Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial

Abstract

Background: 12 months of oral cyclophosphamide has been shown to alter the progression of scleroderma-related interstitial lung disease when compared with placebo. However, toxicity was a concern and without continued treatment the efficacy disappeared by 24 months. We hypothesised that a 2 year course of mycophenolate mofetil would be safer, better tolerated, and produce longer lasting improvements than cyclophosphamide.

Methods: This randomised, double-blind, parallel group trial enrolled patients from 14 US medical centres with scleroderma-related interstitial lung disease meeting defined dyspnoea, pulmonary function, and high-resolution CT (HRCT) criteria. The data coordinating centre at the University of California, Los Angeles (UCLA, CA, USA), randomly assigned patients using a double-blind, double-dummy, centre-blocked design to receive either mycophenolate mofetil (target dose 1500 mg twice daily) for 24 months or oral cyclophosphamide (target dose 2·0 mg/kg per day) for 12 months followed by placebo for 12 months. Drugs were given in matching 250 mg gel capsules. The primary endpoint, change in forced vital capacity as a percentage of the predicted normal value (FVC %) over the course of 24 months, was assessed in a modified intention-to-treat analysis using an inferential joint model combining a mixed-effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data. The study was registered with ClinicalTrials.gov, number NCT00883129.

Findings: Between Sept 28, 2009, and Jan 14, 2013, 142 patients were randomly assigned to either mycophenolate mofetil (n=69) or cyclophosphamide (n=73). 126 patients (mycophenolate mofetil [n=63] and cyclophosphamide [n=63]) with acceptable baseline HRCT studies and at least one outcome measure were included in the primary analysis. The adjusted % predicted FVC improved from baseline to 24 months by 2·19 in the mycophenolate mofetil group (95% CI 0·53-3·84) and 2·88 in the cyclophosphamide group (1·19-4·58). The course of the % FVC did not differ significantly between the two treatment groups based on the prespecified primary analysis using a joint model (p=0·24), indicating that the trial was negative for the primary endpoint. However, in a post-hoc analysis of the primary endpoint, the within-treatment change from baseline to 24 months derived from the joint model showed that the % FVC improved significantly in both the mycophenolate mofetil and cyclophosphamide groups. 16 (11%) patients died (five [7%] mycophenolate mofetil and 11 [15%] cyclophosphamide), with most due to progressive interstitial lung disease. Leucopenia (30 patients vs four patients) and thrombocytopenia (four vs zero) occurred more often in patients given cyclophosphamide than mycophenolate mofetil. Fewer patients on mycophenolate mofetil than on cyclophosphamide prematurely withdrew from study drug (20 vs 32) or met prespecified criteria for treatment failure (zero vs two). The time to stopping treatment was shorter in the cyclophosphamide group (p=0·019).

Interpretation: Treatment of scleroderma-related interstitial lung disease with mycophenolate mofetil for 2 years or cyclophosphamide for 1 year both resulted in significant improvements in prespecified measures of lung function over the 2 year course of the study. Although mycophenolate mofetil was better tolerated and associated with less toxicity, the hypothesis that it would have greater efficacy at 24 months than cyclophosphamide was not confirmed. These findings support the potential clinical effectiveness of both cyclophosphamide and mycophenolate mofetil for progressive scleroderma-related interstitial lung disease, and the present preference for mycophenolate mofetil because of its better tolerability and toxicity profile.

Funding: National Heart, Lung and Blood Institute, National Institutes of Health; with drug supply provided by Hoffmann-La Roche and Genentech.

Figure 1

Disposition of study participants

Figure 2

Figure 2A. Primary Outcome; The course of %-predicted FVC from 3 through 24 months by treatment arm based on the joint model^{† †}Adjustments for baseline FVC%-predicted, baseline HRCT lung fibrosis score (QLF) and non-ignorable missing data (time to premature discontinuation of study drug, deaths and treatment failure). The horizontal dotted line represents the average baseline FVC%-predicted for both treatment arms based on the joint model (baseline values did not differ between the two treatments). The vertical lines (dashed CYC; solid MMF) represent 95% confidence intervals. Of the 142 randomized participants, 126 (63 - CYC; 63- MMF) were included in the primary analysis. The 16 randomized subjects excluded from analysis did not have outcome assessments at ≥3 months or baseline HRCT scans that were suitable for quantitative assessment of the extent of lung fibrosis (a covariate in the joint model). Three and two participants assigned to CYC and MMF, respectively, who did not have a 3-month visit did have assessments at ≥6 month visits and were therefore included in the analysis. On the other hand, two and three participants assigned to CYC and MMF, respectively, who had a 3-month visit did not have a baseline HRCT scan that was suitable for quantitative assessment of the extent of fibrosis and were therefore excluded from the analysis. Figure 2B. Frequency distribution of changes from baseline to 24 months in FVC%-predicted by treatment arm and by whether participants completed the entire study treatment or not (all observed data, ITT). Figure 2C. Tolerability and Toxicity Assessment; Time to premature withdrawal from study medication or treatment failure by treatment arm. The protocol definition of treatment failure was an absolute decline in FVC% predicted of ≥15% that persisted for at least 1 month.

Figure 2

Figure 2A. Primary Outcome; The course of %-predicted FVC from 3 through 24 months by treatment arm based on the joint model^{† †}Adjustments for baseline FVC%-predicted, baseline HRCT lung fibrosis score (QLF) and non-ignorable missing data (time to premature discontinuation of study drug, deaths and treatment failure). The horizontal dotted line represents the average baseline FVC%-predicted for both treatment arms based on the joint model (baseline values did not differ between the two treatments). The vertical lines (dashed CYC; solid MMF) represent 95% confidence intervals. Of the 142 randomized participants, 126 (63 - CYC; 63- MMF) were included in the primary analysis. The 16 randomized subjects excluded from analysis did not have outcome assessments at ≥3 months or baseline HRCT scans that were suitable for quantitative assessment of the extent of lung fibrosis (a covariate in the joint model). Three and two participants assigned to CYC and MMF, respectively, who did not have a 3-month visit did have assessments at ≥6 month visits and were therefore included in the analysis. On the other hand, two and three participants assigned to CYC and MMF, respectively, who had a 3-month visit did not have a baseline HRCT scan that was suitable for quantitative assessment of the extent of fibrosis and were therefore excluded from the analysis. Figure 2B. Frequency distribution of changes from baseline to 24 months in FVC%-predicted by treatment arm and by whether participants completed the entire study treatment or not (all observed data, ITT). Figure 2C. Tolerability and Toxicity Assessment; Time to premature withdrawal from study medication or treatment failure by treatment arm. The protocol definition of treatment failure was an absolute decline in FVC% predicted of ≥15% that persisted for at least 1 month.

Figure 2

Figure 2A. Primary Outcome; The course of %-predicted FVC from 3 through 24 months by treatment arm based on the joint model^{† †}Adjustments for baseline FVC%-predicted, baseline HRCT lung fibrosis score (QLF) and non-ignorable missing data (time to premature discontinuation of study drug, deaths and treatment failure). The horizontal dotted line represents the average baseline FVC%-predicted for both treatment arms based on the joint model (baseline values did not differ between the two treatments). The vertical lines (dashed CYC; solid MMF) represent 95% confidence intervals. Of the 142 randomized participants, 126 (63 - CYC; 63- MMF) were included in the primary analysis. The 16 randomized subjects excluded from analysis did not have outcome assessments at ≥3 months or baseline HRCT scans that were suitable for quantitative assessment of the extent of lung fibrosis (a covariate in the joint model). Three and two participants assigned to CYC and MMF, respectively, who did not have a 3-month visit did have assessments at ≥6 month visits and were therefore included in the analysis. On the other hand, two and three participants assigned to CYC and MMF, respectively, who had a 3-month visit did not have a baseline HRCT scan that was suitable for quantitative assessment of the extent of fibrosis and were therefore excluded from the analysis. Figure 2B. Frequency distribution of changes from baseline to 24 months in FVC%-predicted by treatment arm and by whether participants completed the entire study treatment or not (all observed data, ITT). Figure 2C. Tolerability and Toxicity Assessment; Time to premature withdrawal from study medication or treatment failure by treatment arm. The protocol definition of treatment failure was an absolute decline in FVC% predicted of ≥15% that persisted for at least 1 month.

Figure 3

Figure 3A. Absolute change in modified Rodnan Skin Score (mRSS) from baseline by treatment arm based on the joint model^{† †}Adjustments for baseline skin score (mRSS), baseline HRCT lung fibrosis score and non-ignorable missing data (time to premature discontinuation of study drug, deaths and treatment failure). Vertical lines represent 95% confidence intervals. Dotted horizontal line represents the average baseline skin score for both treatment arms based on the joint model (baseline values did not differ between the two treatments). Figure 3B. Frequency distribution of observed changes at 24 months from baseline in modified Rodnan Skin Score (mRSS). (observed data) Both limited and diffuse cutaneous SSc patients (N= 52 CYC; 53 MMF)

Figure 3

Figure 3A. Absolute change in modified Rodnan Skin Score (mRSS) from baseline by treatment arm based on the joint model^{† †}Adjustments for baseline skin score (mRSS), baseline HRCT lung fibrosis score and non-ignorable missing data (time to premature discontinuation of study drug, deaths and treatment failure). Vertical lines represent 95% confidence intervals. Dotted horizontal line represents the average baseline skin score for both treatment arms based on the joint model (baseline values did not differ between the two treatments). Figure 3B. Frequency distribution of observed changes at 24 months from baseline in modified Rodnan Skin Score (mRSS). (observed data) Both limited and diffuse cutaneous SSc patients (N= 52 CYC; 53 MMF)