Pilot Study of Imatinib Mesylate to Treat Nephrogenic Systemic Fibrosis

Phase 2

Completed

Conditions: Nephrogenic Systemic Fibrosis

Interventions: Drug: Imatinib mesylate

Registration Number: NCT00677092

Lead Sponsor: Massachusetts General Hospital

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 12

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Imatinib Mesylate (IM) Treatment	Imatinib mesylate	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.

Primary Outcome Measures

Name	Time	Method
Percentage Change From Baseline in the Modified Rodnan Skin Score (mRSS) to Assess Skin Tethering	Baseline and Month 4	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.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Maximal Extension of Elbows and Knees	Baseline and Month 4
Change From Baseline in Visual Analog Scale (VAS) for Pain	Baseline and Month 4
Change From Baseline in Histologic Appearance of Skin Biopsy	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