Scleroderma Lung Study III - Combining Pirfenidone With Mycophenolate
Condition: Scleroderma, Systemic; Interstitial Lung Disease
MeSH terms: Lung Diseases; Lung Diseases, Interstitial; Scleroderma, Systemic; Scleroderma, Diffuse; Scleroderma, Localized
Intervention: Pirfenidone (PFD); Placebo (Plac); Mycophenolate Mofetil (MMF)
Intervention description: 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).; 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).; 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).
Intervention MeSH terms: Mycophenolic Acid; Pirfenidone
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 51.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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).
    

Eligibility 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 high-resolution computed
             tomography (HRCT)

          7. Repeat FVC-% at the baseline visit within 10% of the FVC-% value measured at
             screening. If these criteria are not met, a repeat FVC-% may be obtained within 7 days
             and the subject may qualify for randomization if the repeat FVC-% agrees within 10% of
             the FVC-% obtained at screening.

        Exclusion Criteria:

          1. Disease features supporting the primary diagnosis of another connective tissue disease
             such as rheumatoid arthritis, systemic lupus erythematosus or mixed connective tissue
             disease (Features consistent with a secondary Sjogren syndrome or
             scleroderma-associated myopathy will be allowed).

          2. FVC-% of <45% at either screening or baseline.

          3. Forced Expiratory Volume in the first second (FEV1)/Forced Vital Capacity (FVC) ratio
             <0.65 at either screening or baseline.

          4. Diffusing capacity of the lung for carbon monoxide adjusted for hemoglobin, expressed
             as a percentage of the normal predicted value (DLCOHb-%) of <30% at screening or <25%
             at baseline.

             a) All participants with a DLCOHb-% between 30 to 40% must have pulmonary artery
             pressures documented by either echocardiogram, right heart catheterization or magnetic
             resonance imaging in order to be considered for inclusion.

          5. Diagnosis of clinically significant resting pulmonary hypertension requiring treatment
             or mild pulmonary hypertension requiring treatment with more than one oral medication
             as ascertained prior to study evaluation or as part of a standard of care clinical
             assessment performed outside of the study protocol.

          6. Evidence of uncontrolled congestive heart failure, unstable ischemic heart disease,
             history of complicated pulmonary embolism impacting on heart or lung function, or
             unstable cardiac arrhythmia requiring chronic anticoagulation.

          7. Clinically significant abnormalities on HRCT not attributable to SSc

          8. Hematologic abnormality at screening including:

               1. Leukopenia (white blood cells [WBC] <4.0x10^3/µl).

               2. Thrombocytopenia (platelet count <120.0x10^3/µl).

               3. Clinically significant anemia [Hemoglobin (Hgb) <10.0 g/dl].

             Participants with an identified and correctable etiology may be eligible if repeat
             testing within the maximal 90-day screening period meets all criteria.

          9. A diagnosis of chronic liver disease or abnormal baseline liver function test (LFTs)
             or total bilirubin that are >2.0 x upper normal limit

         10. Serum creatinine >2.0mg/dl

         11. History of recurrent aspiration, uncontrolled heartburn, or gastroesophageal reflux
             disease (GERD) with a reflux scale score of >1.00 as determined by a UCLA Scleroderma
             Clinical Trial Consortium Gastrointestinal Scale (UCLA SCTC GIT), Version 2.0.

             Participants with uncontrolled heartburn or GERD that is amenable to medical
             management may be eligible if repeat testing within the maximal 90-day screening
             period meets this criteria.

         12. Known achalasia, esophageal stricture or esophageal dysfunction sufficient to limit
             the ability to swallow medication.

         13. Pregnancy (as documented by blood test) and/or breast feeding

         14. If of child bearing potential (a female participant < 55 years of age who has not been
             postmenopausal for ≥ 5 years or who has not had a bilateral salpingectomy,
             hysterectomy and/or oophorectomy), failure to employ two reliable means of
             contraception which may include surgical sterilization, barrier methods, spermicides,
             intrauterine devices, and/or hormonal contraception, unless the participant chooses
             abstinence (to avoid heterosexual intercourse completely). If a subject chooses
             abstinence, then a second reliable means of contraception is not needed.

         15. Prior use of potential disease modifying antirheumatic drugs (DMARDs) according to the
             following exposure rules:

               1. Use of oral cyclophosphamide (CYC), MMF, azathioprine or other oral or short
                  half-life DMARDs (as detailed in Protocol Section 7.5.1a) for more than 6 months
                  in the past year as determined at the time of the initial screening visit.

               2. Treatment with more than three intravenous doses of CYC, one treatment course of
                  Rituximab or other intravenous or injectable DMARDs (as detailed in Protocol
                  Section 7.5.1b) in the past year.

               3. More distant history of treatment with a DMARD is allowed as long as the patient
                  has a new diagnosis/new episode of active SSc-ILD since stopping that treatment
                  and meets the criteria noted in 15a or 15b.

         16. Use of CYC, MMF, azathioprine, Rituximab or other DMARD (as defined in Protocol
             Section 7.5.1a&b) in the 30 days prior to their baseline visit unless the patient is
             on MMF and the responsible physician indicates that continued use is in the best
             clinical interest of the patient.

         17. Active infection (lung, ulcers or elsewhere) whose management would be compromised by
             immunosuppression.

         18. Other serious concomitant medical illness (e.g., active malignancy within the past 5
             years other than surgically-removed local skin cancer such as a basal cell carcinoma),
             chronic debilitating illness (other than SSc), unreliability or drug abuse that might
             compromise the patient's participation in the trial.

         19. Current use, or use within the 30 days prior to their baseline visit, of prednisone
             (or equivalent) in doses >10 mg/day.

         20. Smoking of cigars, pipes, or cigarettes during the past 6 months.

         21. Use of contraindicated medications, including medications with putative
             disease-modifying properties that do not meet the exposure limits described in
             Exclusion Criteria #15 and #16, moderate or strong inhibitors of cytochrome P450 (CYP)
             isozyme 1A2 (CYP1A2) (note ciprofloxacin allowed up to a dose of 500 mg twice daily),
             and moderate inducers of CYP1A2 (such as tobacco smoke or phenytoin). See Protocol
             Section 7.5 for complete list.