Sample size estimation using a latent variable model for mixed outcome co-primary, multiple primary and composite endpoints.

Mixed outcome endpoints that combine multiple continuous and discrete components are often employed as primary outcome measures in clinical trials. These may be in the form of co-primary endpoints, which conclude effectiveness overall if an effect occurs in all of the components, or multiple primary endpoints, which require an effect in at least one of the components. Alternatively, they may be combined to form composite endpoints, which reduce the outcomes to a one-dimensional endpoint.

Increasing power in the analysis of responder endpoints in rheumatology: a software tutorial.

Background: Composite responder endpoints feature frequently in rheumatology due to the multifaceted nature of many of these conditions. Current analysis methods used to analyse these endpoints discard much of the data used to classify patients as responders and are therefore highly inefficient, resulting in low power. We highlight a novel augmented methodology that uses more of the information available to improve the precision of reported treatment effects.

Employing a latent variable framework to improve efficiency in composite endpoint analysis.

Composite endpoints that combine multiple outcomes on different scales are common in clinical trials, particularly in chronic conditions. In many of these cases, patients will have to cross a predefined responder threshold in each of the outcomes to be classed as a responder overall. One instance of this occurs in systemic lupus erythematosus, where the responder endpoint combines two continuous, one ordinal and one binary measure.

Study protocol for the international Systemic Lupus Erythematosus Prospective Observational Cohort Study (SPOCS): understanding lupus and the role of type I interferon gene signature.

Introduction: The Systemic Lupus Erythematosus (SLE) Prospective Observational Cohort Study (SPOCS) aims to describe the disease course of SLE and its association with type I interferon gene signature (IFNGS) status.

Methods And Analysis: SPOCS is an international, multicentre, prospective, observational cohort study designed to follow patients through biannual study visits during a 3-year observation period. Patients ≥18 years old with a physician diagnosis that meets the American College of Rheumatology or Systemic Lupus International Collaborating Clinics SLE classification criteria will be included.

What matters most? Different stakeholder perspectives on estimands for an invented case study in COPD.

In drug development, we ask ourselves which population, endpoint and treatment comparison should be investigated. In this context, we also debate what matters most to the different stakeholders that are involved in clinical drug development, for example, patients, physicians, regulators and payers. With the publication of draft ICH E9 addendum on estimands in 2017, we now have a common framework and language to discuss such questions in an informed and transparent way.

Trial of Anifrolumab in Active Systemic Lupus Erythematosus.

Background: Anifrolumab, a human monoclonal antibody to type I interferon receptor subunit 1 investigated for the treatment of systemic lupus erythematosus (SLE), did not have a significant effect on the primary end point in a previous phase 3 trial. The current phase 3 trial used a secondary end point from that trial as the primary end point.

Methods: We randomly assigned patients in a 1:1 ratio to receive intravenous anifrolumab (300 mg) or placebo every 4 weeks for 48 weeks.

Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial.

Background: Type I interferons are involved in systemic lupus erythematosus (SLE) pathogenesis. In a phase 2 trial, anifrolumab, a human monoclonal antibody to type I interferon receptor subunit 1, suppressed interferon gene signatures and substantially reduced SLE disease activity. Here, we sought to confirm the efficacy of anifrolumab versus placebo in a phase 3 trial of adult patients with SLE and moderate-to-severe disease activity despite standard-of-care treatment.

Improving the analysis of composite endpoints in rare disease trials.

Background: Composite endpoints are recommended in rare diseases to increase power and/or to sufficiently capture complexity. Often, they are in the form of responder indices which contain a mixture of continuous and binary components. Analyses of these outcomes typically treat them as binary, thus only using the dichotomisations of continuous components.

Safety, tolerability and pharmacokinetics of subcutaneous and intravenous anifrolumab in healthy volunteers.

Objectives: To compare the pharmacokinetics (PK), safety and tolerability of subcutaneous (SC) and intravenous anifrolumab, an anti-type I interferon receptor monoclonal antibody in development for SLE, in healthy volunteers.

Methods: In this Phase I randomised, placebo-controlled study, 30 adults were assigned to three treatment cohorts (anifrolumab 300 mg SC (n=6), anifrolumab 300 mg intravenous (n=6), anifrolumab 600 mg SC (n=6)) and placebo (n=4/cohort). Serial blood samples were collected up to Day 84 to measure anifrolumab concentrations and antidrug antibodies (ADAs).

Lupus Low Disease Activity State (LLDAS) attainment discriminates responders in a systemic lupus erythematosus trial: analysis of the Phase IIb MUSE trial of anifrolumab.

Objectives: In a analysis, we aimed to validate the Lupus Low Disease Activity State (LLDAS) definition as an endpoint in an systemic lupus erythematosus (SLE) Phase IIb randomised controlled trial (RCT) (MUSE [NCT01438489]) and then utilize LLDAS to discriminate between anifrolumab and placebo.

Methods: Patients received intravenous placebo (n=102) or anifrolumab (300 mg, n=99; 1,000 mg, n=104) Q4W plus standard of care for 48 weeks. LLDAS attainment (SLE Disease Activity Index 2000 ≤4 without major organ activity, no new disease activity, Physician's Global Assessment ≤1, prednisolone ≤7.

Randomized, placebo-controlled, single-ascending-dose study of BMS-791325, a hepatitis C virus (HCV) NS5B polymerase inhibitor, in HCV genotype 1 infection.

BMS-791325 is a nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase with low-nanomolar potency against genotypes 1a (50% effective concentration [EC50], 3 nM) and 1b (EC50, 7 nM) in vitro. BMS-791325 safety, pharmacokinetics, and antiviral activity were evaluated in a double-blind, placebo-controlled, single-ascending-dose study in 24 patients (interferon naive and experienced) with chronic HCV genotype 1 infection, randomized (5:1) to receive a single dose of BMS-791325 (100, 300, 600, or 900 mg) or placebo. The prevalence and phenotype of HCV variants at baseline and specific posttreatment time points were assessed.