Principal Investigator: Mary  Scholand
Keywords: scleroderma , ILD , interstitial lung disease , systemic sclerosis , systemic sclerosis ILD Department: Pulmonary
IRB Number: 00099219
Specialty: Pulmonary, Pulmonary, Rheumatology
Sub Specialties: Pulmonary Fibrosis, General Pulmonary,
Recruitment Status: Recruiting

Contact Information

Cassie Larsen
cassie.larsen@hsc.utah.edu
8015815811

Brief Summary

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.
A secondary objective is to demonstrate that combination therapy
with PFD and MMF is well tolerated, in comparison to MMF alone, and
not associated with limiting toxicity that impacts on the overall
treatment effect.

Inclusion Criteria

Screening criteria that must be met prior to moving forward to HRCT imaging
5.1.1 Age >18 yrs
5.1.2 Scleroderma as determined by the 2013 ACR/EULAR classification criteria.
5.1.3 Grade ≥2 on the Magnitude of Task component of the Mahler Modified Dyspnea Index
(Becomes short of breath with moderate or average tasks such as walking up a gradual hill,
climbing less than three flights of stairs, or carrying a light load on the level.
5.1.4 FVC-% of  ≤85% at screening 
5.1.5 Onset of the first non-Raynaud manifestation of SSc within the prior 84 months.
• This criteria is based on the natural history SSc-ILD which is known to be more
progressive early after the onset of scleroderma and become less active over time.
Screening HRCT imaging
5.1.6 Presence of any ground glass opacification (any GGO) on thoracic HRCT
• This criteria defines a population with active and measurable parenchymal lung
involvement.

Final screening criteria fulfilled at Baseline Visit, but prior to randomization
5.1.7 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

5.2.1 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).
5.2.2 FVC-% <45% at either screening or baseline.
• to avoid severe, probably irreparable disease associated with higher morbidity
5.2.3 FEV1/FVC ratio <0.65 at either screening or baseline.
• to avoid concurrent and clinically-significant obstructive lung disease which can increase
the risk for infection, need for corticosteroid therapy, and interferes with use of
spirometry as outcome measure
5.2.4 DLCOHb-% of <30% at screening or <25% at baseline.
5.2.5 Diagnosis of clinically significant resting pulmonary hypertension 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.
• to avoid concurrent scleroderma-related pulmonary vascular disease that could alter
primary and secondary outcome measures in a manner independent of the effect of the
investigational drugs.

• The presence of mild pulmonary hypertension, identified as either an estimated right ventricular systolic pressure of </=40 mmHg on echocardiogram or mean systolic pulmonary artery pressure of </=30 mmhg on right heart catheterization is acceptable for inclusion in the study if there are no signs of right heart dysfunction and treatment includes no more than one oral PAH medication.

5.2.6 Evidence of uncontrolled congestive heart failure, unstable ischemic heart disease, history
of complicated pulmonary embolism impacting on heart of lung function, or unstable cardiac arrhythmia requiring chronic anticoagulation.
• to avoid undiagnosed scleroderma cardiomyopathy and unstable patients whose
concurrent disease might impact on the measured study outcomes.
5.2.7 Clinically significant abnormalities on HRCT not attributable to SSc
• e.g., lung mass, cavitary lesion, airspace consolidation, mediastinal adenopathy, etc. 

5.2.8 Hematologic abnormality at screening including:
a) Leukopenia (white blood cells [WBC] <4.0x103/μl)
b) Thrombocytopenia (platelet count <120.0x103/μl)
c) 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.
• to avoid persistent bone marrow abnormalities or bleeding that would complicate
detection and treatment of a primary side effect of MMF therapy.
5.2.9 A diagnosis of chronic liver disease or abnormal baseline liver function test (LFTs) or total
bilirubin that are >2.0 x upper normal limit.
5.2.10 Serum creatinine >2.0mg/dl
5.2.11 History of recurrent aspiration, uncontrolled heartburn, or gastroesophageal reflux disease
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.
• both medications can exhibit significant GI toxicity and it would be inappropriate to
include patients already exhibiting clinically significant and uncontrolled GI symptoms.
5.2.12 Known achalasia, esophageal stricture or esophageal dysfunction sufficient to limit the
ability to swallow medication.
• this trial reguires that patients take a large number of capsules at frequent intervals
throughout the day and these conditions represent significant obstacles to compliance.
5.2.13 Pregnancy (documented by urine serum pregnancy test) and/or breast feeding
5.2.14 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.
5.2.15 Prior use of potential disease modifying antirheumatic drugs (DMARDs) according to the following exposure rules:
a) Use of oral cyclophosphamide (CYC), MMF, azathioprine or other oral or short half-life DMARDs (as detailed in Section 7.5.1a) for more than  6 months in the past year, as determined at the time of the initial screening visit.
b) Treatment with more than three intravenous doses of CYC, more than one course of Rituximab or other intravenous or injectable DMARDs (as detailed in Section 7.5.1b) in the past year.

c) More distant h/o 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.
5.2.16 Use of CYC, MMF, azathioprine, Rituximab or other DMARD (as detailed in Section 7.5.1a-&b) in the 30 days prior to the 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.
5.2.17 Active infection (lung, ulcers or elsewhere) whose management would be compromised by
immunosuppression.
5.2.18 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.
5.2.19 Current use, or use within the 30 days prior to their baseline visit, of prednisone (or
equivalent) in doses >10 mg/day.
• to avoid increased drug toxicity due to combined immunosuppression.
• subjects who meet all other criteria, but have been on higher doses of prednisone, will
be allowed to decrease their prednisone (or equivalent) dose and proceed to the
baseline visit at the completion of the 30-day washout.
5.2.20 Smoking of cigars, pipes, or cigarettes during the past 6 months.
• to avoid the increased risk of pulmonary complications and variation in lung function that
would be independent from the primary study objectives.
5.2.21 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
Section 7.5 for complete list.