Known or Highly Suspected Body (Excluding CNS) Lesion, Known or Highly Suspected Central Nervous System (CNS) Lesion
Conditions
Keywords
Contrast-enhanced magnetic resonance imaging (MRI), Mn-based contrast agents (MBCAs), Gd-based contrast agents (GBCAs), Lesion visualization
Brief summary
This is an operationally combined Phase 2/3 study, which will be conducted and evaluated in 2 distinct parts: * Phase 2: Prospective, adaptive, multicenter, non-randomized, single-blind, dose-finding, including participants with known or highly suspected lesions of the CNS. The aim of the Phase 2 part is to identify an optimized dose of mangaciclanol for the Phase 3 part of the study. * Phase 3: Prospective, multicenter, randomized, controlled, single-blind, cross-over, including participants with known or highly suspected lesions of the CNS or body. The aim of the Phase 3 part is to further evaluate the efficacy and safety of mangaciclanol-enhanced MRI for the detection and characterization of lesions of the CNS or body. The investigational medicinal products (IMPs) used during the trial are mangaciclanol and gadobutrol (comparator IMP). Primary and key secondary efficacy analyses will be based on independent central blinded image evaluation (BIE), and Phase 2 data will be analyzed prior to commencement of Phase 3.
Interventions
DRUGMangaciclanol, also known as GEH200486 Injection, 0.5 mmol/mL
Single intravenous (IV) administration of Mangaciclanol (GEH200486 Injection, 0.5 mmol/mL) followed by a 20mL saline flush
DIAGNOSTIC_TESTMRI Scan
MRI Scan starting prior to IMP administration and continuing for up to 60 minutes post IMP administration
DRUGGadobutrol
Single intravenous (IV) administration of Gadobutrol (0.1 mmol/kg) followed by a 20mL saline flush
Sponsors
GE Healthcare
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
DIAGNOSTIC
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The participant is of legal majority age, as defined by local laws and regulations at the time of signing the ICF. * The participant is able and willing to comply with study procedures as described in the protocol. * The participant has read, understood, signed and dated the ICF prior to any study procedures. * Phases 2 and 3 CNS: Participants presenting with known or highly suspected enhancing CNS lesions referred as part of standard care for contrast-enhancing MRI of the CNS. The suspicion may be based on a previous imaging procedure such as computed tomography (CT), positron emission tomography (PET)/CT or MRI performed within 12 months prior to ICF signature. * Phase 3 body only: Participants presenting with known or highly suspected enhancing lesions in at least 1 body region (i.e., head and neck, thorax, abdomen, pelvis, and musculoskeletal system \[only breast in the United States in compliance with local approved indications of gadobutrol\]) referred as part of standard care for contrast-enhancing MRI of the body. The suspicion may be based on a previous imaging procedure such as CT, PET/CT, ultrasound or MRI performed within 12 months prior to ICF signature. * The participant is scheduled for a contrast-enhanced MRI examination of the CNS or a body region for clinical reasons and has agreed to have a second contrast-enhanced MRI examination for the purpose of this study. * The participant is in a clinically stable condition (i.e., no acute deterioration within 48 hours before enrollment). * Female Participants: The participant is a female who is either surgically sterile (has had a documented bilateral oophorectomy, bilateral salpingectomy, and/or documented hysterectomy), postmenopausal (cessation of menses for more than 1 year), or non-lactating, or if of childbearing potential the results of a serum human chorionic gonadotropin pregnancy test, performed at screening and the results of a urine pregnancy test, or serum human chorionic gonadotropin pregnancy test performed prior to each administration of IMP (with the result known before IMP administration), must be negative. Female participants of childbearing potential must agree to use adequate contraception and not harvest or donate eggs from screening until 30 days after final dose of IMP. Such methods include hormonal contraception including oral, intravaginal, transdermal, injectable, and implantable contraceptives; intrauterine device; intrauterine hormone-releasing system; bilateral tubal occlusion; vasectomized partner. Total abstinence, in accordance with the lifestyle of the participant, is also acceptable. * Male Participants: The participant is a male who is surgically sterile (vasectomy or bilateral orchidectomy), a male who is sexually active with a partner who is not of childbearing potential, or a male who is sexually active with a partner of childbearing potential who must agree to use adequate contraception and not harvest or donate sperm from screening until 90 days after final dose of IMP. Adequate contraception for the male participant (and any female partner, if she is of childbearing potential) is defined as using hormonal contraception (including oral, intravaginal, transdermal, injectable or implantable contraceptives), an intrauterine device, or an intrauterine hormone-releasing system, combined with at least one of the following forms of contraception: a diaphragm, a cervical cap, or a condom. Total abstinence, in accordance with the lifestyle of the participant, is also acceptable.
Exclusion criteria
* The participant has previously enrolled in this mangaciclanol study, including participation in an earlier phase or cohort. * The participant has a contraindication to MRI examination, such as the presence of a cardiac pacemaker or other electronic devices, presence of ferromagnetic metal foreign bodies in vulnerable positions or within positions that would affect the imaged field of view, presence of certain tattoos that may raise a safety concern for MRI, participant suffering from severe claustrophobia which is not manageable with standard sedation, or participant working as a machinist, welder or metal worker (unless the participant will undergo thorough screening by radiology personnel to rule out the presence of metallic foreign bodies, especially in or near the eyes). * Participant with severe cardiovascular disease (e.g., known long QT syndrome including QTc prolongation based on screening ECG, acute myocardial infarction within the past 14 days, unstable angina, congestive heart failure class III/IV by New York Heart Association classification, or acute stroke within the past 48 hours). * (Phase 2 only) Participant with an estimated glomerular filtration rate (eGFR) \<60 mL/min/1.73 m2 calculated using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) within 14 days prior to the first IMP administration. * (Phase 3 only) Participant with an eGFR \<30 mL/min/1.73m2 calculated using the CKD-EPI within 14 days prior to the first IMP administration. * Participant with increased likelihood of hypersensitivity specifically to mangaciclanol, gadolinium or a component of the formulation. * Participant has received any non-study contrast agent within 72 hours prior to the first study MRI, or is planning to receive any non-study contrast agent during the trial until 24 ± 4 hours after the second study MRI. * Participant has received any investigational product within 30 days or within 5 times the half-life of that drug, whichever is shorter, prior to or concurrent with this study. * Participant is expected/scheduled to have any treatment or medical procedure (e.g., chemotherapy, radiotherapy, biopsy, resection, etc.) that may impact aspects of the imaged lesions from the first study MRI up to 24 hours after the second study MRI. (Participants under corticosteroids and/or maintenance chemotherapy with a stable dose at the time of screening visit and throughout the trial can be included). * Participant may not be able to complete the study, based on their anticipated life expectancy, or where study participation may compromise the management of the participant, or any other reason that in the judgment of the investigator makes the participant unsuitable for participation in the study. * Participant is pregnant or planning to become pregnant, or breast-feeding. * Participant is unable or unlikely to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and/or considered unlikely to complete the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2 Primary Endpoint - Overall diagnostic preference | 4-47 days | Overall diagnostic preference based on global matched pairs reads according to a 3-point scale that is derived from a 5-point scale (1 = greatly prefer mangaciclanol/prefer mangaciclanol, 0 = no preference, -1 = prefer gadobutrol/greatly prefer gadobutrol), as evaluated by 3 blinded independent readers. |
| Phase 3 Primary Endpoint - Lesion visualization criteria | 4-74 days | Lesion visualization criteria (lesion border delineation, internal morphology and degree of lesion contrast enhancement) for paired (unenhanced plus mangaciclanol-enhanced) MRIs compared to unenhanced MRI based on the primary reads on a 4-point scale (1 = poor / none; 2 = moderate; 3 = good; 4 = excellent) for up to 3 of the most representative lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 3 Secondary Endpoints - Incidence of participants with at least 1 new lesion detected | 4-74 days | Incidence of participants with at least 1 new lesion detected on paired MRI compared to unenhanced MRI based on global matched pairs reads. |
| Phase 3 Secondary Endpoints - Incidence of Treatment Emergent Adverse Events (TEAEs) | 4-74 days | Incidence of TEAEs. |
| Phase 3 Secondary Endpoints - Number and percentage of participants with changes from baseline in serum biochemistry laboratory test results | 4-74 days | Absolute value and change from pre-MRI serum biochemistry laboratory test results. |
| Phase 3 Secondary Endpoint - Number and percentage of participants with changes from baseline in hematology laboratory test results | 4-74 days | Absolute value and change from pre-MRI in hematology laboratory test results. |
| Phase 3 Secondary Endpoint - Number and percentage of participants with changes from baseline in urinalysis test results | 4-74 days | Absolute value and change from pre-MRI in urinalysis test results. |
| Phase 3 Secondary Endpoint - Number and percentage of participants with changes from baseline in systolic and diastolic blood pressure | 4-74 days | Absolute value and change from pre-MRI in systolic and diastolic blood pressure in millimeters of mercury. |
| Phase 3 Secondary Endpoint - Number and percentage of participants with changes from baseline in respiratory rate | 4-74 days | Absolute value and change from pre-MRI in respiratory rate (breaths per minute). |
| Phase 3 Secondary Endpoint - Number and percentage of participants with changes from baseline in heart rate | 4-74 days | Absolute value and change from pre-MRI in heart rate (beats per minute). |
| Phase 3 Secondary Endpoint - Number and percentage of participants with changes from baseline in temperature | 4-74 days | Absolute value and change from pre-MRI in temperature (degrees Celsius). |
| Phase 3 Secondary Endpoint - Number and percentage of participants with changes from baseline in physical examination findings | 4-74 days | Absolute value and change from pre-MRI in physical examination findings. |
| Phase 3 Secondary Endpoints - Incidence of abnormal safety parameters | 4-74 days | Incidence of abnormal vital signs, physical examination, clinical laboratory parameters, and urinalysis results. |
| Phase 2 Secondary Endpoint - Lesion visualization criteria | 4-47 days | Lesion visualization criteria (lesion border delineation, internal morphology, and degree of lesion contrast enhancement) on a 4-point scale (1 = poor / none; 2 = moderate; 3 = good; 4 = excellent) for up to 3 of the most representative lesions based on the primary reads. |
| Phase 2 Secondary Endpoint - Number of lesions | 4-47 days | Number of lesions based on global matched pairs reads and primary reads, and size and location of up to 3 of the most representative lesions based on the primary reads. |
| Phase 2 Secondary Endpoint - Technical adequacy of images for diagnosis | 4-47 days | Technical adequacy of images for diagnosis according to categorical assessment of image quality based on the primary reads. |
| Phase 2 Secondary Endpoint - Contrast enhancement percentage (CE%) | 4-47 days | Quantitative measurements of percentage of contrast enhancement (CE%) between unenhanced and contrast-enhanced images, will be determined per participant as the average for up to 3 of the most representative lesions (i.e., the same lesions identified for assessment of lesion visualization scores) based on evaluation of paired (unenhanced and contrast-enhanced) images |
| Phase 2 Secondary Endpoint - contrast-to-noise ratio (CNR) | 4-47 days | Quantitative measurements of contrast-to-noise ratio (CNR) and change in CNR (ΔCNR) between unenhanced and contrast-enhanced images, will be determined per participant as the average for up to 3 of the most representative lesions (i.e., the same lesions identified for assessment of lesion visualization scores) based on evaluation of paired (unenhanced and contrast-enhanced) images. |
| Phase 2 Secondary Endpoint - signal-to-noise ratio (SNR) | 4-47 days | Quantitative measurements of signal-to-noise ratio (SNR) will be determined per participant as the average for up to 3 of the most representative lesions (i.e., the same lesions identified for assessment of lesion visualization scores) based on evaluation of paired (unenhanced and contrast-enhanced) images. |
| Phase 2 Secondary Endpoint - Intra-reader reproducibility regarding overall diagnostic preference (primary endpoint). | 4-47 days | Intra-reader reproducibility (from 10% re-read) will be analyzed for overall diagnostic preference according to a 3-point scale (as nominal response) and a 5-point scale (as ordinal response with linear relationship). |
| Phase 2 Secondary Endpoint - Inter-reader agreement regarding overall diagnostic preference (primary endpoint). | 4-47 days | Inter-reader agreement will be analyzed for overall diagnostic preference according to a 3-point scale (as nominal response) and a 5-point scale (as ordinal response with linear relationship). |
| Phase 2 Secondary Endpoint - Incidence of TEAEs | 4-47 days | Incidence of treatment-emergent adverse events (TEAEs). |
| Number and percentage of participants with changes from baseline in serum biochemistry laboratory test results | 4-47 days | Absolute value and change from pre-MRI in serum biochemistry laboratory test results |
| Phase 2 Secondary Endpoint - Number and percentage of participants with changes from baseline in hematology laboratory test results | 4-47 days | Absolute value and change from pre-MRI in hematology laboratory test results. |
| Phase 2 Secondary Endpoint - Number and percentage of participants with changes from baseline in urinalysis test results | 4-47 days | Absolute value and change from pre-MRI in urinalysis test results. |
| Phase 2 Secondary Endpoint - Number and percentage of participants with changes from baseline in systolic and diastolic blood pressure | 4-47 days | Absolute value and change from pre-MRI in systolic and diastolic blood pressure in millimeters of mercury. |
| Phase 2 Secondary Endpoint - Number and percentage of participants with changes from baseline in respiratory rate | 4-47 days | Absolute value and change from pre-MRI in respiratory rate (breaths per minute). |
| Phase 2 Secondary Endpoint - Number and percentage of participants with changes from baseline in heart rate | 4-47 days | Absolute value and change from pre-MRI in heart rate (beats per minute). |
| Phase 2 Secondary Endpoint - Number and percentage of participants with changes from baseline in temperature | 4-47 days | Absolute value and change from pre-MRI in temperature (degrees Celsius). |
| Phase 2 Secondary Endpoint - Number and percentage of participants with changes from baseline in electrocardiogram examinations | 4-47 days | Absolute value and change from pre-MRI in electrocardiogram examinations (PR, QRS, and QTcF). |
| Phase 2 Secondary Endpoint - Number and percentage of participants with changes from baseline in physical examination findings | 4-47 days | Absolute value and change from pre-MRI in physical examination findings. |
| Phase 2 Secondary Endpoint - Incidence of abnormal safety parameters | 4-47 days | Incidence of abnormal vital signs, 12-lead ECG, physical examination, clinical laboratory parameters, and urinalysis results. |
| Phase 3 Secondary Endpoints - Lesion Visualization | 4-74 days | Lesion visualization criteria (lesion border delineation, internal morphology, and degree of contrast enhancement) for paired (unenhanced and contrast-enhanced) MRIs based on primary reads of images acquired with mangaciclanol as compared to gadobutrol, according to a 4-point scale for up to 3 of the most representative lesions. |
| Phase 3 Secondary Endpoints - Overall diagnostic preference based on global matched pairs reads | 4-74 days | Overall diagnostic preference based on global matched pairs reads according to a 3-point scale that is derived from a 5-point scale (1 = greatly prefer/prefer mangaciclanol; 0 = no preference; ˗1 = greatly prefer/prefer gadobutrol), as evaluated by 3 blinded independent readers. |
| Phase 3 Secondary Endpoints - Number of lesions | 4-74 days | Number of lesions based on global matched pairs reads, on-site investigator reads and primary reads, and size and location of up to 3 of the most representative lesions based on primary reads and on-site investigator reads. |
| Phase 3 Secondary Endpoints - Technical adequacy of images for diagnosis | 4-74 days | Technical adequacy of images for diagnosis according to a categorical assessment of image quality based on the primary reads and the on-site investigator reads will be described only in terms of number and percentage of participants. |
| Phase 3 Secondary Endpoints - Patient diagnosis and diagnostic confidence | 4-74 days | Patient diagnosis and diagnostic confidence according to a 5-point scale (nil, poor, moderate, high, excellent) based on primary reads and on-site investigator reads. |
| Phase 3 Secondary Endpoints - Contrast enhancement percentage (CE%) | 4-74 days | Quantitative measurements of percentage of contrast enhancement (CE%) between unenhanced and contrast-enhanced images, will be determined per participant as the average for up to 3 of the most representative lesions (i.e., the same lesions identified for assessment of lesion visualization scores) based on evaluation of paired (unenhanced and contrast-enhanced) images. |
| Phase 3 Secondary Endpoints - contrast-to-noise ratio (CNR) | 4-74 days | Quantitative measurements of contrast-to-noise ratio (CNR) and change in CNR (ΔCNR) between unenhanced and contrast-enhanced images, will be determined per participant as the average for up to 3 of the most representative lesions (i.e., the same lesions identified for assessment of lesion visualization scores) based on evaluation of paired (unenhanced and contrast-enhanced) images. |
| Phase 3 Secondary Endpoints - signal-to-noise ratio (SNR) | 4-74 days | Quantitative measurements of signal-to-noise ratio (SNR) will be determined per participant as the average for up to 3 of the most representative lesions (i.e., the same lesions identified for assessment of lesion visualization scores) based on evaluation of paired (unenhanced and contrast-enhanced) images. |
| Phase 3 Secondary Endpoints - Intra-reader reproducibility regarding lesion visualization criteria (primary endpoint) | 4-74 days | Intra-reader reproducibility will be evaluated for lesion visualization criteria (lesion border delineation, internal morphology and degree of contrast enhancement) for each treatment using a Bland-Altman plot for absolute agreement on a subset of participants with re-reads (10%). Descriptive statistics will be provided for the first vs. second measurement, as well as for the minimum vs. maximum values. Additionally, descriptive statistics will be presented for the absolute value of the paired differences between the 2 measurements. |
| Phase 3 Secondary Endpoints - Per-lesion sensitivity | 4-74 days | Per-lesion sensitivity of mangaciclanol-enhanced and gadobutrol-enhanced MRI for detection of malignancy, based on histopathological reference standard |
| Phase 3 Secondary Endpoints - Per-lesion specificity | 4-74 days | Per-lesion specificity of mangaciclanol-enhanced and gadobutrol-enhanced MRI for detection of malignancy, based on histopathological reference standard |
| Phase 3 Secondary Endpoints - The impact on patient treatment plan | 4-74 days | The impact on patient treatment plan (yes/no; including resection, biopsy, chemotherapy, radiotherapy, other specified treatment) as assessed by the on-site investigator for each contrast agent. |
| Phase 3 Secondary Endpoints - Lesion visualization criteria | 4-74 days | Lesion visualization criteria for unenhanced and paired (unenhanced and contrast-enhanced) MRIs based on the on-site investigator (radiologists) reads for up to 3 of the most representative lesions. |
| Phase 3 Secondary Endpoints - Inter-reader agreement regarding lesion visualization criteria (primary endpoint) | 4-74 days | Inter-reader agreement will be analyzed using both a 2-way random effect model for consistency and absolute agreement to calculate intraclass correlation coefficients. |
Countries
Georgia, Moldova, South Korea, United States
Contacts
CONTACTJay Chahal
CONTACTCatherine Copse
STUDY_DIRECTORStephanie Van de Ven
GE Healthcare
Outcome results
None listed