti-programmed death ligand 1 (PD-L1) antibody, and danvatirsen (AZD9150; an antisense oligonucleotide inhibiting signal transducer and activator of transcription 3 [STAT3]) or tremelimumab (an anti-cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] antibody) may augment endogenous antitumor activity.

When can maximal efficacy occur with repeat botulinum toxin injection in upper limb spastic paresis?

Repeated injection cycles with abobotulinumtoxinA, a botulinum toxin type A, are recommended in current clinical guidelines as a treatment option for adults with upper limb spastic paresis. However, the magnitude of the maximal therapeutic effect of repeated abobotulinumtoxinA treatment across different efficacy parameters and the number of injection cycles required to reach maximal effect remain to be elucidated. Here, we present a exploratory analysis of a randomized, double-blind, placebo-controlled trial (12-24 weeks; NCT01313299) and open-label extension study (up to 12 months; NCT0131331), in patients aged 18-80 years with hemiparesis for ≥6 months after stroke/traumatic brain injury.

PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma.

Combining PD-L1 blockade with inhibition of oncogenic mitogen-activated protein kinase (MAPK) signaling may result in long-lasting responses in patients with advanced melanoma. This phase 1, open-label, dose-escalation and -expansion study (NCT02027961) investigated safety, tolerability and preliminary efficacy of durvalumab (anti-PD-L1) combined with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for patients with BRAF-mutated melanoma (cohort A, n = 26), or durvalumab and trametinib given concomitantly (cohort B, n = 20) or sequentially (cohort C, n = 22) for patients with BRAF-wild type melanoma. Adverse events and treatment discontinuation rates were more common than previously reported for these agents given as monotherapy.

Folate metabolism biomarkers from two randomised placebo-controlled clinical studies with paroxetine and venlafaxine.

Objectives: Based on the hypothesis of a role for folate and vitamin B12 in major depressive disorders (MDD), we aimed at validating the association between folate pathway biomarkers and depression or antidepressant response in clinical trial populations.

Methods: We investigated serum levels erythrocyte folate and serum levels of homocysteine, vitamin B12, and folate as disease and response biomarkers for MDD in two independent randomised, placebo-controlled clinical trials, where paroxetine or venlafaxine were used as active controls, for a total of 881 patients.

Results: Significant but weak correlations between depression severity and biomarker levels could be detected in the paroxetine study for serum folate and vitamin B12, with no correlations for any biomarker in the venlafaxine study.

Biomarkers for response in major depression: comparing paroxetine and venlafaxine from two randomised placebo-controlled clinical studies.

The identification of biomarkers of response might speed drug development and set the premises to assist clinical practice in psychiatry. In this work, we evaluated a panel of peripheral biomarkers (including IL-6, IL-10, TNF-α, TNFRII, BDNF, CRP, MMP9 and PAI1) in depressed patients receiving paroxetine, venlafaxine, or placebo. Samples were obtained from two randomised placebo-controlled studies evaluating the efficacy and tolerability of a novel drug candidate, using either paroxetine or venlafaxine as active comparators.

Investigation of mixed model repeated measures analyses and non-linear random coefficient models in the context of long-term efficacy data.

The longitudinal data from 2 published clinical trials in adult subjects with upper limb spasticity (a randomized placebo-controlled study [NCT01313299] and its long-term open-label extension [NCT01313312]) were combined. Their study designs involved repeat intramuscular injections of abobotulinumtoxinA (Dysport®), and efficacy endpoints were collected accordingly. With the objective of characterizing the pattern of response across cycles, Mixed Model Repeated Measures analyses and Non-Linear Random Coefficient (NLRC) analyses were performed and their results compared.

Device errors in asthma and COPD: systematic literature review and meta-analysis.

Unlabelled: Inhaler device errors are common and may impact the effectiveness of the delivered drug. There is a paucity of up-to-date systematic reviews (SRs) or meta-analyses (MAs) of device errors in asthma and chronic obstructive pulmonary disease (COPD) patients. This SR and MA provides an estimate of overall error rates (both critical and non-critical) by device type and evaluates factors associated with inhaler misuse.

An investigation of thrust, depth and the impedance cardiogram as measures of cardiopulmonary resuscitation efficacy in a porcine model of cardiac arrest.

Objective: Optimising the depth and rate of applied chest compressions following out of hospital cardiac arrest is crucial in maintaining end organ perfusion and improving survival. The impedance cardiogram (ICG) measured via defibrillator pads produces a characteristic waveform during chest compressions with the potential to provide feedback on cardiopulmonary resuscitation (CPR) and enhance performance. The objective of this pre-clinical study was to investigate the relationship between mechanical and physiological markers of CPR efficacy in a porcine model and examine the strength of correlation between the ICG amplitude, compression depth and end-tidal CO2 (ETCO2).

Identification of five chronic obstructive pulmonary disease subgroups with different prognoses in the ECLIPSE cohort using cluster analysis.

Rationale: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease that likely includes clinically relevant subgroups.

Objectives: To identify subgroups of COPD in ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) subjects using cluster analysis and to assess clinically meaningful outcomes of the clusters during 3 years of longitudinal follow-up.

Methods: Factor analysis was used to reduce 41 variables determined at recruitment in 2,164 patients with COPD to 13 main factors, and the variables with the highest loading were used for cluster analysis.

Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial.

Background: We aimed to investigate the efficacy and tolerability of empagliflozin, an oral, potent, and selective inhibitor of sodium-glucose co-transporter 2, in patients with type 2 diabetes who had not received drug treatment in the preceding 12 weeks.

Methods: In our multicentre, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) who had not received oral or injected anti-diabetes treatment in the previous 12 weeks. Eligible patients had HbA1c concentrations of 7-10%.

Distinct modulatory effects of satiety and sibutramine on brain responses to food images in humans: a double dissociation across hypothalamus, amygdala, and ventral striatum.

We used functional magnetic resonance imaging to explore brain responses to food images in overweight humans, examining independently the impact of a prescan meal ("satiety") and the anti-obesity drug sibutramine, a serotonin and noradrenaline reuptake inhibitor. We identified significantly different responses to these manipulations in amygdala, hypothalamus, and ventral striatum. Each region was specifically responsive to high-calorie compared to low-calorie food images.