Pilot Study of Imatinib Mesylate to Treat Nephrogenic Systemic Fibrosis (GENESYF)

An Open Label Phase 2 Pilot Study to Determine the Safety, Efficacy and Tolerability of Gleevec (Imatinib Mesylate) in the Treatment of Nephrogenic Systemic Fibrosis

The purpose of this study is to determine the efficacy of imatinib mesylate in reducing cutaneous thickening and tethering in patients with nephrogenic systemic fibrosis (NSF). The study will also work to assess the safety and tolerability of imatinib mesylate in patients with chronic kidney disease and NSF.

Study Overview

• Status: Completed
• Conditions: Nephrogenic Systemic Fibrosis
• Intervention / Treatment: Drug: Imatinib mesylate

Detailed Description

Nephrogenic systemic fibrosis (NSF) is a recently described, extremely debilitating and painful condition that affects individuals with renal failure. Recent reports suggest an association between gadolinium exposure during magnetic resonance (MR) studies and the subsequent development of NSF in patients with chronic renal failure. NSF is characterized by rapidly progressive skin hardening, tethering and hyperpigmentation, predominantly on the extremities. Visceral involvement is rare. Skin biopsies of early NSF lesions demonstrate thickened collagen bundles, mucin deposition, angiogenesis and numerous dermal spindle cells that stain with antibodies to cluster of differentiation 34 (CD34) and procollagen. Cutaneous changes of NSF are present in up to 13% of individuals receiving hemodialysis. Among those patients with clinical evidence of NSF, the principle investigator of this protocol has recently reported that NSF is associated with increased early mortality at 24-months.

There is no proven therapy for this devastating disorder. Anecdotal reports have shown modest improvement in joint mobility and decreased skin thickening with extracorporeal photopheresis and pentoxyphylline.

Increased transforming growth factor (TGF)-beta1 messenger ribonucleic acid (mRNA) on immunostaining has been observed in skin, fascia and striated muscle. Imatinib mesylate, a tyrosine kinase inhibitor, prevents TGF-beta-induced stimulation of collagen and extracellular matrix protein synthesis as well as mRNA expression by normal fibroblasts. This observation led the principal investigator to evaluate imatinib mesylate 400 milligrams (mg) orally (p.o.) daily for 1 year in two participants with NSF. The result was significant softening of previously hardened skin with increased mobility of skin that previously had been tethered to the underlying fascia. After one month of imatinib mesylate, one of the two participants had a 20 degree reduction of his knee flexion contractures.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age > 18 years
• Biopsy-proven NSF
• Ability to give consent

Exclusion Criteria:

• Known sensitivity to imatinib mesylate or to any of its components
• Pregnant or lactating woman
• Bullous dermatologic disease
• Aspartate aminotransferase / alanine aminotransferase (AST/ALT) >3 x upper limit of normal
• Severe congestive heart failure [New York Heart Association (NYHA) Class III or IV]
• Patients who have received Gleevec in the past 12 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Imatinib Mesylate (IM) Treatment; Imatinib mesylate 400 milligrams (mg) orally once daily for 4 months. Dosage was reduced to 200 mg if the participant developed gastrointestinal intolerance or alopecia.	Drug: Imatinib mesylate; 400 mg p.o. daily for 4 months. Dosage was reduced to 200 mg if participants develop gastrointestinal intolerance or alopecia.; Other Names: Gleevec

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change From Baseline in the Modified Rodnan Skin Score (mRSS) to Assess Skin Tethering	The modified Rodnan Skin Score is the accepted clinical measure of scleroderma skin activity. The investigator assessed the thickening of the skin using the modified Rodnan Skin Score through simple palpation on 17 different skin sites in the fingers, hands, forearms, arms, feet, legs, and thighs (bilaterally) and face, chest, and abdomen (singly). Skin thickness was assessed on a scale of 0 to 3; 0 representing normal skin and 3 being severe thickening. The sum of the individual scores can range from 0 (normal) to 51 (severe thickening in all 17 areas). Percentage change is calculated as the Month 4 Score - Baseline Score/Baseline Score * 100. A negative percentage change indicates improvement.	Baseline and Month 4

Secondary Outcome Measures

Outcome Measure	Time Frame
Change From Baseline in Maximal Extension of Elbows and Knees	Baseline and Month 4
Change From Baseline in Histologic Appearance of Skin Biopsy	Baseline and Month 4
Change From Baseline in Visual Analog Scale (VAS) for Pain	Baseline and Month 4
Change From Baseline in Health Assessment Questionnaire (HAQ) Score	Baseline and Month 4
Change From Baseline in Short Form 36 (SF-36) Score	Baseline and Month 4

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: Novartis Pharmaceuticals
• Investigators: Principal Investigator: Jonathan Kay, MD, Massachusetts General Hospital

Publications and helpful links

General Publications

• Todd DJ, Kagan A, Chibnik LB, Kay J. Cutaneous changes of nephrogenic systemic fibrosis: predictor of early mortality and association with gadolinium exposure. Arthritis Rheum. 2007 Oct;56(10):3433-41. doi: 10.1002/art.22925.
• Kay J, High WA. Imatinib mesylate treatment of nephrogenic systemic fibrosis. Arthritis Rheum. 2008 Aug;58(8):2543-8. doi: 10.1002/art.23696.
• Kay J, Czirjak L. Gadolinium and systemic fibrosis: guilt by association. Ann Rheum Dis. 2010 Nov;69(11):1895-7. doi: 10.1136/ard.2010.134791. No abstract available.
• Schmidt-Lauber C, Bossaller L, Abujudeh HH, Vladimer GI, Christ A, Fitzgerald KA, Latz E, Gravallese EM, Marshak-Rothstein A, Kay J. Gadolinium-based compounds induce NLRP3-dependent IL-1beta production and peritoneal inflammation. Ann Rheum Dis. 2015 Nov;74(11):2062-9. doi: 10.1136/annrheumdis-2013-204900. Epub 2014 Jun 9.
• Todd DJ, Kay J. Gadolinium-Induced Fibrosis. Annu Rev Med. 2016;67:273-91. doi: 10.1146/annurev-med-063014-124936.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2007
• Primary Completion (Actual): July 1, 2009
• Study Completion (Actual): July 1, 2009

Study Registration Dates

• First Submitted: May 8, 2008
• First Submitted That Met QC Criteria: May 12, 2008
• First Posted (Estimate): May 13, 2008

Study Record Updates

• Last Update Posted (Actual): May 19, 2017
• Last Update Submitted That Met QC Criteria: April 10, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: Treatment; Chronic kidney disease; Imatinib mesylate; Fibrosing disorders
• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Fibrosis; Nephrogenic Fibrosing Dermopathy; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Imatinib Mesylate
• Other Study ID Numbers: 2007-P-001945

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No