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

This study has been completed.
Sponsor:
Collaborator:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Jonathan Kay, MD, Massachusetts General Hospital
ClinicalTrials.gov Identifier:
NCT00677092
First received: May 8, 2008
Last updated: April 10, 2017
Last verified: April 2017
  Purpose
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.

Condition Intervention Phase
Nephrogenic Systemic Fibrosis Drug: Imatinib mesylate Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Jonathan Kay, MD, Massachusetts General Hospital:

Primary Outcome Measures:
  • Percentage Change From Baseline in the Modified Rodnan Skin Score (mRSS) to Assess Skin Tethering [ Time Frame: 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:
  • Change From Baseline in Maximal Extension of Elbows and Knees [ Time Frame: Baseline and Month 4 ]
  • Change From Baseline in Histologic Appearance of Skin Biopsy [ Time Frame: Baseline and Month 4 ]
  • Change From Baseline in Visual Analog Scale (VAS) for Pain [ Time Frame: Baseline and Month 4 ]
  • Change From Baseline in Health Assessment Questionnaire (HAQ) Score [ Time Frame: Baseline and Month 4 ]
  • Change From Baseline in Short Form 36 (SF-36) Score [ Time Frame: Baseline and Month 4 ]

Enrollment: 12
Actual Study Start Date: December 2007
Study Completion Date: July 2009
Primary Completion Date: July 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Gleevec

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

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00677092

Locations
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Sponsors and Collaborators
Massachusetts General Hospital
Novartis Pharmaceuticals
Investigators
Principal Investigator: Jonathan Kay, MD Massachusetts General Hospital
  More Information

Publications:
Responsible Party: Jonathan Kay, MD, Principal Investigator, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT00677092     History of Changes
Other Study ID Numbers: 2007-P-001945
Study First Received: May 8, 2008
Results First Received: April 10, 2017
Last Updated: April 10, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Jonathan Kay, MD, Massachusetts General Hospital:
Treatment
Chronic kidney disease
Fibrosing disorders
Imatinib mesylate

Additional relevant MeSH terms:
Fibrosis
Nephrogenic Fibrosing Dermopathy
Pathologic Processes
Skin Diseases
Imatinib Mesylate
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 24, 2017