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

• ClinicalTrials.gov Identifier: NCT03221257
• Recruitment Status: Completed
• First Posted: July 18, 2017
• Last Update Posted: February 23, 2023
• Sponsor: Michael Roth
• Collaborators: University of Michigan; Genentech, Inc.; University of California, Los Angeles
• Information provided by (Responsible Party): Michael Roth, University of California, Los Angeles

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Scleroderma, Systemic; Interstitial Lung Disease	Drug: Pirfenidone (PFD); Drug: Placebo (Plac); Drug: Mycophenolate Mofetil (MMF)	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 51 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Scleroderma Lung Study III (SLS III): Combining the Anti-fibrotic Effects of Pirfenidone (PFD) With Mycophenolate (MMF) for Treating Scleroderma-related Interstitial Lung Disease
• Actual Study Start Date: November 28, 2017
• Actual Primary Completion Date: March 23, 2022
• Actual Study Completion Date: June 13, 2022

Arms and Interventions

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 Name: 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 Name: 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: 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 Name: Esbriet; 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 Name: generic for Cellcept

Outcome Measures

Primary Outcome Measures :

1. Percent predicted forced vital capacity (FVC-%) [ Time Frame: Baseline to 18 months, measured at 3 month intervals. ]
   Change from baseline, measured at 3-month intervals, in the mean forced vital capacity (represented as the percentage of the age-; height-; gender-; and race-adjusted predicted value, i.e. FVC-%).

Other Outcome Measures:

1. Percent predicted single-breath diffusing capacity for carbon monoxide (DLCOHb-%) [ Time Frame: Baseline to 18 months, measured at 3 month intervals. ]
   Change from baseline, measured at 3-month intervals, 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-%).
2. Modified Rodnan Skin Score (mRSS) [ Time Frame: Baseline to 18 months, measured at 3 month intervals. ]
   Change from baseline, measured at 3-month intervals, in the mRSS.
3. Forced Vital Capacity volume (FVC, in ml) [ Time Frame: Baseline to 18 months, measured at 3 month intervals. ]
   Change from baseline, measured at 3-month intervals, in the Forced Vital Capacity volume (FVC, in ml)
4. Mahler Modified Transitional Dyspnea Index (TDI) [ Time Frame: Baseline to 18 months, measured at 3 month intervals. ]
   Change from baseline, measured at 3-month intervals, in dyspnea as measured by the TDI.
5. Health assessment questionnaire modified for scleroderma (SHAQ) [ Time Frame: Baseline to 18 months, measured at 6 month intervals. ]
   Change from baseline, measured at 6-month intervals, as a subjective measure of dyspnea and quality of life.
6. St. George's Respiratory Questionnaire (SGRQ) [ Time Frame: Baseline to 18 months, measured at 3 month intervals. ]
   Change from baseline, measured at 3-month intervals, as a subjective measure of dyspnea and quality of life.
7. High resolution computerized tomography (HRCT) measures of Quantitative lung fibrosis score in the whole lung (QLF-WL) [ Time Frame: Screening to 18 months ]
   Change from screening to 18 months in computer-quantified HRCT scores of lung involvement related to lung fibrosis in the whole lung.
8. High resolution computerized tomography (HRCT) measures of Quantitative lung fibrosis score in the lobe of maximal involvement (QLF-LM) [ Time Frame: Screening to 18 months ]
   Change from screening to 18 months in computer-quantified HRCT scores of lung involvement related to lung fibrosis in the lobe of maximal involvement.
9. High resolution computerized tomography (HRCT) measures of Quantitative interstitial lung disease score in the whole lung (QILD-WL) [ Time Frame: Screening to 18 months ]
   Change from screening to 18 months in computer-quantified HRCT scores of lung involvement related to all features of interstitial lung disease (fibrosis, ground glass opacification and honeycomb change) in the whole lung.
10. High resolution computerized tomography (HRCT) measures of Quantitative interstitial lung disease score in the lobe of maximal involvement (QILD-LM) [ Time Frame: Screening to 18 months ]
    Change from screening to 18 months in computer-quantified HRCT scores of lung involvement related to all features of lung disease (fibrosis, ground glass opacification and honeycomb change) in the lobe of maximal involvement.
11. High resolution computerized tomography (HRCT) measures of Total Lung Capacity (TLC) [ Time Frame: Screening to 18 months ]
    Change from screening to 18 months in quantitative HRCT measurement of TLC at maximal inspiration (HRCT-TLC).
12. 3.0% or greater improvement from baseline in FVC-%. [ Time Frame: Baseline to 18 months ]
    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.
13. Greater than 5% improvement in FVC-% [ Time Frame: Baseline to 18 months ]
    A threshold analysis based on the percentage of subjects in each treatment arm achieving greater than a 5% improvement in FVC-% over the 18-month treatment period.
14. Proportion of participants achieving specified absolute changes of FEV-% [ Time Frame: Baseline to 18 months ]
    An analysis of the proportion 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%.
15. Proportion of participants achieving specified absolute changes of FEV-% defined as positive or negative responders [ Time Frame: Baseline to 18 months ]
    An analysis of the proportion 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%).
16. Proportion of participants achieving specified absolute changes of FEV-% defined as any responders or any non-responders [ Time Frame: Baseline to 18 months ]
    An analysis of the proportion of participants in each treatment arm who are defined as any responders (improved >0%) or any non-responders (worsened </=0%).
17. Proportion of participants achieving specified absolute changes of mRSS [ Time Frame: Baseline to 18 months ]
    An analysis of the proportion 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).
18. Proportion of participants achieving specified absolute changes of mRSS defined as improved, no change and decreased. [ Time Frame: Baseline to 18 months ]
    An analysis of the proportion of participants in each treatment arm achieving changes defined as improved (</=-5), no change (-5 to 5), and decreased (>5).
19. Proportion of participants achieving specified TDI focal score at 18 months [ Time Frame: 18 months ]
    An analysis of the proportion 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.
20. Proportion of participants achieving specified TDI focal score at 18 months defined as improved, no change or deterioration [ Time Frame: 18 months ]
    An analysis of the proportion of participants in each treatment arm achieving TDI focal scores defined as improved (>0), no change and deterioration (<0).
21. Time to withdrawal from the study drug or treatment failure [ Time Frame: Baseline to 18 months ]
    The time from start of treatment to withdrawal or removal from active drug therapy for any reason will be plotted over the course of the 18-month treatment as a measure of tolerability and toxicity.
22. Number of participants with treatment-related adverse events as assessed by system organ classification using preferred Medical Dictionary for Regulatory Activities (MedDRA) terms. [ Time Frame: Baseline to 18 months ]
    Adverse Events and Serious Adverse Events will be recorded over the course of the 18-month treatment as a measure of toxicity.

Eligibility Criteria

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

Criteria

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 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. 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, spermicidals, 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.

Contacts and Locations

Locations

United States, California

University of California Los Angeles

Los Angeles, California, United States, 90095

United States, Colorado

University of Colorado

Aurora, Colorado, United States, 80045

United States, District of Columbia

Georgetown University

Washington, District of Columbia, United States, 20007

United States, Illinois

Northwestern University

Chicago, Illinois, United States, 60611

United States, Indiana

Indiana University Health

Indianapolis, Indiana, United States, 46202

United States, Maryland

Johns Hopkins University

Baltimore, Maryland, United States, 21224

United States, Massachusetts

Harvard Medical School, Brigham & Women's Hospital

Boston, Massachusetts, United States, 02115

Boston University, School of Medicine

Boston, Massachusetts, United States, 02118

United States, Michigan

University of Michigan

Ann Arbor, Michigan, United States, 48109

United States, New Jersey

Rutgers University

New Brunswick, New Jersey, United States, 08901

United States, New York

Hospital for Special Surgery

New York, New York, United States, 10021

United States, Pennsylvania

University of Pittsburgh

Pittsburgh, Pennsylvania, United States, 15261

United States, South Carolina

Medical University of South Carolina

Charleston, South Carolina, United States, 29425

United States, Texas

University of Texas Medical School at Houston

Houston, Texas, United States, 77030

United States, Utah

University of Utah

Salt Lake City, Utah, United States, 84108

United States, Washington

University of Washington Medical Center

Seattle, Washington, United States, 98195

Sponsors and Collaborators

Michael Roth

University of Michigan

Genentech, Inc.

University of California, Los Angeles

Investigators

• Principal Investigator: Michael D Roth, MD; Pulmonary & Critical Care Medicine, Geffen School of Medicine at UCLA

More Information

Publications:

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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Michael Roth, Professor of Pulmonary and Critical Care Medicine, University of California, Los Angeles
• ClinicalTrials.gov Identifier: NCT03221257
• Other Study ID Numbers: UCLA-SLS3
• First Posted: July 18, 2017
• Last Update Posted: February 23, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Time Frame: Sharing will be made available after completion of the clinical trial and reporting of the primary outcome.
• Access Criteria: Access criteria will be made available after 01/01/2018 through the study website noted below.
• URL: http://sclerodermalungstudy.org

• 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

Additional relevant MeSH terms:

Scleroderma, Systemic; Scleroderma, Diffuse; Scleroderma, Localized; Pirfenidone; Lung Diseases; Lung Diseases, Interstitial; Respiratory Tract Diseases; Connective Tissue Diseases; Skin Diseases; Mycophenolic Acid; Antibiotics, Antineoplastic; Antineoplastic Agents; Antibiotics, Antitubercular; Antitubercular Agents; Anti-Bacterial Agents; Anti-Infective Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents