Gadobutrol Pharmacokinetic and Safety Study in Pediatric Subjects Aged <2 Years (Term Newborn Infants to Toddlers 23 Months of Age Inclusive)

Study Overview
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Brief Summary
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The main purpose of this study is to collect data on the way gadobutrol is taken into, moves around, and is eliminated from, the body of children aged 0 to less than 2 years. The study will also evaluate safety and tolerability, and efficacy of gadobutrol. A maximum total amount of approximately 5 ml of blood will be needed for these analyses which will be drawn within 2-3 days. Gadobutrol is a contrast agent used for enhancement of Magnetic Resonance Imaging (MRI), potentially allowing better visibility of tissues in the body. Children aged under 2 years scheduled for a routine contrast-enhanced MRI examination of any body region may take part in this study, in which case they will receive gadobutrol as contrast agent intravenously at the standard dose of 0.1 mmol/kg (0.1 ml/Kg) of body weight. Only subjects without renal insufficiency of any intensity (i.e. estimated Glomerular Filtration Rate <80% of age adjusted normal value calculated based on the Schwartz formula) will be included in the trial. The duration of this study as a whole is around 1 year and the total number of children to be enrolled is 50. A child will be expected to take part in the study for around 7 days.

Official Title
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Open-label, Multicenter, Pharmacokinetic, and Safety Study in Children (Term Newborn Infants to 23 Months of Age) Undergoing a Contrast-enhanced MRI With an Intravenous Injection of 0.1 mmol/kg BW Gadobutrol 1.0 M

Conditions
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Magnetic Resonance Imaging

Intervention / Treatment
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* Drug: Gadobutrol (Gadavist, BAY86-4875)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pediatric subjects aged <2 years (term newborn infants to toddlers 23 months of age inclusive) Subject is scheduled to undergo routine gadolinium-enhanced MRI of any body region Exclusion Criteria: Subjects undergoing a change in chemotherapy within 48 hours prior to and up to 24 hours after gadobutrol injection Any planned intervention during the study and up to 24 hours after gadobutrol injection (excluding lumbar puncture) Subjects who received or will receive any investigational product within 48 hours before gadobutrol injection or during study participation Subjects who received or will receive any other contrast agent within 48 hours prior to gadobutrol injection or up to 24 hours after gadobutrol injection Subjects with contraindication for MRI such as iron metal implants (e.g. aneurysm clips) History of anaphylactoid or anaphylactic reaction to any allergen including drugs and contrast agents Subject with renal insufficiency of any intensity, i.e. estimated Glomerular Filtration Rate <80% of age adjusted normal value calculated based on the Schwartz formula

Ages Eligible for Study
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Maximum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Overall study<br> | Drug: Gadobutrol (Gadavist, BAY86-4875)<br>* Single intravenous bolus injection of gadobutrol 0.1 mmol/kg BW in term newborns to infants <2 years of age.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to Infinity of Gadobutrol: Individual | AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUC from time 0 (start of injection) to infinity was reported in micromole*hour per liter (micromole*h/L). | Blood samples were collected at 3 timepoints between 15 minutes and 8 hours post administration of gadobutrol | 
| Body Weight-Normalized Total Body Clearance (CL) of Gadobutrol From Plasma: Individual | Clearance is the volume of the fluid presented to the eliminating organ that is effectively completely cleared of drug per unit time and depends on the rate of elimination. CL of gadobutrol normalized for body weight, was reported in Liter per hour per kilogram (L/(h*kg). | Blood samples were collected at 3 timepoints between 15 minutes and 8 hours post administration of gadobutrol | 
| Body Weight-Normalized Apparent Volume of Distribution at Steady State (Vss) of Gadobutrol in Plasma: Individual | Vss is an estimate of drug distribution independent of the elimination process and is proportional to the amount of drug in the body versus the drug plasma concentration at steady-state. | Blood samples were collected at 3 timepoints between 15 minutes and 8 hours post administration of gadobutrol | 
| Mean Residence Time (MRT) of Gadobutrol in Plasma: Individual | MRT is the average time that the molecules introduced into the body stay in the body. MRT of Gadobutrol is expressed in hours. | Blood samples were collected at 3 timepoints between 15 minutes and 8 hours post administration of gadobutrol | 
| Terminal Elimination Half-Life (t1/2) of Gadobutrol From Plasma: Individual | Half-life refers to the elimination of the drug, that is, the time it takes for the blood plasma concentration to reach half the concentration. Terminal elimination half-life of gadobutrol from plasma is expressed in hours and is derived from the terminal slope of the concentration versus time curve. | Blood samples were collected at 3 timepoints between 15 minutes and 8 hours post administration of gadobutrol | 
| Simulation of Plasma Concentration of Gadobutrol at 20 Minutes Post-Injection (C20) | Simulation is the use of the model to predict data other than observed data, in this case early Gadobutrol plasma concentration after intravenous injection. Plasma concentration serves as a surrogate for efficacy (signal and contrast enhancement) in MRI. C20 was simulated for virtual pediatric subjects with homogenous distribution over age. Simulated median (5th and 95th percentile in parenthesis) gadolinium plasma concentrations for a dose of 0.1 mmol/kg body weight were presented. | 20 minutes post-injection | 
| Simulation of Plasma Concentration of Gadobutrol at 30 Minutes Post-Injection (C30) | Simulation is the use of the model to predict data other than observed data, in this case early Gadobutrol plasma concentration after intravenous injection. Plasma concentration serves as a surrogate for efficacy (signal and contrast enhancement) in MRI. C30 was simulated for virtual pediatric subjects with homogenous distribution over age. Simulated median (5th and 95th percentile in parenthesis) gadolinium plasma concentrations for a dose of 0.1 mmol/kg body weight were presented. | 30 minutes post-injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Anatomical Area Evaluated | Subjects were referred for MRI of any body region. The primary anatomical area to be evaluated by MRI was assessed. Anatomical Area was recorded prior to gadobutrol injection for the unenhanced MRI procedure and after gadobutrol injection for the gadobutrol-enhanced MRI procedure. Evaluation was done on pre-injection and combined (pre- and post-injection) images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects With Technical Adequacy for Diagnosis | The technical adequacy of the unenhanced image set and the combined unenhanced and enhanced image set was assessed based on the following 4 point scale: 1=Region visualized with artifacts compromising quality and interpretability of images, 2=Only partial evaluation of images possible, region not covered adequately anatomically, 3=Region visualized with artifacts, partially compromising image quality but evaluation and diagnosis still possible, 4=Region clearly visualized, excellent quality. Evaluation was done on pre-injection and combined (pre- and post-injection) images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects With Technical Adequacy for Diagnosis by Body Region | The technical adequacy of the the unenhanced image set and the combined unenhanced and enhanced image set was assessed based 4-point scale and body region. Four-point scale: 1=Region visualized with artifacts compromising quality and interpretability of images, 2=Only partial evaluation of images possible, region not covered adequately anatomically, 3=Region visualized with artifacts, partially compromising image quality but evaluation and diagnosis still possible, 4=Region clearly visualized, excellent quality. Evaluation was done on pre-injection and combined images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects by Overall Contrast Quality | A qualitative assessment of the overall contrast using the following pre-defined 5-point scale: 1= None (for example, in case of a non-enhancing vessel), 2= Poor, 3= Moderate, 4= Good, 5= Excellent, was done. This parameter was assessed in the postcontrast MRI only, which is evaluated together with the unenhanced, this is why it is called combined. Data for combined MRI set was reported. | Images were taken post-injection (within about 15 minutes) | 
| Number of Subjects by Overall Contrast Quality by Body Region | A qualitative assessment of the overall contrast using the following pre-defined 5-point scale: 1= None (for example, in case of a non-enhancing vessel), 2= Poor, 3= Moderate, 4= Good, 5= Excellent, was done in the postcontrast MRI only, which is evaluated together with the unenhanced, this is why it is called combined. Data for combined MRI set was reported. | Images were taken post-injection (within about 15 minutes) | 
| Number of Subjects With Presence of Pathology | Presence of pathology was assessed for unenhanced and combined MRI sets and recorded as yes/no. The number of lesions identified for each MRI set was recorded. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects With Presence of Pathology by Body Region | Presence of pathology was assessed for unenhanced and combined MRI sets and recorded as yes/no. The number of lesions identified for each MRI set was recorded. Results per body region were reported. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects With Number of Lesions Detected | Presence of pathology included presence of lesions and was recorded as yes/no. If yes the number of subjects with specified lists of lesions and body region was reported. Evaluation was done on pre- injection and combined (pre- and post-injection) images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects With Number of Lesions Detected by Body Region | Presence of pathology included presence of lesions and was recorded as yes/no. If yes the number of subjects with specified lists of lesions and body region was reported. Evaluation was done on pre- injection and combined (pre- and post-injection) images. Data of subjects with missing number of lesions or at least one lesion in unenhanced and combined MRI sets were reported. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Contrast Enhancement in Lesion or Vessel | The contrast-enhancement for each lesion or vessel was recorded on a 4-point scale: 1 = None, lesion or vessel is not enhanced; 2 = Moderate, lesion or vessel is weakly enhanced; 3 = Good, lesion or vessel is clearly enhanced; 4 = Excellent, lesion or vessel is clearly and brightly enhanced. Evaluation was done on pre-injection and combined (pre- and post-injection) images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Contrast Enhancement in Lesion or Vessel by Body Region | The contrast-enhancement for each lesion or vessel was recorded on a 4-point scale: 1 = None, lesion or vessel is not enhanced; 2 = Moderate, lesion or vessel is weakly enhanced; 3 = Good, lesion or vessel is clearly enhanced; 4 = Excellent, lesion or vessel is clearly and brightly enhanced. Results per body regions were reported. Evaluation was done on pre-injection and combined (pre- and post-injection) images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects With Border Delineation of Lesion of Vessel | The border delineation for each lesion or vessel was recorded on a 4-point scale: 1 = None, no or unclear delineation of the boundary between the lesion or vessel and the surrounding tissue; 2 = Moderate, some aspects of border delineation covered; 3 = Good, almost clear delineation, but not complete on relevant slices; 4 = Excellent, clear and complete delineation.Evaluation was done on pre-injection and combined (pre- and post-injection) images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects With Border Delineation of Lesion of Vessel by Body Region | The border delineation for each lesion or vessel was recorded on a 4-point scale: 1 = None, no or unclear delineation of the boundary between the lesion or vessel and the surrounding tissue; 2 = Moderate, some aspects of border delineation covered; 3 = Good, almost clear delineation, but not complete on relevant slices; 4 = Excellent, clear and complete delineation.The results per body regions were reported. Evaluation was done on pre-injection and combined (pre- and post-injection) images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects by Visualization of Lesion-Internal Morphology or Homogeneity of Vessel Enhancement | The degree of visualization of internal morphology and structure was recorded on a 3-point scale: 1= Poor, the structure and internal morphology of the lesion or vessel is poorly visible; 2 = Moderate, the structure and internal morphology of the lesion or vessel is visible but sufficient information cannot be obtained; 3 = Good, the structure and internal morphology of the lesion or vessel is sufficiently visible for diagnostic purposes.Evaluation was done on pre-injection and combined (pre- and post-injection) images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects by Visualization of Lesion-Internal Morphology or Homogeneity of Vessel Enhancement by Body Region | The degree of visualization of internal morphology and structure was recorded on a 3-point scale: 1 = Poor, the structure and internal morphology of the lesion or vessel is poorly visible; 2 = Moderate, the structure and internal morphology of the lesion or vessel is visible but sufficient information cannot be obtained; 3 = Good, the structure and internal morphology of the lesion or vessel is sufficiently visible for diagnostic purposes. Results per body regions were reported. Evaluation was done on pre-injection and combined (pre- and post-injection) images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects With Diagnoses | The following diagnoses were reported for both the unenhanced MRI and the combined MRI image sets: Other diagnoses, No lesions/normal, Congenital disease/syndrome, Malignant lesion, Inflammation, Structural malformation, Benign lesion, and Vascular malformation. Evaluation was done on pre- injection and combined (pre- and post-injection) images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects With Diagnoses by Body Region | The following diagnoses were reported for both the unenhanced MRI and the combined MRI image sets: Other diagnoses, No lesions/normal, Congenital disease/syndrome, Malignant lesion, Inflammation, Structural malformation, Benign lesion, and Vascular malformation. Results per body regions were reported. Evaluation was done on pre-injection and combined (pre- and post-injection) images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects With Additional Diagnostic Gain | Additional diagnostic gain by the contrast-enhanced image set was assessed on a 3-point scale: scale 1 = Initial diagnosis unchanged, scale 2 = Initial diagnosis changed - improved, i.e. more specific, and scale 3 = Initial diagnosis changed -new diagnosis. Evaluation was done on combined (pre- and post- injection) images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects With Additional Diagnostic Gain by Body Region | Additional diagnostic gain by the contrast-enhanced image set was assessed on a 3-point scale: scale 1 = Initial diagnosis unchanged, scale 2 = Initial diagnosis changed - improved, i.e. more specific, and scale 3 = Initial diagnosis changed -new diagnosis. Results per body regions were reported. Evaluation was done on pre-injection and combined (pre- and post-injection) images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects With Confidence in Diagnosis | Diagnostic confidence based on the unenhanced MRI image sets and thereafter on the combined MRI image sets were assessed on a 3-point scale, as 1 = Not confident, 2 = Confident and 3 = Very confident. Evaluation was done on pre-injection and combined (pre- and post-injection) images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects With Confidence in Diagnosis by Body Region | Diagnostic confidence based on the unenhanced MRI image sets and thereafter on the combined MRI image sets were assessed on a 3-point scale, as 3 = Very confident, 2 = Confident, and 1 = Not confident. Results per body regions were reported. Evaluation was done on pre-injection and combined (pre- and post-injection) images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects With Final Diagnosis | The final diagnosis of the subjects was based on all clinical information available and was provided separately within 4 weeks after MRI. Evaluation was done on pre-injection and combined (pre- and post- injection) images. | Up to 4 weeks post-injection | 
| Number of Subjects With Final Diagnosis by Body Region | The final diagnosis of the subjects was based on all clinical information available and was provided separately within 4 weeks after MRI. Results per body regions were reported. Evaluation was done on pre-injection and combined (pre- and post-injection) images. Only subjects with final diagnosis were reported. | Up to 4 weeks post-injection | 
| Number of Subjects With Change in Diagnosis From Unenhanced to Combined MRI | The analysis value for change in diagnosis was recorded as yes/no. Evaluation was done on pre- injection and combined (pre- and post-injection) images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects With Change in Diagnosis From Unenhanced to Combined MRI by Body Region | The analysis value for change in diagnosis was recorded as yes/no. Results per body regions were reported. Evaluation was done on pre-injection and combined (pre- and post-injection) images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects With Change in Diagnosis From Unenhanced MRI to Final Diagnosis | The analysis value for change in diagnosis was recorded as yes/no. Evaluation was done on pre- injection and combined (pre- and post-injection) images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects With Change in Diagnosis From Unenhanced MRI to Final Diagnosis by Body Region | The analysis value for change in diagnosis was recorded as yes/no. Results per body regions were reported. Evaluation was done on pre-injection and combined (pre- and post-injection) images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects With Change in Diagnosis From Combined MRI to Final Diagnosis | The analysis value for change in diagnosis was recorded as yes/no. Evaluation was done on pre- injection and combined (pre- and post-injection) images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects With Change in Diagnosis From Combined MRI to Final Diagnosis by Body Region | The analysis value for change in diagnosis was recorded as yes/no. Results per body regions were reported. Evaluation was done on pre-injection and combined (pre- and post-injection) images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects With Change in Management From Unenhanced to Combined MRI | The subject management was indicated based on the unenhanced images alone. The analysis value for change in subject management was recorded as yes/no. Evaluation was done on pre-injection and combined (pre- and post-injection) images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects With Change in Management From Unenhanced to Combined MRI by Body Region | The subject management was indicated based on the unenhanced images alone. The analysis value for change in subject management was recorded as yes/no. Results per body regions were reported. Evaluation was done on pre-injection and combined (pre- and post-injection) images. | Images were taken pre-injection and post-injection (within about 15 minutes) | 
| Number of Subjects With Clinically Significant Abnormal Laboratory Values | Change in post-injection test values, such as resulting in a change in subject management or which were not the result of laboratory error and were considered clinically significant by the investigator was reported. | Baseline (not exceeding 24 hours before Gadobutrol injection) up to 24 hours post injection | 
| Estimated Glomerular Filtration Rate (eGFR) Prior to Gadobutrol Injection | eGFR was calculated based on the Schwartz formula with blood sampling for serum creatinine (Scr) not exceeding 14 days prior to gadobutrol injection. Otherwise, the eGFR was obtained from the original Schwartz formula: eGFR = k * height / Scr where k = 0.45 in term newborn infants < 1 year of age, and k = 0.55 in children up to 13 years of age. If Scr was measured by an enzymatic creatinine method that had been calibrated to be traceable to Isotope dilution mass spectroscopy (IDMS), the updated Schwartz formula was used: eGFR = 0.413*height/Scr. | Before gadobutrol injection | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gadolinium, Pediatrics, MRI, contrast