CNS Lesion, Blood Brain Barrier Defect
Conditions
Brief summary
The purpose of this study was to determine a safe and effective dose of a new gadolinium-based contrast agent (GBCA) P03277 based on the Contrast to Noise Ratio (CNR) when comparing with gadobenate dimeglumine (MultiHance®) at 0.1 mmol/kg body weight (BW). Contrast to Noise Ratio (CNR), a well-known quantitative parameter directly related to contrast medium/GBCA efficacy, was chosen as the primary endpoint in order to have a precise determination of P03277 clinical dose. This was a multi-center, international, prospective, double-blind, randomized, controlled, parallel dose groups, cross-over with comparator study in male and female subjects presenting with known or highly suspected focal areas of disruption of the Blood Brain Barrier including at least one expected enhancing lesion of minimum 5 mm, who were scheduled to undergo a routine contrast-enhanced Magnetic Resonance Imaging (MRI) of Central Nervous System.
Detailed description
Two subsets of subjects were included in the study: * The subset 1 included the first randomized subject of each study center. Subjects were randomly assigned in a 1:1 ratio to receive 0.05 or 0.1 mmol/kg BW of P03277 and 0.1 mmol/kg BW of gadobenate dimeglumine. * Subset 2 was composed of all subjects (except the first one of each study center) selected by the study center. Subjects were randomly assigned in a 1:1:1:1 ratio to receive 0.025, 0.05, 0.1 or 0.2 mmol/kg BW of P03277 and 0.1 mmol/kg BW of gadobenate dimeglumine. During the course of the study, two MRIs were obtained from each subject: one unenhanced and P03277-enhanced MRI; and one unenhanced and gadobenate dimeglumine-enhanced MRI. MRI images were evaluated off-site by 3 independent blinded readers for the primary endpoint (CNR).
Interventions
DRUGP03277
Single intravenous (IV) bolus injection at a rate of 2 mL/second
Single IV bolus injection at a rate of 2 mL/second
DEVICEMRI
Sponsors
Guerbet
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Female or male adult subjects, with known or highly suspected focal areas of disrupted Blood Brain Barrier including at least one expected enhancing lesion of minimum 5 mm (long axis). This lesion had been detected on a previous imaging procedure (computerized Tomography \[CT\] or MRI). * Subject scheduled for a routine contrast-enhanced MRI examination of Central Nervous System for clinical reasons and agreeing to have a second contrast-enhanced MRI examination for the purpose of the study.
Exclusion criteria
* Subject presenting with acute or chronic Grade III (at least) renal insufficiency, defined as an estimated Glomerular Filtration Rate (eGFR) \<60 mL/min/1.73 m² based on one eGFR assessment performed the day of the MRI prior to the first contrast agent injection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Contrast to Noise Ratio (CNR) Difference | 1 day procedure | The Contrast-to-Noise Ratio (CNR) was calculated from the signal intensity measurement of maximum 3 enhanced lesions by 3 independent blinded readers. Only lesions detected by both MRIs after lesion tracking were used. The difference in CNR was calculated as follow: CNR (P03277) - CNR (gadobenate dimeglumine). |
Countries
Belgium, Czechia, Hungary, Italy, Mexico, Poland, South Korea, United States
Participant flow
Pre-assignment details
Among the 312 screened subjects, 32 subjects were screening failure. 280 subjects were randomized: 28 in subset 1 and 252 in subset 2. Images from the subset 1 were used for training of off-site readers and validation of imaging protocol. Consequently, these subjects were not included in the efficacy analysis but only in the safety assessment.
Participants by arm
| Arm | Count |
|---|---|
| Subset 2 - P03277 0.025 mmol/kg/Gadobenate Dimeglumine P03277 (0.025 mmol/kg)-enhanced MRI and gadobenate dimeglumine (0.1 mmol/kg)-enhanced MRI | 57 |
| Subset 2 - P03277 0.05 mmol/kg/Gadobenate Dimeglumine P03277 (0.05 mmol/kg)-enhanced MRI and gadobenate dimeglumine (0.1 mmol/kg)-enhanced MRI | 62 |
| Subset 2 - P03277 0.1 mmol/kg/Gadobenate Dimeglumine P03277 (0.1 mmol/kg)-enhanced MRI and gadobenate dimeglumine (0.1 mmol/kg)-enhanced MRI | 61 |
| Subset 2 - P03277 0.2 mmol/kg/Gadobenate Dimeglumine P03277 (0.2 mmol/kg)-enhanced MRI and gadobenate dimeglumine (0.1 mmol/kg)-enhanced MRI | 60 |
| Subset 1 - P03277 0.05 mmol/kg/Gadobenate Dimeglumine P03277 (0.05 mmol/kg)-enhanced MRI and gadobenate dimeglumine (0.1 mmol/kg)-enhanced MRI | 14 |
| Subset 1 - P03277 0.1 mmol/kg/Gadobenate Dimeglumine P03277 (0.1 mmol/kg)-enhanced MRI and gadobenate dimeglumine (0.1 mmol/kg)-enhanced MRI | 14 |
| Total | 268 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 | 2 | 0 |
| Overall Study | Various other reasons | 0 | 2 | 4 | 1 | 7 | 11 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 2 | 2 | 1 | 3 |
Baseline characteristics
| Characteristic | Subset 1 - P03277 0.05 mmol/kg/Gadobenate Dimeglumine | Total | Subset 1 - P03277 0.1 mmol/kg/Gadobenate Dimeglumine | Subset 2 - P03277 0.2 mmol/kg/Gadobenate Dimeglumine | Subset 2 - P03277 0.1 mmol/kg/Gadobenate Dimeglumine | Subset 2 - P03277 0.05 mmol/kg/Gadobenate Dimeglumine | Subset 2 - P03277 0.025 mmol/kg/Gadobenate Dimeglumine |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 54.9 years STANDARD_DEVIATION 13.3 | 53.8 years STANDARD_DEVIATION 13.5 | 56.1 years STANDARD_DEVIATION 16 | 52.1 years STANDARD_DEVIATION 13.7 | 54.2 years STANDARD_DEVIATION 14.4 | 54.0 years STANDARD_DEVIATION 14.8 | 54.8 years STANDARD_DEVIATION 10.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 28 Participants | 1 Participants | 4 Participants | 8 Participants | 5 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 12 Participants | 2 Participants | 2 Participants | 4 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 226 Participants | 11 Participants | 54 Participants | 49 Participants | 55 Participants | 47 Participants |
| Sex: Female, Male Female | 10 Participants | 157 Participants | 5 Participants | 39 Participants | 30 Participants | 39 Participants | 34 Participants |
| Sex: Female, Male Male | 4 Participants | 111 Participants | 9 Participants | 21 Participants | 31 Participants | 23 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 56 | 0 / 74 | 0 / 70 | 0 / 56 | 0 / 256 |
| other Total, other adverse events | 14 / 56 | 12 / 74 | 19 / 70 | 18 / 56 | 57 / 256 |
| serious Total, serious adverse events | 0 / 56 | 0 / 74 | 1 / 70 | 1 / 56 | 2 / 256 |
Outcome results
Primary
Contrast to Noise Ratio (CNR) Difference
The Contrast-to-Noise Ratio (CNR) was calculated from the signal intensity measurement of maximum 3 enhanced lesions by 3 independent blinded readers. Only lesions detected by both MRIs after lesion tracking were used. The difference in CNR was calculated as follow: CNR (P03277) - CNR (gadobenate dimeglumine).
Time frame: 1 day procedure
Population: The analysis was done for each of the 3 independent off-site readers using the Per Protocol Set that included all subjects without major protocol deviations. A subject was analyzed as soon as he had a matching evaluation of the CNR at both MRIs by at least 1 off-site reader. Therefore, the numbers of subjects analyzed by reader could be different.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| P03277 0.025 mmol/kg - Gadobenate Dimeglumine - Reader 1 | Contrast to Noise Ratio (CNR) Difference | -10.59 Ratio |
| P03277 0.05 mmol/kg - Gadobenate Dimeglumine - Reader 1 | Contrast to Noise Ratio (CNR) Difference | 2.18 Ratio |
| P03277 0.1 mmol/kg - Gadobenate Dimeglumine - Reader 1 | Contrast to Noise Ratio (CNR) Difference | 8.66 Ratio |
| P03277 0.2 mmol/kg - Gadobenate Dimeglumine - Reader 1 | Contrast to Noise Ratio (CNR) Difference | 14.45 Ratio |
| P03277 0.025 mmol/kg - Gadobenate Dimeglumine - Reader 2 | Contrast to Noise Ratio (CNR) Difference | -14.14 Ratio |
| P03277 0.05 mmol/kg - Gadobenate Dimeglumine - Reader 2 | Contrast to Noise Ratio (CNR) Difference | 1.91 Ratio |
| P03277 0.1 mmol/kg - Gadobenate Dimeglumine - Reader 2 | Contrast to Noise Ratio (CNR) Difference | 19.38 Ratio |
| P03277 0.2 mmol/kg - Gadobenate Dimeglumine - Reader 2 | Contrast to Noise Ratio (CNR) Difference | 38.37 Ratio |
| P03277 0.025 mmol/kg - Gadobenate Dimeglumine - Reader 3 | Contrast to Noise Ratio (CNR) Difference | -23.96 Ratio |
| P03277 0.05 mmol/kg - Gadobenate Dimeglumine - Reader 3 | Contrast to Noise Ratio (CNR) Difference | 2.47 Ratio |
| P03277 0.1 mmol/kg - Gadobenate Dimeglumine - Reader 3 | Contrast to Noise Ratio (CNR) Difference | 29.23 Ratio |
| P03277 0.2 mmol/kg - Gadobenate Dimeglumine - Reader 3 | Contrast to Noise Ratio (CNR) Difference | 51.96 Ratio |
Comparison: Holm's Step-Down MethodMixed Models Analysis
Comparison: Holm's Step-Down Methodp-value: 0.1858Mixed Models Analysis
Comparison: Holm's Step-Down Methodp-value: 0.0007Mixed Models Analysis
Comparison: Holm's Step-Down Methodp-value: <0.0001Mixed Models Analysis
Comparison: Holm's Step-Down MethodMixed Models Analysis
Comparison: Holm's Step-Down Methodp-value: 0.3384Mixed Models Analysis
Comparison: Holm's Step-Down Methodp-value: <0.0001Mixed Models Analysis
Comparison: Holm's Step-Down Methodp-value: 0.0002Mixed Models Analysis
Comparison: Holm's Step-Down MethodMixed Models Analysis
Comparison: Holm's Step-Down Methodp-value: 0.3249Mixed Models Analysis
Comparison: Holm's Step-Down Methodp-value: <0.0001Mixed Models Analysis
Comparison: Holm's Step-Down Methodp-value: <0.0001Mixed Models Analysis