Clinical trial NCT00677092: Pilot Study of Imatinib Mesylate to Treat Nephrogenic Systemic Fibrosis
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Nephrogenic Systemic Fibrosis
Keywords: Treatment
Chronic kidney disease
Fibrosing disorders
Imatinib mesylate
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: Novartis Pharmaceuticals
First posted: 2008-05-13
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Percentage Change From Baseline in the Modified Rodnan Skin Score (mRSS) to Assess Skin Tethering
timeFrame: Baseline and Month 4
Secondary outcomes:
measure: Change From Baseline in Maximal Extension of Elbows and Knees
timeFrame: Baseline and Month 4
measure: Change From Baseline in Histologic Appearance of Skin Biopsy
timeFrame: Baseline and Month 4
measure: Change From Baseline in Visual Analog Scale (VAS) for Pain
timeFrame: Baseline and Month 4
measure: Change From Baseline in Health Assessment Questionnaire (HAQ) Score
timeFrame: Baseline and Month 4
measure: Change From Baseline in Short Form 36 (SF-36) Score
timeFrame: Baseline and Month 4
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
Study officials:
affiliation: Massachusetts General Hospital
name: Jonathan Kay, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Kay J, High WA. Imatinib mesylate treatment of nephrogenic systemic fibrosis. Arthritis Rheum. 2008 Aug;58(8):2543-8. doi: 10.1002/art.23696.
citation: 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.
citation: 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.
citation: Todd DJ, Kay J. Gadolinium-Induced Fibrosis. Annu Rev Med. 2016;67:273-91. doi: 10.1146/annurev-med-063014-124936.