CNS Lesion, Lesion in Body Region
Conditions
Brief summary
GDX-44-014 - GDX-101 study was conducted in Japan including 2 cohorts (adult cohort for adult population and pediatric cohort for pediatric population), with different designs: * The adult cohort had a prospective, multi-center, randomized, double-blind, controlled, and cross-over design. * The pediatric cohort had a prospective, multi-center, non-randomized, open-label and single arm design. The primary objective was to demonstrate the non-inferiority of gadopiclenol-enhanced MRI at 0.05 mmol/kg body weight (BW) compared to gadobutrol-enhanced MRI at 0.1 mmol/kg BW in terms of lesion visualization for adult patients referred for contrast-enhanced MRI of Central Nervous System (CNS) or Body regions.
Detailed description
Adult cohort: The trial included a maximum of 5 visits and the record of patient's diagnosis as standard of truth: * One screening visit (V1) up to 7 days prior to the imaging visit (V2) (V1 could be done on the same day as V2 if all the inclusion/non-inclusion criteria were met). * Two sequential imaging visits (V2 and V4, minimum interval 2 days and up to 14 days): each visit consisted of gadopiclenol injection or comparator injection and MRI procedure. * Two safety visits (V3 and V5): 1 day after each injection and MRI examination. Pediatric cohort: The inclusions was divided into 4 age groups: patients from birth to 23 months of age inclusive, patients from 2 to 6 years, patients from 7 to 11 years and patients from 12 to 17 years. The recruitment in the 3 older groups of pediatric patients could be conducted in parallel with adult patients' enrolment. The decision to start the inclusion in the group of patients aged from birth to 23 months was taken by the Trial Safety Review Board (TSRB). The trial included a maximum of 3 visits and the record of patient's diagnosis as standard of truth: * One screening visit (V1) up to 7 days prior to the imaging visit (V2) (V1 could be done on the same day as V2 if all the inclusion/non-inclusion criteria were met). * One imaging visit (V2) consisted of gadopiclenol injection and MRI procedure. * pharmacokinetics (PK) group: Blood sampling for PK started after gadopiclenol injection according to defined blood sampling schedule and took up to 8 hours. * One safety visit (V3): 1 day after gadopiclenol injection and MRI examination. All Patients: Images were assessed off-site in a centralized manner. Pediatric group for pharmacokinetics (PK) analysis : Up to 24 patients of the pediatric cohort would be included in gadopiclenol PK profile assessment. The approach implemented for PK analyses allowed sparse blood sampling only and was selected to minimize the clinical burden to children. All cohorts : During the trial, the safety of the patients was monitored and assessed based on the reporting of adverse events (AEs), including vital signs, ECG for pediatric patients and clinical laboratory parameters (blood samples).
Interventions
DRUGGadopiclenol
Dose/volume: Gadopiclenol administered was calculated based on patient's weight at the dose of 0.05 mmol/kg BW
DRUGComparator (gadobutrol)
Dose/volume of comparator: Gadobutrol administered was calculated based on patient's weight at the dose of 0.1 mmol/kg BW.
Sponsors
Guerbet
Bracco Imaging S.p.A.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
DIAGNOSTIC
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Randomized, double-blind, controlled, and cross-over design only for adult cohort with 2 arms. Non-randomized, open-label and single arm design for pediatric cohort.
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Inclusion criteria for all patients: 1. All Patient presenting with known or suspected enhancing abnormality(ies) and/or lesion(s) in CNS or in at least one body region among head \& neck, thorax (e.g. breast), abdomen (e.g. liver, pancreas and kidney), pelvis (e.g. uterus, ovary and prostate) and musculoskeletal (e.g. extremities) based on a previous imaging procedure performed within 12 months prior to Informed Consent Form (ICF) signature. 2. All If the patient was treated (either with radiation, surgery, biopsy, or other relevant treatments) between previous imaging evaluation and trial MRI, there should still be a high suspicion of remaining enhancing abnormality(ies) and/or lesion(s) based on available clinical information. 3. All Patient able and willing to participate in the trial. 4. All Patient affiliated to national health insurance according to local regulatory requirements. * Inclusion criteria for adult patients: 1. Female or male adult patient having reached legal majority age of 18 years. 2. Patient scheduled for a contrast-enhanced MRI examination of CNS or a Body region for clinical reasons and agreeing to have a second contrast-enhanced MRI examination for the purpose of the trial. 3. Patient having read the information and having provided his/her consent to participate in writing by dating and signing the informed consent prior to any trial related procedure being conducted. * Inclusion criteria for pediatric patients: 1. Female or male pediatric patient from birth to 17 years. For patients aged from birth to 27 days, only term newborn infants were eligible. Patients might not have reached the age of 18 years at the MRI examination. 2. Patient whose parent(s) or legal guardian (where applicable) having read the information provided his/her/their consent to patient's participation in writing by dating and signing the informed consent prior to any trial related procedure being conducted. 3. Patient with capacity of understanding who received age- and maturity-appropriate information and provided his/her assent to participate in the trial. 4. PK Patient and his/her parent(s) or legal guardian (where applicable) having read the information and provided his/her consent in writing by dating and signing the Informed Consent form or respectively in the patient assent form their consent to participate in the PK analyses.
Exclusion criteria
* Non-inclusion criteria for all patients: 1. All Patient referred for contrast-enhanced cardiac MRI as primary examination (e.g. imaging protocol requiring stress or more than a single injection of gadolinium contrast agent) except for late-enhancement cardiac imaging. 2. All Patient having received any investigational medicinal product (IMP) within 7 days prior to trial entry or scheduled to receive any investigational treatment during the trial. 3. All Patient presenting with any contraindication to MRI examinations. 4. All Patient having received any contrast agent (for MRI or CT) within 3 days (or 7 days for patients \<1 year old) prior to trial product administration or scheduled to receive any contrast agent during the trial or within 24 hours after the last trial product administration (or 7 days after for patients \<1 year old). 5. All Patient with anticipated, current, or past condition (medical, psychological, social or geographical) that would compromise the patient's safety or her/his ability to participate in the trial in the Investigator's opinion. 6. All Female patient of childbearing potential with a positive urine pregnancy test done within 1 day prior to each contrast agent administration and not able / not willing to use highly effective birth-controlled method during the trial duration. Female had to have effective medically approved contraception until the last trial visit, if of childbearing potential or with amenorrhea for less than 12 months or must be surgically sterilized or post-menopausal (\> 2 years amenorrhea). 7. All Patient unlikely to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits and/or unlikelihood of completing the trial. 8. All Patient related to the Investigator or any other trial staff or relative directly involved in the trial conduct. 9. All Patient with known contra-indication(s) to the use or with known sensitivity to one of the products under investigation or to other gadolinium based contrast agents (GBCAs) (such as hypersensitivity, post contrast acute kidney injury). * Non-inclusion criteria for adult patients: 1. Patient with acute disease that might rapidly evolve between the 2 MRI examinations 2. Patient previously randomized in this trial. 3. Patient expected/scheduled to have any treatment or medical procedure (e.g., chemotherapy, radiotherapy, biopsy, or surgery etc.) that might impact the aspects of the imaged lesions between the 2 MRI examinations. (Patients under corticosteroids and/or maintenance chemotherapy with a stable dose at the time of screening visit and throughout the trial could be included). 4. Patient presenting an estimated Glomerular Filtration Rate (eGFR) \< 30 mL/min/1.73 m\^2 (based on Japanese coefficient-modified CKD-EPI (Chronic Kidney Disease - Epidemiology Collaboration) formula) assessed within 1 week prior to the first contrast agent administration. * Non-inclusion criteria for pediatric patients: 1. Patient with previously attributed IMP number in this trial. 2. Patient with known long QT syndrome. 3. Patient presenting an estimated Glomerular Filtration Rate (eGFR) outside age-adjusted normal ranges (based on bedside Schwartz equation) assessed within one week prior to contrast agent administration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Lesion Visualization on Paired Images: Border Delineation | At each MRI exam: the first MRI at Day 1 and the second MRI performed after a wash out period of 2 to 14 days (adult cohort) | The lesion visualization criterion (per patient) was based on 3 co-primary criteria (border delineation, internal morphology and degree of contrast enhancement) assessed by 3 independent off-site blinded readers. The IBR recorded each of the 3 co-primary criteria for up to 10 largest and most enhancing lesions on Paired (pre+post) images performed with gadopiclenol and Paired (pre+post) images performed with gadobutrol. Delineation of the lesion border was defined as the distinction of lesion from surrounding tissues, structures, or edema, and the detection of extent of the lesion. This criterion was assessed through the following scale: 1. = None 2. = Moderate 3. = Good 4. = Excellent: For this co-primary criterion, a mean of scores for each patient and for each reader was calculated and ranged from 1 to 4. |
| Lesion Visualization on Paired Images: Internal Morphology | At each MRI exam: the first MRI at Day 1 and the second MRI performed after a wash out period of 2 to 14 days (adult cohort) | The lesion visualization criterion (per patient) was based on 3 co-primary criteria (border delineation, internal morphology and degree of contrast enhancement) assessed by 3 independent off-site blinded readers. The IBR recorded each of the 3 co-primary criteria for up to 10 largest and most enhancing lesions on Paired (pre+post) images performed with gadopiclenol and Paired (pre+post) images performed with gadobutrol. Internal morphology of the lesion included an identification of lesion architecture and the intra-lesion features such as necrosis, hemorrhage, and vascularity. This criterion was assessed through the following scale: 1. = Poor 2. = Moderate 3. = Good 4. = Excellent For this co-primary criterion "internal morphology", a mean of scores for each patient and for each reader was calculated and ranged from 1 to 4. |
| Lesion Visualization on Paired Images: Degree of Contrast Enhancement | At each MRI exam: the first MRI at Day 1 and the second MRI performed after a wash out period of 2 to 14 days (adult cohort) | The lesion visualization criterion (per patient) was based on 3 co-primary criteria (border delineation, internal morphology and degree of contrast enhancement) assessed by 3 independent off-site blinded readers. The IBR recorded each of the 3 co-primary criteria for up to 10 largest and most enhancing lesions on Paired (pre+post) images performed with gadopiclenol and Paired (pre+post) images performed with gadobutrol. The criterion "degree of contrast enhancement" was a qualitative assessment (not based on signal intensity measurement) according to the following scale: 1. = No: no enhancement 2. = Moderate: weakly enhanced 3. = Good: clearly enhanced 4. = Excellent: clearly and brightly enhanced For each co-primary criterion, a mean of scores for each patient and for each reader was calculated and ranged from 1 to 4. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pediatric Cohort: Lesion Visualization on Paired Images Compared With Pre Images: Border Delineation | At MRI exam, Day 1 (pediatric cohort) | The lesion visualization criterion based on 3 co-criteria: border delineation, internal morphology and degree of contrast enhancement assessed on the images acquired during the MRI performed with gadopiclenol assessed by 3 independent off-site blinded readers (IBR). The IBR recorded each of the 3 co-criteria for up to 10 largest and most enhancing lesions on Paired (pre+post) images and Pre images performed with gadopiclenol as contrast agent. Definitions of each co-criteria and score calculation were provided in the section for primary outcome measure. |
| Pediatric Cohort: Lesion Visualization on Paired Images Compared With Pre Images: Internal Morphology | At MRI exam, Day 1 (pediatric cohort) | The lesion visualization criterion based on 3 co-criteria: border delineation, internal morphology and degree of contrast enhancement assessed on the images acquired during the MRI performed with gadopiclenol assessed by 3 independent off-site blinded readers (IBR). The IBR recorded each of the 3 co-criteria for up to 10 largest and most enhancing lesions on Paired (pre+post) images and Pre images performed with gadopiclenol. Definitions of each co-criteria and score calculation were provided in the section for primary outcome measure. |
| Pediatric Cohort: Lesion Visualization on Paired Images Compared With Pre Images: Degree of Contrast Enhancement | At MRI exam, day 1 (pediatric cohort) | The lesion visualization criterion based on 3 co-criteria: border delineation, internal morphology and degree of contrast enhancement assessed on the images acquired during the MRI performed with gadopiclenol assessed by 3 independent off-site blinded readers (IBR). The IBR recorded each of the 3 co-criteria for up to 10 largest and most enhancing lesions on Paired (pre+post) images and Pre images performed with gadopiclenol. Definitions of each co-criteria and score calculation were provided in the section for primary outcome measure. |
Countries
Japan
Contacts
PRINCIPAL_INVESTIGATORToshiaki Taoka, MD
Nagoya University, JAPAN
Participant flow
Pre-assignment details
Among the 209 screened adult patients, 9 were screen failure. 200 patients were randomized (100 in each arm), of whom 197 (99 in Arm 1 and 98 in Arm 2) received the first contrast agent and underwent the first MRI. After a washout period of 2-14 days, 192 patients (96 in each arm) received the second contrast agent and underwent the second MRI (cross over study with 3 periods). All the 40 screened pediatric patients received the gadopiclenol injection and underwent an MRI (Overall period).
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 8.43 years STANDARD_DEVIATION 5.26 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 40 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 38 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 195 | 0 / 194 | 0 / 40 |
| other Total, other adverse events | 26 / 195 | 24 / 194 | 4 / 40 |
| serious Total, serious adverse events | 1 / 195 | 3 / 194 | 0 / 40 |
Outcome results
None listed