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

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

The overall objective of this study is to evaluate the safety and diagnostic efficacy of Mangoral in liver MRI in participants with known or suspected focal liver lesions and severe renal impairment. The diagnostic efficacy of Mangoral will be assessed in terms of visualization of detected focal liver lesions in combined MRI (CMRI: combined Mangoral-enhanced and unenhanced MRI) compared to unenhanced MRI.

Study Overview

• Status: Completed
• Conditions: Severe Renal Impairment; Known or Suspected Focal Liver Lesions
• Intervention / Treatment: Drug: Mangoral

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 87
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1425 BEE
    • Centro Rossi Body Imaging
  • Cordoba, Argentina, X5000JHQ
    • Sanatorio Allende Nueva Córdoba
  • Río Negro
    • San Carlos De Bariloche, Río Negro, Argentina, R8405AZA
      • Fundacion Intecnus
• Colombia
  • Antioquia
    • Medellín, Antioquia, Colombia, 69-240
      • Hospital Pablo Tobon Uribe
  • Cundinamarca
    • Bogotá, Cundinamarca, Colombia, 111221
      • Clínica Universitaria Colombia
    • Bogotá, Cundinamarca, Colombia, 111611
      • Sociedad de Cirugía de Bogotá - Hospital de San José
• Germany
  • Berlin, Germany
    • Charité - Universitätsmedizin Berlin
  • Frankfurt, Germany, 60590
    • Universitätsklinikum Frankfurt Institut für Diagnostische und Interventionelle Radiologie
  • Göttingen, Germany
    • Universitatsmedizin Gottingen
  • Karlsruhe, Germany, 76227
    • Städtisches Klinikum KarlsruheDiagnostische und interventionelle Radiologie
  • Kiel, Germany, 24105
    • Universitättsklinikum Schleswig-Holstein/Campus KielKlinik für Radiologie und Neuroradiologie
  • Munich, Germany, 81377
    • Klinik und Poliklinik für Radiologie Klinikum der Universität München LMU Campus
  • Regensburg, Germany, 93053
    • Institut für Röntgendiagnostik
• Italy
  • Bologna, Italy, 40138
    • Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi
  • Milano, Italy, 20162
    • Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda
  • Napoli, Italy, 80147
    • Ospedale del Mare
  • Napoli, Italy
    • Istituto Nazionale Tumori IRCCS Fondazione G. Pascale
  • Roma, Italy, 00168
    • Universita Cattolica del Sacro Cuore
  • Rome, Italy, 00161
    • Azienda Ospedaliero-Universitaria Policlinico Umberto I
  • Viterbo, Italy, 01100
    • Ospedale di Belcolle
  • Lombardy
    • Milano, Lombardy, Italy, 20157
      • Azienda Socio Sanitaria Territoriale (ASST)
• Mexico
  • Cuernavaca, Mexico, 62290
    • Panamerican Clinical Research - Cuernavaca Rio Mayo
  • Guadalajara, Mexico, 44670
    • Panamerican Clinical Research Mexico
  • Querétaro, Mexico, 76230
    • Panamerican Clinical Research - Querétaro Avenida Paseo de la República
• Poland
  • Bydgoszcz, Poland
    • Szpital Uniwersytecki nr 1 im. Dr A. Jurasza, Wydział Katedra i Zakład Radiologii i Diagnostyki Obrazowej
  • Kraków, Poland, 31-501
    • Szpital Uniwersytecki w Krakowie Zakład Diagnostyki Obrazowej CUMRiK Ul
  • Szczecin, Poland, 70-111
    • Euromedis Sp. z o.o.
• Russian Federation
  • Barnaul, Russian Federation, Zmeigorsky trakt 110
    • Altay Regional Oncology Dispencery
  • Irkutsk, Russian Federation, 664035
    • State Institution of Healthcare "Regional Oncology Dispensary"
  • Moscow, Russian Federation, 115478
    • Scientific and Research Institute of Oncology named after N.N. Blokhin
  • Moscow, Russian Federation, 117997
    • A.V. Vishnevsky Institute of Surgery
  • Moscow, Russian Federation, 125284
    • National Medical Research Radiology Center Named After Herzen
  • Novosibirsk, Russian Federation, 630099
    • JSC "Avicenna"
  • Omsk, Russian Federation, 644013
    • State Institution of Healthcare of Omsk region
  • Pskov, Russian Federation, 180004
    • SBIH of Pskov Regional Clinical Oncologic Dispensary
  • Pyatigorsk, Russian Federation, 357500
    • LLC "Clinica YZI 4D"
  • Saint Petersburg, Russian Federation, 197758
    • N.N. Petrov Research Institute Of Oncology
  • Saint Petersburg, Russian Federation, 198255
    • Saint-Petersburg State Budgetary Healthcare Institution
  • Smolensk, Russian Federation, 214006
    • Smolensk Clinical Hospital
  • Tyumen, Russian Federation, 625033
    • State Autonomous Healthcare Institution of the Tyumen Region
• Sweden
  • Stockholm, Sweden
    • Karolinska University Hospital Huddinge
• Turkey
  • Ankara, Turkey, 06230
    • Hacettepe University Medical Faculty Hospital
  • Istanbul, Turkey, 34093
    • İstanbul Üniversitesi - Istanbul Tıp Fakültesi
  • Kayseri
    • Melikgazi, Kayseri, Turkey, 38030
      • Erciyes University Medical Faculty Hospital
  • Kocaeli
    • İzmit, Kocaeli, Turkey, 41001
      • Kocaeli University
  • İzmir
    • Bornova, İzmir, Turkey, 35100
      • Ege University Medical Faculty Hospital
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic - Arizona
  • California
    • Los Angeles, California, United States, 90095
      • University of California at Los Angeles Ronald Reagan Medical Center
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic - Jacksonville
    • Miami, Florida, United States, 33136
      • Schiff Center for Liver Diseases
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Bayview Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02118
      • Boston University Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63103
      • Saint Louis University
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
  • Texas
    • Brownsville, Texas, United States, 78521
      • PanAmerican Clinical Research LLC
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin - Madison

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male and female participants 18 years and older.
• Known or suspected focal liver lesions based on medical history and previous laboratory and/or imaging examinations.
• Severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m^2) based on medical history and previous laboratory examinations, at least once, within the last 3 months prior to the Baseline Visit, or participants with an increase in serum creatinine ≥ 0.3 mg/dL within 48 hours or ≥ 50% within 7 days prior to the Baseline Visit.

Exclusion Criteria:

• Participants with simple liver cysts only.
• Any investigational drug or device within 6 weeks prior to the Baseline Visit.
• Any magnetic resonance imaging (MRI) contrast media within 6 weeks prior to Baseline Visit or scheduled to receive any contrast medium before the last study visit.
• Participants with severe hepatic impairment (according to Child-Pugh score C).
• Participants scheduled for surgery before last study visit.
• Participants with encephalopathy / neurodegenerative or acute neurological disorders.
• Participants with hemochromatosis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mangoral; 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; Other Names: Orviglance; CMC-001; ACE-MBCA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Co-primary Endpoint: Lesion Border Delineation in Combined MRI Compared to Unenhanced MRI	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.	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
Co-primary Endpoint: Lesion Contrast in Combined MRI Compared to Unenhanced MRI	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.	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Lesions Detected by Each MRI Method	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.	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
Lesion Border Delineation in Mangoral-enhanced MRI Compared to Unenhanced MRI	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.	Unenhanced MRI: Baseline Period (Day -1 to Day 0); mangoral-enhanced MRI: 4 hours after mangoral administration on Day 0
Lesion Contrast in Mangoral-enhanced MRI Compared to Unenhanced MRI	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.	Unenhanced MRI: Baseline Period (Day -1 to Day 0); mangoral-enhanced MRI: 4 hours after mangoral administration on Day 0
Confidence in Lesion Detection Score	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.	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
Confidence in Lesion Localization Score	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.	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
Longest Diameter of Largest and Smallest Lesion	Assessments of unenhanced MRI and mangoral-enhanced MRI for lesion dimensions were undertaken during central reading sessions by 3 independent, blinded readers.	Unenhanced MRI: Baseline Period (Day -1 to Day 0); mangoral-enhanced MRI: 4 hours after mangoral administration on Day 0
Percentage Liver Signal Intensity (SI) Enhancement in 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. 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.	Unenhanced MRI: Baseline Period (Day -1 to Day 0); mangoral-enhanced MRI: 4 hours after mangoral administration on Day 0
Liver-to-lesion Contrast (LLC) in 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. 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.	Unenhanced MRI: Baseline Period (Day -1 to Day 0); mangoral-enhanced MRI: 4 hours after mangoral administration on Day 0
Signal-to-noise Ratio (SNR) in 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.	Unenhanced MRI: Baseline Period (Day -1 to Day 0); mangoral-enhanced MRI: 4 hours after mangoral administration on Day 0
Contrast-to-noise Ratio (CNR) in 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. 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.	Unenhanced MRI: Baseline Period (Day -1 to Day 0); mangoral-enhanced MRI: 4 hours after mangoral administration on Day 0
Number of Participants With Change(s) in Recommended Management Based on Diagnostic Performance of Combined MRI or Mangoral-enhanced MRI Compared to Unenhanced MRI	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).	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

Collaborators and Investigators

• Sponsor: Ascelia Pharma AB
• Investigators: Principal Investigator: Bernd Hamm, MD, Charite Berlin, Dept. of Radiology

Study record dates

Study Major Dates

• Study Start (Actual): February 19, 2020
• Primary Completion (Actual): February 17, 2023
• Study Completion (Actual): February 17, 2023

Study Registration Dates

• First Submitted: September 29, 2019
• First Submitted That Met QC Criteria: October 7, 2019
• First Posted (Actual): October 8, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 15, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Renal Insufficiency
• Other Study ID Numbers: ASC-Man-P016; 11-3429 (Other Identifier: FDA Orphan Designation Request)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No