Risk of Nephrogenic Systemic Fibrosis (NSF) in Patients With Moderate Renal Insufficiency After the Administration of Magnevist

Conditions

Fibrosis, Kidney Failure, Renal Insufficiency

Keywords

Gadolinium, NSF, Renal Impairment, chemically induced, adverse effects, Contrast Media, complications

Brief summary

Assess potential risk for NSF in subjects with renal impairment (moderate) post magnevist injection. Subjects will be screened within 48 hours of previously scheduled MRI, those meeting the enrollment criteria will be enrolled prior to MRI and followed for 2 years post MRI with visits occuring at 1yr and 2 yr timepoints, in addition follow-up phone calls conducted at 1, 3, 6 and 18 months to assess for skin changes suggestive of NSF.

Related papers

No related papers found yet.

Interventions

DRUGGadopentetate dimeglumine (Magnevist, BAY86-4882)

Patients will be followed for 2 years after the administration of Magnevist at the approved dose to see if symptoms consistent with NSF develop

Study design

Observational model

COHORT

Time perspective

PROSPECTIVE

Eligibility

Sex/Gender

ALL

Age

2 Years to No maximum

Healthy volunteers

No

Inclusion criteria

* Patients must have moderate (eGFR 30-59 ml/min/1.73 m\^2) renal impairment and be scheduled for a contrast enhanced MRI with Magnevist Injection at the recommended dose of 0.1 mmol/kg.

Exclusion criteria

* Gadolinium Based Contrast Agent (other then Magnevist) enhanced MRI within 12 months prior to administration of Magnevist * History of NSF * Clinically unstable or age \<2 yrs

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants Who Developed Nephrogenic Systemic Fibrosis (NSF), Based on Diagnostically Specific Clinical and Histopathological Information-cohort Analysis and Full Analysis Set	Up to 24 months following the administration of Magnevist	Either clinical or histopathology score had to be at least 2 and the other at least 3 for diagnosis of NSF. Clinical score 2, 3 or 4 was derived from more than one minor criterion finding, one major criterion finding or more than one major criterion finding respectively. Major Criteria include patterned plaques, joint contractures, cobblestoning and marked induration/Peau d'orange (upper extremity or above knee); minor Criteria include puckering/linear banding, superficial (plaque/patch), dermal papules and scleral plaques (subject aged \<45 years). Pathology score 2, 3 or 4 was derived from 2, 3 or at least 4 histological criteria findings respectively. Histological Criteria include increased cellularity (spindled and/or epithelioid) with few other inflammatory cells, CD34+ spindle or epithelioid cells in a reticular or parallel arrangement with tram-tracking, presence of both fine collagen and ropey collagen surrounded by clefts, elastic fibers preserved and septal involvement.
Number of Participants Who Developed NSF, Based on Diagnostically Specific Clinical and Histopathological Information-full Analysis Set	Up to 24 months following the administration of Magnevist	Either clinical or histopathology score had to be at least 2 and the other at least 3 for diagnosis of NSF. Clinical score 2, 3 or 4 was derived from more than one minor criterion finding, one major criterion finding or more than one major criterion finding respectively. Major Criteria include patterned plaques, joint contractures, cobblestoning and marked induration/Peau d'orange (upper extremity or above knee); minor Criteria include puckering/linear banding, superficial (plaque/patch), dermal papules and scleral plaques (subject aged \<45 years). Pathology score 2, 3 or 4 was derived from 2, 3 or at least 4 histological criteria findings respectively. Histological Criteria include increased cellularity (spindled and/or epithelioid) with few other inflammatory cells, CD34+ spindle or epithelioid cells in a reticular or parallel arrangement with tram-tracking, presence of both fine collagen and ropey collagen surrounded by clefts, elastic fibers preserved and septal involvement.
Number of Participants Who Developed NSF, Based on Diagnostically Specific Clinical and Histopathological Information-cohort Analysis and Per Protocol Set	Up to 24 months following the administration of Magnevist	Either clinical or histopathology score had to be at least 2 and the other at least 3 for diagnosis of NSF. Clinical score 2, 3 or 4 was derived from more than one minor criterion finding, one major criterion finding or more than one major criterion finding respectively. Major Criteria include patterned plaques, joint contractures, cobblestoning and marked induration/Peau d'orange (upper extremity or above knee); minor Criteria include puckering/linear banding, superficial (plaque/patch), dermal papules and scleral plaques (subject aged \<45 years). Pathology score 2, 3 or 4 was derived from 2, 3 or at least 4 histological criteria findings respectively. Histological Criteria include increased cellularity (spindled and/or epithelioid) with few other inflammatory cells, CD34+ spindle or epithelioid cells in a reticular or parallel arrangement with tram-tracking, presence of both fine collagen and ropey collagen surrounded by clefts, elastic fibers preserved and septal involvement.
Number of Participants Who Developed NSF, Based on Diagnostically Specific Clinical and Histopathological Information-per Protocol Set	Up to 24 months following the administration of Magnevist	Either clinical or histopathology score had to be at least 2 and the other at least 3 for diagnosis of NSF. Clinical score 2, 3 or 4 was derived from more than one minor criterion finding, one major criterion finding or more than one major criterion finding respectively. Major Criteria include patterned plaques, joint contractures, cobblestoning and marked induration/Peau d'orange (upper extremity or above knee); minor Criteria include puckering/linear banding, superficial (plaque/patch), dermal papules and scleral plaques (subject aged \<45 years). Pathology score 2, 3 or 4 was derived from 2, 3 or at least 4 histological criteria findings respectively. Histological Criteria include increased cellularity (spindled and/or epithelioid) with few other inflammatory cells, CD34+ spindle or epithelioid cells in a reticular or parallel arrangement with tram-tracking, presence of both fine collagen and ropey collagen surrounded by clefts, elastic fibers preserved and septal involvement.

Secondary

Measure	Time frame	Description
Number of Participants With Adverse Events (AEs) Reported in Association With the Administration of Magnevist-cohort Analysis and Full Analysis Set	Up to 24 months following the administration of Magnevist	Adverse events occurring within 1 day after administration of Magnevist or skin-related adverse events occurring during follow-up (FU) were recorded.
Number of Participants With Adverse Events (AEs) Reported in Association With the Administration of Magnevist-full Analysis Set	Up to 24 months following the administration of Magnevist	Adverse events occurring within 1 day after administration of Magnevist or skin-related adverse events occurring during follow-up (FU) were recorded.
Total Number of Participants With Clinicopathological Correlation of 'NSF' or 'Consistent With NSF' and Subjects Without Biopsy Developing Clinical Signs Consistent With NSF-cohort Analysis and Full Analysis Set	Up to 24 months following the administration of Magnevist	Either clinical or histopathology score need at least 2 and the other at least 3 for diagnosis of NSF. Clinical score 2, 3 or 4 required more than 1 minor criterion, 1 major criterion or more than 1 major criterion respectively. Major criteria: patterned plaques, joint contractures, cobblestoning, marked induration/Peau d'orange (upper extremity or above knee); minor Criteria: puckering/linear banding, superficial (plaque/patch), dermal papules, scleral plaques (subject aged \<45 yrs). Pathology score 2, 3 or 4 required 2, 3 or at least 4 histological criteria respectively. Histological criteria include Increased cellularity with few other inflammatory cells, CD34+ spindle or epithelioid cells in a reticular or parallel arrangement with tram-tracking, presence of fine collagen and ropey collagen surrounded by clefts, elastic fibers preserved and Septal involvement. A clinical score of 4 was suggestive of developing clinical signs consistent with NSF in subjects without biopsy.
Number of Participants With Adverse Events (AEs) Reported in Association With the Administration of Magnevist-per Protocol Set	Up to 24 months following the administration of Magnevist	Adverse events occurring within 1 day after administration of Magnevist or skin-related adverse events occurring during follow-up (FU) were recorded.
Number of Participants With Adverse Events (AEs) Reported in Association With the Administration of Magnevist-cohort Analysis and Per Protocol Set	Up to 24 months following the administration of Magnevist	Adverse events occurring within 1 day after administration of Magnevist or skin-related adverse events occurring during follow-up (FU) were recorded.
Total Number of Participants With Clinicopathological Correlation of 'NSF' or 'Consistent With NSF' and Subjects Without Biopsy Developing Clinical Signs Consistent With NSF-full Analysis Set	Up to 24 months following the administration of Magnevist	Either clinical or histopathology score need at least 2 and the other at least 3 for diagnosis of NSF. Clinical score 2, 3 or 4 required more than 1 minor criterion, 1 major criterion or more than 1 major criterion respectively. Major criteria: patterned plaques, joint contractures, cobblestoning, marked induration/Peau d'orange (upper extremity or above knee); minor Criteria: puckering/linear banding, superficial (plaque/patch), dermal papules, scleral plaques (subject aged \<45 yrs). Pathology score 2, 3 or 4 required 2, 3 or at least 4 histological criteria respectively. Histological criteria include Increased cellularity with few other inflammatory cells, CD34+ spindle or epithelioid cells in a reticular or parallel arrangement with tram-tracking, presence of fine collagen and ropey collagen surrounded by clefts, elastic fibers preserved and Septal involvement. A clinical score of 4 was suggestive of developing clinical signs consistent with NSF in subjects without biopsy.
Total Number of Participants With Clinicopathological Correlation of 'NSF' or 'Consistent With NSF' and Subjects Without Biopsy Developing Clinical Signs Consistent With NSF-cohort Analysis and Per Protocol Set	Up to 24 months following the administration of Magnevist	Either clinical or histopathology score need at least 2 and the other at least 3 for diagnosis of NSF. Clinical score 2, 3 or 4 required more than 1 minor criterion, 1 major criterion or more than 1 major criterion respectively. Major criteria: patterned plaques, joint contractures, cobblestoning, marked induration/Peau d'orange (upper extremity or above knee); minor Criteria: puckering/linear banding, superficial (plaque/patch), dermal papules, scleral plaques (subject aged \<45 yrs). Pathology score 2, 3 or 4 required 2, 3 or at least 4 histological criteria respectively. Histological criteria include Increased cellularity with few other inflammatory cells, CD34+ spindle or epithelioid cells in a reticular or parallel arrangement with tram-tracking, presence of fine collagen and ropey collagen surrounded by clefts, elastic fibers preserved and Septal involvement. A clinical score of 4 was suggestive of developing clinical signs consistent with NSF in subjects without biopsy.
Total Number of Participants With Clinicopathological Correlation of 'NSF' or 'Consistent With NSF' and Subjects Without Biopsy Developing Clinical Signs Consistent With NSF-per Protocol Set	Up to 24 months following the administration of Magnevist	Either clinical or histopathology score need at least 2 and the other at least 3 for diagnosis of NSF. Clinical score 2, 3 or 4 required more than 1 minor criterion, 1 major criterion or more than 1 major criterion respectively. Major criteria: patterned plaques, joint contractures, cobblestoning, marked induration/Peau d'orange (upper extremity or above knee); minor Criteria: puckering/linear banding, superficial (plaque/patch), dermal papules, scleral plaques (subject aged \<45 yrs). Pathology score 2, 3 or 4 required 2, 3 or at least 4 histological criteria respectively. Histological criteria include Increased cellularity with few other inflammatory cells, CD34+ spindle ore epithelioid cells in a reticular or parallel arrangement with tram-tracking, presence of fine collagen and ropey collagen surrounded by clefts, elastic fibers preserved and Septal involvement. A clinical score of 4 was suggestive of developing clinical signs consistent with NSF in subjects without biopsy.

Countries

United States

Participant flow

Recruitment details

The first participant's first visit was on 21 Nov 2008. Nineteen study centers in the United States screened and enrolled participants scheduled to undergo contrast enhanced magnetic resonance imaging (CE-MRI) with Magnevist within the approved indications at the recommended dose of 0.1 mmol/kg body weight.

Pre-assignment details

A total of 168 participants were enrolled.

Participants by arm

Arm	Count
Mild Renal Impairment Participants with estimated glomerular filtration rate (eGFR) \>65 mL/min/1.73 m\^2 prior to Magnevist injection was classified into cohort of Mild renal impairment.	14
Extended Moderate Renal Impairment Participants with eGFR between \>59 and ≤65 mL/min/1.73 m\^2 prior to Magnevist injection was classified into cohort of extended moderate renal impairment.	9
Moderate Renal Impairment Participants with eGFR between ≥30 and ≤59 mL/min/1.73 m\^2 prior to Magnevist injection was classified into cohort of moderate renal impairment.	109
Severe Renal Impairment Participants on dialysis or subjects with eGFR \<30 mL/min/1.73 m\^2 prior to Magnevist injection was classified into cohort of severe renal impairment.	9
Total	141

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	coma	1
Overall Study	Death	24
Overall Study	Did not receive Magnevist	7
Overall Study	distance	4
Overall Study	Failed inclusion/exclusion criteria	19
Overall Study	incorrect race	1
Overall Study	Lost to Follow-up	12
Overall Study	Medical history exclusionary	1
Overall Study	Protocol Violation	13
Overall Study	Withdrawal by Subject	9

Baseline characteristics

Characteristic	Extended Moderate Renal Impairment	Total	Severe Renal Impairment	Moderate Renal Impairment	Mild Renal Impairment
Age, Continuous	66.9 Years STANDARD_DEVIATION 9.91	66.0 Years STANDARD_DEVIATION 11.75	62.4 Years STANDARD_DEVIATION 9.51	66.4 Years STANDARD_DEVIATION 12.09	65.0 Years STANDARD_DEVIATION 12.03
Age, Customized <65 years	5 Participants	63 Participants	6 Participants	47 Participants	5 Participants
Age, Customized >=65 years	4 Participants	78 Participants	3 Participants	62 Participants	9 Participants
Cause of renal disease Collagen disease	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Cause of renal disease Diabetes	2 Participants	38 Participants	5 Participants	28 Participants	3 Participants
Cause of renal disease Glomerulonephritis	0 Participants	1 Participants	0 Participants	1 Participants	0 Participants
Cause of renal disease Hypertension	3 Participants	53 Participants	2 Participants	41 Participants	7 Participants
Cause of renal disease Other	5 Participants	84 Participants	3 Participants	68 Participants	8 Participants
Cause of renal disease Polycystic kidney disease	0 Participants	5 Participants	2 Participants	3 Participants	0 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants	9 Participants	0 Participants	7 Participants	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	8 Participants	132 Participants	9 Participants	102 Participants	13 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
MRI region of main interest Brain	3 Participants	36 Participants	1 Participants	28 Participants	4 Participants
MRI region of main interest Kidney	2 Participants	20 Participants	1 Participants	15 Participants	2 Participants
MRI region of main interest Liver	1 Participants	24 Participants	3 Participants	19 Participants	1 Participants
MRI region of main interest Musculoskeletal	0 Participants	9 Participants	0 Participants	8 Participants	1 Participants
MRI region of main interest Other	3 Participants	39 Participants	3 Participants	28 Participants	5 Participants
MRI region of main interest Spine	0 Participants	13 Participants	1 Participants	11 Participants	1 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	1 Participants	0 Participants	1 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	2 Participants	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) Black or African American	0 Participants	21 Participants	1 Participants	18 Participants	2 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	5 Participants	0 Participants	5 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	3 Participants	0 Participants	3 Participants	0 Participants
Race (NIH/OMB) White	9 Participants	109 Participants	8 Participants	81 Participants	11 Participants
Receiving dialysis Any	0 Participants	2 Participants	2 Participants	0 Participants	0 Participants
Receiving dialysis Hemodialysis	0 Participants	2 Participants	2 Participants	0 Participants	0 Participants
Receiving dialysis Peritoneal dialysis	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Sex: Female, Male Female	3 Participants	62 Participants	4 Participants	52 Participants	3 Participants
Sex: Female, Male Male	6 Participants	79 Participants	5 Participants	57 Participants	11 Participants
Vascular injuries Any	1 Participants	43 Participants	3 Participants	36 Participants	3 Participants
Vascular injuries Organ transplant surgery	0 Participants	8 Participants	3 Participants	5 Participants	0 Participants
Vascular injuries Other	0 Participants	4 Participants	0 Participants	4 Participants	0 Participants
Vascular injuries Other surgeries	0 Participants	15 Participants	0 Participants	13 Participants	2 Participants
Vascular injuries Shunt surgery/repair	0 Participants	6 Participants	2 Participants	4 Participants	0 Participants
Vascular injuries Thrombotic events	1 Participants	26 Participants	0 Participants	24 Participants	1 Participants
Weight	81.9 Kilograms STANDARD_DEVIATION 13.3	85.5 Kilograms STANDARD_DEVIATION 17.5	83.2 Kilograms STANDARD_DEVIATION 18.4	86.0 Kilograms STANDARD_DEVIATION 18.3	85.2 Kilograms STANDARD_DEVIATION 13.1
Years since renal diagnosis	0 Years STANDARD_DEVIATION 0	2.4 Years STANDARD_DEVIATION 3.4	3.1 Years STANDARD_DEVIATION 4.6	2.2 Years STANDARD_DEVIATION 3.2	4.4 Years STANDARD_DEVIATION 4.5

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	0 / 14	3 / 9	12 / 109	0 / 9
serious Total, serious adverse events	0 / 14	0 / 9	1 / 109	0 / 9

Outcome results

Primary

Number of Participants Who Developed Nephrogenic Systemic Fibrosis (NSF), Based on Diagnostically Specific Clinical and Histopathological Information-cohort Analysis and Full Analysis Set

Either clinical or histopathology score had to be at least 2 and the other at least 3 for diagnosis of NSF. Clinical score 2, 3 or 4 was derived from more than one minor criterion finding, one major criterion finding or more than one major criterion finding respectively. Major Criteria include patterned plaques, joint contractures, cobblestoning and marked induration/Peau d'orange (upper extremity or above knee); minor Criteria include puckering/linear banding, superficial (plaque/patch), dermal papules and scleral plaques (subject aged \<45 years). Pathology score 2, 3 or 4 was derived from 2, 3 or at least 4 histological criteria findings respectively. Histological Criteria include increased cellularity (spindled and/or epithelioid) with few other inflammatory cells, CD34+ spindle or epithelioid cells in a reticular or parallel arrangement with tram-tracking, presence of both fine collagen and ropey collagen surrounded by clefts, elastic fibers preserved and septal involvement.