Evidence map›Paper›PMID 27469583›Full record

Trial reportThe Lancet. Respiratory medicine2016

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

Donald P Tashkin, Michael D Roth, Philip J Clements, Daniel E Furst, Dinesh Khanna, Eric C Kleerup, Jonathan Goldin, Edgar Arriola, Elizabeth R Volkmann, Suzanne Kafaja and 35 more

4 registry-linked trialsAbstract readMulticenter StudyRandomized Controlled Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in The Lancet. Respiratory medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 4 registered trials, which are not on this map. Cited by 535 papers, 15 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
535citing papers in PubMed, 15 pooled it
62.7field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT00883129 phase2completednot on this map

Mycophenolate vs. Oral Cyclophosphamide in Scleroderma Interstitial Lung Disease (Scleroderma Lung Study II)

TypeinterventionalSponsorMichael RothRan2009 to 2015Enrolled142ConditionsScleroderma, Interstitial Lung DiseaseArmsMycophenolate mofetil, Cyclophosphamide, Placebo
NCT02896205 phase3completednot on this map

A Randomized Controlled Trial to Compare the Efficacy of Oral Mycophenolate Mofetil With Placebo in Patients With Systemic Sclerosis Related Early Interstitial Lung Disease

TypeinterventionalSponsorPost Graduate Institute of Medical Education and Research, ChandigarhRan2016 to 2017Enrolled41ConditionsSystemic Sclerosis, Scleroderma, Interstitial Lung DiseaseArmsMycophenolate mofetil, Placebo
NCT03221257 phase2completednot on this mapstarted 2017, after this paper: background citation

Scleroderma Lung Study III (SLS III): Combining the Anti-fibrotic Effects of Pirfenidone (PFD) With Mycophenolate (MMF) for Treating Scleroderma-related Interstitial Lung Disease

TypeinterventionalSponsorMichael RothRan2017 to 2022Enrolled51ConditionsScleroderma, Systemic, Interstitial Lung DiseaseArmsPirfenidone (PFD), Placebo (Plac), Mycophenolate Mofetil (MMF)
NCT04630782 unknown statusnot on this mapstarted 2020, after this paper: background citation

Precision Medicine in Systemic Sclerosis Gastrointestinal Disease: Evaluating Imaging and Stool Biomarkers for Differentiating Disease Stages and Treatment Responses

TypeobservationalSponsorSingapore General HospitalRan2020 to 2023Enrolled70ConditionsSystemic Sclerosis, SclerodermaArmsPET-MRI scan
3 · Its place in the literature

Who cites it

535 citing papers in PubMed, 15 syntheses or guidelines pooled it, 1,039 citations in OpenAlex.

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475 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

45 authors at 20 institutions in 2 countries.

Donald P TashkinDepartment of Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA. Electronic address: dtashkin@mednet.ucla.edu.
Michael D RothDepartment of Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA.
Philip J ClementsDepartment of Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA.
Daniel E FurstDepartment of Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA.
Dinesh KhannaDepartment of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
Eric C KleerupDepartment of Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA.
Jonathan GoldinDepartment of Radiological Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA.
Edgar ArriolaDivision of Pharmaceutical Services, Ronald Reagan UCLA Medical Center, University of California, Los Angeles, CA, USA.
Elizabeth R VolkmannDepartment of Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA.
Suzanne KafajaDepartment of Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA.
Richard SilverDepartment of Medicine, Medical University of South Carolina, Charleston, SC, USA.
Virginia SteenDepartment of Medicine, Georgetown University School of Medicine, Washington, DC, USA.
Charlie StrangeDepartment of Medicine, Medical University of South Carolina, Charleston, SC, USA.
Robert WiseDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Fredrick WigleyDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Maureen MayesDepartment of Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
David J RileyDepartment of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
Sabiha HussainDepartment of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
Shervin AssassiDepartment of Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
Vivien M HsuDepartment of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
Bela PatelDepartment of Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
Kristine PhillipsDepartment of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
Fernando MartinezDepartment of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
Jeffrey GoldenDepartment of Medicine, University of California, San Francisco, CA, USA.
M Kari ConnollyDepartment of Medicine, University of California, San Francisco, CA, USA.
John VargaDepartment of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Jane DematteDepartment of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Monique E HinchcliffDepartment of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Aryeh FischerDepartment of Medicine, National Jewish Health, Denver, CO, USA.
Jeffrey SwigrisDepartment of Medicine, National Jewish Health, Denver, CO, USA.
Richard MeehanDepartment of Medicine, National Jewish Health, Denver, CO, USA.
Arthur TheodoreDepartment of Medicine, Boston University School of Medicine, Boston, MA, USA.
Robert SimmsDepartment of Medicine, Boston University School of Medicine, Boston, MA, USA.
Suncica VolkovDepartment of Medicine, University of Illinois College of Medicine at Chicago, Chicago, IL, USA.
Dean E SchraufnagelDepartment of Medicine, University of Illinois College of Medicine at Chicago, Chicago, IL, USA.
Mary Beth ScholandDepartment of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
Tracy FrechDepartment of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
Jerry A MolitorDepartment of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.
Kristin HighlandDepartment of Medicine, Medical University of South Carolina, Charleston, SC, USA.
Charles A ReadDepartment of Medicine, Georgetown University School of Medicine, Washington, DC, USA.
Marvin J FritzlerDepartments of Medicine, Biochemistry, and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
Grace Hyun J KimDepartment of Radiological Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA.
Chi-Hong TsengDepartment of Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA.
Robert M ElashoffDepartment of Biomathematics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA.
Sclerodema Lung Study II Investigators
University of California, Los Angeles · USMedical University of South Carolina · USNorthwestern University · USThe University of Texas Health Science Center at Houston · USUniversity of Michigan–Ann Arbor · USBoston University · USGeorgetown University · USRutgers, The State University of New Jersey · USUniversity of California, San Francisco · USUniversity of Colorado Denver · USUniversity of Utah · USIllinois College · USJohns Hopkins Medicine · USJohns Hopkins University · USJohnson University · USNational Jewish Health · USRonald Reagan UCLA Medical Center · USUniversity of Calgary · CAUniversity of Illinois Chicago · USUniversity of Minnesota Medical Center · US

Funding

MOCSLID-DCCR01HL089901 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ELASHOFF, ROBERT M · 2008 to 2012
$9.1M
MOCSLID-CCCR01HL089758 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI TASHKIN, DONALD P · 2008 to 2012
$2.0M
Pain Mechanisms and Outcomes in OsteoarthritisK23AR060241 · NIAMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI PHILLIPS, KRISTINE · 2011 to 2015
$670k
Predictive Ability of Gene Expression Signatures In Skin as SSc BiomarkersK23AR059763 · NIAMS · NORTHWESTERN UNIVERSITY AT CHICAGO · PI HINCHCLIFF, MONIQUE EVANGELINE · 2013 to 2015
$390k
NHLBI NIH HHS R01 HL089758NHLBI NIH HHS R01 HL089901NIAMS NIH HHS K23 AR059763NIAMS NIH HHS K23 AR060241
6 · The paper itself

Abstract

background12 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.

methodsThis 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.

findingsBetween 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).

interpretationTreatment 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.

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

Indexed as

AdultAgedCyclophosphamideDisease ProgressionDouble-Blind MethodFemaleHumansImmunosuppressive AgentsLungLung Diseases, InterstitialMaleMiddle AgedMycophenolic AcidRespiratory Function TestsScleroderma, SystemicTreatment OutcomeCyclophosphamideImmunosuppressive AgentsMycophenolic Acid

Identifiers

PMID27469583
PMCPMC5014629
OpenAlexW2498506084

What OpenQuestion holds

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LicenceCC BY-NC-ND
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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.