Renal Insufficiency
Conditions
Keywords
contrast-induced nephropathy, creatinemia
Brief summary
Although there is a well documented risk of acute renal failure with the iodinated contrast agents, the implication of intravenous gadolinium-based contrast agents in nephrotoxicity remains controversial. The aim of this study was to evaluate the safety profile of gadoterate meglumine (Dotarem®) in patients with chronic renal insufficiency by evaluating the rate of patients experiencing contrast-induced nephrotoxicity following the injection of gadoterate meglumine.
Detailed description
Patients with renal insufficiency not requiring hemodialysis and scheduled to undergo a contrast enhanced MRI or unenhanced MRI examination to specify a diagnosis, were selected for inclusion. Two groups of patients were defined on the basis of the planned imaging procedure selected to obtain a diagnosis: those undergoing a Dotarem®-enhanced MRI and those undergoing an unenhanced MRI. A clinically significant increase in serum creatinine levels after the contrast-enhanced MRI exam was used as an indication of contrast induced nephrotoxicity. A blood test was performed 24h before the MRI in order to evaluate baseline creatinine values. 72h after the exam, a second blood test was performed. An increase in creatinemia above 25% from baseline levels was defined as a contrast-induced nephrotoxic reaction. The primary endpoint of the study assessed the percentage of patients presenting a contrast-induced nephrotoxic reaction in order to show a non inferiority of enhanced as compared to non-enhanced MRI exams.
Interventions
DRUGDotarem®-enhanced MRI
Single IV administration before MRI exam
OTHERnon-enhanced MRI
non injected MRI
Sponsors
Guerbet
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female, \> or equal 18 years ; * Patient with a known stable renal insufficiency ; * Patient scheduled to undergo an MRI examination to specify a diagnosis ; * Patient able to understand and provide written informed consent to participate in the trial ;
Exclusion criteria
* Patient with a contra-indication to MRI ; * Patient who has a diagnosis of an hemodynamic instability or acute myocardial infarction within 15 days prior the inclusion ; * Patient who needs hemodialysis ; * Patient with known allergy to gadolinium chelates ; * Patient receiving medications known to be nephrotoxic or to cause increases in serum creatinine level within 2 weeks before the inclusion ; * Patients planned to either undergo surgery or receive chemotherapy ; * Any condition which, based on the investigator's clinical judgement, would prevent the patient from completing all trial assessments and visits ; * Patient under guardianship and/or inability or unwillingness to cooperate with the requirements of this trial ; * Patient with newly discovered unstable diabetes.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Presenting Contrast-induced Nephropathy as Defined by an Increase in Serum Creatinine Levels of a Least 25% Over Baseline Levels, in the Full Analysis Set Population. | baseline pre MRI and 3 days post MRI | Comparing the number of patients experiencing an increase of creatinine of at least 25% over baseline levels after Dotarem®-enhanced MRI and after non-enhanced MRI in patients with at least a moderate renal insufficiency. |
| Number of Patients Presenting Contrast-induced Nephropathy as Defined by an Increase in Serum Creatinine Levels of at Least 25% Over Baseline Levels, in the Per Protocol Population. | Baseline pre MRI and 3 days post MRI | Comparing the number of patients experiencing an increase of creatinine of at least 25% over baseline levels after Dotarem®-enhanced MRI and after non-enhanced MRI in patients with at least a moderate renal insufficiency. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change of Serum Creatinine Level From Baseline to 72±24 Hours After Examination, in the Full Analysis Set Population. | Baseline pre MRI and 3 days post MRI | Serum creatinine levels were measured at baseline and at 72±24 hours after examination. The percentage of change in creatinemia from baseline was calculated for both the Dotarem® and the non-enhanced groups. |
| Percent Change of Serum Creatinine Level Variation From Baseline to 72±24 Hours After Examination, in the Per Protocol Population | Baseline pre MRI and 3 days post MRI | Serum creatinine levels were measured at baseline and at 72±24 hours after examination. The percentage of change in creatinemia from baseline was calculated for both the Dotarem® and the non-enhanced groups. |
| Percent Change of Estimated Glomerular Filtration Rate (eGFR) Values From Baseline to 72±24 Hours After Examination, in the Full Analysis Set Population | Baseline pre MRI and 3 days post MRI | eGFR was assessed using creatinemia and the Modification of Diet in Renal Disease (MDRD) study equation. eGFR were evaluated in terms of mean difference between the pre- and post-MRI procedure. The eGFR variation was expressed as a percentage of change from baseline values. |
| eGFR Values Variation Between Baseline and 72±24 Hours After Examination, in the Per Protocol Population | Baseline pre MRI and 3 days post MRI | eGFR (estimated Glomerular Filtration Rate) was assessed using creatinemia and the Modification of Diet in Renal Disease (MDRD) study equation. eGFR were evaluated in terms of mean difference between the pre- and post-MRI procedure. The eGFR variation was expressed as a percentage of change from baseline values. |
Countries
Belgium, France, Italy, Spain
Participant flow
Recruitment details
This study did not use randomization. Eligible patients who provided written consent were enrolled chronologically in each investigational center. A total of 142 patients were screened between 29 January 2008 and 05 May 2011, 135 of whom were included in 15 European centers, eight centers in France, three in Belgium, two in Spain and two in Italy.
Pre-assignment details
10 patients were screened but did not undergo the planned procedure: 7 were screen failures and 3 were included but dropped out prior to undergoing the planned procedure. Hence the total number of patients who were assigned to both groups is 132.
Participants by arm
| Arm | Count |
|---|---|
| Dotarem®-Enhanced MRI Dotarem®: Single IV administration before the MRI | 75 |
| Non-enhanced MRI non-enhanced MRI: non injected MRI | 57 |
| Total | 132 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 0 | 13 |
| Overall Study | Withdrawal by Subject | 5 | 0 |
Baseline characteristics
| Characteristic | Dotarem®-Enhanced MRI | Non-enhanced MRI | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 51 Participants | 37 Participants | 88 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants | 20 Participants | 44 Participants |
| Age, Continuous | 69.6 years STANDARD_DEVIATION 11.5 | 66.2 years STANDARD_DEVIATION 12.2 | 67.9 years STANDARD_DEVIATION 12 |
| Region of Enrollment Belgium | 14 participants | 7 participants | 21 participants |
| Region of Enrollment France | 44 participants | 11 participants | 55 participants |
| Region of Enrollment Italy | 0 participants | 16 participants | 16 participants |
| Region of Enrollment Spain | 17 participants | 23 participants | 40 participants |
| Sex: Female, Male Female | 24 Participants | 23 Participants | 47 Participants |
| Sex: Female, Male Male | 51 Participants | 34 Participants | 85 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 70 | 0 / 44 |
| serious Total, serious adverse events | 0 / 70 | 0 / 44 |
Outcome results
Primary
Number of Patients Presenting Contrast-induced Nephropathy as Defined by an Increase in Serum Creatinine Levels of a Least 25% Over Baseline Levels, in the Full Analysis Set Population.
Comparing the number of patients experiencing an increase of creatinine of at least 25% over baseline levels after Dotarem®-enhanced MRI and after non-enhanced MRI in patients with at least a moderate renal insufficiency.
Time frame: baseline pre MRI and 3 days post MRI
Population: Full analysis set population: all included patients with a pre and post-procedure blood sample for creatinine measures.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dotarem®-Enhanced MRI | Number of Patients Presenting Contrast-induced Nephropathy as Defined by an Increase in Serum Creatinine Levels of a Least 25% Over Baseline Levels, in the Full Analysis Set Population. | 1 Number of patients |
| Non-enhanced MRI | Number of Patients Presenting Contrast-induced Nephropathy as Defined by an Increase in Serum Creatinine Levels of a Least 25% Over Baseline Levels, in the Full Analysis Set Population. | 0 Number of patients |
Comparison: The clinical non-inferiority limit of (non-enhanced - Dotarem®-enhanced) was fixed at -15%. The exact 95%Confidence Interval (CI) of the difference (non-enhanced - Dotarem®-enhanced) was \[-7.9%; +6.7%\]95% CI: [-7.9, 6.7]
Primary
Number of Patients Presenting Contrast-induced Nephropathy as Defined by an Increase in Serum Creatinine Levels of at Least 25% Over Baseline Levels, in the Per Protocol Population.
Comparing the number of patients experiencing an increase of creatinine of at least 25% over baseline levels after Dotarem®-enhanced MRI and after non-enhanced MRI in patients with at least a moderate renal insufficiency.
Time frame: Baseline pre MRI and 3 days post MRI
Population: Per protocol population: This population is comprised of the full analysis set population (i.e. all included patients with a pre and post-procedure blood sample for creatinine measurement) deprived of patients with protocol deviations/violations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dotarem®-Enhanced MRI | Number of Patients Presenting Contrast-induced Nephropathy as Defined by an Increase in Serum Creatinine Levels of at Least 25% Over Baseline Levels, in the Per Protocol Population. | 1 Number of patients |
| Non-enhanced MRI | Number of Patients Presenting Contrast-induced Nephropathy as Defined by an Increase in Serum Creatinine Levels of at Least 25% Over Baseline Levels, in the Per Protocol Population. | 0 Number of patients |
Comparison: The clinical non-inferiority limit of (non-enhanced - Dotarem®-enhanced) was fixed at -15%. The exact 95%CI of the difference (non-enhanced - Dotarem®-enhanced) was \[-14.1%; +8.9%\]95% CI: [-14.1, 8.9]
Secondary
eGFR Values Variation Between Baseline and 72±24 Hours After Examination, in the Per Protocol Population
eGFR (estimated Glomerular Filtration Rate) was assessed using creatinemia and the Modification of Diet in Renal Disease (MDRD) study equation. eGFR were evaluated in terms of mean difference between the pre- and post-MRI procedure. The eGFR variation was expressed as a percentage of change from baseline values.
Time frame: Baseline pre MRI and 3 days post MRI
Population: Per protocol population: This population is comprised of the full analysis set population (i.e. all included patients with a pre and a post- procedure blood sample for creatinine measurements) deprived of patients with protocol deviations/violations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dotarem®-Enhanced MRI | eGFR Values Variation Between Baseline and 72±24 Hours After Examination, in the Per Protocol Population | 1.37 Percentage of change from baseline | Standard Deviation 12.65 |
| Non-enhanced MRI | eGFR Values Variation Between Baseline and 72±24 Hours After Examination, in the Per Protocol Population | 7.58 Percentage of change from baseline | Standard Deviation 12.82 |
Comparison: eGFR fluctuation in terms of percentage and mean difference between baseline and 72 ±24hours after imaging procedure values was computed for both MRI procedures and compared between the 2 groups. A linear regression model was used to model the relative or absolute eGFR variation from baseline as a function of the MRI procedure with adjustment on centers.p-value: 0.051t-test, 2 sided
Secondary
Percent Change of Estimated Glomerular Filtration Rate (eGFR) Values From Baseline to 72±24 Hours After Examination, in the Full Analysis Set Population
eGFR was assessed using creatinemia and the Modification of Diet in Renal Disease (MDRD) study equation. eGFR were evaluated in terms of mean difference between the pre- and post-MRI procedure. The eGFR variation was expressed as a percentage of change from baseline values.
Time frame: Baseline pre MRI and 3 days post MRI
Population: Full analysis set population: all included patients with a pre and a post-procedure blood sample for creatinine measurements.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dotarem®-Enhanced MRI | Percent Change of Estimated Glomerular Filtration Rate (eGFR) Values From Baseline to 72±24 Hours After Examination, in the Full Analysis Set Population | 3.02 Percentage of change from baseline | Standard Deviation 12.51 |
| Non-enhanced MRI | Percent Change of Estimated Glomerular Filtration Rate (eGFR) Values From Baseline to 72±24 Hours After Examination, in the Full Analysis Set Population | 5.55 Percentage of change from baseline | Standard Deviation 12.94 |
Comparison: eGFR fluctuation in terms of percentage and mean difference between baseline and 72 ±24hours after imaging procedure values was computed for both MRI procedures and compared between the 2 groups. A linear regression model was used to model the relative or absolute eGFR variation from baseline as a function of the MRI procedure with adjustment on centers.p-value: 0.301t-test, 2 sided
Secondary
Percent Change of Serum Creatinine Level From Baseline to 72±24 Hours After Examination, in the Full Analysis Set Population.
Serum creatinine levels were measured at baseline and at 72±24 hours after examination. The percentage of change in creatinemia from baseline was calculated for both the Dotarem® and the non-enhanced groups.
Time frame: Baseline pre MRI and 3 days post MRI
Population: Full analysis set population:all included patients with a pre and post-procedure blood sample for creatinine measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dotarem®-Enhanced MRI | Percent Change of Serum Creatinine Level From Baseline to 72±24 Hours After Examination, in the Full Analysis Set Population. | -1.40 Percentage of change from baseline | Standard Deviation 10.36 |
| Non-enhanced MRI | Percent Change of Serum Creatinine Level From Baseline to 72±24 Hours After Examination, in the Full Analysis Set Population. | -3.48 Percentage of change from baseline | Standard Deviation 9.92 |
Comparison: Serum creatinine level fluctuation in terms of difference between baseline and 72 ±24hours after imaging procedure values was computed for both MRI procedures and compared between the 2 groups. A linear regression model was used to model the serum creatinine changes from baseline as a function of the MRI procedure with adjustment on centers.p-value: 0.291t-test, 2 sided
Secondary
Percent Change of Serum Creatinine Level Variation From Baseline to 72±24 Hours After Examination, in the Per Protocol Population
Serum creatinine levels were measured at baseline and at 72±24 hours after examination. The percentage of change in creatinemia from baseline was calculated for both the Dotarem® and the non-enhanced groups.
Time frame: Baseline pre MRI and 3 days post MRI
Population: Per protocol population. This population is comprised of the full analysis set population (i.e. all included patients with a pre and post-procedure blood sample for creatinine measurement) deprived of patients with protocol deviations/violations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dotarem®-Enhanced MRI | Percent Change of Serum Creatinine Level Variation From Baseline to 72±24 Hours After Examination, in the Per Protocol Population | 0.05 Percentage of change from baseline | Standard Deviation 10.84 |
| Non-enhanced MRI | Percent Change of Serum Creatinine Level Variation From Baseline to 72±24 Hours After Examination, in the Per Protocol Population | -5.17 Percentage of change from baseline | Standard Deviation 9.16 |
Comparison: Serum creatinine level fluctuation in terms of difference between baseline and 72 ±24hours after imaging procedure values was computed for both MRI procedures and compared between the 2 groups. A linear regression model was used to model the serum creatinine changes from baseline as a function of the MRI procedure with adjustment on centers.p-value: 0.04t-test, 2 sided