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Proposal 911

Title of the Proposed Research

Outcome Measures in Systemic Lupus Erythematosus: Constructing a Meaningful Response Index from Existing Clinical Trial Data

Lead Researcher

Lindsy Forbess, MD, MSc

Affiliation

Cedars-Sinai Medical Center
Los Angeles, CA
US

Funding Source

We plan to apply for the NIAMS Clinical Trial Outcome Instrument Development Grant Program (UO1). The funding opportunity announcement (FOA) number is RFA-AR-14-008 and can be found here: http://grants.nih.gov/grants/guide/rfa-files/RFA-AR-14-008.html. This FOA solicits applications for research awards designed to develop new and evaluate existing clinical trial outcome instruments/measures to better assess the benefits (efficacy and effectiveness) and adverse impacts of therapies employed to treat diseases and injuries of interest to the NIAMS. This grant awards up to $150,000 per year for 3 years.

Potential Conflicts of Interest

Lead Researcher: None

Researcher 1: Receives consulting fees and does data safety monitoring for Astellas Pharma Global Development, Crescendo Bioscience, Inc, Abbvie, Lilly and UCB. He has contracted research with Amgen, Biogen, Cephalon, Centocor, Dynavax, Lilly, Genentech, Human Genome Sciences, Pfizer, Rigel, Sanofi-Aventis, Teva and UCB

Researcher 2: None

Researcher 3: None

Researcher 4: None

Researcher 5: Receives consulting fees in the last 12 months from Abbvie, Merck Serono, Lilly, GSK, Horizon, and Fizer, all less than $10,000.

Management of Real or Potential Conflicts of Interest

All consultancies and board memberships for the authors will be revealed when the research is presented and published. None of these are anticipated to be real conflicts of interest with respect to the proposed research

Data Sharing Agreement Date

1 August 2014

Lay Summary

The purpose of this project is to develop a systemic lupus erythematosus (SLE) response index as the standard outcome measure in future trials. Currently, there is no widely accepted method for defining response to therapy and as a result, most SLE trials to date have failed to meet predesigned endpoints, leading to the controversy over whether it is the drug treatments or outcome measures that are unsuccessful in SLE. A similar controversy in rheumatoid arthritis (RA) many years ago was resolved by examining data from placebo-controlled trials with drugs that were only modestly effective. Important clinical variables were selected, criteria for patient improvement determined, and an index was developed that adequately distinguished treated patients from those getting placebo (1). This index (ACR 20/50/70) is used in RA trials and has led to approval of more than 20 drug therapies (2). Recently, a new response index, the SLE responder index (SRI), was developed by examining early phase trial data of belimumab in the treatment of SLE (3). Adjusting this index to later phase trials assisted in belimumab FDA approval, the first drug in almost 40 years to be approved for SLE.

Although the SRI attempts to standardize outcome measures for future SLE trials, it has not yet been widely adopted and has inherent flaws. It comprises criteria from 3 indices, SELENA-SLE Disease Activity Index (SELENA-SLEDAI), Physician Global Assessment, and the British Isles Lupus Assessment Group (BILAG). These instruments were developed from observational cohort data and not meaningful change for individual patients in clinical trials (4,5). The BILAG is available only in English, requires expensive software and extensive training, is time-consuming, and subject to frequent revision. The SELENA-SLEDAI is heavily weighted toward less common clinical manifestations, and does not reflect graded change in SLE activity over time. In addition, the SRI does not include patient-reported outcome instruments, which are important given the known discrepancies between patient and physician perceptions of disease activity (6). The FDA guidance document for developing SLE therapies encourages “the use of patient-reported outcome instruments to measure all relevant and important SLE symptoms” (7).

Now that large scale phase III SLE clinical trial data exist, we plan to move down the same path as in RA and deconstruct the elements that comprise the BILAG and SELENA-SLEDAI, select important clinical and laboratory variables, determine the criteria for patient improvement, and develop an index that distinguishes patients receiving treatment from those getting placebo. This index will be simple to use, based on real individual patient clinical trial data, developed for the purpose of future trial use, and include patient reported outcome measures. It should serve to prevent useful drugs from being discarded due to inadequate trial designs.

Study Data Provided

Study HGS1006-C1056: A Phase 3, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 76-Week Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006, LymphoStat-B™), a Fully Human Monoclonal Anti-BLyS Antibody, in Subjects with Systemic Lupus Erythematosus (SLE)
Study HGS1006-C1057: A Phase 3, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 52-Wk Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006, LymphoStat-B™), a Fully Human Monoclonal Anti-BLyS Antibody, in Subjects With Systemic Lupus Erythematosus (SLE)

Statistical Analysis Plan

Publication Citation

Failure of a systemic lupus erythematosus response index developed from clinical trial data: lessons examined and learned.
Forbess LJ, Bresee C, Wallace DJ, Weisman MH.
Lupus. 2017 Jan 1:961203317692433. doi: 10.1177/0961203317692433. [Epub ahead of print]
PMID:
28173737

Summary Results

Results summary or link will be posted when available.