Clinical trial NCT03221257: Scleroderma Lung Study III - Combining Pirfenidone With Mycophenolate
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Scleroderma, Systemic
Interstitial Lung Disease
Lead sponsor: University of California, Los Angeles
Sponsor class: OTHER
Collaborators: name: University of Michigan
name: Genentech, Inc.
name: University of California, Los Angeles
First posted: 2017-07-18
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Percent Predicted Forced Vital Capacity (FVC-%)
timeFrame: Baseline to 18 months
Secondary outcomes:
Other outcomes:
measure: Percent Predicted Single-breath Diffusing Capacity for Carbon Monoxide (DLCOHb-%)
timeFrame: Baseline to 18 months
measure: Modified Rodnan Skin Score (mRSS)
timeFrame: Baseline to 18 months
measure: Forced Vital Capacity Volume (FVC, in ml)
timeFrame: Baseline to 18 months
measure: Mahler Modified Transitional Dyspnea Index (TDI)
timeFrame: Baseline to 18 months
measure: Health Assessment Questionnaire Modified for Scleroderma (HAQ-DI)
timeFrame: Baseline to 18 months
measure: St. George's Respiratory Questionnaire (SGRQ)
timeFrame: Baseline to 18 months
measure: High Resolution Computerized Tomography (HRCT) Measures of Quantitative Lung Fibrosis Score in the Whole Lung (QLF-WL)
timeFrame: Screening to 18 months
measure: High Resolution Computerized Tomography (HRCT) Measures of Quantitative Lung Fibrosis Score in the Lobe of Maximal Involvement (QLF-LM)
timeFrame: Screening to 18 months
measure: High Resolution Computerized Tomography (HRCT) Measures of Quantitative Interstitial Lung Disease Score in the Whole Lung (QILD-WL)
timeFrame: Screening to 18 months
measure: High Resolution Computerized Tomography (HRCT) Measures of Quantitative Interstitial Lung Disease Score in the Lobe of Maximal Involvement (QILD-LM)
timeFrame: Screening to 18 months
measure: High Resolution Computerized Tomography (HRCT) Measures of Total Lung Capacity (TLC)
timeFrame: Screening to 18 months
measure: 3.0% or Greater Improvement From Baseline in FVC-%.
timeFrame: Baseline to 18 months
measure: Greater Than 5% Improvement in FVC-%
timeFrame: Baseline to 18 months
measure: Percentage of Participants Achieving Specified Absolute Changes of FVC-%
timeFrame: Baseline to 18 months
measure: Percentage of Participants Achieving Specified Absolute Changes of FVC-% Defined as Positive or Negative Responders
timeFrame: Baseline to 18 months
measure: Percentage of Participants Achieving Specified Absolute Changes of FVC-% Defined as Any Responders or Any Non-responders
timeFrame: Baseline to 18 months
measure: Percentage of Participants Achieving Specified Absolute Changes of mRSS
timeFrame: Baseline to 18 months
measure: Percentage of Participants Achieving Specified Absolute Changes of mRSS Defined as Improved, no Change and Decreased.
timeFrame: Baseline to 18 months
measure: Percentage of Participants Achieving Specified TDI Focal Score at 18 Months
timeFrame: 18 months
measure: Percentage of Participants Achieving Specified TDI Focal Score at 18 Months Defined as Improved, no Change or Deterioration
timeFrame: 18 months
measure: Time to Withdrawal From the Study Drug or Treatment Failure
timeFrame: Baseline to 18 months
measure: Number of Participants With Treatment-related Adverse Events as Assessed by System Organ Classification Using Preferred Medical Dictionary for Regulatory Activities (MedDRA) Terms.
timeFrame: Baseline to 18 months
Locations:
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Health
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Harvard Medical School, Brigham & Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston University, School of Medicine
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: New Brunswick
country: United States
facility: Rutgers University
state: New Jersey
city: New York
country: United States
facility: Hospital for Special Surgery
state: New York
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Houston
country: United States
facility: University of Texas Medical School at Houston
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
Study officials:
affiliation: Pulmonary & Critical Care Medicine, Geffen School of Medicine at UCLA
name: Michael D Roth, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.