Scleroderma Lung Study III - Combining Pirfenidone With Mycophenolate
NCT ID: NCT03221257
Last Updated: 2023-12-15
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE2
51 participants
INTERVENTIONAL
2017-11-28
2022-06-13
Brief Summary
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
TRIPLE
Study Groups
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Placebo (Plac) + Mycophenolate (MMF)
Participants will receive Placebo (Plac) as add-on to a background therapy of Mycophenolate Mofetil (MMF).
Placebo (Plac)
Participants will receive a Plac, matched to resemble PFD, titrated up to a target dose of 801 mg taken three times daily as tolerated (3-step titration occurring at 2 week intervals).
Mycophenolate Mofetil (MMF)
Participants will receive MMF titrated up to a target dose of 1500 mg taken twice daily as tolerated (4-step titration occurring at monthly intervals).
Pirfenidone (PFD) + Mycophenolate (MMF)
Participants will receive Pirfenidone (PFD) as add-on to a background therapy of Mycophenolate Mofetil (MMF).
Pirfenidone (PFD)
Participants will receive PFD titrated up to a target dose of 801 mg taken three times daily as tolerated (3-step titration occurring at 2 week intervals).
Mycophenolate Mofetil (MMF)
Participants will receive MMF titrated up to a target dose of 1500 mg taken twice daily as tolerated (4-step titration occurring at monthly intervals).
Interventions
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Pirfenidone (PFD)
Participants will receive PFD titrated up to a target dose of 801 mg taken three times daily as tolerated (3-step titration occurring at 2 week intervals).
Placebo (Plac)
Participants will receive a Plac, matched to resemble PFD, titrated up to a target dose of 801 mg taken three times daily as tolerated (3-step titration occurring at 2 week intervals).
Mycophenolate Mofetil (MMF)
Participants will receive MMF titrated up to a target dose of 1500 mg taken twice daily as tolerated (4-step titration occurring at monthly intervals).
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Scleroderma as determined by the 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria.
3. Grade ≥2 on the Magnitude of Task component of the Mahler Modified Dyspnea Index
4. FVC-% of ≤85% at screening
5. Onset of the first non-Raynaud manifestation of SSc within the prior 84 months.
6. Presence of any ground-glass opacification (GGO) on thoracic high-resolution computed tomography (HRCT)
7. Repeat FVC-% at the baseline visit within 10% of the FVC-% value measured at screening. If these criteria are not met, a repeat FVC-% may be obtained within 7 days and the subject may qualify for randomization if the repeat FVC-% agrees within 10% of the FVC-% obtained at screening.
Exclusion Criteria
2. FVC-% of \<45% at either screening or baseline.
3. Forced Expiratory Volume in the first second (FEV1)/Forced Vital Capacity (FVC) ratio \<0.65 at either screening or baseline.
4. Diffusing capacity of the lung for carbon monoxide adjusted for hemoglobin, expressed as a percentage of the normal predicted value (DLCOHb-%) of \<30% at screening or \<25% at baseline.
a) All participants with a DLCOHb-% between 30 to 40% must have pulmonary artery pressures documented by either echocardiogram, right heart catheterization or magnetic resonance imaging in order to be considered for inclusion.
5. Diagnosis of clinically significant resting pulmonary hypertension requiring treatment or mild pulmonary hypertension requiring treatment with more than one oral medication as ascertained prior to study evaluation or as part of a standard of care clinical assessment performed outside of the study protocol.
6. Evidence of uncontrolled congestive heart failure, unstable ischemic heart disease, history of complicated pulmonary embolism impacting on heart or lung function, or unstable cardiac arrhythmia requiring chronic anticoagulation.
7. Clinically significant abnormalities on HRCT not attributable to SSc
8. Hematologic abnormality at screening including:
1. Leukopenia (white blood cells \[WBC\] \<4.0x10\^3/µl).
2. Thrombocytopenia (platelet count \<120.0x10\^3/µl).
3. Clinically significant anemia \[Hemoglobin (Hgb) \<10.0 g/dl\].
Participants with an identified and correctable etiology may be eligible if repeat testing within the maximal 90-day screening period meets all criteria.
9. A diagnosis of chronic liver disease or abnormal baseline liver function test (LFTs) or total bilirubin that are \>2.0 x upper normal limit
10. Serum creatinine \>2.0mg/dl
11. History of recurrent aspiration, uncontrolled heartburn, or gastroesophageal reflux disease (GERD) with a reflux scale score of \>1.00 as determined by a UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Scale (UCLA SCTC GIT), Version 2.0.
Participants with uncontrolled heartburn or GERD that is amenable to medical management may be eligible if repeat testing within the maximal 90-day screening period meets this criteria.
12. Known achalasia, esophageal stricture or esophageal dysfunction sufficient to limit the ability to swallow medication.
13. Pregnancy (as documented by blood test) and/or breast feeding
14. If of child bearing potential (a female participant \< 55 years of age who has not been postmenopausal for ≥ 5 years or who has not had a bilateral salpingectomy, hysterectomy and/or oophorectomy), failure to employ two reliable means of contraception which may include surgical sterilization, barrier methods, spermicides, intrauterine devices, and/or hormonal contraception, unless the participant chooses abstinence (to avoid heterosexual intercourse completely). If a subject chooses abstinence, then a second reliable means of contraception is not needed.
15. Prior use of potential disease modifying antirheumatic drugs (DMARDs) according to the following exposure rules:
1. Use of oral cyclophosphamide (CYC), MMF, azathioprine or other oral or short half-life DMARDs (as detailed in Protocol Section 7.5.1a) for more than 6 months in the past year as determined at the time of the initial screening visit.
2. Treatment with more than three intravenous doses of CYC, one treatment course of Rituximab or other intravenous or injectable DMARDs (as detailed in Protocol Section 7.5.1b) in the past year.
3. More distant history of treatment with a DMARD is allowed as long as the patient has a new diagnosis/new episode of active SSc-ILD since stopping that treatment and meets the criteria noted in 15a or 15b.
16. Use of CYC, MMF, azathioprine, Rituximab or other DMARD (as defined in Protocol Section 7.5.1a\&b) in the 30 days prior to their baseline visit unless the patient is on MMF and the responsible physician indicates that continued use is in the best clinical interest of the patient.
17. Active infection (lung, ulcers or elsewhere) whose management would be compromised by immunosuppression.
18. Other serious concomitant medical illness (e.g., active malignancy within the past 5 years other than surgically-removed local skin cancer such as a basal cell carcinoma), chronic debilitating illness (other than SSc), unreliability or drug abuse that might compromise the patient's participation in the trial.
19. Current use, or use within the 30 days prior to their baseline visit, of prednisone (or equivalent) in doses \>10 mg/day.
20. Smoking of cigars, pipes, or cigarettes during the past 6 months.
18 Years
ALL
No
Sponsors
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University of Michigan
OTHER
Genentech, Inc.
INDUSTRY
University of California, Los Angeles
OTHER
Michael Roth
OTHER
Responsible Party
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Michael Roth
Professor of Pulmonary and Critical Care Medicine
Principal Investigators
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Michael D Roth, MD
Role: PRINCIPAL_INVESTIGATOR
Pulmonary & Critical Care Medicine, Geffen School of Medicine at UCLA
Locations
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University of California Los Angeles
Los Angeles, California, United States
University of Colorado
Aurora, Colorado, United States
Georgetown University
Washington D.C., District of Columbia, United States
Northwestern University
Chicago, Illinois, United States
Indiana University Health
Indianapolis, Indiana, United States
Johns Hopkins University
Baltimore, Maryland, United States
Harvard Medical School, Brigham & Women's Hospital
Boston, Massachusetts, United States
Boston University, School of Medicine
Boston, Massachusetts, United States
University of Michigan
Ann Arbor, Michigan, United States
Rutgers University
New Brunswick, New Jersey, United States
Hospital for Special Surgery
New York, New York, United States
University of Pittsburgh
Pittsburgh, Pennsylvania, United States
Medical University of South Carolina
Charleston, South Carolina, United States
University of Texas Medical School at Houston
Houston, Texas, United States
University of Utah
Salt Lake City, Utah, United States
University of Washington Medical Center
Seattle, Washington, United States
Countries
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References
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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; Sclerodema Lung Study II Investigators. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med. 2016 Sep;4(9):708-719. doi: 10.1016/S2213-2600(16)30152-7. Epub 2016 Jul 25.
Tashkin DP, Volkmann ER, Tseng CH, Roth MD, Khanna D, Furst DE, Clements PJ, Theodore A, Kafaja S, Kim GH, Goldin J, Ariolla E, Elashoff RM. Improved Cough and Cough-Specific Quality of Life in Patients Treated for Scleroderma-Related Interstitial Lung Disease: Results of Scleroderma Lung Study II. Chest. 2017 Apr;151(4):813-820. doi: 10.1016/j.chest.2016.11.052. Epub 2016 Dec 22.
Volkmann ER, Tashkin DP, Li N, Roth MD, Khanna D, Hoffmann-Vold AM, Kim G, Goldin J, Clements PJ, Furst DE, Elashoff RM. Mycophenolate Mofetil Versus Placebo for Systemic Sclerosis-Related Interstitial Lung Disease: An Analysis of Scleroderma Lung Studies I and II. Arthritis Rheumatol. 2017 Jul;69(7):1451-1460. doi: 10.1002/art.40114. Epub 2017 May 23.
Namas R, Tashkin DP, Furst DE, Wilhalme H, Tseng CH, Roth MD, Kafaja S, Volkmann E, Clements PJ, Khanna D; Participants in the Scleroderma Lung Study I and members of the Scleroderma Lung Study II Research Group. Efficacy of Mycophenolate Mofetil and Oral Cyclophosphamide on Skin Thickness: Post Hoc Analyses From Two Randomized Placebo-Controlled Trials. Arthritis Care Res (Hoboken). 2018 Mar;70(3):439-444. doi: 10.1002/acr.23282. Epub 2018 Feb 9.
Khanna D, Albera C, Fischer A, Khalidi N, Raghu G, Chung L, Chen D, Schiopu E, Tagliaferri M, Seibold JR, Gorina E. An Open-label, Phase II Study of the Safety and Tolerability of Pirfenidone in Patients with Scleroderma-associated Interstitial Lung Disease: the LOTUSS Trial. J Rheumatol. 2016 Sep;43(9):1672-9. doi: 10.3899/jrheum.151322. Epub 2016 Jul 1.
King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, Sahn SA, Sussman R, Swigris JJ, Noble PW; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014 May 29;370(22):2083-92. doi: 10.1056/NEJMoa1402582. Epub 2014 May 18.
Takizawa A, Kamita M, Kondoh Y, Bando M, Kuwana M, Inoue Y. Current monitoring and treatment of progressive fibrosing interstitial lung disease: a survey of physicians in Japan, the United States, and the European Union. Curr Med Res Opin. 2021 Feb;37(2):327-339. doi: 10.1080/03007995.2020.1860920. Epub 2021 Jan 11.
Provided Documents
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Document Type: Study Protocol and Informed Consent Form
Document Type: Statistical Analysis Plan
Other Identifiers
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UCLA-SLS3
Identifier Type: -
Identifier Source: org_study_id