Pilot Study of Imatinib Mesylate to Treat Nephrogenic Systemic Fibrosis

Nephrogenic Systemic Fibrosis Clinical Trial

— GENESYF  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00677092
• Other study ID #: 2007-P-001945
• Status: Active, not recruiting
• Phase: Phase 2
• First received: May 8, 2008
• Last updated: March 25, 2009
• Start date: May 2008
• Est. completion date: July 2009

Study information

• Verified date: March 2009
• Source: Massachusetts General Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

• To determine the efficacy of imatinib mesylate in reducing cutaneous thickening and tethering in patients with nephrogenic systemic fibrosis (NSF).

• To assess the safety and tolerability of imatinib mesylate in patients with chronic kidney disease and NSF.

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 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 TGF-beta1 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 mg p.o. daily for 1 year in two patients 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 patients had a 20 degree reduction of his knee flexion contractures.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 12
• Est. completion date: July 2009
• Est. primary completion date: July 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

• AST/ALT >3 x upper limit of normal

• Severe congestive heart failure (NYHA Class III or IV)

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Fibrosis
• Nephrogenic Fibrosing Dermopathy
• Nephrogenic Systemic Fibrosis

Intervention

Drug:
• Imatinib mesylate
400 mg p.o. daily for four months

Locations

Country	Name	City	State
United States	Massachusetts General Hospital	Boston	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Massachusetts General Hospital	Novartis Pharmaceuticals

Country where clinical trial is conducted

United States, 

References & Publications (5)

Kay J, Bazari H, Avery LL, Koreishi AF. Case records of the Massachusetts General Hospital. Case 6-2008. A 46-year-old woman with renal failure and stiffness of the joints and skin. N Engl J Med. 2008 Feb 21;358(8):827-38. doi: 10.1056/NEJMcpc0708697. — View 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. — View Citation

Kay J. Gadolinium and nephrogenic systemic fibrosis: the evidence of things not seen. Cleve Clin J Med. 2008 Feb;75(2):112, 114, 117. Review. — View Citation

Kay J. Nephrogenic systemic fibrosis: a gadolinium-associated fibrosing disorder in patients with renal dysfunction. Ann Rheum Dis. 2008 Dec;67 Suppl 3:iii66-9. doi: 10.1136/ard.2008.102475. Review. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in modified Rodnan skin score (mRSS) to assess skin tethering		4 months	No
Secondary	Change in maximal extension of elbows and knees		4 months	No
Secondary	Change in histologic appearance of skin biopsy		4 months	No
Secondary	Change in visual analog scale (VAS) for pain		4 months	No
Secondary	Change in health assessment questionnaire (HAQ) score		4 months	No
Secondary	Change in SF-36 score		4 months	No