A randomized, double-blind, placebo-controlled, multicenter study of secukinumab to demonstrate the efficacy at 24 weeks and to assess the long term safety, tolerability and efficacy up to 2 years in patients with active psoriatic arthritis List of tables List of figures Glossary of termsAssessment A procedure used to generate data required by the study Control drug A study drug used as a comparator to reduce assessment bias, preserve blinding of investigational drug, assess internal study validity, and/or evaluate comparative effects of the investigational drug Enrollment Point/time of patient entry into the study; the point at which informed consent must be obtained (i.e. prior to starting any of the procedures described in the protocol)Inadequate response to TNFα Active disease despite stable treatment with anti-TNFa for at least 3 months at a stable dose or for at least one dose in the case of lack of tolerance Investigational drugThe study drug whose properties are being tested in the study; this definition is consistent with US CFR 21 Section 312.3 and is synonymous with "investigational new drug."Medication number A unique identifier on the label of each study drug package in studies that dispense study drug using an IVR systemPatient number A number assigned to each patient who enrolls in the study. When combined with the center number, a unique identifier is created for each patient in the study. PeriodA minor subdivision of the study timeline; divides phases into smaller functional segments such as screening, baseline, titration, washout, etc.Phase A major subdivision of the study timeline; begins and ends with major study milestones such as enrollment, randomization, completion of treatment, etc.Premature patient withdrawal Point/time when the patient exits from the study prior to the planned completion of all study drug administration and assessments; at this time all study drug administration is discontinued and no further assessments are plannedRandomization number A unique identifier assigned to each randomized patient, corresponding to a specific treatment arm assignment Stop study participation Point/time at which the patient came in for a final evaluation visit or when study drug was discontinued whichever is later Study drug Any drug administered to the patient as part of the required study procedures; includes investigational drug and any control drugs Study drug discontinuation Point/time when patient permanently stops taking study drug for any reason; may or may not also be the point/time of premature patient withdrawal Variable Information used in the data analysis; derived directly or indirectly from data collected using specified assessments at specified timepointsThis document (090095a88362b521 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI. Protocol synopsisTitle of study: A randomized, double-blind, placebo-controlled, multicenter study of secukinumab to demonstrate the efficacy at 24 weeks and to assess the safety, tolerability and...

The goal of clinical trial research is to deliver safe and efficacious new treatments to patients in need in a timely and cost-effective manner. There is precedent in using historical control data to reduce the number of concurrent control subjects required in developing medicines for rare diseases and other areas of unmet need. The purpose of this paper is to provide a review for a regulatory and industry audience of the current state of relevant statistical methods, and of the uptake of these approaches and the opportunities for broader use of historical data in confirmatory clinical trials. General principles to consider when incorporating historical control data in a new trial are presented. Bayesian and frequentist approaches are outlined including how the operating characteristics for such a trial can be obtained. Finally, examples of approved new treatments that incorporated historical controls in their confirmatory trials are presented.

Introduction: Nonalcoholic steatohepatitis (NASH) is a sub-classification of nonalcoholic fatty liver disease (NAFLD) characterized by increased risk of progressive liver fibrosis. Cenicriviroc (CVC) is a novel, orally administered, potent chemokine 2 and 5 receptor antagonist currently in development for the treatment of liver fibrosis in adults with NASH. Methods and analysis: Efficacy and safety of CVC will be comprehensively evaluated in a global, Phase 3, multicenter, randomized, double-blind, placebo-controlled study (AURORA, NCT03028740) of subjects with NASH and Stage F2 or F3 fibrosis. Approximately 2000 adults (Part 1, 1200 subjects; Part 2, 800 additional subjects) aged 18-75 years with histological evidence of NASH with Stage F2 or F3 fibrosis (NASH Clinical Research Network classification system) will be randomized 2:1 to CVC 150 mg or placebo orally once daily. Primary efficacy endpoints will include the proportion of subjects with ≥1-stage improvement in liver fibrosis and no worsening of steatohepatitis at Month 12 relative to screening (Part 1), and time to first occurrence of any adjudicated event: death; histopathologic progression to cirrhosis; liver transplant; Model of End-Stage Liver Disease score ≥ 15; ascites; hospitalization due to liver decompensation (Part 2). Patient-reported outcomes will assess changes in health outcomes from baseline (Chronic Liver Disease Questionnaire-NAFLD; Work Productivity and Activity Impairment in NASH; 36-Item Short Form Health Survey version 2). Adverse events will be assessed throughout the study. As there are currently no approved treatments indicated for NASH, the AURORA CVC Phase 3 study addresses an unmet medical need.

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In drug development, when the drug class has a relatively well defined path to regulatory approval and the enrollment is slow with certain patient populations, one may want to consider combining studies of different phases. This paper considers combining a proof of concept (POC) study and a dose finding (DF) study with a control treatment. Conventional DF study designs sometimes are not efficient, or do not have a high probability to find the optimal dose(s) for phase III trials. This paper seeks more efficient DF strategies that allow economical testing of more doses. Hypothetical examples are simulated to compare the proposed adaptive design versus the conventional design based on different models of the overall quantitative representation of efficacy, safety and tolerability. The results show that the proposed adaptive design tests more active doses with higher power and comparable or smaller sample size in a shorter overall study duration for POC and DF, compared to a conventional design.

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INTRODUCTION: CVC, a novel, oral, and potent inhibitor of C-C chemokine receptor types 2 and 5, was well tolerated and demonstrated clinically meaningful antifibrotic activity in a 2-year Phase 2b study. The AURORA Phase 3 study will assess the efficacy and safety of CVC for the treatment of liver fibrosis in adults with NASH. METHODS: AURORA is a global, multicenter, randomized, double-blind, placebo-controlled study (NCT03028740) which will enroll 2000 subjects to evaluate a surrogate histology endpoint in the first 1200 subjects and clinical outcomes in the totality of enrolled subjects (∼2000 subjects) (Figure 1). Subjects will be randomized 2:1 to receive CVC 150 mg or placebo orally once daily with food. Adults aged 18–75 years with histologic diagnosis of NASH and Stage 2 or 3 liver fibrosis per NASH Clinical Research Network classification will be enrolled (≥60% with Stage 3). Subjects with cirrhosis or other known causes of chronic liver disease will be excluded. Liver biopsies will be performed at screening and Months 12 and 60 and will be evaluated by a central pathologist. An online tool (AURORA Toolbox) was developed to help assess the individual risk of fibrotic NASH (low, intermediate, or high) to inform pre-screening and whether to conduct a new liver biopsy during screening. RESULTS: The primary endpoint of improvement in fibrosis by ≥1 stage (NASH Clinical Research Network) AND no worsening of NASH (lobular inflammation or hepatocellular ballooning) on liver histology at Month 12 relative to screening biopsy will be evaluated in the first 1200 enrolled subjects. The key secondary endpoint will be improvement in fibrosis by ≥2 stages AND no worsening of NASH. Another primary endpoint to be evaluated in all 2000 enrolled subjects will be time to first occurrence of any adjudicated events of mortality (all causes), progression to cirrhosis (defined by NASH fibrosis Stage 4), liver transplant, Model for End-Stage Liver Disease score ≥15, ascites, or liver decompensation. The study will be terminated when adjudicated events have been accrued in 367 unique subjects overall. Safety, patient-reported outcome measures, serum hepatic fibrosis indices, liver stiffness measure, and biomarkers of systemic inflammation will also be evaluated. CONCLUSION: The AURORA Phase 3 study aims to confirm the efficacy and safety of CVC for the treatment of liver fibrosis in adults with NASH.

In clinical trials, it is often desirable to test for superiority conditioned on establishment of noninferiority based on the same primary endpoint. According to a guidance document issued by the European regulatory agency Committee for Proprietary Medicinal Products in 2001, no type I error rate adjustment is necessary for switching between superiority and noninferiority because the family-wise type I error rate is controlled at the same nominal level. However, Ng raised the issues of switching between superiority and noninferiority even though there is no inflation of the family-wise type I error rate and showed that the false discovery rate could be increased.l To alleviate these concerns, we propose to control the conditional type I error rate of the second-step superiority test at the nominal Significance level, which leads to a lower (unconditional) significance level of the secondstep superiority test. The suggested adjustment posts a more rigorous condition to claim superiority, which is an effort to decrease the number of erroneous claims of superiority.