High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial: lessons learned.
OBJECTIVE
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 (< or =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.
Division of Rheumatology, UCLA School of Medicine, Los Angeles, CA 90095-1670, USA. pclements@mednet.ucla.edu
Philip J
PJ
Clements
James R
JR
Seibold
Daniel E
DE
Furst
Maureen
M
Mayes
Barbara
B
White
Fredrick
F
Wigley
Michael D
MD
Weisman
Water
W
Barr
Larry
L
Moreland
Thomas A
TA
Medsger
Virginia
V
Steen
Richard W
RW
Martin
David
D
Collier
Arthur
A
Weinstein
Edward
E
Lally
John
J
Varga
Steven R
SR
Weiner
Brian
B
Andrews
Micha
M
Abeles
Weng Kee
WK
Wong
D000328:Adult; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D004185:Disability Evaluation; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006304:Health Status; D006801:Humans; D008297:Male; D008875:Middle Aged; D010396:Penicillamine / Q000008:administration & dosage* / Q000627:therapeutic use; D012107:Research Design; D012595:Scleroderma, Systemic / Q000188:drug therapy* / Q000473:pathology; D012867:Skin / Q000473:pathology; D013997:Time Factors
D018501:Antirheumatic Agents; D010396:Penicillamine