Safety and Diagnostic Efficacy of Mangoral in Participants With Focal Liver Lesions and Reduced Kidney Function

The overall objective of this multicenter, open-label, study is to evaluate the safety and diagnostic efficacy of Mangoral in participants with known or suspected focal liver lesions and severe renal impairment. Study treatment is a single oral dose of Mangoral (800 mg manganese chloride \[II\] tetrahydrate, 500 mg L-alanine, and 800 IU vitamin D3). Adult male and female participants with severe renal impairment or acute kidney injury and who are being evaluated for known or suspected focal liver lesions will be included. Primary diagnostic efficacy in terms of visualization of detected lesions will be evaluated centrally by 3 independent readers. Study MRIs will also be evaluated by the on-site radiologists for the assessment of secondary objectives and for clinical purposes.

All participants will receive a single dose of Mangoral (800 mg Manganese (II) chloride tetrahydrate \[MnCl2 4H2O\]).

Drug: Mangoral

800 mg manganese chloride \[II\] tetrahydrate, 500 mg L-alanine, and 800 IU vitamin D3

Time frame: Unenhanced MRI: Baseline Period (Day -1 to Day 0); combined MRI: Baseline Period (Day -1 to Day 0) and 4 hours after mangoral administration on Day 0

Visualization of focal liver lesions was measured by 2 co-primary variables: 'lesion border delineation' and 'lesion contrast' compared to liver background. Qualitative assessment determined on the 4-point scales for up to 15 lesions per participant. Each lesion was assessed for lesion border delineation from 1 (poor: lesion border is poorly distinct) to 4 (excellent: lesion border is sharply and clearly distinct). Central reading sessions were undertaken by 3 independent, blinded readers.

The scores were calculated for each participant by summing the individual lesion scores and calculating the mean. The total score could range from 1 to 4 for each participant with higher scores representing a better outcome.

Time frame: Unenhanced MRI: Baseline Period (Day -1 to Day 0); combined MRI: Baseline Period (Day -1 to Day 0) and 4 hours after mangoral administration on Day 0

Visualization of focal liver lesions was measured by 2 co-primary variables: 'lesion border delineation' and 'lesion contrast' compared to liver background. Qualitative assessment determined on the 4-point scales for up to 15 lesions per participant. Each lesion was assessed for lesion contrast from 1 (poor: difference in signal intensity between the lesion and the surrounding normal liver tissue is poor) to 4 (excellent: difference in signal intensity between the lesion and the surrounding liver is marked). Central reading sessions were undertaken by 3 independent, blinded readers.

The scores were calculated for each participant by summing the individual lesion scores and calculating the mean. The total score could range from 1 to 4 for each participant with higher scores representing a better outcome.

Time frame: Unenhanced MRI: Baseline Period (Day -1 to Day 0); mangoral-enhanced MRI: 4 hours after mangoral administration on Day 0; and combined MRI: Baseline Period (Day -1 to Day 0) and 4 hours after mangoral administration on Day 0

Assessments of unenhanced MRI, mangoral-enhanced MRI, and combined MRI for detection of lesions were undertaken by on-site readers (assessing participants at their own site) and during central reading sessions by 3 independent, blinded readers.

Time frame: Unenhanced MRI: Baseline Period (Day -1 to Day 0); mangoral-enhanced MRI: 4 hours after mangoral administration on Day 0

Visualization of focal liver lesions was measured by variables: 'lesion border delineation' and 'lesion contrast' compared to liver background. Qualitative assessment determined on the 4-point scales for up to 15 lesions per participant. Each lesion was assessed for lesion border delineation from 1 (poor: lesion border is poorly distinct) to 4 (excellent: lesion border is sharply and clearly distinct). Central reading sessions were undertaken by 3 independent, blinded readers.

The scores were calculated for each participant by summing the individual lesion scores and calculating the mean. The total score could range from 1 to 4 for each participant with higher scores representing a better outcome.

Time frame: Unenhanced MRI: Baseline Period (Day -1 to Day 0); mangoral-enhanced MRI: 4 hours after mangoral administration on Day 0

Visualization of focal liver lesions was measured by variables: 'lesion border delineation' and 'lesion contrast' compared to liver background. Qualitative assessment determined on the 4-point scales for up to 15 lesions per participant. Each lesion was assessed for lesion contrast from 1 (poor: difference in signal intensity between the lesion and the surrounding normal liver tissue is poor) to 4 (excellent: difference in signal intensity between the lesion and the surrounding liver is marked). Central reading sessions were undertaken by 3 independent, blinded readers.

The scores were calculated for each participant by summing the individual lesion scores and calculating the mean. The total score could range from 1 to 4 for each participant with higher scores representing a better outcome.

Time frame: Unenhanced MRI: Baseline Period (Day -1 to Day 0); mangoral-enhanced MRI: 4 hours after mangoral administration on Day 0; and combined MRI: Baseline Period (Day -1 to Day 0) and 4 hours after mangoral administration on Day 0

Each lesion was evaluated on a 3-point scale: 1 (lesion is detected with low confidence), 2 (lesion is detected with moderate confidence), 3 (lesion is detected with high confidence). Higher confidence in lesion detection scores represent better outcomes.

Assessments of unenhanced MRI, mangoral-enhanced MRI, and combined MRI for confidence in lesion detection were undertaken by on-site readers (assessing participants are their own site) and during central reading sessions by 3 independent, blinded readers.

Time frame: Unenhanced MRI: Baseline Period (Day -1 to Day 0); mangoral-enhanced MRI: 4 hours after mangoral administration on Day 0; and combined MRI: Baseline Period (Day -1 to Day 0) and 4 hours after mangoral administration on Day 0

Each lesion was evaluated on a 3-point scale: 1 (lesion is localized to a liver segment with low confidence), 2 (lesion is localized to a liver segment with moderate confidence), 3 (lesion is localized to a liver segment with high confidence).

Assessments of unenhanced MRI, mangoral-enhanced MRI, and combined MRI for confidence in lesion localization were undertaken by on-site readers (assessing participants at their own site) and during central reading sessions by 3 independent, blinded readers.

Time frame: Unenhanced MRI: Baseline Period (Day -1 to Day 0); mangoral-enhanced MRI: 4 hours after mangoral administration on Day 0

Assessments of unenhanced MRI and mangoral-enhanced MRI for lesion dimensions were undertaken during central reading sessions by 3 independent, blinded readers.

Time frame: Unenhanced MRI: Baseline Period (Day -1 to Day 0); mangoral-enhanced MRI: 4 hours after mangoral administration on Day 0

Quantitative SI was measured by positioning circular regions of interest in a homogenous area in the liver and the assessed liver lesion on the same image. SI liver was defined as the SI of the liver. Liver SI enhancement (%) = (\[SI liver post contrast - SI liver pre contrast\] / \[SI liver pre contrast\]) × 100.

Assessments of unenhanced MRI and mangoral-enhanced MRI for liver SI were undertaken during central reading sessions by the 3 independent, blinded readers.

Time frame: Unenhanced MRI: Baseline Period (Day -1 to Day 0); mangoral-enhanced MRI: 4 hours after mangoral administration on Day 0

Quantitative SI was measured by positioning circular regions of interest in a homogenous area in the liver and the assessed liver lesion on the same image. Up to 5 lesions per participant of ≥ 2 cm in diameter were evaluated and these lesions were the same on pre-and post-contrast images. SI lesion was defined as the SI of these lesions. SI liver was defined as the SI of the liver. LLC = (SI liver - SI lesion) / (SI liver + SI lesion). Higher ratio scores represent a better outcome.

Assessments of unenhanced MRI and mangoral-enhanced MRI for LLC ratio were undertaken during central reading sessions by the 3 independent, blinded readers.

Time frame: Unenhanced MRI: Baseline Period (Day -1 to Day 0); mangoral-enhanced MRI: 4 hours after mangoral administration on Day 0

Quantitative SI was measured by positioning circular regions of interest in a homogenous area in the liver and the assessed liver lesion on the same image. SI liver was defined as the SI of the liver. Standard deviation of the background noise was measured using the largest possible rectangular region of interest vertical to the patient's abdomen in the direction of the phase-encoding gradient. SNR = SI liver / standard deviation noise. Higher ratio scores represent a better outcome.

Assessments of unenhanced MRI and mangoral-enhanced MRI for SNR were undertaken during central reading sessions by the 3 independent, blinded readers.

Time frame: Unenhanced MRI: Baseline Period (Day -1 to Day 0); mangoral-enhanced MRI: 4 hours after mangoral administration on Day 0

Quantitative SI was measured by positioning circular regions of interest in a homogenous area in the liver and the assessed liver lesion on the same image. Up to 5 lesions per participant of ≥ 2 cm in diameter were evaluated and these lesions were the same on pre-and post-contrast images. SI lesion was defined as the SI of these lesions. SI liver was defined as the SI of the liver. Standard deviation of the background noise was measured using the largest possible rectangular region of interest vertical to the patient's abdomen in the direction of the phase-encoding gradient. CNR = (SI liver - mean of SI lesion) / standard deviation noise. Higher ratio scores represent a better outcome.

Assessments of unenhanced MRI and mangoral-enhanced MRI for CNR were undertaken during central reading sessions by the 3 independent, blinded readers.

Time frame: Unenhanced MRI: Baseline Period (Day -1 to Day 0); mangoral-enhanced MRI: 4 hours after mangoral administration on Day 0; and combined MRI: Baseline Period (Day -1 to Day 0) and 4 hours after mangoral administration on Day 0

A participant was considered to have a change in recommended management when compared to unenhanced MRI if recommended management was different following assessment of the combined MRI or mangoral-enhanced MRI, including next steps in management (i.e. chemotherapy, surgery, local ablation procedure, combination therapy, or other \[specify\]). Recommended patient management from "other" in unenhanced MRI to "other" in combined MRI or mangoral-enhanced MRI was considered not a change regardless of the free text.

Assessments of unenhanced MRI, mangoral-enhanced MRI, and combined MRI for confidence in lesion detection were undertaken by on-site readers (assessing participants at their own site with access to patient records) and during central reading sessions by 3 independent, blinded readers (without access to patient records).

A Multicenter, Open-label Study to Evaluate the Safety and Diagnostic Efficacy of Mangoral in Patients With Known or Suspected Focal Liver Lesions and Severe Renal Impairment