Scleroderma Lung Study III - Combining Pirfenidone With Mycophenolate

NCT03221257 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: UCLA-SLS3
• Study Type: interventional
• Target: 51
• Locations: 1 country
• Sites: 16

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).

Conditions

Scleroderma, Systemic; Interstitial Lung Disease

Outcome Measures

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-%).

  Baseline to 18 months

Other Outcomes (22)

• Percent Predicted Single-breath Diffusing Capacity for Carbon Monoxide (DLCOHb-%)

  Baseline to 18 months

• Modified Rodnan Skin Score (mRSS)

  Baseline to 18 months

• Forced Vital Capacity Volume (FVC, in ml)

  Baseline to 18 months

Study Arms (2)

Placebo (Plac) + Mycophenolate (MMF)

PLACEBO COMPARATOR

Participants will receive Placebo (Plac) as add-on to a background therapy of Mycophenolate Mofetil (MMF).

Drug: Placebo (Plac); Drug: Mycophenolate Mofetil (MMF)

Pirfenidone (PFD) + Mycophenolate (MMF)

EXPERIMENTAL

Participants will receive Pirfenidone (PFD) as add-on to a background therapy of Mycophenolate Mofetil (MMF).

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

Interventions

Pirfenidone (PFD) DRUG

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

Pirfenidone (PFD) + Mycophenolate (MMF)

Placebo (Plac) DRUG

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

Placebo (Plac) + Mycophenolate (MMF)

Mycophenolate Mofetil (MMF) DRUG

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

Pirfenidone (PFD) + Mycophenolate (MMF); Placebo (Plac) + Mycophenolate (MMF)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥18 yrs
• Scleroderma as determined by the 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria.
• Grade ≥2 on the Magnitude of Task component of the Mahler Modified Dyspnea Index
• FVC-% of ≤85% at screening
• Onset of the first non-Raynaud manifestation of SSc within the prior 84 months.
• Presence of any ground-glass opacification (GGO) on thoracic high-resolution computed tomography (HRCT)
• 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.

You may not qualify if:

• 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).
• FVC-% of \<45% at either screening or baseline.
• Forced Expiratory Volume in the first second (FEV1)/Forced Vital Capacity (FVC) ratio \<0.65 at either screening or baseline.
• 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.
• 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.
• 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.
• Clinically significant abnormalities on HRCT not attributable to SSc
• Hematologic abnormality at screening including:
• Leukopenia (white blood cells \[WBC\] \<4.0x10\^3/µl).
• Thrombocytopenia (platelet count \<120.0x10\^3/µl).
• 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.
• A diagnosis of chronic liver disease or abnormal baseline liver function test (LFTs) or total bilirubin that are \>2.0 x upper normal limit
• Serum creatinine \>2.0mg/dl
• 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.

Sponsors & Collaborators

• Michael Roth: lead
• University of Michigan: collaborator
• Genentech, Inc.: collaborator
• University of California, Los Angeles: collaborator

Study Sites (16)

University of California Los Angeles

Los Angeles, California, 90095, United States

Location

University of Colorado

Aurora, Colorado, 80045, United States

Location

Georgetown University

Washington D.C., District of Columbia, 20007, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Indiana University Health

Indianapolis, Indiana, 46202, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21224, United States

Location

Harvard Medical School, Brigham & Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Boston University, School of Medicine

Boston, Massachusetts, 02118, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Rutgers University

New Brunswick, New Jersey, 08901, United States

Location

Hospital for Special Surgery

New York, New York, 10021, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15261, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

University of Texas Medical School at Houston

Houston, Texas, 77030, United States

Location

University of Utah

Salt Lake City, Utah, 84108, United States

Location

University of Washington Medical Center

Seattle, Washington, 98195, United States

Location

Related Publications (7)

• 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.

  PMID: 27469583 BACKGROUND

• 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.

  PMID: 28012804 BACKGROUND

• 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.

  PMID: 28376288 BACKGROUND

• 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.

  PMID: 28544580 BACKGROUND

• 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.

  PMID: 27370878 BACKGROUND

• 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.

  PMID: 24836312 BACKGROUND

• 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.

  PMID: 33287583 DERIVED

MeSH Terms

Conditions

Scleroderma, Systemic; Lung Diseases, Interstitial

Interventions

pirfenidone; 5'-palmitoyl cytarabine; Mycophenolic Acid; Drugs, Generic

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Skin Diseases; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids; Pharmaceutical Preparations

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.

Results Point of Contact

• Title: Dr. Michael D. Roth
• Organization: University of California, Los Angeles

mroth@mednet.ucla.edu

3102067389

Study Officials

• Michael D Roth, MD

  Pulmonary & Critical Care Medicine, Geffen School of Medicine at UCLA

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Pulmonary and Critical Care Medicine

Study Record Dates

• First Submitted: July 12, 2017
• First Posted: July 18, 2017
• Study Start: November 28, 2017
• Primary Completion: March 23, 2022
• Study Completion: June 13, 2022
• Last Updated: December 15, 2023
• Results First Posted: December 15, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will share
• 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.

Locations

US (16)