Contrast Enhancement in Magnetic Resonance Imaging, Central Nervous System Pathology
Conditions
Brief summary
Researchers are looking for a better way to help people with known or suspected brain or spinal cord-related problems scheduled for a "contrast-enhanced" Magnetic Resonance Imaging (MRI). MRI is used by doctors to create detailed images of the inside of the body to identify health problems. Sometimes doctors need to inject a contrast agent into a patient's vein to perform a so called "contrast-enhanced" MRI (CE-MRI). Such CE-MRI examinations may support doctors to identify certain health problems or improve the evaluation. The contrast agents commonly used in MRI are gadolinium-based contrast agents (GBCAs). GBCAs contain a "rare earth" element called gadolinium (Gd). Gadoquatrane is a new contrast agent under development with a lower amount of Gd needed per CE-MRI. The main purpose of this study is to learn whether CE-MRI scans with gadoquatrane work better than MRI scans without the use of a contrast agent (GBCA). The researchers will compare the ability to detect brain and spinal cord-related problems in gadoquatrane-MRI scans to plain-MRI scans without the use of a contrast agent. The participants will undergo 2 MRI scans, one with gadoquatrane and one with currently used GBCA. Both contrast agents will be injected into the vein. Each participant will be in the study for between 6 and 42 days with up to 7 doctor visits. At the start or during the study, the doctors and their study team will: * take blood and urine samples * do physical examinations * check blood pressure and heart rate * review the MRI scans obtained in the study and decide on the diagnosis * ask the participants questions about how they are feeling and what adverse events they are having. An adverse event is any medical problem that a participant has during a study. Doctors keep track of all adverse events, irrespective if they think it is related or not to the study treatments.
Interventions
0.04 mmol Gd/kg body weight, solution for intravenous injection, single dose
DRUGGadobutrol
Approved standard of care macrocyclic GBCA, 0.1 mmol Gd/kg body weight, solution for intravenous injection, single dose
Approved standard of care macrocyclic GBCA, 0.1 mmol Gd/kg body weight, solution for intravenous injection, single dose
DRUGGadoteridol
Approved standard of care macrocyclic GBCA, 0.1 mmol Gd/kg body weight, solution for intravenous injection, single dose
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
DIAGNOSTIC
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The site staff in charge of the preparation and administration of study intervention will be unblinded and will not be involved in any evaluation of safety and efficacy. The site staff in charge of conducting all other study procedures as per the schedule of activities (SoA) will remain blinded to the study intervention administered.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant must be \>= 18 years of age inclusive, at the time of signing the informed consent form * Participants with a clinical indication for a contrast-enhanced MRI (including MRA), with any approved standard of care macrocyclic GBCA with proven efficacy, safety and tolerability in clinical routine CE-MRI/MRA (gadobutrol, gadoterate meglumine/ gadoteric acid or gadoteridol) that is used at the site for the indication, for a known or suspected CNS pathology * Participants who can undergo study-related procedures, including 2 contrast-enhanced MRI examinations (one with gadoquatrane and one with a comparator macrocyclic GBCA), as per participant and Investigator's judgement * Contraceptive use by female participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies: Is a woman of nonchildbearing potential (WONCBP) OR Is a woman of childbearing potential (WOCBP) and using an acceptable contraceptive method during the study intervention period (at a minimum of 24 hours after the last dose of study intervention)
Exclusion criteria
* Considered clinically unstable or has a concurrent/concomitant condition that may significantly alter image comparability between the 2 study MRIs or between study parameters (e.g. safety, pharmacokinetics \[PK\] parameters) or would not allow participation for the full planned study period, in the judgement of the investigator * Participants presenting with severe renal insufficiency, defined as an estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73 m\^2, derived from a serum or plasma creatinine sample obtained within 48 hours prior to the first contrast agent injection in the study * Participants with acute kidney injury (i.e., acute renal failure), regardless of eGFR * History of moderate to severe allergic-like reaction to any GBCA * Bronchial asthma considered unstable or who have had recent modification to their medical therapy * Receipt of any contrast agent \< 72 h prior to the study MRIs or planned to receive any contrast agent during the trial until 24 h +/- 4 h after the second study MRI * Planned or expected interventional diagnostic or therapeutic procedure (e.g. biopsy or surgery in the region of interest) or change in treatment (e.g. start of chemotherapy or antiangiogenic therapy, significant change in corticosteroids dose) that may significantly alter image comparability between the 2 MRIs or other study parameters (i.e. safety/adverse events (AEs) \[e.g. confounding AEs or safety events due to surgery or chemotherapy\], PK parameters), from the first study MRI up to 24 h after the second study MRI * Has received any investigational product within 30 days, or within 5 times half-life of the investigational product, whatever is shorter, prior to or concurrent with this study * Contraindications to the administration of macrocyclic GBCAs (depending on local product label), or history of adverse reaction to gadoquatrane * Any contraindication to MRI examinations based on institution policy and investigator's clinical judgement (e.g. some metallic implants or active implants)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Visualization Parameter Contrast Enhancement Assessed by Separate Blinded Evaluation of Unenhanced and Combined Pre- and Post-gadoquatrane MRI, by a BICR (Mean Score) | 1 day procedure | contrast enhancement was assessed by blinded independent central review (BICR) readers using separate blinded evaluations of unenhanced MRI image sets and combined pre- and post-contrast gadoquatrane MRI image sets. Contrast enhancement was rated on a 4-point scale (1 = not enhanced; 2 = weakly enhanced; 3 = clearly enhanced; 4 = clearly and brightly enhanced), and mean scores with standard deviation are reported. |
| Visualization Parameter Delineation Assessed by Separate Blinded Evaluation of Unenhanced and Combined Pre- and Post-gadoquatrane MRI, by a BICR (Mean Score) | 1 day procedure | Delineation was assessed by blinded independent central review (BICR) readers using separate blinded evaluations of unenhanced MRI image sets and combined pre- and post-contrast gadoquatrane MRI image sets. Delineation was rated on a 4-point scale (1 = no or unclear delineation; 2 = moderate delineation, with some aspects visible; 3 = good delineation, almost clear but not complete; 4 = excellent delineation, clear and complete), and mean scores with standard deviation are reported. |
| Visualization Parameter Morphology Assessed by Separate Blinded Evaluation of Unenhanced and Combined Pre- and Post-gadoquatrane MRI, by a BICR (Mean Score) | 1 day procedure | Morphology was assessed by blinded independent central review (BICR) readers using separate blinded evaluations of unenhanced MRI image sets and combined pre- and post-contrast gadoquatrane MRI image sets. Morphology was rated on a 3-point scale (1 = poor: no or poorly evaluable; 2 = moderate: partially evaluable; 3 = good: sufficiently evaluable), and mean scores with standard deviation are reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Visualization Parameter Contrast Enhancement Assessed by Blinded Independent Central Review (BICR) Readers on Combined Pre- and Post- Gadoquatrane MRI and Combined Pre- and Post- Comparator MRI With Macrocyclic GBCAs (Mean Score) | 1 day procedure | Contrast enhancement was assessed by blinded independent central review (BICR) readers on combined pre- and post-contrast MRI image sets for gadoquatrane and comparator macrocyclic GBCAs. Enhancement was rated using a 4-point scale (1 = not enhanced; 2 = weakly enhanced; 3 = clearly enhanced; 4 = clearly and brightly enhanced), and mean scores with standard deviation are reported. |
| Visualization Parameter Delineation Assessed by Blinded Independent Central Review (BICR) Readers on Combined Pre- and Post- Gadoquatrane MRI and Combined Pre- and Post- Comparator MRI With Macrocyclic GBCAs (Mean Score) | 1 day procedure | Delineation was assessed by blinded independent central review (BICR) readers on combined pre- and post-contrast MRI image sets for gadoquatrane and comparator macrocyclic GBCAs. Delineation was rated using a 4-point scale (1 = no or unclear delineation; 2 = moderate delineation; 3 = good delineation; 4 = excellent delineation), and mean scores with standard deviation are reported |
| Visualization Parameter Morphology Assessed by Blinded Independent Central Review (BICR) Readers on Combined Pre- and Post- Gadoquatrane MRI and Combined Pre- and Post- Comparator MRI With Macrocyclic GBCAs (Mean Score) | 1 day procedure | Morphology was assessed by blinded independent central review (BICR) readers on combined pre- and post-contrast MRI image sets for gadoquatrane and comparator macrocyclic GBCAs. Morphology was rated on a 3-point scale (1 = poor: no or poorly evaluable; 2 = moderate: partially evaluable; 3 = good: sufficiently evaluable), and mean scores with standard deviation are reported. |
| Sensitivity (%) for the Detection of Lesions of Combined Pre- and Post-gadoquatrane MRI and Combined Pre- and Post-comparator MRI With Macrocyclic GBCAs, by a BICR | 1 day procedure | Sensitivity for the detection of lesions was evaluated by blinded independent central review (BICR) readers using combined pre- and post-contrast MRI image sets for gadoquatrane and comparator macrocyclic GBCAs. Lesion classifications were compared with the composite Standard of Truth (SoT), and sensitivity with corresponding 95% confidence intervals was calculated. |
| Specificity (%) for the Detection of Lesions of Combined Pre- and Post-gadoquatrane MRI and Combined Pre- and Post-comparator MRI With Macrocyclic GBCAs, by a BICR | 1 day procedure | Specificity for the detection of lesions was evaluated by blinded independent central review (BICR) readers using combined pre- and post-contrast MRI image sets for gadoquatrane and comparator macrocyclic GBCAs. Lesion classifications were compared with the composite Standard of Truth (SoT), and specificity with corresponding 95% confidence intervals was calculated. |
| Mean Overall Diagnostic Clinical Value Score From Combined Pre- and Post-gadoquatrane MRI and Combined Pre- and Post-comparator MRI With Macrocyclic GBCAs | 1 day procedure | Overall diagnostic clinical value was assessed by blinded independent central review (BICR) readers based on combined pre- and post-contrast MRI image sets for gadoquatrane and comparator macrocyclic GBCAs. Clinical value was rated using a 5-point scale (1 = no diagnostic clinical value to 5 = excellent diagnostic clinical value), reflecting diagnostic performance and impact on patient management. Mean scores with standard deviation are reported. |
| Sensitivity (%) for the Detection of Malignant Lesions of Combined Pre- and Post-gadoquatrane MRI and Combined Pre- and Post-comparator MRI With Macrocyclic GBCAs Assessed by BICR and the Investigator | 1 day procedure | Sensitivity for the detection of malignant lesions was evaluated by blinded independent central review (BICR) readers and by the investigator/designee using combined pre- and post-contrast MRI image sets for gadoquatrane and comparator macrocyclic GBCAs. Lesion assessments were compared with the composite Standard of Truth (SoT), and sensitivity with corresponding 95% confidence intervals was calculated. |
| Specificity (%) for the Detection of Malignant Lesions of Combined Pre- and Post-gadoquatrane MRI and Combined Pre- and Post-comparator MRI With Macrocyclic GBCAs Assessed by BICR and the Investigator | 1 day procedure | Specificity for the detection of malignant lesions was evaluated by blinded independent central review (BICR) readers and by the investigator/designee using combined pre- and post-contrast MRI image sets for gadoquatrane and comparator macrocyclic GBCAs. Lesion assessments were compared with the composite Standard of Truth (SoT), and specificity with corresponding 95% confidence intervals was calculated. |
| Number of Cases With Concordance Between Final Diagnosis and MRI Diagnosis From Combined Pre- and Post- Gadoquatrane MRI and Combined Pre- and Post- Comparator MRI With Macrocyclic GBCAs, as Assessed by the Investigator | 1 day procedure | The investigator or designee, who remained blinded to the contrast agent used, assessed the diagnosis based on combined pre- and post-contrast MRI image sets for each period. Concordance between the MRI-based diagnosis and the final clinical diagnosis was evaluated, and the number of cases with matching and non-matching diagnoses was summarized. |
| Mean Confidence in Diagnosis Score From Combined Pre- and Post- Gadoquatrane MRI and Combined Pre- and Post-comparator MRI With Macrocyclic GBCAs by BICR and by Investigator on 4PS | 1 day procedure | Confidence in diagnosis was assessed by blinded independent central review (BICR) readers and the investigator to determine the level of certainty in the assigned diagnosis based on combined pre- and post-contrast MRI image sets for gadoquatrane and comparator macrocyclic GBCAs. Confidence was scored using a 4-point scale (1 = Not confident, 2 = Somewhat confident, 3 = Confident, 4 = Very confident), and mean scores with standard deviation are reported. |
| Mean Number of Lesions Seen on Unenhanced MRI Image Set and Combined Pre- and Post-gadoquatrane MRI and Combined Pre- and Post-comparator MRI With Macrocyclic GBCAs, by a BICR | 1 day procedure | Determination of the mean number of lesions visualized on the combined CE-MR image sets for gadoquatrane and SoC GBCAs, in comparison to the respective pre-contrast MRI, assessed by blinded independent central review (BICR). A lesion is defined as a localized, clinically relevant pathological change in a tissue due to injury or disease. In the context of medical imaging, it is defined as the localization of a pathology which might be visualized on the MRI; the term lesion will be used when referring to a pathology noted on the MR image. |
| Number of Enhancing Lesions Seen on Combined Pre- and Post- Gadoquatrane MRI and Combined Pre- and Post-comparator MRI With Macrocyclic GBCAs, by a BICR | 1 day procedure | Evaluation of any differences in the number of enhancing lesions between the combined gadoquatrane and SoC GBCA MR image sets, as assessed by blinded independent central review (BICR) readers |
| Number of Participants With Treatment Emergent Adverse Events, Including Number of Serious Adverse Events, After Administration of Gadoquatrane Compared to Macrocyclic GBCAs Reported by the Investigator | Within 24 ± 4 hours after administration of gadoquatrane or any approved macrocyclic GBCAs | Treatment-emergent adverse events (AEs), including serious adverse events, are defined as events occurring from the start of study intervention until follow-up (24 ± 4 hours post-injection) |
| Number of Participants With Treatment Emergent Adverse Events, Per Intensity, After Administration of Gadoquatrane Compared to Macrocyclic GBCAs Reported by the Investigator | Within 24 ± 4 hours after administration of gadoquatrane or any approved macrocyclic GBCAs | Treatment-emergent (serious) AEs are defined as events occurring from the start of study intervention until follow-up (24 ± 4 hours post-injection). Participants with at least one treatment-emergent adverse event are counted once and categorized according to the maximum intensity of their adverse events (mild, moderate, or severe), as assessed by the investigator. |
Countries
Argentina, Bulgaria, Canada, China, Czechia, France, Germany, Hungary, Italy, Japan, South Korea, Sweden, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Overall, 321 participants were enrolled, defined in the protocol as participants who signed the Inform Consent Form (ICF) at 71 study centers in 15 countries. Of these,16 were screen failures. A total of 305 participants were assigned to one of the randomization groups and started period 1. 301 participants completed the study Period 1, and 294 completed the study period 2. First patient first visit (FPFV) was conducted on 24 JUL 2023, last patient last visit (LPLV) completed on 31 MAY 2024.
Pre-assignment details
During period 1 of the cross-over, each participant was randomized in a 1:1 ratio to first receive either gadoquatrane or an approved macrocyclic GBCA (gadobutrol, gadoterate meglumine/ gadoteric acid, or gadoteridol). After a wash-out period, of at least 72 hours, participants switched treatments in a blinder manner for Period 2, which was performed 72 hours to 14 days after Period 1.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 55.9 years STANDARD_DEVIATION 14.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 42 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) White | 196 Participants |
| Sex: Female, Male Female | 77 Participants |
| Sex: Female, Male Male | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 299 | 0 / 299 |
| other Total, other adverse events | 40 / 299 | 44 / 299 |
| serious Total, serious adverse events | 2 / 299 | 0 / 299 |
Outcome results
None listed