High-Dose Versus Low-Dose D-Penicillamine in Early Diffuse Systemic Sclerosis Trial: Lessons Learned

Philip J. Clements, James R. Seibold, Daniel E. Furst, Maureen Mayes, Barbara White, Fredrick Wigley, Michael D. Weisman, Water Barr, Larry Moreland, Thomas A. Medsger, Virginia Steen, Richard W. Martin, David Collier, Arthur Weinstein, Edward Lally, John Varga, Steven R. Weiner, Brian Andrews, Micha Abeles, Weng Kee Wong

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


Objectives: To 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. Methods: One 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. Results: This 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. Conclusions: Even 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.

Original languageEnglish (US)
Pages (from-to)249-263
Number of pages15
JournalSeminars in Arthritis and Rheumatism
Issue number4
StatePublished - Feb 2004


  • Health Assessment Questionnaire-Disability Index
  • Modified Rodnan Skin Score
  • Mortality
  • Scleroderma
  • Scleroderma renal crisis
  • Systemic sclerosis

ASJC Scopus subject areas

  • Rheumatology
  • Anesthesiology and Pain Medicine


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