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

Study Overview
=================
Brief Summary
-----------------
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

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

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: Gadobutrol (Gadavist, Gadovist, BAY86-4875)


Participation Criteria
=================
Eligibility 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gadobutrol (Gadavist, BAY86-4875)<br>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)<br>* A single bolus injection of gadobutrol 1.0 M; 0.1 mmol/kg body weight<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference of 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 | 
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Breast Level Specificity of CMRM Based on Malignant Breasts | 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). | 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 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. | Immediately before injection and after injection | 
| Percentage Difference of Participants Whose Additional Index 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 | 
| 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 | 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. | Immediately before injection and after injection | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Breast Cancer, Gadobutrol-enhanced MRI, Mammography, Diagnostic Imaging