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

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ClinicalTrials.gov Identifier: NCT03221257
Recruitment Status : Active, not recruiting
First Posted : July 18, 2017
Last Update Posted : October 12, 2020
Sponsor:
Collaborators:
University of Michigan
Genentech, Inc.
University of California, Los Angeles
Information provided by (Responsible Party):
Michael Roth, University of California, Los Angeles

Tracking Information
First Submitted Date  ICMJE July 12, 2017
First Posted Date  ICMJE July 18, 2017
Last Update Posted Date October 12, 2020
Actual Study Start Date  ICMJE November 28, 2017
Estimated Primary Completion Date April 15, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 14, 2017)
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-%).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures
 (submitted: July 14, 2017)
  • 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-%).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Scleroderma Lung Study III - Combining Pirfenidone With Mycophenolate
Official Title  ICMJE Scleroderma Lung Study III (SLS III): Combining the Anti-fibrotic Effects of Pirfenidone (PFD) With Mycophenolate (MMF) for Treating Scleroderma-related Interstitial Lung Disease
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).
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Scleroderma, Systemic
  • Interstitial Lung Disease
Intervention  ICMJE
  • 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: 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
Study Arms  ICMJE
  • Placebo Comparator: Placebo (Plac) + Mycophenolate (MMF)
    Participants will receive Placebo (Plac) as add-on to a background therapy of Mycophenolate Mofetil (MMF).
    Interventions:
    • Drug: Placebo (Plac)
    • Drug: Mycophenolate Mofetil (MMF)
  • Experimental: Pirfenidone (PFD) + Mycophenolate (MMF)
    Participants will receive Pirfenidone (PFD) as add-on to a background therapy of Mycophenolate Mofetil (MMF).
    Interventions:
    • Drug: Pirfenidone (PFD)
    • Drug: Mycophenolate Mofetil (MMF)
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: July 14, 2017)
150
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 1, 2022
Estimated Primary Completion Date April 15, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03221257
Other Study ID Numbers  ICMJE UCLA-SLS3
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
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
Responsible Party Michael Roth, University of California, Los Angeles
Study Sponsor  ICMJE Michael Roth
Collaborators  ICMJE
  • University of Michigan
  • Genentech, Inc.
  • University of California, Los Angeles
Investigators  ICMJE
Principal Investigator: Michael D Roth, MD Pulmonary & Critical Care Medicine, Geffen School of Medicine at UCLA
PRS Account University of California, Los Angeles
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP