Scleroderma Lung Study III - Combining Pirfenidone With Mycophenolate (SLSIII)

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

A Phase II multi-center, double-blind, parallel group, randomized and placebo-controlled clinical trial addressing the treatment of patients with active and symptomatic Scleroderma-related interstitial lung disease (SSc-ILD).

Study Overview

• Status: Completed
• Conditions: Scleroderma, Systemic; Interstitial Lung Disease
• Intervention / Treatment: Drug: Placebo (Plac); Drug: Mycophenolate Mofetil (MMF); Drug: Pirfenidone (PFD)

Detailed Description

A Phase II multi-center, double-blind, parallel group, randomized and placebo-controlled clinical trial addressing the treatment of patients with active and symptomatic Scleroderma-related interstitial lung disease (SSc-ILD). Patients who are either treatment naive or only recently started treatment (</= 6 months of prior treatment) will be randomized in a 1:1 assignment to receive either oral mycophenolate mofetil (MMF) and a placebo (Plac) or a combination of oral MMF and oral pirfenidone (PFD), with both regimens administered for 18 months. The primary hypothesis is that the rapid onset and anti-fibrotic effects of PFD, which have been observed in the treatment of Idiopathic Pulmonary Fibrosis (IPF), will complement the delayed antiinflammatory and immunosuppressive effects of MMF, to produce a significantly more rapid and/or greater improvement in lung function over time than occurs in patients receiving control therapy with MMF and Plac.

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston University, School of Medicine
    • Boston, Massachusetts, United States, 02115
      • Harvard Medical School, Brigham & Women's Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Rutgers University
  • New York
    • New York, New York, United States, 10021
      • Hospital for Special Surgery
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15261
      • University of Pittsburgh
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas Medical School at Houston
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18 yrs
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:

1. Disease features supporting the primary diagnosis of another connective tissue disease such as rheumatoid arthritis, systemic lupus erythematosus or mixed connective tissue disease (Features consistent with a secondary Sjogren syndrome or scleroderma-associated myopathy will be allowed).
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.
21. Use of contraindicated medications, including medications with putative disease-modifying properties that do not meet the exposure limits described in Exclusion Criteria #15 and #16, moderate or strong inhibitors of cytochrome P450 (CYP) isozyme 1A2 (CYP1A2) (note ciprofloxacin allowed up to a dose of 500 mg twice daily), and moderate inducers of CYP1A2 (such as tobacco smoke or phenytoin). See Protocol Section 7.5 for complete list.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo (Plac) + Mycophenolate (MMF); Participants will receive Placebo (Plac) as add-on to a background therapy of Mycophenolate Mofetil (MMF).	Drug: 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).; Other Names: Inactive capsule; Drug: 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 Names: generic for Cellcept
Experimental: Pirfenidone (PFD) + Mycophenolate (MMF); Participants will receive Pirfenidone (PFD) as add-on to a background therapy of Mycophenolate Mofetil (MMF).	Drug: 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 Names: generic for Cellcept; Drug: 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).; Other Names: Esbriet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Predicted Forced Vital Capacity (FVC-%)	Change from baseline to month 18 in the mean forced vital capacity (represented as the percentage of the age-; height-; gender-; and race-adjusted predicted value, i.e. FVC-%).	Baseline to 18 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Predicted Single-breath Diffusing Capacity for Carbon Monoxide (DLCOHb-%)	Change from baseline to month 18 in DLCO, calculated as a percent of the age-; height-; gender-; race-; and hemoglobin-adjusted predicted value (DLCOHb-%). The raw DLCO value and adjusting it for all of these factors and presenting it as a percent of predicted (expected) is the outcome measure (DLCOHb-%).	Baseline to 18 months
Modified Rodnan Skin Score (mRSS)	Change from baseline to month 18 in the mRSS. mRSS scores have a range from 0 to 51, with higher score indicating greater skin involvement.	Baseline to 18 months
Forced Vital Capacity Volume (FVC, in ml)	Change from baseline to month 18 in the Forced Vital Capacity volume (FVC, in ml)	Baseline to 18 months
Mahler Modified Transitional Dyspnea Index (TDI)	The change from baseline to 18 months in dyspnea. The TDI score for each of three domains ranges from -3 (major deterioration) to +3 (major improvement). The sum of all domains yields the TDI total score (-9 to +9).	Baseline to 18 months
Health Assessment Questionnaire Modified for Scleroderma (HAQ-DI)	Change from baseline to month 18 as a subjective measure of dyspnea and quality of life. HAQ-DI ranges from 0 (no disability) to 3 (severe disability).	Baseline to 18 months
St. George's Respiratory Questionnaire (SGRQ)	Change from baseline to month 18 as a subjective measure of dyspnea and quality of life. SGRQ ranges from 0 (no impairment) to 100 (maximum impairment).	Baseline to 18 months
High Resolution Computerized Tomography (HRCT) Measures of Quantitative Lung Fibrosis Score in the Whole Lung (QLF-WL)	Change from screening to month 18 in computer-generated scoring of HRCT data from the whole lung for the percentage of imaging pixels that exhibit features characteristic for lung fibrosis. Individual image scores range 0 to 100%, with higher percentages representing greater extent of quantitative lung fibrosis.	Screening to 18 months
High Resolution Computerized Tomography (HRCT) Measures of Quantitative Lung Fibrosis Score in the Lobe of Maximal Involvement (QLF-LM)	Change from screening to month 18 in computer-generated scoring of HRCT data for the percentage of imaging pixels that exhibit features characteristic for lung fibrosis within the lobe of maximal involvement at baseline. Individual image score range 0 to 100%, with higher percentages representing greater extent of quantitative lung fibrosis.	Screening to 18 months
High Resolution Computerized Tomography (HRCT) Measures of Quantitative Interstitial Lung Disease Score in the Whole Lung (QILD-WL)	Change from screening to month 18 in computer-generated scoring of HRCT data from the whole lung for the percentage of imaging pixels that exhibit features of any of the three patterns of interstitial lung disease (ILD) including quantitative ground-glass opacity (QGG), lung fibrosis (QLF) and quantitative honeycombing (QHC). Individual image scores range 0 to 100%, with higher percentages representing greater extent of quantitative interstitial lung disease.	Screening to 18 months
High Resolution Computerized Tomography (HRCT) Measures of Quantitative Interstitial Lung Disease Score in the Lobe of Maximal Involvement (QILD-LM)	Change from screening to month 18 in computer-generated scoring of HRCT data for the percentage of imaging pixels exhibiting features characteristic for any of three patterns of ILD (including QGG, QLF and QHC) within the lobe of maximal involvement at baseline. Individual image scores range 0 to 100%, with higher percentages representing greater extent of quantitative interstitial lung disease.	Screening to 18 months
High Resolution Computerized Tomography (HRCT) Measures of Total Lung Capacity (TLC)	Change from screening to 18 months in quantitative HRCT measurement of TLC at maximal inspiration (HRCT-TLC). Higher scores indicates a better outcome.	Screening to 18 months
3.0% or Greater Improvement From Baseline in FVC-%.	The time (in months) required for each treatment arm to achieve a 3.0% or greater improvement from baseline in the FVC-% over the 18-month treatment period.	Baseline to 18 months
Greater Than 5% Improvement in FVC-%	The percentage of subjects in each treatment arm achieving greater than a 5% improvement in FVC-% over the 18-month treatment period.	Baseline to 18 months
Percentage of Participants Achieving Specified Absolute Changes of FVC-%	The percentage of participants in each treatment arm achieving either improvements in the absolute change of FVC-% from baseline to 18 months by up to 5%, from 5% to <10% and from 10% to <15% or worsening by up to 5%, from 5% to <10% and from 10% to <15%. The descriptive analysis is presented.	Baseline to 18 months
Percentage of Participants Achieving Specified Absolute Changes of FVC-% Defined as Positive or Negative Responders	The percentage of participants in each treatment arm who are defined as positive responders (improved at least 3% or more) or negative responders (worsened at least 3% or more), and stable (>-3% to <3%). The descriptive analysis is presented.	Baseline to 18 months
Percentage of Participants Achieving Specified Absolute Changes of FVC-% Defined as Any Responders or Any Non-responders	The percentage of participants in each treatment arm who are defined as any responders (improved >0%) or any non-responders (worsened </=0%). The descriptive analysis is presented.	Baseline to 18 months
Percentage of Participants Achieving Specified Absolute Changes of mRSS	The percentage of participants in each treatment arm achieving changes in 4 point increments: worsen (1 to 4, >/=5), no change (=0), improved (</=-13, -12 to -9, -8 to -5, -4 to -1). The descriptive analysis is presented.	Baseline to 18 months
Percentage of Participants Achieving Specified Absolute Changes of mRSS Defined as Improved, no Change and Decreased.	The percentage of participants in each treatment arm achieving changes defined as improved (</=-5), no change (-5 to 5), and decreased (>5). The descriptive analysis is presented.	Baseline to 18 months
Percentage of Participants Achieving Specified TDI Focal Score at 18 Months	The percentage of participants in each treatment arm achieving either improvements in the TDI focal score at 18 months by 1-3, 4-6 and 7-9 points, no change (0) and worsened by 1-3, 4-6and 7-9 points. The descriptive analysis is presented.	18 months
Percentage of Participants Achieving Specified TDI Focal Score at 18 Months Defined as Improved, no Change or Deterioration	The percentage of participants in each treatment arm achieving TDI focal scores defined as improved (>0), no change and deterioration (<0). The descriptive analysis is presented.	18 months
Time to Withdrawal From the Study Drug or Treatment Failure	The time from start of treatment to withdrawal or removal from active drug therapy (MMF or Plac/PFD separately) for any reason will be plotted over the course of the 18-month treatment as a measure of tolerability and toxicity. Median times to withdrawal are not available for reporting as less than half of the participants discontinued the study drugs.	Baseline to 18 months
Number of Participants With Treatment-related Adverse Events as Assessed by System Organ Classification Using Preferred Medical Dictionary for Regulatory Activities (MedDRA) Terms.	Adverse Events (AE) and Serious Adverse Events (SAE), classified according to preferred MedDRA terms, were systematically recorded over the course of the 18-month treatment period as a measure of toxicity. Total number of participants experiencing adverse events reported here. Complete breakdown of AE and SAE by MedDRA terms is reported in the Adverse Events section.	Baseline to 18 months

Collaborators and Investigators

• Sponsor: Michael Roth
• Collaborators: University of California, Los Angeles; University of Michigan; Genentech, Inc.
• Investigators: Principal Investigator: Michael D Roth, MD, Pulmonary & Critical Care Medicine, Geffen School of Medicine at UCLA

Publications and helpful links

General Publications

• 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.
• 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.
• 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. Erratum In: N Engl J Med. 2014 Sep 18;371(12):1172.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 28, 2017
• Primary Completion (Actual): March 23, 2022
• Study Completion (Actual): June 13, 2022

Study Registration Dates

• First Submitted: July 12, 2017
• First Submitted That Met QC Criteria: July 14, 2017
• First Posted (Actual): July 18, 2017

Study Record Updates

• Last Update Posted (Actual): December 15, 2023
• Last Update Submitted That Met QC Criteria: December 13, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Respiratory Tract Diseases; Connective Tissue Diseases; Lung Diseases; Scleroderma, Systemic; Scleroderma, Diffuse; Lung Diseases, Interstitial; Scleroderma, Localized; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Pirfenidone; Mycophenolic Acid
• Other Study ID Numbers: UCLA-SLS3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: A bio-specimen repository will be created in which de-identified blood specimens will be made available to qualified researchers who submit meritorious applications for the access and use of such samples. Requests for specimens and correlative analyses related to other linked and de-identified clinical data will be overseen by the Study Executive and Steering Committees and/or any sub-committees that they may appoint for this process.
• IPD Sharing Time Frame: Sharing will be made available after completion of the clinical trial and reporting of the primary outcome.
• IPD Sharing Access Criteria: Access criteria will be made available after 01/01/2018 through the study website noted below.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No