grip was a prospective , nonrandomized , open - label phase iv study performed in 55 centers in 9 countries ( germany [ 18 centers ] , italy , spain , austria , switzerland , canada , australia , south korea , and thailand ) .
the primary objective was to assess the magnitude of potential risk of developing nsf after gadobutrol administration in patients with moderate to severe renal impairment .
the study population consisted of patients with moderate to severe renal impairment scheduled for gadobutrol - enhanced mri within the approved indications and dose .
the study was conducted in accordance with all international and local guidelines and laws stated by the involved institutional review boards .
the classification of cohorts based on the degree of renal impairment was already described by lauenstein et al in a study on gadoxetate disodium .
the definitions in brief are as follows :  severe  renal impairment was defined by an egfr of < 30 ml / min per 1.73 m or dialysis .  moderate 
renal impairment was defined as an egfr between 30 and 59 ml / min per 1.73 m. however , renal status was tested twice 
first during screening within 6 weeks before the gadobutrol injection at the local laboratory and second at baseline ( ie , 48 hours before gadobutrol administration ) at a central laboratory . as a result
, 2 additional cohorts were defined post hoc : ( 1 ) an  extended moderate 
renal impairment cohort ( presenting an egfr 59 ml / min per 1.73 m at screening , but > 59 and 65 ml / min per 1.73 m at baseline ) and ( 2 ) a  mild  renal impairment cohort ( presenting an egfr 59 ml / min per 1.73 m at screening , but an egfr > 65 ml / min per 1.73 m at baseline ) ( table 1 ) . classification of study cohorts all patients received a single intravenous bolus injection of 0.1 mmol / kg ( 0.1 ml / kg ) bw gadobutrol followed by a 20 ml saline flush in the framework of the clinical routine diagnostic workup .
gadobutrol is marketed in all participating countries and was provided by the local hospital pharmacies .
the primary target variable was defined as the number of patients with moderate to severe renal impairment who developed nsf during the 2-year follow - up period .
secondary target variables included ( 1 ) number of patients without biopsy but who later developed nsf - like symptoms based solely on the clinical score by girardi et al ; and ( 2 ) number and characteristics of adverse events reported in association with the administration of gadobutrol .
our focus was to establish a standardized diagnostic workup and data collection for potential nsf cases in the daily clinical routine .
blood sampling to assess egfr was performed twice  first during screening within 6 weeks before the mri examination at the local laboratory and second at baseline ( ie , 48 hours before gadobutrol administration ) at a central laboratory .
after gadobutrol administration , patients were followed for clinical examination and review of source documents after 12 and 24 months .
in addition , telephone interviews were performed 1 , 3 , 6 , and 18 months after gadobutrol administration by health care professionals who were trained on the study protocol and specifically for identification of clinical signs of nsf .
any skin finding with the faintest suspicion of nsf was clinically assessed . in cases where a biopsy was taken , a histopathological assessment had to be performed . here , the girardi criteria had to be applied .
this strategy ensured that the risk to miss a potential case of nsf was minimized .
descriptive statistics including sample size , mean , standard deviation , minimum , and maximum were calculated for quantitative variables .
summaries are presented by renal status cohort ( mild , extended moderate , moderate , and severe renal impairment ) and overall study population .
the joint meeting of the cardiovascular and renal drugs and drug safety and risk management advisory committee of the fda ( december 8 , 2009 ) stipulated a 2-year observational study for all gbcas approved in the united states to assess the likelihood of nsf development .
the fda proposed a sample size of 1000 patients , consisting of 600 patients with moderate and 400 patients with severe renal impairment .
the fda 's sample size suggestion was based on a retrospective study of 370 patients with severe renal insufficiency who received gadodiamide .
on june 2 , 2011 , the fda released the pharmaceutical companies manufacturing gbcas from completing study enrollment but the full 2-year follow - up was required for all patients already enrolled .
we continued the grip study in accordance with the study protocol and concluded enrollment by december 31 , 2012 , with 927 of the 1000 originally planned patients enrolled .
grip was a prospective , nonrandomized , open - label phase iv study performed in 55 centers in 9 countries ( germany [ 18 centers ] , italy , spain , austria , switzerland , canada , australia , south korea , and thailand ) .
the primary objective was to assess the magnitude of potential risk of developing nsf after gadobutrol administration in patients with moderate to severe renal impairment .
the study population consisted of patients with moderate to severe renal impairment scheduled for gadobutrol - enhanced mri within the approved indications and dose .
the study was conducted in accordance with all international and local guidelines and laws stated by the involved institutional review boards .
the classification of cohorts based on the degree of renal impairment was already described by lauenstein et al in a study on gadoxetate disodium .
the definitions in brief are as follows :  severe  renal impairment was defined by an egfr of < 30 ml / min per 1.73 m or dialysis .  moderate 
renal impairment was defined as an egfr between 30 and 59 ml / min per 1.73 m. however , renal status was tested twice 
first during screening within 6 weeks before the gadobutrol injection at the local laboratory and second at baseline ( ie , 48 hours before gadobutrol administration ) at a central laboratory . as a result , 2 additional cohorts were defined post hoc : ( 1 ) an  extended moderate 
renal impairment cohort ( presenting an egfr 59 ml / min per 1.73 m at screening , but > 59 and 65 ml / min per 1.73 m at baseline ) and ( 2 ) a  mild  renal impairment cohort ( presenting an egfr 59 ml / min per 1.73 m at screening , but an egfr > 65 ml / min per 1.73 m at baseline ) ( table 1 ) .
all patients received a single intravenous bolus injection of 0.1 mmol / kg ( 0.1 ml / kg ) bw gadobutrol followed by a 20 ml saline flush in the framework of the clinical routine diagnostic workup .
gadobutrol is marketed in all participating countries and was provided by the local hospital pharmacies .
the primary target variable was defined as the number of patients with moderate to severe renal impairment who developed nsf during the 2-year follow - up period .
secondary target variables included ( 1 ) number of patients without biopsy but who later developed nsf - like symptoms based solely on the clinical score by girardi et al ; and ( 2 ) number and characteristics of adverse events reported in association with the administration of gadobutrol .
the study procedures were identical to those described by lauenstein et al . our focus was to establish a standardized diagnostic workup and data collection for potential nsf cases in the daily clinical routine .
blood sampling to assess egfr was performed twice  first during screening within 6 weeks before the mri examination at the local laboratory and second at baseline ( ie , 48 hours before gadobutrol administration ) at a central laboratory .
after gadobutrol administration , patients were followed for clinical examination and review of source documents after 12 and 24 months .
in addition , telephone interviews were performed 1 , 3 , 6 , and 18 months after gadobutrol administration by health care professionals who were trained on the study protocol and specifically for identification of clinical signs of nsf .
any skin finding with the faintest suspicion of nsf was clinically assessed . in cases where a biopsy was taken ,
a histopathological assessment had to be performed . here , the girardi criteria had to be applied .
this strategy ensured that the risk to miss a potential case of nsf was minimized .
descriptive statistics including sample size , mean , standard deviation , minimum , and maximum were calculated for quantitative variables .
summaries are presented by renal status cohort ( mild , extended moderate , moderate , and severe renal impairment ) and overall study population .
the joint meeting of the cardiovascular and renal drugs and drug safety and risk management advisory committee of the fda ( december 8 , 2009 ) stipulated a 2-year observational study for all gbcas approved in the united states to assess the likelihood of nsf development .
the fda proposed a sample size of 1000 patients , consisting of 600 patients with moderate and 400 patients with severe renal impairment .
the fda 's sample size suggestion was based on a retrospective study of 370 patients with severe renal insufficiency who received gadodiamide .
on june 2 , 2011 , the fda released the pharmaceutical companies manufacturing gbcas from completing study enrollment but the full 2-year follow - up was required for all patients already enrolled .
we continued the grip study in accordance with the study protocol and concluded enrollment by december 31 , 2012 , with 927 of the 1000 originally planned patients enrolled .
nine hundred eight patients received gadobutrol and completed the mri examination and were included in the analysis : 284 with severe , 540 with moderate , 46 with extended moderate , and 38 with mild renal impairment ( table 2 ) .
a total of 581 patients ( 64.0% ) completed the 24 months ' follow - up .
demographic and baseline characteristics by degree of renal impairment ( fas ) the mean age was 66.7 years ( range , 1994 years ) with 63.4% of patients being 65 years or older .
there were no apparent differences in the degree of renal impairment among the various demographic subgroups ( table 2 ) .
the period from initial diagnosis of renal disease increased with the severity of renal impairment and ranged from 1.83 years in the extended moderate renal impairment cohort to 5.49 years in the severe renal impairment cohort ( overall range less than 0.1 to 60.4 years ) .
hypertension and diabetes were the most frequently reported causes of renal disease , with incidence rates of 58.5% and 31.9% , respectively .
eighty - three patients ( 9.1% ) were dependent on dialysis and thus assigned to the severe renal impairment cohort .
vascular injuries were reported by 386 patients ( 42.5% ) , with the majority in the cohort with moderate ( 43.0% ) and severe ( 46.1% ) renal impairment .
seventy patients ( 7.7% ) had a history of organ transplant surgery , all in the moderate and severe renal impairment cohort ( table 3 ) .
history of renal disease by degree of renal impairment ( fas ) overall , 228 patients ( 25.1% ) underwent contrast - enhanced mri with another gbca within 12 months before the inclusion in the study start or in the follow - up period .
ninety - seven patients ( 10.7% ) of the 908 were exposed to gadobutrol before the inclusion in the study , and 184 patients ( 20.3% ) received additional different gbcas during follow - up , that is , after gadobutrol administration at baseline .
the number of gbca administrations ranged from 1 ( 114 patients , 12.6% ) to > 5 ( 14 patients , 1.5% ) ( table 4 ) .
two of the patients with more than 5 additional injections of gbcas had received these injections at baseline , and 6 patients received more than 5 additional injections during follow - up .
patients with and number of gbca injections from 12 months before study start ( gadobutrol administration ) and during follow - up ( fas ) during the period immediately after gadobutrol administration and before leaving the mri facility , 3 patients ( 0.3% ) experienced drug - related adverse events ( aes ) : urticaria , retching , and rash .
none of these aes were considered serious or life threatening . during the 24-month follow - up , ae reporting focused on skin - related findings and other findings suggestive of nsf .
patients with mild renal impairment were not included in the follow - up . during this follow - up ,
four patients ( 0.4% ) ( 3 in the moderate , 1 in the severe renal impairment cohort ) suffered a rash , but no patient developed symptoms indicative of nsf .
no serious adverse events occurred between the date of informed consent and the date the patient left the mri facility on the day of gadobutrol injection or during the follow - up .
the frequency of deaths was related to the severity of renal impairment , with 10.9% , 18.1% , and 22.2% of patients in the cohorts with extended moderate , moderate , and severe renal impairment , respectively .
following the fda 's postmarketing requirement for all us - approved gbcas , we voluntarily initiated this study on gadobutrol adhering to the fda 's proposed study design .
this was a preemptive measure as we expected gadobutrol to be approved in the united states shortly .
no case of nsf was detected in our study . to the best of our knowledge ,
this is the first publication of prospective data on the incidence of nsf after gadobutrol administration . as of may 2016 ,
another recent study by amet et al investigated the risk of gadoteric acid in 255 patients on dialysis with no findings of nsf .
in addition , soulez et al reported 2 prospective 2-year studies in 534 patients with either stage 3 chronic kidney disease ( ckd ) or stage 4 to 5 ckd .
no signs or symptoms of nsf were reported after administration of gadobenate dimeglumine or gadoteridol .
smorodinsky et al retrospectively evaluated 1167 patients with chronic liver disease where 72% also had some degree of renal insufficiency .
the gbcas applied in that study were gadobenate dimeglumine , gadoversetamide , gadopentetate dimeglumine , gadodiamide , and gadoteridol .
a total of 284 patients had severe , and 586 had moderate renal impairment , consistent with the target population requested by the fda . in a number of patients ,
the 2 egfr determinations ( one at screening and one immediately before the mri examination at baseline ) resulted in different patient classifications based on the cutoff values for mild , moderate , or severe renal impairment .
some patients who originally fulfilled the criterion for moderate renal impairment at the time of screening actually showed improved renal function at the time of contrast injection .
to reflect a worst - case scenario , we subsumed those patients still in the category of moderate renal impairment and performed a 2-year follow - up . however , to be fully transparent , we reported these patients in a subgroup as  extended moderate 
for the 38 patients in the mild renal disease group an elevated nsf risk has not been established , so follow - up was waived according to protocol .
a total of 228 patients ( 25.1% ) received other , additional gbca administrations 12 months before study start and/or during the 2-year follow - up .
being fully aware that this might confound / harm our primary objective , we still decided to include all these patients in our analysis .
thus , we chose the most conservative approach and report the full - analysis data set that includes all patients who have received at least 1 dose of gadobutrol .
therefore , we feel confident that our study population reflects the clinical reality of patients with renal impairment . in addition , as the increasing number and dose of gbca administrations is postulated to increase the likelihood of triggering nsf development , it appears reassuring that even in patients with exposure to multiple gbcas no case of nsf was observed . in our study cohort , most patients had renal disease caused by hypertension ( 58.5% ) or diabetes ( 31.9% ) , both being very common in the modern western world .
no serious adverse events occurred between the date of informed consent and the date the patient left the mri facility or on the day of gadobutrol injection or during the follow - up period .
our results are in accordance with other reports on gadobutrol use in patients with renal impairment . even in patients with chronic renal impairment , including hemodialysis
, gadobutrol can safely be applied at doses up to 0.3 mmol / kg , providing evidence that gadobutrol is safe in patients with renal impairment . today , gadobutrol is approved in more than 100 countries worldwide , including the european union , switzerland , australia , united states , canada , japan , and china . since its introduction to the market in february 1998 until december 2015 , the cumulative patient exposure is estimated to be more than 29 million patients . as of may 2016 , the pharmacovigilance department of bayer pharma ag has received 3 single - agent reports , so - called unconfounded reports , for gadobutrol consistent with the clinicohistopathological definition of nsf .
this classification was rigorously performed after a most stringent and conservative approach according to the criteria by girardi et al . in case clinicopathological criteria or laboratory parameters
bayer continues to follow a policy of total transparency regarding nsf , with expedited case reporting to health authorities all over the world . finally , it is important to note that the fda and the european medicines agency have defined risk categories for gbcas .
gadobutrol , as well as the 2 other macrocyclic gbcas , gadoterate meglumine and gadoteridol , belong to the class with the lowest risk for nsf development . also , the european society of urogenital radiology ( esur ) followed those categories in their recommendations .
the esur classified macrocyclic agents as  low risk  but still recommends that they should be used with caution in patients with ckd 4 and 5 ( gfr < 30 ml / min per 1.73 m ) , and there should be at least 7 days between 2 injections . furthermore
, pregnant women should only be imaged with contrast - enhanced mri if the expected diagnostic information is essential
. however , laboratory testing of renal function ( egfr ) is not mandatory , and the esur contrast medium safety committee guidelines state that a questionnaire on renal function should be sufficient . on may 23 , 2007 ,
there are several limitations to our study that need to be taken into account when interpreting the results .
although we followed the fda 's stipulations , the sample size must be considered as a major limitation . in a letter dated june 2 , 2011 ,
the fda stated that  the estimate of the incidence of nsf in patients with renal insufficiency , based on postmarketing surveillance reports , is lower than the original literature - based estimate .
 therefore , the trial 's sample size became inadequate to assess the magnitude of nsf risk of gbcas in patients with renal insufficiency .
we stopped enrollment on december 31 , 2012 , but still conducted the 2-year follow - up .
the second limitation is related to the concomitant application of other gbcas during the course of the study .
however , we consider it reassuring that none of these patients developed signs of nsf . because the fda asked all manufacturers of gbcas marketed in the united states to run similar studies , further reports on other gbcas
once all results are available , we suggest that a final assessment of the impact of gbca administration on nsf development should be performed .
gadobutrol in patients with moderate to severe renal impairment did not raise any clinically significant safety signals .
 objectivethe aim of this study was to assess the potential risk of gadobutrol - enhanced magnetic resonance imaging ( mri ) in patients with moderate to severe renal impairment for the development of nephrogenic systemic fibrosis ( nsf).materials and methodswe performed a prospective , international , multicenter , open - label study in 55 centers . 
 patients with moderate to severe renal impairment scheduled for any gadobutrol - enhanced mri were included . 
 all patients received a single intravenous bolus injection of gadobutrol at a dose of 0.1 mmol / kg body weight . 
 the primary target variable was the number of patients who develop nsf within a 2-year follow - up period.resultsa total of 908 patients were enrolled , including 586 with moderate and 284 with severe renal impairment who are at highest risk for developing nsf . 
 the mean time since renal disease diagnosis was 1.83 and 5.49 years in the moderate and severe renal impairment cohort , respectively . 
 overall , 184 patients ( 20.3% ) underwent further contrast - enhanced mri with other gadolinium - based contrast agents within the 2-year follow - up . 
 no patient developed symptoms conclusive of nsf.conclusionsno safety concerns with gadobutrol in patients with moderate to severe renal impairment were identified . 
 there were no nsf cases . 
MATERIALS AND METHODS
Study Design
Study Population
Treatment
Target Variables
Study Procedures
Statistics and Sample Size
RESULTS
DISCUSSION
CONCLUSIONS