Pilot Study of Imatinib Mesylate to Treat Nephrogenic Systemic Fibrosis

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00677092

Acronym

GENESYF

Enrollment

Registered

2008-05-13

Start date

2007-12-31

Completion date

2009-07-31

Last updated

2017-05-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Nephrogenic Systemic Fibrosis

Keywords

Treatment, Chronic kidney disease, Fibrosing disorders, Imatinib mesylate

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.

Interventions

DRUGImatinib mesylate

400 mg p.o. daily for 4 months. Dosage was reduced to 200 mg if participants develop gastrointestinal intolerance or alopecia.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
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

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

Countries

United States

Participant flow

Participants by arm

Arm	Count
Imatinib Mesylate Treatment Imatinib mesylate 400 mg orally once daily for 4 months. Dosage was reduced to 200 mg if the participant developed gastrointestinal intolerance or alopecia.	10
Total	10

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	1
Overall Study	Death Prior to Receiving Treatment	1
Overall Study	Lost to Follow-up	1
Overall Study	Withdrawal by Subject	3

Baseline characteristics

Characteristic	Imatinib Mesylate Treatment
Age, Continuous	61.7 years STANDARD_DEVIATION 14.2
Sex: Female, Male Female	3 Participants
Sex: Female, Male Male	7 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	0 / 0
serious Total, serious adverse events	0 / 0

Outcome results

Primary

Percentage Change From Baseline in the Modified Rodnan Skin Score (mRSS) to Assess Skin Tethering

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.