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Efficacy and Safety of Gadobutrol 1.0 Molar (Gadovist) for Breast Magnetic Resonance Imaging (MRI) (GEMMA 2)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bayer
ClinicalTrials.gov Identifier:
NCT01104584
First received: April 14, 2010
Last updated: November 10, 2014
Last verified: November 2014
  Purpose

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


Condition Intervention Phase
Breast Cancer
Drug: Gadobutrol (Gadavist, Gadovist, BAY86-4875)
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Bayer:

Primary Outcome Measures:
  • Difference of Sensitivity for Detection of Full Extent of Malignant Breast Disease Using CMRM vs UMRM Per Reader [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
    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).

  • Sensitivity for Detection of Full Extent of Malignant Breast Disease Using CMRM vs UMRM Per Reader [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
    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.

  • Breast Level Specificity of CMRM for Non-malignant Breasts by Reader [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Breast Level Specificity of CMRM Based on Malignant Breasts [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
    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).

  • Percentage Difference of Participants Whose Index Cancers Were Detected Using CMRM vs UMRM, CMRM vs XRM, and CMRM vs CMRM+XRM [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
    Index cancer was 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.

  • Percentage Difference of Participants Whose Additional Index Cancers Were Detected Using CMRM vs UMRM, CMRM vs XRM, and CMRM vs CMRM+XRM [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
    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.

  • Difference of Confidence in Diagnosis for Breast Region Diagnosis Using CMRM vs UMRM, CMRM+XRM vs UMRM+XRM and CMRM+XRM vs XRM by Reader, Participant Level [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
    The investigator and the 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). For each participant, the mean of the confidence responses for the diagnosed breast regions was calculated, and rounded to the nearest 0.5. The difference was calculated as CMRM value minus UMRM value, CMRM+XRM value minus UMRM+XRM value, CMRM+XRM value minus XRM value respectively.


Other Outcome Measures:
  • Sensitivity for Detection of Full Extent of Malignant Breast Disease Using XRM, CMRM+XRM and UMRM+XRM Per Reader [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
    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.

  • Breast Level Specificity of in Non-malignant Breasts Using UMRM, XRM, CMRM+XRM and UMRM+XRM by Reader [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
    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.

  • Breast Level Specificity in Malignant Breasts Using UMRM, XRM, CMRM+XRM and UMRM+XRM by Reader [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
    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).

  • Breast Level Specificity for All Breasts by Imaging Modality and by Reader [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
    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 point estimates were calculated based on the mean of the sensitivities across all participants. Regions with malignant disease verified by SoT comprise unifocal and multifocal regions. Difference in sensitivity is calculated as CMRM value minus UMRM value, CMRM+XRM value minus UMRM+XRM value, CMRM+XRM value minus XRM value respectively.

  • 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 [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
    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 point estimates were calculated based on the mean of the sensitivities across all participants. The difference in sensitivity is calculated as CMRM value minus UMRM value, CMRM+XRM value minus UMRM+XRM value, CMRM+XRM value minus XRM value respectively.

  • 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 [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
    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 point estimates were calculated based on the mean of the sensitivities across all participants. The difference in sensitivity is calculated as CMRM value minus UMRM value, CMRM+XRM value minus UMRM+XRM value, CMRM+XRM value minus XRM value respectively.

  • 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 [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
    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 difference was calculated as CMRM value minus UMRM value, CMRM+XRM value minus UMRM+XRM value, CMRM+XRM value minus XRM value respectively.

  • 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 [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
    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 difference was calculated as CMRM value minus UMRM value, CMRM+XRM value minus UMRM+XRM value, CMRM+XRM value minus XRM value respectively.

  • 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 [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
    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 difference was calculated as CMRM value minus UMRM value, CMRM+XRM value minus UMRM+XRM value, CMRM+XRM value minus XRM value respectively.

  • Sensitivity of Detection of Multicentric Malignant Disease Verified by SoT, Breast Level [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
    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 point estimates were calculated based on the mean of the sensitivities across all participants. The difference was calculated as CMRM value minus UMRM value, CMRM+XRM value minus UMRM+XRM value, CMRM+XRM value minus XRM value respectively.

  • Accuracy Difference of Presence of Bilateral Malignant Disease Verified by SoT by Clinical Investigator, Participant Level [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
    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 were 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.

  • Blinded Readers: Inter-reader Agreement on Sensitivity Based on Assessment for UMRM vs CMRM - Breast Region Level [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
    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).

  • Blinded Reader 1: Intra-reader Variability Based on Assessment for CMRM - Breast Level [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
    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).

  • Blinded Reader 2: Intra-reader Variability Based on Assessment for CMRM - Breast Level [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
    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).

  • Blinded Reader 3: Intra-reader Variability Based on Assessment for CMRM - Breast Level [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
    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).

  • Categorical Accuracy Difference of Extent of Malignant Disease Verified by SoT by Majority Reader, Breast Region Level [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
  • Categorical Accuracy Difference of Extent of Malignant Disease Verified by Histopathology by Majority Reader, Breast Region Level [ Time Frame: Immediately before injection and after injection ] [ Designated as safety issue: No ]
  • Vital Signs Change From Baseline and Follow-up 24 Hours Post Injection - Systolic and Diastolic Blood Pressure [ Time Frame: Baseline, 24 hours post injection ] [ Designated as safety issue: Yes ]
    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.

  • Vital Signs Change From Baseline and Follow-up 24 Hours Post Injection - Heart Rate [ Time Frame: Baseline, Follow-up visit (24 hours post injection) ] [ Designated as safety issue: Yes ]
    Heart rate was measured in a supine position.

  • 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 [ Time Frame: Baseline, Follow-up visit (24 hours post injection) ] [ Designated as safety issue: Yes ]
    Number of participants with at least one occurrence of changing from low or normal at baseline to high at follow-up.


Enrollment: 460
Study Start Date: May 2010
Study Completion Date: January 2012
Primary Completion Date: September 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Gadobutrol (Gadavist, BAY86-4875)
Patients first received an unenhanced magnetic resonance mammography (MRM), followed by a gadobutrol-enhanced MRM. Gadobutrol was administered at the standard dose of 0.1 mmol/kg body weight (bw) [0.1 ml/kg bw] as an intravenous injection (i.v.) at a rate of 2 ml/sec. Unenhanced MRM (UMRM) and combined unenhanced and contrast (gadobutrol)-enhanced MRM (CMRM) image sets were evaluated in a randomized fashion. After the evaluation of the UMRM or CMRM the respective X-ray mammography (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; 0.1 mmol/kg body weight

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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:

    • a. patient is younger than 50 years;
    • b. patient has heterogeneously or extremely dense breasts;
    • c. 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01104584

  Show 48 Study Locations
Sponsors and Collaborators
Bayer
Investigators
Study Director: Bayer Study Director Bayer
  More Information

Additional Information:
No publications provided

Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT01104584     History of Changes
Other Study ID Numbers: 91782, 2009-009598-90
Study First Received: April 14, 2010
Results First Received: July 10, 2014
Last Updated: November 10, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Spain: Spanish Agency of Medicines
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Taiwan: Department of Health
India: Central Drugs Standard Control Organization
Canada: Health Canada
Turkey: Ethics Committee
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
United States: Food and Drug Administration

Keywords provided by Bayer:
Breast Cancer
Gadobutrol-enhanced MRI
Mammography
Diagnostic Imaging

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms
Neoplasms by Site
Skin Diseases
Gadobutrol
Contrast Media
Diagnostic Uses of Chemicals
Pharmacologic Actions

ClinicalTrials.gov processed this record on November 25, 2014