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CompletedNCT03221257SLSIIIUpdated Dec 15, 2023Results posted

Scleroderma Lung Study III - Combining Pirfenidone With Mycophenolate

A Phase 2 interventional study of Pirfenidone (PFD) and Placebo (Plac) in Scleroderma, Systemic and Interstitial Lung Disease, sponsored by Michael Roth. Completed at 16 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2023-12-15.

Sponsored by Michael Roth · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
51
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study 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).

Read the 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.

02

Conditions studied

  • Scleroderma, Systemic
  • Interstitial Lung Disease
03

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

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

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.
04

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Triple (Participant, Care provider, Investigator)
Enrollment
51 participants (actual)

Study arms

  • 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) · 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).

    Drug: Pirfenidone (PFD) · Drug: Mycophenolate Mofetil (MMF)

Interventions

  • DrugPirfenidone (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).

    Also known as: Esbriet

  • DrugPlacebo (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).

    Also known as: Inactive capsule

  • DrugMycophenolate 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).

    Also known as: generic for Cellcept

05

What researchers measure

Primary outcomes

  1. 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-%).

    Time frame: Baseline to 18 months

Other outcomes

  1. 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-%).

    Time frame: Baseline to 18 months

  2. 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.

    Time frame: Baseline to 18 months

  3. Forced Vital Capacity Volume (FVC, in ml)

    Change from baseline to month 18 in the Forced Vital Capacity volume (FVC, in ml)

    Time frame: Baseline to 18 months

  4. 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).

    Time frame: Baseline to 18 months

  5. 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).

    Time frame: Baseline to 18 months

  6. 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).

    Time frame: Baseline to 18 months

  7. 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.

    Time frame: Screening to 18 months

  8. 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.

    Time frame: Screening to 18 months

  9. 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.

    Time frame: Screening to 18 months

  10. 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.

    Time frame: Screening to 18 months

  11. 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.

    Time frame: Screening to 18 months

  12. 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.

    Time frame: Baseline to 18 months

  13. 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.

    Time frame: Baseline to 18 months

  14. 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.

    Time frame: Baseline to 18 months

  15. 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.

    Time frame: Baseline to 18 months

  16. 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.

    Time frame: Baseline to 18 months

  17. 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.

    Time frame: Baseline to 18 months

  18. 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.

    Time frame: Baseline to 18 months

  19. 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.

    Time frame: 18 months

  20. 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.

    Time frame: 18 months

  21. 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.

    Time frame: Baseline to 18 months

  22. 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.

    Time frame: Baseline to 18 months

06

Results

Posted Dec 15, 2023
Limitations and caveats
Only 51 (34%) of our planned recruitment goal of 150 were randomized. During the recruitment period MMF became a standard of care for treatment in early systemic sclerosis (SSc)-ILD, including the treatment of both lung and skin disease, thereby increasing the difficulty in recruiting treatment-naïve patients. Other barriers to recruitment included the Coronavirus Disease 2019 (COVID-19) epidemic and FDA approval of nintedanib as an alternative treatment during the initial phase of the trial.

Participant flow

Participant flow — Overall Study
MilestonePlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
Started2427
Completed2325
Not completed12
Withdrew: Lost to follow-up01
Withdrew: Withdrawal by subject11

Outcome measures

PrimaryPercent 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-%).

Time frame:
Baseline to 18 months
Reported as:
Least squares mean · percent predicted
Percent Predicted Forced Vital Capacity (FVC-%)
percent predictedPlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
Percent Predicted Forced Vital Capacity (FVC-%)2.24 ± 1.3512.09 ± 1.278
Statistical analysis
  • Placebo (Plac) + Mycophenolate (MMF) vs Pirfenidone (PFD) + Mycophenolate (MMF) · Mixed Models Analysis · p = 0.9326 · Mean difference (net): -0.14
Other pre-specifiedPercent 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-%).

Time frame:
Baseline to 18 months
Reported as:
Least squares mean · percent predicted
Percent Predicted Single-breath Diffusing Capacity for Carbon Monoxide (DLCOHb-%)
percent predictedPlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
Percent Predicted Single-breath Diffusing Capacity for Carbon Monoxide (DLCOHb-%)1.25 ± 1.5491.24 ± 1.505
Statistical analysis
  • Placebo (Plac) + Mycophenolate (MMF) vs Pirfenidone (PFD) + Mycophenolate (MMF) · Mixed Models Analysis · p = 0.9968 · Mean difference (net): -0.01
Other pre-specifiedModified 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.

Time frame:
Baseline to 18 months
Reported as:
Least squares mean · score on a scale
Modified Rodnan Skin Score (mRSS)
score on a scalePlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
Modified Rodnan Skin Score (mRSS)-5.42 ± 1.164-4.96 ± 1.109
Statistical analysis
  • Placebo (Plac) + Mycophenolate (MMF) vs Pirfenidone (PFD) + Mycophenolate (MMF) · Mixed Models Analysis · p = 0.7489 · Mean difference (net): 0.46
Other pre-specifiedForced Vital Capacity Volume (FVC, in ml)

Change from baseline to month 18 in the Forced Vital Capacity volume (FVC, in ml)

Time frame:
Baseline to 18 months
Reported as:
Least squares mean · ml
Forced Vital Capacity Volume (FVC, in ml)
mlPlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
Forced Vital Capacity Volume (FVC, in ml)121.53 ± 62.41112.33 ± 59.055
Statistical analysis
  • Placebo (Plac) + Mycophenolate (MMF) vs Pirfenidone (PFD) + Mycophenolate (MMF) · Mixed Models Analysis · p = 0.8898 · Mean difference (net): -9.2
Other pre-specifiedMahler 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).

Time frame:
Baseline to 18 months
Reported as:
Least squares mean · score on a scale
Mahler Modified Transitional Dyspnea Index (TDI)
score on a scalePlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
Mahler Modified Transitional Dyspnea Index (TDI)1.13 ± 0.7541.99 ± 0.710
Statistical analysis
  • Placebo (Plac) + Mycophenolate (MMF) vs Pirfenidone (PFD) + Mycophenolate (MMF) · Mixed Models Analysis · p = 0.3826 · Mean difference (net): 0.86
Other pre-specifiedHealth 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).

Time frame:
Baseline to 18 months
Reported as:
Least squares mean · score on a scale
Health Assessment Questionnaire Modified for Scleroderma (HAQ-DI)
score on a scalePlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
Health Assessment Questionnaire Modified for Scleroderma (HAQ-DI)-0.03 ± 0.109-0.17 ± 0.103
Statistical analysis
  • Placebo (Plac) + Mycophenolate (MMF) vs Pirfenidone (PFD) + Mycophenolate (MMF) · Mixed Models Analysis · p = 0.2819 · Mean difference (net): -0.14
Other pre-specifiedSt. 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).

Time frame:
Baseline to 18 months
Reported as:
Least squares mean · score on a scale
St. George's Respiratory Questionnaire (SGRQ)
score on a scalePlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
St. George's Respiratory Questionnaire (SGRQ)-4.77 ± 3.487-6.11 ± 3.212
Statistical analysis
  • Placebo (Plac) + Mycophenolate (MMF) vs Pirfenidone (PFD) + Mycophenolate (MMF) · Mixed Models Analysis · p = 0.7534 · Mean difference (net): -1.35
Other pre-specifiedHigh 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.

Time frame:
Screening to 18 months
Reported as:
Least squares mean · percent
High Resolution Computerized Tomography (HRCT) Measures of Quantitative Lung Fibrosis Score in the Whole Lung (QLF-WL)
percentPlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
High Resolution Computerized Tomography (HRCT) Measures of Quantitative Lung Fibrosis Score in the Whole Lung (QLF-WL)1.46 ± 0.994-0.11 ± 0.935
Statistical analysis
  • Placebo (Plac) + Mycophenolate (MMF) vs Pirfenidone (PFD) + Mycophenolate (MMF) · ANCOVA · p = 0.1701 · Mean difference (net): -1.58
Other pre-specifiedHigh 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.

Time frame:
Screening to 18 months
Reported as:
Least squares mean · percent
High Resolution Computerized Tomography (HRCT) Measures of Quantitative Lung Fibrosis Score in the Lobe of Maximal Involvement (QLF-LM)
percentPlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
High Resolution Computerized Tomography (HRCT) Measures of Quantitative Lung Fibrosis Score in the Lobe of Maximal Involvement (QLF-LM)2.57 ± 2.2760.13 ± 2.132
Statistical analysis
  • Placebo (Plac) + Mycophenolate (MMF) vs Pirfenidone (PFD) + Mycophenolate (MMF) · ANCOVA · p = 0.3515 · Mean difference (net): -2.44
Other pre-specifiedHigh 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.

Time frame:
Screening to 18 months
Reported as:
Least squares mean · percent
High Resolution Computerized Tomography (HRCT) Measures of Quantitative Interstitial Lung Disease Score in the Whole Lung (QILD-WL)
percentPlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
High Resolution Computerized Tomography (HRCT) Measures of Quantitative Interstitial Lung Disease Score in the Whole Lung (QILD-WL)2.36 ± 1.919-1.15 ± 1.829
Statistical analysis
  • Placebo (Plac) + Mycophenolate (MMF) vs Pirfenidone (PFD) + Mycophenolate (MMF) · ANCOVA · p = 0.1177 · Mean difference (net): -3.51
Other pre-specifiedHigh 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.

Time frame:
Screening to 18 months
Reported as:
Least squares mean · percent
High Resolution Computerized Tomography (HRCT) Measures of Quantitative Interstitial Lung Disease Score in the Lobe of Maximal Involvement (QILD-LM)
percentPlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
High Resolution Computerized Tomography (HRCT) Measures of Quantitative Interstitial Lung Disease Score in the Lobe of Maximal Involvement (QILD-LM)2.99 ± 2.634-0.99 ± 2.486
Statistical analysis
  • Placebo (Plac) + Mycophenolate (MMF) vs Pirfenidone (PFD) + Mycophenolate (MMF) · ANCOVA · p = 0.1931 · Mean difference (net): -3.98
Other pre-specifiedHigh 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.

Time frame:
Screening to 18 months
Reported as:
Least squares mean · ml
High Resolution Computerized Tomography (HRCT) Measures of Total Lung Capacity (TLC)
mlPlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
High Resolution Computerized Tomography (HRCT) Measures of Total Lung Capacity (TLC)70.69 ± 78.986191.99 ± 73.738
Statistical analysis
  • Placebo (Plac) + Mycophenolate (MMF) vs Pirfenidone (PFD) + Mycophenolate (MMF) · ANCOVA · p = 0.1811 · Mean difference (net): 121.30
Other pre-specified3.0% 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.

Time frame:
Baseline to 18 months
Reported as:
Median · months
3.0% or Greater Improvement From Baseline in FVC-%.
monthsPlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
3.0% or Greater Improvement From Baseline in FVC-%.17.8 (8.9 to NA)12.3 (3.6 to 18.3)
Statistical analysis
  • Placebo (Plac) + Mycophenolate (MMF) vs Pirfenidone (PFD) + Mycophenolate (MMF) · Stratified log rank · p = 0.3261 · Hazard ratio (hr): 1.433
Other pre-specifiedGreater 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.

Time frame:
Baseline to 18 months
Reported as:
Count of participants · Participants
Greater Than 5% Improvement in FVC-%
ParticipantsPlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
Greater Than 5% Improvement in FVC-%69
Statistical analysis
  • Placebo (Plac) + Mycophenolate (MMF) vs Pirfenidone (PFD) + Mycophenolate (MMF) · Regression, Logistic · p = 0.454 · Odds ratio (or): 1.6
Other pre-specifiedPercentage 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.

Time frame:
Baseline to 18 months
Reported as:
Count of participants · Participants
Percentage of Participants Achieving Specified Absolute Changes of FVC-%
ParticipantsPlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
≥ 10% to < 15%11
≥ 5% to < 10%58
> 0% to < 5%106
> -5% to ≤ 0%56
> -10% to ≤ -5%12
Other pre-specifiedPercentage 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.

Time frame:
Baseline to 18 months
Reported as:
Count of participants · Participants
Percentage of Participants Achieving Specified Absolute Changes of FVC-% Defined as Positive or Negative Responders
ParticipantsPlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
Positive responder (≥ 3%)811
Stable (> -3 to < 3)108
Negative responder (≤ -3%)44
Other pre-specifiedPercentage 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.

Time frame:
Baseline to 18 months
Reported as:
Count of participants · Participants
Percentage of Participants Achieving Specified Absolute Changes of FVC-% Defined as Any Responders or Any Non-responders
ParticipantsPlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
Responder (> 0%)1615
Non-responder (≤ 0%)68
Other pre-specifiedPercentage 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.

Time frame:
Baseline to 18 months
Reported as:
Count of participants · Participants
Percentage of Participants Achieving Specified Absolute Changes of mRSS
ParticipantsPlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
≤ -1326
-12 to -910
-8 to -544
-4 to -189
033
1 to 411
≥ 510
Other pre-specifiedPercentage 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.

Time frame:
Baseline to 18 months
Reported as:
Count of participants · Participants
Percentage of Participants Achieving Specified Absolute Changes of mRSS Defined as Improved, no Change and Decreased.
ParticipantsPlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
Worsening (change > 5)00
No Change (-5 ≤ change ≤ 5)1513
Improvement (change < -5)510
Other pre-specifiedPercentage 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.

Time frame:
18 months
Reported as:
Count of participants · Participants
Percentage of Participants Achieving Specified TDI Focal Score at 18 Months
ParticipantsPlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
7 to 900
4 to 611
1 to 345
088
-3 to -162
-6 to -435
-9 to -714
Other pre-specifiedPercentage 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.

Time frame:
18 months
Reported as:
Count of participants · Participants
Percentage of Participants Achieving Specified TDI Focal Score at 18 Months Defined as Improved, no Change or Deterioration
ParticipantsPlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
Worsening (change < 0)56
No Change (change = 0)88
Improvement (change > 0)1011
Other pre-specifiedTime 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.

Time frame:
Baseline to 18 months
Reported as:
Median · days
Time to Withdrawal From the Study Drug or Treatment Failure
daysPlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
Time to Withdrawal From the Study Drug or Treatment FailureNA (NA to NA)NA (NA to NA)
Other pre-specifiedNumber 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.

Time frame:
Baseline to 18 months
Reported as:
Count of participants · Participants
Number of Participants With Treatment-related Adverse Events as Assessed by System Organ Classification Using Preferred Medical Dictionary for Regulatory Activities (MedDRA) Terms.
ParticipantsPlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
Number of Participants With Treatment-related Adverse Events as Assessed by System Organ Classification Using Preferred Medical Dictionary for Regulatory Activities (MedDRA) Terms.2327

Adverse events

Collected over 1 year and 6 months. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Placebo (Plac) + Mycophenolate (MMF)0/24 (0%)2/24 (8.3%)23/24 (95.8%)
Pirfenidone (PFD) + Mycophenolate (MMF)0/27 (0%)4/27 (14.8%)27/27 (100%)
Most frequent serious events
Most frequent serious events
EventPlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
ColitisGastrointestinal disorders1/240/27
Covid-19 InfectionInfections and infestations1/240/27
Acute Chronic Hypoxemic Respiratory FailureRespiratory, thoracic and mediastinal disorders1/240/27
Right Sided Chest PainCardiac disorders0/241/27
Herpes Zoster OphthalmicusInfections and infestations0/241/27
Basal Cell Carcinoma, NodularNeoplasms benign, malignant and unspecified (incl cysts and polyps)0/241/27
Extra-nodal Marginal Zone B-cell Lymphoma of the Stomach and AntrumNeoplasms benign, malignant and unspecified (incl cysts and polyps)0/241/27
Scleroderma Renal CrisisRenal and urinary disorders0/241/27
DyspneaRespiratory, thoracic and mediastinal disorders0/241/27
Most frequent other events
Showing 10 of 48
Most frequent other events
EventPlacebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)
NauseaGastrointestinal disorders7/2422/27
DiarrheaGastrointestinal disorders10/2412/27
Vomiting (Emesis)Gastrointestinal disorders4/2411/27
FatigueGeneral disorders5/248/27
CoughRespiratory, thoracic and mediastinal disorders5/247/27
HeadacheGeneral disorders5/246/27
Abdominal PainGastrointestinal disorders5/244/27
BronchitisRespiratory, thoracic and mediastinal disorders5/240/27
DizzinessGeneral disorders1/245/27
Dry EyesEye disorders4/240/27

Baseline characteristics

Safety population includes all the randomized participants who received at least one dose of study medication.

Age, Continuous
Age, Continuous(years)Placebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)Total
Mean52.6 ± 1056.6 ± 9.954.7 ± 10.1
Sex: Female, Male
Sex: Female, Male(Participants)Placebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)Total
Female171936
Male7815
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Placebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)Total
American Indian or Alaska Native000
Asian112
Native Hawaiian or Other Pacific Islander000
Black or African American235
White192241
More than one race000
Unknown or Not Reported213
Region of Enrollment
Region of Enrollment(participants)Placebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)Total
United States242751
Scleroderma Classification
Scleroderma Classification(Participants)Placebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)Total
Sine336
Limited131124
Diffuse81321
Disease Duration
Disease Duration(months)Placebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)Total
Mean32.9 ± 24.228.9 ± 25.430.8 ± 24.7
Percent predicted forced vital capacity (FVC-%)
Percent predicted forced vital capacity (FVC-%)(percent predicted)Placebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)Total
Mean71.5 ± 9.970.6 ± 11.071.0 ± 10.4
Forced Vital Capacity volume (FVC)
Forced Vital Capacity volume (FVC)(ml)Placebo (Plac) + Mycophenolate (MMF)Pirfenidone (PFD) + Mycophenolate (MMF)Total
Mean2705 ± 5402610 ± 7812655 ± 674

9 further baseline measures are reported on the registry.

07

Study locations

16 sites
  • University of California Los Angeles
    Los Angeles, California 90095, United States
  • University of Colorado
    Aurora, Colorado 80045, United States
  • Georgetown University
    Washington, District of Columbia 20007, United States
  • Northwestern University
    Chicago, Illinois 60611, United States
  • Indiana University Health
    Indianapolis, Indiana 46202, United States
  • Johns Hopkins University
    Baltimore, Maryland 21224, United States
  • Harvard Medical School, Brigham & Women's Hospital
    Boston, Massachusetts 02115, United States
  • Boston University, School of Medicine
    Boston, Massachusetts 02118, United States
  • University of Michigan
    Ann Arbor, Michigan 48109, United States
  • Rutgers University
    New Brunswick, New Jersey 08901, United States
  • Hospital for Special Surgery
    New York, New York 10021, United States
  • University of Pittsburgh
    Pittsburgh, Pennsylvania 15261, United States
  • Medical University of South Carolina
    Charleston, South Carolina 29425, United States
  • University of Texas Medical School at Houston
    Houston, Texas 77030, United States
  • University of Utah
    Salt Lake City, Utah 84108, United States
  • University of Washington Medical Center
    Seattle, Washington 98195, United States
08

References and documents

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. PubMed 27469583 ↗
  • 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. PubMed 28012804 ↗
  • 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. PubMed 28376288 ↗
  • 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. PubMed 28544580 ↗
  • 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. PubMed 27370878 ↗
  • 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. PubMed 24836312 ↗
  • 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. PubMed 33287583 ↗

Study documents

  • Protocol and informed consent form · Nov 17, 2021
  • Statistical analysis plan · May 24, 2022

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — 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.

09

Registry details

Key details

Study ID
NCT03221257
Lead sponsor
Michael Roth
Collaborators
University of Michigan, Genentech, Inc., University of California, Los Angeles
Responsible party
Michael Roth (Professor of Pulmonary and Critical Care Medicine, University of California, Los Angeles) — Sponsor-investigator
First posted
Jul 18, 2017
Start date
Nov 28, 2017
Primary completion
Mar 23, 2022
Completion
Jun 13, 2022
Results posted
Dec 15, 2023
Last update
Dec 15, 2023

Study contacts

Michael D Roth, MD
principal investigator · Pulmonary & Critical Care Medicine, Geffen School of Medicine at UCLA

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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