Efficacy and Safety of Gadobutrol 1.0 Molar (Gadovist) for Breast MRI

An Open Label, Multi-center, Phase 3 Study With Corresponding Blinded Image Reading to Determine the Efficacy and Safety of a Single Intravenous Injection of 0.1 mmol/kg Body Weight of Gadobutrol 1.0 Molar (Gadovist®) in Patients With Newly Diagnosed Breast Cancer Referred for Contrast-enhanced Breast MRI

The purpose of this study is to look at the efficacy (how does it work) and safety of gadobutrol when used for obtaining MR images of both breasts.Women with a recent diagnosis of breast cancer by mammogram (X-ray examination of the breasts) may benefit from MRI of the breasts as MRI may detect additional breast cancers.

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Diagnostic Imaging
• Intervention / Treatment: Drug: Gadobutrol (Gadavist, Gadovist, BAY86-4875)

• Study Type: Interventional
• Enrollment (Actual): 446
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Ciudad Auton. de Buenos Aires
    • Buenos Aires, Ciudad Auton. de Buenos Aires, Argentina, C1181ACH
    • Buenos Aires, Ciudad Auton. de Buenos Aires, Argentina, C1082A
    • Buenos Aires, Ciudad Auton. de Buenos Aires, Argentina, C1425BEE
• Brazil
  • Rio de Janeiro, Brazil, 22649
  • Sao Paulo, Brazil
  • Sao Paulo
    • São Paulo, Sao Paulo, Brazil, 05651-901
• Colombia
  • Barranquilla, Colombia
  • Antioquia
    • Medellin, Antioquia, Colombia
  • Cundinamarca
    • Bogotá, Cundinamarca, Colombia
• Finland
  • Helsinki, Finland, 00180
  • Tampere, Finland, 33521
• Germany
  • Potsdam, Germany, 14467
  • Baden-Württemberg
    • Tübingen, Baden-Württemberg, Germany, 72076
  • Hessen
    • Marburg, Hessen, Germany, 35033
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
  • Nordrhein-Westfalen
    • Bielefeld, Nordrhein-Westfalen, Germany
    • Dortmund, Nordrhein-Westfalen, Germany, 44263
    • Essen, Nordrhein-Westfalen, Germany, 45147
    • Essen, Nordrhein-Westfalen, Germany, 45257
  • Sachsen-Anhalt
    • Magdeburg, Sachsen-Anhalt, Germany, 39120
  • Schleswig-Holstein
    • Lübeck, Schleswig-Holstein, Germany, 23538
• Italy
  • Milano, Italy, 20132
  • Milano, Italy, 20141
  • Napoli, Italy, 80131
  • Udine, Italy, 33100
  • Milano
    • San Donato Milanese, Milano, Italy, 20097
• Korea, Republic of
  • Ansan Si, Kyungki Do, Korea, Republic of, 425-021
  • Seoul, Korea, Republic of, 150-713
  • Seoul, Korea, Republic of, 138-736
  • Seoul, Korea, Republic of, 135-710
• Switzerland
  • Baden, Switzerland, 5404
  • Bern, Switzerland, 3010
  • Graubünden
    • Chur, Graubünden, Switzerland, 7000
• United States
  • California
    • La Jolla, California, United States, 92093
    • Los Angeles, California, United States, 90033
    • Newport Beach, California, United States, 92658-6100
  • District of Columbia
    • Washington, District of Columbia, United States, 20007-2197
  • Illinois
    • Springfield II, Illinois, United States, 62781
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
  • Texas
    • San Antonio, Texas, United States, 78229

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Recent histologically proven diagnosis of breast cancer after having obtained X-Ray Mammography (XRM) of both breasts (according to American College of Radiology [ACR] and performed no longer than 6 weeks prior to enrollment into the study) and has been referred for a contrast-enhanced Magnetic Resonance Mammography (MRM) prior to surgery of the breast.

• If female, a digital XRM is required if any of the following criteria is met:

  1. patient is younger than 50 years;
  2. patient has heterogeneously or extremely dense breasts;
  3. is not post-menopausal (post-menopause defined as at least 12 months prior to inclusion without menstruation).
• If female of childbearing potential, MRM should be performed on the 7-14th day of the menstrual cycle.
• Has an estimated glomerular filtration rate (eGFR) value >/= 60 mL/min/1.73m^2 derived from a serum creatinine result within 2 weeks prior to study enrollment.

Exclusion Criteria:

• Is a female patient who is pregnant or lactating
• Has any contraindication to the MRM examination (e.g. metal implants, phobia) or the use of gadolinium-containing contrast agents.
• Has received any contrast agent within 24 hours prior to the study MRM, or is scheduled to receive any contrast agent within 24 hours after the study MRM.
• Has severe cardiovascular disease (e.g., known long QT syndrome, acute myocardial infarction [< 14 days], unstable angina, congestive heart failure New York Heart Association class IV) or acute stroke (< 48 hours)).
• Has acute renal insufficiency of any severity due to hepato-renal syndrome or in the peri-operative liver transplantation period or who has acute or chronic moderate or severe renal insufficiency (glomerular filtration rate < 60 mL/min/1.73m^2).
• Has received chemotherapy or hormonal therapy for breast cancer within 6 months.
• Has received hormone replacement therapy within 4 weeks prior to study drug administration.
• Is scheduled or likely to require a surgery and/or biopsy in the time period up to 24 hours following study drug application
• Has prior excisional biopsy or breast surgery less than 6 months before enrollment and between XRM and study MRM

Study Plan

How is the study designed?

Design Details

• Primary Purpose: DIAGNOSTIC
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Gadobutrol (Gadavist, BAY86-4875); Patients first received an unenhanced MRM, followed by a gadobutrol-enhanced MRM. Gadobutrol was administered at the standard dose of 0.1 mmol/kg bw [0.1 ml/kg bw] as an intravenous injection (i.v.) injection at a rate of 2 ml/sec. UMRM and CMRM image sets were evaluated in a randomized fashion. After the evaluation of the UMRM or CMRM the respective XRM was added and evaluated together with the UMRM images.

Drug: Gadobutrol (Gadavist, Gadovist, BAY86-4875); A single bolus injection of gadobutrol 1.0 M 0.1mmol/kg body weight

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sensitivity for Detection of Full Extent of Malignant Breast Disease Using CMRM vs UMRM Per Reader	For a single participant the sensitivity was defined as the proportion of malignant breast regions that were recognized by the clinical investigators and the 3 blinded readers using the respective imaging modality as malignant. Subsequently the sensitivity percentage was calculated based on the mean of the sensitivities across all participants.	Immediately before injection and after injection
Breast Level Specificity of CMRM for Non-malignant Breasts by Reader	A non-malignant breast was defined as false positive (FP), when the reader assessed at least one breast region as malignant. When all breast regions were assessed as non-malignant, the breast was defined as true negative (TN). Breast level specificity was first defined in participant as number of TN-breasts in participant divided by number of non-malignant breasts in participant. Subsequently the specificity percentage was calculated based on the mean of the specificities across all participants who contributed with at least one non-malignant breast.	Immediately before injection and after injection
Difference for Sensitivity for Detection of Full Extent of Malignant Breast Disease Using CMRM vs UMRM Per Reader	For a single participant the sensitivity was defined as the proportion of malignant breast regions that were recognized by the clinical investigators and the 3 blinded readers using the respective imaging modality as malignant. Subsequently the sensitivity percentage was calculated based on the mean of the sensitivities across all participants. The difference was calculated as CMRM value minus UMRM value. For ease of expression, the following abbreviations will be used: Magnetic Resonance Mammography (MRM), Unenhanced MRM (UMRM), combined unenhanced and contrast (gadobutrol)-enhanced MRM (CMRM), X-ray mammography (XRM).	Immediately before injection and after injection

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Breast Level Specificity of CMRM Based on Malignant Breasts	A malignant breast was defined as false positive (FP), when the reader using the respective imaging modality assessed more breast regions as malignant as were present according to SoT. Otherwise the breast was assessed as true negative (TN). Specificity was then defined as TN/(TN+FP).	Immediately before injection and after injection
Percentage Difference of Participants Whose Index Cancers Were Detected Using CMRM vs UMRM, CMRM vs XRM, and CMRM vs CMRM+XRM	Index cancer is defined as the cancer confirmed by histology prior to inclusion which made the participants eligible for the study. The difference in percentage of participants was calculated as CMRM value minus UMRM value, CMRM value minus XRM value, CMRM value minus CMRM+XRM value respectively.	Immediately before injection and after injection
Percentage Difference of Participants Whose Additional Cancers Were Detected Using CMRM vs UMRM, CMRM vs XRM, and CMRM vs CMRM+XRM	Additional cancer was defined as cancer which was present according to SoT, but which was not defined as index cancer, i.e. was not known when the participant was enrolled into the study. The difference in percentage of participants was calculated as CMRM value minus UMRM value, CMRM value minus XRM value, CMRM value minus CMRM+XRM value respectively.	Immediately before injection and after injection

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Breast Level Specificity for All Breasts by Imaging Modality and by Reader	A non-malignant breast was defined as FP when the reader assessed at least one breast region as malignant. A malignant breast was defined as FP, when the reader using the respective imaging modality assessed more breast regions as malignant as were present according to SoT. Otherwise the breast was assessed as TN. Specificity was then defined as (N-FP)/N, where N was total number of breasts.	Immediately before injection and after injection
Blinded Reader 1: Intra-reader Variability Based on Assessment for CMRM - Breast Level	Intra-reader variability was assessed using a kappa on the match to SoT for the different regions within each participant (match, no match SoT). For each of the 3 readers, intra-reader agreement was assessed by considering each breast region to have 2 possibilities for an assessment by CMRM: matched SoT or did not match SoT. Kappa value varies from 0 (no agreement) to 1 (perfect agreement).	Immediately before injection and after injection
Blinded Reader 2: Intra-reader Variability Based on Assessment for CMRM - Breast Level	Intra-reader variability was assessed using a kappa on the match to SoT for the different regions within each participant (match, no match SoT). For each of the 3 readers, intra-reader agreement was assessed by considering each breast region to have 2 possibilities for an assessment by CMRM: matched SoT or did not match SoT. Kappa value varies from 0 (no agreement) to 1 (perfect agreement).	Immediately before injection and after injection
Blinded Reader 3: Intra-reader Variability Based on Assessment for CMRM - Breast Level	Intra-reader variability was assessed using a kappa on the match to SoT for the different regions within each participant (match, no match SoT). For each of the 3 readers, intra-reader agreement was assessed by considering each breast region to have 2 possibilities for an assessment by CMRM: matched SoT or did not match SoT. Kappa value varies from 0 (no agreement) to 1 (perfect agreement).	Immediately before injection and after injection
Vital Signs Change From Baseline and Follow-up 24 Hours Post Injection - Heart Rate	Heart rate was measured in a supine position.	Baseline, Follow-up visit (24 hours post injection)
Number of Participants With at Least One Laboratory Parameter Change From Low or Normal at Baseline to Abnormally High at Follow-up 24 Hours Post Injection	Number of participants with at least one occurrence of changing from low or normal at baseline to high at follow-up.	Baseline, Follow-up visit (24 hours post injection)
Categorical Accuracy Difference of Extent of Malignant Disease Verified by SoT by Majority Reader, Breast Region Level	For each region the reader chose the category which best described the extent of malignant disease, i.e. no, unifocal, or multifocal malignant breast disease. The proportion of correct matches of each defined image set to the SoT for the extent of malignant breast disease was referred to as the categorical accuracy. The majority read value for the 3 blinded readers was determined at the disease state level (no disease, unifocal, multifocal). If 2 of 3 or all 3 readers gave the same categorical determination of malignant disease for a breast region, the majority reader response was that category. If all 3 readers gave different categorical determination, the majority reader response was the most severe disease category given by any of the 3 readers. The difference was calculated as CMRM value minus UMRM value, CMRM+XRM value minus UMRM+XRM value, CMRM+XRM value minus XRM value respectively.	Immediately before injection and after injection
Categorical Accuracy Difference of Extent of Malignant Disease Verified by Histopathology by Majority Reader, Breast Region Level	For each region the reader chose the category which best described the extent of malignant disease, i.e. no, unifocal, or multifocal malignant breast disease. The proportion of correct matches of each defined image set to the SoT for the extent of malignant breast disease was referred to as the categorical accuracy. The majority read value for the 3 blinded readers was determined at the disease state level (no disease, unifocal, multifocal). If 2 of 3 or all 3 readers gave the same categorical determination of malignant disease for a breast region, the majority reader response was that category. If all 3 readers gave different categorical determination, the majority reader response was the most severe disease category given by any of the 3 readers. The difference was calculated as CMRM value minus UMRM value, CMRM+XRM value minus UMRM+XRM value, CMRM+XRM value minus XRM value respectively.	Immediately before injection and after injection
Sensitivity Difference in the Determination of Malignant Breast Disease Using CMRM vs UMRM, CMRM+XRM vs UMRM+XRM, and CMRM+XRM vs XRM Verified by SoT, Breast Region Level	For a single participant the sensitivity was defined as the proportion of malignant breast regions that were recognized by the reader using the respective imaging modality as malignant. Subsequently the sensitivity percentage was calculated based on the mean of the sensitivities across all participants. The majority read value for the 3 blinded readers was determined at the disease state level (evaluable regions for sensitivity). If 2 of 3 or all 3 readers gave the same categorical determination of malignant disease for a breast region, the majority reader response was that category. If all 3 readers gave a different categorical determination, the majority response was the most severe disease category given by any of the 3 readers. The difference was calculated as CMRM value minus UMRM value, CMRM+XRM value minus UMRM+XRM value, CMRM+XRM value minus XRM value respectively.	Immediately before injection and after injection
Sensitivity Difference in the Determination of Unifocal Malignant Breast Disease Using CMRM vs UMRM, CMRM+XRM vs UMRM+XRM, and CMRM+XRM vs XRM Verified by SoT, Breast Region Level	For a single participant the sensitivity was defined as the proportion of malignant breast regions that were recognized by the reader using the respective imaging modality as malignant. Subsequently the sensitivity percentage was calculated based on the mean of the sensitivities across all participants. The majority read value for the 3 blinded readers was determined at the disease state level (evaluable regions for sensitivity). If 2 of 3 or all 3 readers gave the same categorical determination of malignant disease for a breast region, the majority reader response was that category. If all 3 readers gave a different categorical determination, the majority response was the most severe disease category given by any of the 3 readers. The difference was calculated as CMRM value minus UMRM value, CMRM+XRM value minus UMRM+XRM value, CMRM+XRM value minus XRM value respectively.	Immediately before injection and after injection
Sensitivity Difference in the Determination of Multifocal Malignant Breast Disease Using CMRM vs UMRM, CMRM+XRM vs UMRM+XRM, and CMRM+XRM vs XRM Verified by SoT, Breast Region Level	For a single participant the sensitivity was defined as the proportion of malignant breast regions that were recognized by the reader using the respective imaging modality as malignant. Subsequently the sensitivity percentage was calculated based on the mean of the sensitivities across all participants. The majority read value for the 3 blinded readers was determined at the disease state level (evaluable regions for sensitivity). If 2 of 3 or all 3 readers gave the same categorical determination of malignant disease for a breast region, the majority reader response was that category. If all 3 readers gave a different categorical determination, the majority response was the most severe disease category given by any of the 3 readers. The difference was calculated as CMRM value minus UMRM value, CMRM+XRM value minus UMRM+XRM value, CMRM+XRM value minus XRM value respectively.	Immediately before injection and after injection
Specificity Difference in the Determination of Malignant Breast Disease Using CMRM vs UMRM, CMRM+XRM vs UMRM+XRM, and CMRM+XRM vs XRM Verified by SoT, Breast Region Level	A malignant breast was defined as FP, when the reader using the respective imaging modality assessed more breast regions as malignant as were present according to SoT. Otherwise the breast was assessed as TN. Specificity was then defined as TN/(TN+FP). The majority read value for the 3 blinded readers was determined at the disease state level (evaluable regions for specificity). If 2 of 3 or all 3 readers gave the same categorical determination of malignant disease for a breast region, the majority reader response was that category. If all 3 readers gave a different categorical determination, the majority reader response was the most severe disease category given by any of the 3 readers. The difference was calculated as CMRM value minus UMRM value, CMRM+XRM value minus UMRM+XRM value, CMRM+XRM value minus XRM value respectively.	Immediately before injection and after injection
Specificity Difference in the Determination of Unifocal Malignant Breast Disease Using CMRM vs UMRM, CMRM+XRM vs UMRM+XRM, and CMRM+XRM vs XRM Verified by SoT, Breast Region Level	A malignant breast was defined as FP, when the reader using the respective imaging modality assessed more breast regions as malignant as were present according to SoT. Otherwise the breast was assessed as TN. Specificity was then defined as TN/(TN+FP). The majority read value for the 3 blinded readers was determined at the disease state level (evaluable regions for specificity). If 2 of 3 or all 3 readers gave the same categorical determination of malignant disease for a breast region, the majority reader response was that category. If all 3 readers gave a different categorical determination, the majority reader response was the most severe disease category given by any of the 3 readers. The difference was calculated as CMRM value minus UMRM value, CMRM+XRM value minus UMRM+XRM value, CMRM+XRM value minus XRM value respectively.	Immediately before injection and after injection
Specificity Difference in the Determination of Multifocal Malignant Breast Disease Using CMRM vs UMRM, CMRM+XRM vs UMRM+XRM, and CMRM+XRM vs XRM Verified by SoT, Breast Region Level	A malignant breast was defined as FP, when the reader using the respective imaging modality assessed more breast regions as malignant as were present according to SoT. Otherwise the breast was assessed as TN. Specificity was then defined as TN/(TN+FP). The majority read value for the 3 blinded readers was determined at the disease state level (evaluable regions for specificity). If 2 of 3 or all 3 readers gave the same categorical determination of malignant disease for a breast region, the majority reader response was that category. If all 3 readers gave a different categorical determination, the majority reader response was the most severe disease category given by any of the 3 readers. The difference was calculated as CMRM value minus UMRM value, CMRM+XRM value minus UMRM+XRM value, CMRM+XRM value minus XRM value respectively.	Single examination
Sensitivity Difference of Detection of Multicentric Malignant Disease Verified by SoT by Majority Reader, Breast Level	For a single participant the sensitivity was defined as the proportion of malignant breast regions that were recognized by the reader using the respective imaging modality as malignant. Subsequently the sensitivity percentage was calculated based on the mean of the sensitivities across all participants. The majority read value for the 3 blinded readers was determined at the disease state level (evaluable regions for sensitivity). If 2 of 3 or all 3 readers gave the same categorical determination of malignant disease for a breast region, the majority reader response was that category. If all 3 readers gave a different categorical determination, the majority response was the most severe disease category given by any of the 3 readers. The difference was calculated as CMRM value minus UMRM value, CMRM+XRM value minus UMRM+XRM value, CMRM+XRM value minus XRM value respectively.	Immediately before injection and after injection
Accuracy Difference of Presence of Bilateral Malignant Disease Verified by SoT by Majority Reader, Participant Level	The disease state "bilateral malignant disease" was derived from the assessment of the different regions for each breast (right and left) for investigators for each imaging modality (UMRM, CMRM, XRM, UMRM+XRM, and CMRM+XRM) based on the following rule: If the participant had at least one breast with no malignant region, the assessment of bilateral malignant disease was categorized as "No". If the participant had at least one malignant lesion in both breasts, the assessment of bilateral malignant disease was categorized as "Yes". The proportion of correct matches of each different image set to the SoT for the existence of bilateral malignant disease was derived. The analysis was based on the difference in accuracy for the evaluation of bilateral malignant disease for the following image comparisons on a participant level. The difference was calculated as CMRM value minus UMRM value, CMRM+XRM value minus UMRM+XRM value, CMRM+XRM value minus XRM value respectively.	Immediately before injection and after injection
Difference of Confidence in Diagnosis for Breast Region Diagnosis Using CMRM vs UMRM, CMRM+XRM vs UMRM+XRM and CMRM+XRM vs XRM by Majority Reader, Participant Level	The 3 blinded readers each recorded his/her confidence in diagnosis for each breast region based on a 4-point scale (1=not confident, 2=somewhat confident, 3=confident, and 4=very confident). The majority read value for the 3 readers was determined at the disease state level (no disease, unifocal, multifocal). If 2 of 3 or all 3 readers gave the same categorical determination of malignant disease for a breast region, the majority reader response was that category. If all 3 readers gave different categorical determination, the majority reader response was the most severe disease category given by any of the 3 readers, i.e. multifocal. For each participant, the mean of the confidence responses for the diagnosed breast regions was calculated, and rounded to the nearest 0.5. value respectively. The difference was calculated as CMRM value minus UMRM value, CMRM+XRM value minus UMRM+XRM value, CMRM+XRM value minus XRM value respectively.	Immediately before injection and after injection
Blinded Readers: Inter-reader Agreement on Categorical Accuracy Based on Assessment for UMRM vs CMRM - Breast Region Level	Inter-reader agreement was assessed by considering each breast region to have 2 possibilities (malignant disease / no malignant disease) for an assessment by the 2 image sets (UMRM and CMRM). Kappa value varies from 0 (no agreement) to 1 (perfect agreement).	Immediately before injection and after injection
Vital Signs Change From Baseline and Follow-up 24 Hours Post Injection - Systolic and Diastolic Blood Pressure	Systolic and diastolic blood pressure were measured in a supine position. Blood pressure was not to be measured on the arm used for the injection.	Baseline, Follow-up visit (24 hours post injection)

Collaborators and Investigators

• Sponsor: Bayer

Publications and helpful links

General Publications

• Endrikat J, Schmidt G, Haverstock D, Weber O, Trnkova ZJ, Barkhausen J. Sensitivity of Contrast-Enhanced Breast MRI vs X-ray Mammography Based on Cancer Histology, Tumor Grading, Receptor Status, and Molecular Subtype: A Supplemental Analysis of 2 Large Phase III Studies. Breast Cancer (Auckl). 2022 Apr 19;16:11782234221092155. doi: 10.1177/11782234221092155. eCollection 2022.
• Sardanelli F, Newstead GM, Putz B, Jirakova Trnkova Z, Trimboli RM, Abe H, Haverstock D, Rosenberg M. Gadobutrol-Enhanced Magnetic Resonance Imaging of the Breast in the Preoperative Setting: Results of 2 Prospective International Multicenter Phase III Studies. Invest Radiol. 2016 Jul;51(7):454-61. doi: 10.1097/RLI.0000000000000254.

Helpful Links

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Study record dates

Study Major Dates

• Study Start: February 1, 2010
• Primary Completion (ACTUAL): July 1, 2011
• Study Completion (ACTUAL): January 1, 2012

Study Registration Dates

• First Submitted: February 11, 2010
• First Submitted That Met QC Criteria: February 11, 2010
• First Posted (ESTIMATE): February 12, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): November 11, 2014
• Last Update Submitted That Met QC Criteria: November 10, 2014
• Last Verified: November 1, 2014

More Information

Terms related to this study

• Keywords: Breast Cancer; Mammography; Gadobutrol-enhanced MRI
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: 91743; GEMMA 1 (OTHER: Company internal); 2009-009597-27 (EUDRACT_NUMBER)