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

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

Population: Full Analysis Set (FAS): All participants of the Safety Population who received the IMP and for whom the primary efficacy variable was assessable, i.e. all unenhanced / enhanced liver MRI images are assessable. The overall number of participants analyzed includes all participants that contributed data for the outcome measure. The number of participants analyzed per row includes only participants with matched lesions (detected and scored on both unenhanced MRI and combined MRI) by each reader.

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

Population: FAS: All participants of the Safety Population who received the IMP and for whom the primary efficacy variable was assessable, i.e. all unenhanced / enhanced liver MRI images are assessable. The overall number of participants analyzed includes all participants that contributed data for the outcome measure. The number of participants analyzed per row includes only participants with matched lesions (detected and scored on both unenhanced MRI and combined MRI) by each reader.

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

Population: FAS: All participants of the Safety Population who received the IMP and for whom the primary efficacy variable was assessable, i.e. all unenhanced / enhanced liver MRI images are assessable. The number of participants analyzed represents the number of participants with analyzed MRI images. Independent readers analyzed a maximum of 15 lesions per participant.

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

Population: FAS: All participants of the Safety Population who received the IMP and for whom the primary efficacy variable was assessable, i.e. all unenhanced / enhanced liver MRI images are assessable. The number of participants analyzed represents the number of participants with analyzed MRI images. Independent readers analyzed a maximum of 15 lesions per participant.

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

Population: FAS: All participants of the Safety Population who received the IMP and for whom the primary efficacy variable was assessable, i.e. all unenhanced / enhanced liver MRI images are assessable. The overall number of participants analyzed includes all participants that contributed data for the outcome measure. The number of participants analyzed per row includes only participants with matched lesions (detected and scored on both unenhanced MRI and combined MRI) by each reader.

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

Population: FAS: All participants of the Safety Population who received the IMP and for whom the primary efficacy variable was assessable, i.e. all unenhanced / enhanced liver MRI images are assessable. The overall number of participants analyzed includes all participants that contributed data for the outcome measure. The number of participants analyzed per row includes only participants with matched lesions (detected and scored on both unenhanced MRI and combined MRI) by each reader.

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

Population: FAS: All participants of the Safety Population who received the IMP and for whom the primary efficacy variable was assessable, i.e. all unenhanced / enhanced liver MRI images are assessable. The overall number of participants analyzed includes all participants that contributed data for the outcome measure. The number of participants analyzed per row includes only participants with matched lesions (detected and scored on both unenhanced MRI and combined MRI) by each reader.

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

Population: FAS: All participants of the Safety Population who received the IMP and for whom the primary efficacy variable was assessable, i.e. all unenhanced / enhanced liver MRI images are assessable. The overall number of participants analyzed includes all participants that contributed data for the outcome measure. The number of participants analyzed per row includes only participants with matched lesions (detected and scored on both unenhanced MRI and combined MRI) by each reader.

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

Population: FAS: All participants of the Safety Population who received the IMP and for whom the primary efficacy variable was assessable, i.e. all unenhanced / enhanced liver MRI images are assessable. The overall number of participants analyzed includes all participants that contributed data for the outcome measure. The number of participants analyzed per row includes only participants with detected and scored lesions by each reader.

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

Population: FAS: All participants of the Safety Population who received the IMP and for whom the primary efficacy variable was assessable, i.e. all unenhanced / enhanced liver MRI images are assessable.

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).

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

Population: FAS: All participants of the Safety Population who received the IMP and for whom the primary efficacy variable was assessable, i.e. all unenhanced / enhanced liver MRI images are assessable. As pre-specified in the statistical analysis plan, results are presented for change in recommended management following combined MRI and mangoral-enhanced MRI only.

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

Population: FAS: All participants of the Safety Population who received the IMP and for whom the primary efficacy variable was assessable, i.e. all unenhanced / enhanced liver MRI images are assessable. As pre-specified in the statistical analysis plan, results are presented for SI enhancement following mangoral-enhanced MRI compared to unenhanced MRI.

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

Population: FAS: All participants of the Safety Population who received the IMP and for whom the primary efficacy variable was assessable, i.e. all unenhanced / enhanced liver MRI images are assessable. The overall number of participants analyzed includes all participants that contributed data for the outcome measure. The number of participants analyzed per row includes only participants with matched lesions (detected and scored on both unenhanced MRI and combined MRI) by each reader.