A multicenter, randomized, double-blind, placebo-controlled trial of oral type I collagen treatment in patients with diffuse cutaneous systemic sclerosis: I. oral type I collagen does not improve skin in all patients, but may improve skin in late-phase disease

Abstract

Objective: To investigate the safety and efficacy of oral bovine type I collagen (CI) treatment in patients who have had diffuse cutaneous systemic sclerosis (dcSSc; scleroderma) for <or=10 years.

Methods: One hundred sixty-eight patients with dcSSc were enrolled in a double-blind, placebo-controlled trial of oral CI (500 microg/day) or placebo administered over 12 months, with a followup visit at month 15. The primary outcome was the modified Rodnan skin thickness score (MRSS). Other clinical and immune system parameters were also assessed.

Results: Intent-to-treat and modified intent-to-treat analyses showed that for the total population of patients with dcSSc, there were no significant differences in the mean change in MRSS or other key clinical parameters between the CI and placebo treatment groups at 12 months or at 15 months. However, in a subanalysis of the available data at month 15, the CI-treated group of patients with late-phase dcSSc experienced a significant reduction in the MRSS compared with that in the placebo-treated patients with late-phase dcSSc (change in MRSS at month 15 -7.9 versus -2.9; P = 0.0063).

Conclusion: Although the results from this trial did not meet the primary outcome goals, the findings from exploratory analyses indicated that CI treatment may benefit patients with late-phase dcSSc. This new treatment strategy and preliminary clinical observations in patients with dcSSc need to be corroborated.

Trial registration: ClinicalTrials.gov NCT00005675.

Figures

Figure 1

Overall summary of study enrollment and dropouts among patients with diffuse cutaneous systemic sclerosis randomized to receive either oral bovine type I collagen or placebo, with subgroups according to disease duration (early phase ≤3 years, late phase >3–10 years). * = available data analysis, involving patients with data at baseline and at 12 or 15 months, including dropouts who returned for the 12- or 15-month visit; ** = intent-to-treat (ITT) analysis, involving last observation carried forward to the 12- or 15-month visit; *** = modified ITT analysis, involving last observation carried forward but including patients who were in the trial for at least 6 months. MRSS = modified Rodnan skin thickness score.

Figure 2

Mean change in the MRSS from baseline to month 4, month 8, month 12, and month 15 in A, the total population, B, patients with early-phase diffuse cutaneous systemic sclerosis (dcSSc), and C, patients with late-phase dcSSc in the bovine type I collagen (CI)–treated and placebo (PL)–treated groups using available data. At 15 months, the median MRSS value for the CI-treated group of patients with late-phase dcSSc was substantially lower than the median values in the other groups, indicating that these patients experienced the greatest improvement in the MRSS. D, Mean change in the MRSS from baseline to each time point in patients with late-phase dcSSc using ITT analysis. Bars show the mean ± SD. See Figure 1 for other definitions.

Figure 3

Percentage of patients achieving percentage levels of improvement in the MRSS at month 12 (A) and month 15 (B) in the bovine type I collagen (CI)–treated and placebo-treated groups. Among the patients with late-phase diffuse cutaneous systemic sclerosis (dcSSc) receiving oral CI, ~50% had a 25% reduction in the MRSS at 12 months, but only 19% of the patients in the early-phase dcSSc group experienced similar improvements in the MRSS at 12 months (A). At month 15, the patients with late-phase dcSSc receiving oral CI had the greatest improvement in the MRSS (B). Also shown are the percentage of patients achieving minimum improvement in the MRSS according to incremental units of change scores at month 12 (C) and month 15 (D). See Figure 1 for other definitions.

Figure 4

Change in the MRSS from baseline to 15 months using available data from the patients with late-phase diffuse cutaneous systemic sclerosis in the bovine type I collagen (CI) and placebo (PL) treatment groups, defined according to disease duration groups in 0.25-year increments from >1.25–10 years up to >3–10 years. Bars show the mean and SD. P values for comparisons between treatment groups were determined by Student’s 2-sample t -test. See Figure 1 for other definitions.