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2016 ; 4
(9
): 708-719
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Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related
interstitial lung disease (SLS II): a randomised controlled, double-blind,
parallel group trial
#MMPMID27469583
Tashkin DP
; Roth MD
; Clements PJ
; Furst DE
; Khanna D
; Kleerup EC
; Goldin J
; Arriola E
; Volkmann ER
; Kafaja S
; Silver R
; Steen V
; Strange C
; Wise R
; Wigley F
; Mayes M
; Riley DJ
; Hussain S
; Assassi S
; Hsu VM
; Patel B
; Phillips K
; Martinez F
; Golden J
; Connolly MK
; Varga J
; Dematte J
; Hinchcliff ME
; Fischer A
; Swigris J
; Meehan R
; Theodore A
; Simms R
; Volkov S
; Schraufnagel DE
; Scholand MB
; Frech T
; Molitor JA
; Highland K
; Read CA
; Fritzler MJ
; Kim GHJ
; Tseng CH
; Elashoff RM
Lancet Respir Med
2016[Sep]; 4
(9
): 708-719
PMID27469583
show ga
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.