Alternative Endoscopy Reading Paradigms Determine Score Reliability and Effect Size in Ulcerative Colitis.

Objective: Central reading of endoscopy is advocated by regulatory agencies for clinical trials in ulcerative colitis [UC]. It is uncertain whether the local/site reader should be included in the reading paradigm. We explore whether using locally- and centrally-determined endoscopic Mayo subscores [eMS] provide a reliable final assessment and whether the paradigm used has an impact on effect size.

Efficacy and safety of topical brepocitinib cream for mild-to-moderate chronic plaque psoriasis: a phase IIb randomized double-blind vehicle-controlled parallel-group study.

Background: Plaque psoriasis (PsO) is an inflammatory skin disease driven, in part, by the activation of Janus kinase (JAK) signalling pathways.

Objectives: To assess the efficacy and safety of multiple doses of topical brepocitinib, a tyrosine kinase 2/JAK1 inhibitor, in participants with mild-to-moderate PsO.

Methods: This phase IIb multicentre randomized double-blind study was conducted in two stages.

Efficacy and safety of topical brepocitinib for the treatment of mild-to-moderate atopic dermatitis: a phase IIb, randomized, double-blind, vehicle-controlled, dose-ranging and parallel-group study.

Background: Atopic dermatitis (AD) is a prevalent inflammatory, pruritic skin disease. The Janus kinase (JAK) pathway is a treatment target.

Objectives: To assess the efficacy, safety and pharmacokinetics of topical cream brepocitinib, a small-molecule tyrosine kinase 2 (TYK2)/JAK1 inhibitor, in participants with mild-to-moderate AD.

In Search of Ambiguity: A Three-Stage Workflow Design to Clarify Annotation Guidelines for Crowd Workers.

We propose a novel three-stage FIND-RESOLVE-LABEL workflow for crowdsourced annotation to reduce ambiguity in task instructions and, thus, improve annotation quality. Stage 1 (FIND) asks the crowd to find examples whose correct label seems ambiguous given task instructions. Workers are also asked to provide a short tag that describes the ambiguous concept embodied by the specific instance found.

Oral tyrosine kinase 2 inhibitor PF-06826647 demonstrates efficacy and an acceptable safety profile in participants with moderate-to-severe plaque psoriasis in a phase 2b, randomized, double-blind, placebo-controlled study.

Background: Psoriasis treatments lack durable efficacy and have inconvenient administration, highlighting the need for new therapies.

Objective: To evaluate the efficacy and safety of tyrosine kinase 2 inhibitor, PF-06826647, in moderate-to-severe plaque psoriasis.

Methods: This phase 2b, double-blind study randomized participants to oral, once-daily PF-06826647 (1:1:2:2:2) 50:100:200:400 mg:placebo (16 weeks), then 200 or 400 mg (24 weeks) (NCT03895372).

Safety, tolerability, efficacy, pharmacokinetics, and pharmacodynamics of the oral TYK2 inhibitor PF-06826647 in participants with plaque psoriasis: a phase 1, randomised, double-blind, placebo-controlled, parallel-group study.

Background: Blockade of tyrosine kinase 2 (TYK2) signalling has previously shown therapeutic potential in the treatment of psoriasis. The primary objective of this study was to assess the safety and tolerability of the TYK2 inhibitor PF-06826647.

Methods: This phase 1, randomised, double-blind, placebo-controlled, parallel-group study assessed once daily oral dosing of PF-06826647 in participants with plaque psoriasis, at a single clinical research site in the USA.

Molecular Profiling of Ulcerative Colitis Subjects from the TURANDOT Trial Reveals Novel Pharmacodynamic/Efficacy Biomarkers.

Background And Aims: To define pharmacodynamic and efficacy biomarkers in ulcerative colitis [UC] patients treated with PF-00547659, an anti-human mucosal addressin cell adhesion molecule-1 [MAdCAM-1] monoclonal antibody, in the TURANDOT study.

Methods: Transcriptome, proteome and immunohistochemistry data were generated in peripheral blood and intestinal biopsies from 357 subjects in the TURANDOT study.

Results: In peripheral blood, C-C motif chemokine receptor 9 [CCR9] gene expression demonstrated a dose-dependent increase relative to placebo, but in inflamed intestinal biopsies CCR9 gene expression decreased with increasing PF-00547659 dose.

Effect of PF-00547659 on Central Nervous System Immune Surveillance and Circulating β7+ T Cells in Crohn's Disease: Report of the TOSCA Study.

Background And Aims: Progressive multifocal leukoencephalopathy [PML], a brain infection associated with anti-integrin drugs that inhibit lymphocyte translocation from bloodstream to tissue, can be fatal. Decreased central nervous system [CNS] immune surveillance leading to this infection has been reported in patients with multiple sclerosis or Crohn's disease treated with anti-integrin antibody natalizumab. PF-00547659 is an investigational human monoclonal antibody for inflammatory bowel disease, targeted against α4β7-mucosal addressin cell-adhesion molecule-1 [the integrin ligand selectively expressed in the gut].

Normal intrathecal leukocyte cell number and composition do not decrease the incidence of post-lumbar puncture headache.

The pathogenesis of post-lumbar puncture headache (PLPH) has remained unclear. A beneficial role of CSF cells in the repair of a post-traumatic dural CSF leak has been suggested. The primary purpose of this study was to investigate the effects of 8weeks of induction therapy with high-dose PF-00547659 on the cellular elements of CNS immune surveillance in patients with active Crohn's Disease and a history of immunosuppressive therapy (Clinicaltrials.

Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial.

Background: PF-00547659 is a fully human monoclonal antibody that binds to human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) to selectively reduce lymphocyte homing to the intestinal tract. We aimed to assess the efficacy and safety of PF-00547659 in patients with moderate to severe ulcerative colitis.

Methods: This phase 2, randomised, double-blind, placebo-controlled clinical trial recruited patients aged 18-65 years from 105 centres in 21 countries, with a history (≥3 months) of active ulcerative colitis extending more than 15 cm beyond the anal verge (with a total Mayo score ≥6 and a Mayo endoscopic subscore ≥2) who had failed or were intolerant to at least one conventional therapy.

Safety, Pharmacokinetic, and Pharmacodynamic Evaluation After Single and Multiple Ascending Doses of a Novel Selective Androgen Receptor Modulator in Healthy Subjects.

Purpose: Tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) properties of single ascending doses (SADs) and multiple ascending doses (MADs) of PF-06260414, a novel selective androgen receptor modulator, were assessed after oral administration in healthy subjects.

Methods: Range of SAD and MAD levels tested were 1 to 400 mg and 3 to 100 mg BID, respectively (n = 8 per cohort). In addition, a 60-mg once-daily (n = 8) cohort and a Japanese cohort receiving 30 mg BID (n = 7) also received PF-06260414.

Weighted profile likelihood-based confidence interval for the difference between two proportions with paired binomial data.

Inference on the difference between two binomial proportions in the paired binomial setting is often an important problem in many biomedical investigations. Tang et al. (2010, Statistics in Medicine) discussed six methods to construct confidence intervals (henceforth, we abbreviate it as CI) for the difference between two proportions in paired binomial setting using method of variance estimates recovery.

Binomial confidence intervals for testing non-inferiority or superiority: a practitioner's dilemma.

In testing for non-inferiority or superiority in a single arm study, the confidence interval of a single binomial proportion is frequently used. A number of such intervals are proposed in the literature and implemented in standard software packages. Unfortunately, use of different intervals leads to conflicting conclusions.

Corrected profile likelihood confidence interval for binomial paired incomplete data.

Clinical trials often use paired binomial data as their clinical endpoint. The confidence interval is frequently used to estimate the treatment performance. Tang et al.

Bias reduction and a solution for separation of logistic regression with missing covariates.

Logistic regression is an important statistical procedure used in many disciplines. The standard software packages for data analysis are generally equipped with this procedure where the maximum likelihood estimates of the regression coefficients are obtained iteratively. It is well known that the estimates from the analyses of small- or medium-sized samples are biased.

A comparative study of the bias corrected estimates in logistic regression.

Logistic regression is frequently used in many areas of applied statistics. The maximum likelihood estimates (MLE) of the logistic regression parameters are usually computed using the iterative Newton-Raphson method. It is well known that these estimates are biased.