GENESYF: Pilot Study of Imatinib Mesylate to Treat Nephrogenic Systemic Fibrosis

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00677092
• Collaborator: Novartis Pharmaceuticals (Industry)
• Enrollment: 12
• Location: 1
• Arm: 1
• Actual Duration (Months): 19
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Nephrogenic Systemic Fibrosis	Drug: Imatinib mesylate	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• 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
• Actual Study Start Date: Dec 1, 2007
• Actual Primary Completion Date: Jul 1, 2009
• Actual Study Completion Date: Jul 1, 2009

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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

1. Change From Baseline in Maximal Extension of Elbows and Knees [Baseline and Month 4]

2. Change From Baseline in Histologic Appearance of Skin Biopsy [Baseline and Month 4]

3. Change From Baseline in Visual Analog Scale (VAS) for Pain [Baseline and Month 4]

4. Change From Baseline in Health Assessment Questionnaire (HAQ) Score [Baseline and Month 4]

5. Change From Baseline in Short Form 36 (SF-36) Score [Baseline and Month 4]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Publications

• Kay J, Czirják L. Gadolinium and systemic fibrosis: guilt by association. Ann Rheum Dis. 2010 Nov;69(11):1895-7. doi: 10.1136/ard.2010.134791.
• Kay J, High WA. Imatinib mesylate treatment of nephrogenic systemic fibrosis. Arthritis Rheum. 2008 Aug;58(8):2543-8. doi: 10.1002/art.23696.
• 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-1β 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, 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.
• Todd DJ, Kay J. Gadolinium-Induced Fibrosis. Annu Rev Med. 2016;67:273-91. doi: 10.1146/annurev-med-063014-124936. Review.

• Responsible Party: Jonathan Kay, MD, Principal Investigator, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT00677092
• Other Study ID Numbers: 2007-P-001945
• First Posted: May 13, 2008
• Last Update Posted: May 19, 2017
• Last Verified: Apr 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Jonathan Kay, MD, Principal Investigator, Massachusetts General Hospital: Treatment; Chronic kidney disease; Fibrosing disorders; Imatinib mesylate
• Additional relevant MeSH terms: Nephrogenic Fibrosing Dermopathy; Fibrosis; Imatinib Mesylate

Study Results

Participant Flow

Arm/Group Title	Imatinib Mesylate Treatment
Arm/Group Description	Imatinib mesylate 400 mg orally once daily for 4 months. Dosage was reduced to 200 mg if participant developed gastrointestinal intolerance or alopecia.
Period Title: Overall Study
STARTED	12
Received Study Treatment	11
COMPLETED	6
NOT COMPLETED	6

Baseline Characteristics

Arm/Group Title	Imatinib Mesylate Treatment
Arm/Group Description	Imatinib mesylate 400 mg orally once daily for 4 months. Dosage was reduced to 200 mg if the participant developed gastrointestinal intolerance or alopecia.
Overall Participants	10
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.7 (14.2)
Sex: Female, Male (Count of Participants)
Female	3 30%
Male	7 70%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All enrolled participants with Baseline and Month 4 data available for analysis.

Arm/Group Title	Imatinib Mesylate Treatment
Arm/Group Description	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.
Measure Participants	6
Mean (Standard Deviation) [percentage change in mRSS score]	-24 (14)

2. Secondary Outcome

Title	Change From Baseline in Maximal Extension of Elbows and Knees
Time Frame	Baseline and Month 4

Outcome Measure Data

Analysis Population Description

PI left institution in 2009; Data collected cannot be associated with specific participants and analyzed for secondary outcome measure.

Arm/Group Title	Imatinib Mesylate Treatment
Arm/Group Description	Imatinib mesylate 400 mg orally once daily for 4 months. Dosage was reduced to 200 mg if the participant developed gastrointestinal intolerance or alopecia.
Measure Participants	0

3. Secondary Outcome

Title	Change From Baseline in Histologic Appearance of Skin Biopsy
Time Frame	Baseline and Month 4

Outcome Measure Data

Analysis Population Description

PI left institution in 2009; Data collected cannot be associated with specific participants and analyzed for secondary outcome measure.

Arm/Group Title	Imatinib Mesylate Treatment
Arm/Group Description	Imatinib mesylate 400 mg orally once daily for 4 months. Dosage was reduced to 200 mg if the participant developed gastrointestinal intolerance or alopecia.
Measure Participants	0

4. Secondary Outcome

Title	Change From Baseline in Visual Analog Scale (VAS) for Pain
Time Frame	Baseline and Month 4

Outcome Measure Data

Analysis Population Description

PI left institution in 2009; Data collected cannot be associated with specific participants and analyzed for secondary outcome measure.

Arm/Group Title	Imatinib Mesylate Treatment
Arm/Group Description	Imatinib mesylate 400 mg orally once daily for 4 months. Dosage was reduced to 200 mg if the participant developed gastrointestinal intolerance or alopecia.
Measure Participants	0

5. Secondary Outcome

Title	Change From Baseline in Health Assessment Questionnaire (HAQ) Score
Time Frame	Baseline and Month 4

Outcome Measure Data

Analysis Population Description

PI left institution in 2009; Data collected cannot be associated with specific participants and analyzed for secondary outcome measure.

Arm/Group Title	Imatinib Mesylate Treatment
Arm/Group Description	Imatinib mesylate 400 mg orally once daily for 4 months. Dosage was reduced to 200 mg if the participant developed gastrointestinal intolerance or alopecia.
Measure Participants	0

6. Secondary Outcome

Title	Change From Baseline in Short Form 36 (SF-36) Score
Time Frame	Baseline and Month 4

Outcome Measure Data

Analysis Population Description

PI left institution in 2009; Data collected cannot be associated with specific participants and analyzed for secondary outcome measure.

Arm/Group Title	Imatinib Mesylate Treatment
Arm/Group Description	Imatinib mesylate 400 mg orally once daily for 4 months. Dosage was reduced to 200 mg if the participant developed gastrointestinal intolerance or alopecia.
Measure Participants	0

Adverse Events

Time Frame	6 Months
Adverse Event Reporting Description	PI left institution in 2009; Data collected cannot be associated with specific participants and analyzed for adverse event data entry.
Arm/Group Title	Imatinib Mesylate Treatment
Arm/Group Description	Imatinib mesylate 400 mg orally once daily for 4 months. Dosage was reduced to 200 mg if the participant developed gastrointestinal intolerance or alopecia.
All Cause Mortality
	Imatinib Mesylate Treatment
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Imatinib Mesylate Treatment
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Imatinib Mesylate Treatment
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)

Limitations/Caveats

PI left institution in 2009; Data collected cannot be associated with specific participants and analyzed for secondary outcome measure or adverse event data entry.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.