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High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial: lessons learned |
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| Authors: | Clements Philip J Seibold James R Furst Daniel E Mayes Maureen White Barbara Wigley Fredrick Weisman Michael D Barr Water Moreland Larry Medsger Thomas A Steen Virginia Martin Richard W Collier David Weinstein Arthur Lally Edward Varga John Weiner Steven R Andrews Brian Abeles Micha Wong Weng Kee |
| Affiliation: | a Division of Rheumatology, UCLA School of Medicine, Los Angeles, CA, USA b Scleroderma Program, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ, USA c Division of Rheumatology and Clinical Immunogenetics, University of Texas, Houston, TX, USA d Rheumatology and Clinical Immunology, University of Maryland School of Medicine, Baltimore, MD, USA e Rheumatology Division, The Johns Hopkins University, Baltimore, MD, USA f Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA g Northwestern University Medical School, Chicago, IL, USA h Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA i Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA j Division of Rheumatology Georgetown University Medical Center, Washington, DC, USA k College of Human Medicine, Michigan State University, Grand Rapids, MI, USA l University of Colorado Health Sciences Center, Denver, CO, USA m Division of Rheumatology, Immunology, and Allergy, George Washington University Medical Center, Washington, DC, USA n Boston University School of Medicine, Boston, MA, USA o Section of Rheumatology University of Illinois, Chicago, IL, USA p Division of Rheumatology, University of California, Irvine, CA, USA q Division of Rheumatic Diseases, University of Connecticut Health Center, Farmington, CT, USA r Department of Biostatistics, UCLA School of Public Health, Los Angeles, CA, USA |
| Abstract: | ObjectivesTo review important findings, or lessons, that were learned about measures of response, design, conduct, and analysis of a randomized, controlled trial (RCT), even though the trial failed to demonstrate efficacy of d-penicillamine.MethodsOne hundred thirty-four patients with early (≤18 months), diffuse systemic sclerosis (SSc) were entered into an RCT (high-dose [822 mg daily] vs low-dose [120 mg every other day] d-penicillamine) and were followed up regularly for up to 4 years. Because analysis failed to show efficacy for d-penicillamine in early diffuse SSc, all data were pooled for additional secondary analyses.ResultsThis RCT showed that trials of potential disease-modifying interventions can be completed in SSc using the American College of Rheumatology guidelines. This RCT used an active control. After analysis, we were not able to tell whether either dose was effective or ineffective. That experience argues in favor of using placebo controls until such time as an active control can be found that truly modifies the disease. Skin score and the disability index of the Health Assessment Questionnaire (HAQ-DI) were valid predictors of outcome. Along with the physician global assessment, they also were valid measures of response.ConclusionsEven in studies that are therapeutically “negative,” careful evaluation of the data can examine other hypotheses and thereby provide important insights into other aspects of trial design, outcome measures, patient function, and trial conduct. |
| Keywords: | Scleroderma systemic sclerosis scleroderma renal crisis modified Rodnan Skin Score mortality Health Assessment Questionnaire-Disability Index |
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