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

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ClinicalTrials.gov Identifier: NCT03221257
Recruitment Status : Recruiting
First Posted : July 18, 2017
Last Update Posted : September 10, 2018
Sponsor:
Collaborators:
University of Michigan
Genentech, Inc.
University of California, Los Angeles
Information provided by (Responsible Party):
Michael Roth, University of California, Los Angeles

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 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  (Clinical Trial)
Estimated Enrollment : 150 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
Estimated Primary Completion Date : April 2021
Estimated Study Completion Date : May 2021


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




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. 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.

  4. Health assessment questionnaire modified for scleroderma (SHAQ) [ Time Frame: Baseline to 18 months, measured at 6 month intervals. ]
    Change from baseline, measured at 3-month intervals, as a subjective measure of dyspnea and quality of life.

  5. 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.

  6. High resolution computerized tomography (HRCT) measures of scleroderma-related interstitial lung disease (SSc-ILD) [ Time Frame: Baseline to 18 months ]
    Change from baseline to 18 months in computer-quantified HRCT scores of lung involvement by imaging patterns consistent with interstitial lung disease.

  7. High resolution computerized tomography (HRCT) measures of Total Lung Capacity (TLC) [ Time Frame: Baseline to 18 months ]
    Change from baseline to 18 months in quantitative HRCT measurement of TLC at maximal inspiration (HRCT-TLC).

  8. 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.

  9. 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.

  10. 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.

  11. 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.



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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 ≤80% at screening (and ≤85% at baseline, when participant completes baseline visit)
  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 and ≤85%. 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%.

    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 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 pulmonary embolism, or 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 <150.0x10^3/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 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.
  15. Prior use, as determined at the time of screening, of oral cyclophosphamide (CYC), MMF, azathioprine or other putative disease modifying medications for more than 12 weeks or the receipt of three or more intravenous doses of CYC, Rituximab or other injectable medication with putative disease-modifying activity in the past 6 months.
  16. Use of CYC, MMF, azathioprine, Rituximab or other putative disease modifying medications in the 30 days prior to their baseline visit.
  17. Active infection (lung, ulcers or elsewhere) whose management would be compromised by immunosuppression.
  18. Other serious concomitant medical illness (e.g., cancer), 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 within the past month, 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, montelukast or phenytoin).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03221257


Contacts
Contact: Grace D Ibrahim (310) 206-0396 GIbrahim@mednet.ucla.edu

Locations
United States, California
University of California Los Angeles Recruiting
Los Angeles, California, United States, 90095
Contact: Eileen Callahan    310-794-2466    ecallahan@mednet.ucla.edu   
Principal Investigator: Stephen S Weigt, MD         
United States, Colorado
University of Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Mallory Crow Adams    303-724-8403    mallary.crowadams@ucdenver.edu   
Principal Investigator: Aryeh Fischer, MD         
United States, District of Columbia
Georgetown University Recruiting
Washington, District of Columbia, United States, 20007
Contact: Sabrina Elliott    202-444-6210    sabrina.elliott@georgetown.edu   
Principal Investigator: Virginia Steen, MD         
United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Adeeb Ansari    312-695-6021    Adeeb.ansari@northwestern.edu   
Principal Investigator: Jane Dematte, MD         
United States, Massachusetts
Harvard Medical School, Brigham & Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Maura Alvarez Baumgartner    617-525-8686    malvarezbaumgartner@bwh.harvard.edu   
Principal Investigator: Ivan Rosas, MD         
Boston University, School of Medicine Recruiting
Boston, Massachusetts, United States, 02118
Contact: Eric Stratton, MTS, MPH    617-358-6777    eas@bu.edu   
Principal Investigator: Robert W. Simms, MD         
United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Monica Sanborn    734-232-2090    monsan@med.umich.edu   
Principal Investigator: Vivek Nagaraja, MD         
United States, Pennsylvania
University of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15261
Contact: Maureen Laffoon    412-648-7871    laffoonm@pitt.edu   
Principal Investigator: Robyn T. Domsic, MD, MPH         
United States, Texas
University of Texas Medical School at Houston Recruiting
Houston, Texas, United States, 77030
Contact: Pat Gonzalez, LVN, CCRP    713-500-7118    Patricia.Gonzales@uth.tmc.edu   
Principal Investigator: Maureen D. Mayes, MD, MPH         
Sponsors and Collaborators
Michael Roth
University of Michigan
Genentech, Inc.
University of California, Los Angeles
Investigators
Principal Investigator: Michael D Roth, MD Division of Pulmonary & Critical Care, Department of Medicine, RM# 37-131 CHS, David Geffen School of Medicine/UCLA. 90095-1690

Publications:

Responsible Party: Michael Roth, Professor of Pulmonary and Critical Care Medicine, University of California, Los Angeles
ClinicalTrials.gov Identifier: NCT03221257     History of Changes
Other Study ID Numbers: UCLA-SLS3
First Posted: July 18, 2017    Key Record Dates
Last Update Posted: September 10, 2018
Last Verified: September 2018
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
Lung Diseases, Interstitial
Lung Diseases
Respiratory Tract Diseases
Connective Tissue Diseases
Skin Diseases
Mycophenolic Acid
Pirfenidone
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