E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
MRI in terms of visualization of detected focal liver lesions in patients with known or Suspected focal liver lesions and severe renal impairment
|
|
E.1.1.1 | Medical condition in easily understood language |
Magnetic resonance Imaging of the liver |
|
E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Diagnosis [E01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 22.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028049 |
E.1.2 | Term | MRI |
E.1.2 | System Organ Class | 100000004848 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the diagnostic efficacy of Mangoral in liver MRI in terms of visualization of detected focal liver lesions in combined MRI (CMRI: combined Mangoral-enhanced and unenhanced MRI) compared to unenhanced MRI.
Lesion visualization will be determined by qualitative assessments of lesion border delineation and lesion contrast compared to background liver on 4-point scales for up to 15 lesions per patient.
|
|
E.2.2 | Secondary objectives of the trial |
• To assess the diagnostic efficacy of Mangoral in liver MRI in terms of:
- no. lesions detected by each MRI method;
- visualization of detected focal liver lesions in Mangoral-enhanced MRI comp. to unenhanced MRI;
- confidence in lesion detection and localization in each MRI method;
- lesion dimensions...
- quantitative assessments … signal intensity enhancement of liver, liver-to-lesion contrast, signal-to-noise ratio, contrast-to-noise ratio - up to 5 lesions/pat.;
- no. of patients who had at least 1 new lesion identified on CMRI compared to unenhanced MRI
• To assess a proportion of pat. having at least 1 malignant lesion identified on postmangoral images that was not identified on pre-mangoral images.
• To evaluate the safety and tolerability of Mangoral;
• To evaluate the pharmacokinetics of manganese after a single dose of Mangoral in a subgroup of pat.
• To evaluate the impact of diagnostic performance of CMRI and Mangoral-enhanced MRI versus unenhanced MRI ... |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Male and female patients 18 years and older
Known or suspected focal liver lesions based on medical history and previous laboratory and/or imaging examinations
Severe renal impairment such as:
a. Chronic kidney disease [CKD] (estimated glomerular filtrationrate [eGFR] < 30 mL/min/1.73 m2) based on medical history and previous laboratory examinations at least once within the last 3 months prior to the Baseline Visit , OR
b. Acute kidney injury (AKI) with an increase in serum creatinine ≥ 0.3 mg/dL within 48 hours or ≥ 50% within 7 days prior to the Baseline Visit |
|
E.4 | Principal exclusion criteria |
Patients with simple liver cysts only
Any investigational drug or device within 6 weeks prior to the Baseline Visit.
Any MRI contrast media within 6 weeks prior to Baseline Visit or scheduled to receive any contrast medium before the last study visit.
Patients severe hepatic impairment (according to Child-Pugh score C).
Patients scheduled for surgery before last study visit.
Patients with encephalopathy / neurodegenerative or acute neurological disorders.
Patients with hemochromatosis
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be the visualization of detected focal liver lesions in combined MRI (CMRI, Mangoral-enhanced MRI plus unenhanced MRI) as compared to unenhanced MRI.
Efficacy will be assessed by testing the superiority of each of the 2 co-primary variables:
•lesion border delineation (BD), and
•lesion contrast compared to liver background (LC).
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Assessments will be done during central reading sessions.
All unenhanced and Mangoral-enhanced MRI image sets will be evaluated centrally at the imaging core lab by 3 independent readers.
The central evaluation of all MRI images will consist of 3 parts:
•Part I:unenhanced MRI alone;
•Part II:combined MRI, i.e. paired reading of both unenhanced and Mangoral-enhanced images;
•Part III:Mangoral-enhanced MRI alone.
Each of the 3 independent readers will assess all images of all patients in each part of the reading. There will be a 2-weeks gap between read parts to reduce recall bias.
The analysis of the primary efficacy variable will be based on the qualitative assessments performed centrally at the imaging core lab.
|
|
E.5.2 | Secondary end point(s) |
- Number of lesions detected by each MRI method: unenhanced MRI, Mangoral-enhanced MRI, and CMRI.
- Visualization of focal liver lesions in Mangoral-enhanced MRI as compared to unenhanced MRI
- Confidence in lesion detection separately in unenhanced MRI, Mangoral-enhanced MRI, and CMRI
- Confidence in lesion localization separately in unenhanced MRI, Mangoral-enhanced MRI, and CMRI
- Lesion dimensions
- Quantitative assessments
- Change(s) in patients’ management based on diagnostic performance of CMRI or Mangoral-enhanced MRI vs. unenhanced MRI.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Assessments will be done during central reading sessions as described in E.5.1.1.
Additionally on-site evaluation will be done by each site investigator (or on-site radiologist) at the respective study site and will include separate assessments of all unenhanced and Mangoral-enhanced images of each patient. Data of on-site assessments will be used for analysis of specific secondary efficacy variables.
In addition, brain MRI images will be evaluated by the independent off-site radiologist. Offsite evaluations should be performed within 5 working days after the respective MRI examination. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Central evaluation by 3 independent readers |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Unenhanced MRI will serve as control |
|
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Colombia |
Mexico |
Turkey |
Argentina |
Germany |
Italy |
Poland |
Russian Federation |
Sweden |
United States |
|
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |