Efficacy and Safety of Primovist in Chinese Patients

Study Overview
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Brief Summary
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Participants who had been diagnosed or suspected by doctors to have focal liver lesions that need further evaluation in order to make an accurate diagnosis. Participants would need to have an enhanced magnetic resonance imaging (MRI) scan so that doctors could have further information about the number and characteristics of the focal liver lesions. Participants were invited to take part in this clinical study. The purpose of this study was to evaluate Primovist, which is a liver-specific MRI contrast medium, on the efficacy of lesion detection and characterization, and tolerability in Chinese patients with known or suspected focal liver lesions. Primovist, the investigational drug in this study, is a liver-specific MRI contrast medium developed by Bayer Schering Pharma AG. Its active substance is Gd-EOB-DTPA. Primovist was first approved in 2004 in Sweden followed by an approval in the European community, in Switzerland and Australia in the same year. Procedures: Before entry into the study and after entry of the study a physical examination was conducted, blood pressure and heart rate were measured, blood and urine samples were taken. Current medications and medical conditions (including suspected pregnancy) and medical and surgical history were elicited by doctors. After entry into the study, participants were scheduled to have an MRI examination, which lasted about 25-35 minutes. During the MRI examination, an initial MRI scan without contrast was acquired which followed by another MRI series after the intravenous administration of Primovist. The following day participants were asked to return to the hospital for a follow-up safety evaluation. Possible Benefit Participants were scheduled to receive an enhanced magnetic resonance imaging scan. Clinical studies indicated that Primovist increased the efficacy of detection and characterization of focal liver lesions by providing better contrast between the focal liver lesions and surrounding normal tissue. Primovist were shown to provide additional information regarding existence, number and characterization (lesion or non-lesion, malignant or benign) of these abnormalities. Based on the experience with patients given Primovist, some adverse reactions were observed. Most of undesirable effects were transient and of mild to moderate intensity. The most commonly noted adverse events (AEs) in subjects receiving Primovist for MRI were nausea and headache with an incidence of 1.1%. Other AEs that occurred in 0.5% of the subject population were feeling hot (0.8%), back pain (0.6%) and dizziness (0.5%). All other AEs occurred in less than 0.5% of the patients, e.g. anxiety; coughing; eye disorder; fever; flatulence; generalized spasm; hypertension; injection site symptoms including edema, inflammation, and reaction; lightheadedness; parosmia; postural hypotension; taste perversion, motoric unrest; acute respiratory distress; fatigue; malaise; vomiting; palpitations, erythema, chest pain and back pain. Coldness, warmth or pain at the injection site, injection site reaction, and injection site accumulation of fluid were rare. In very rare cases strong allergy-like reactions ranging to shock may occur. Post-marketing tachycardia and restlessness have been reported. As in the case of other investigational drugs, there may also be unforeseen side effects. Additional information concerning all Gadolinium- based contrast agents Primovist contains the rare earth metal gadolinium as active ingredient. There have been reports of nephrogenic systemic fibrosis (NSF) associated with use of some gadolinium-containing contrast agents (especially Omniscan) in patients with severe renal impairment. NSF is a systemic disease characterised by formation of connective tissue in the skin, which becomes thickened and hard, sometimes leading to contractures and joint immobility. The clinical course is usually progressive and currently no treatment is available. To date NSF has only been reported in association with some Gd-containing contrast agents, but the role of these contrast agents in the overall pathogenesis of the disease is still not completely understood. No reports of patients with NSF after administration of Primovist® are known. The risk to trigger NSF in risk patients with severe renal impairment is considered to be low for Primovist® due to the low dose given and the additional excretion via feces. Furthermore the participation of patients with severe renal impairment are excluded from this study. In case the participants were suffering from renal insufficiency, they were told to tell their doctors prior to application of the contrast agent. In case the participants experienced any new alterations of the skin following the administration of the contrast agent, they were told to contact their doctors as soon as possible after they had recognized these symptoms.

Detailed Description
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Adult Chinese patients with known focal or suspected liver lesions, referred for magnetic resonance imaging (MRI) for further diagnostic work-up, who have undergone or are scheduled to undergo a defined SOR procedure, within one month before or after the study MRI. The data for the Secondary Outcome Measure Lesion size and location has been documented but not analyzed. The data for the Secondary Outcome Measure Safety are reflected in the Adverse Event section.

Official Title
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A Multicenter, Open-label Phase III Study of the Efficacy and Safety of Primovist as a Contrast Agent for Enhanced MR Imaging of Focal Liver Lesions in Chinese Patients

Conditions
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Known or Suspected Focal Liver Lesions

Intervention / Treatment
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* Drug: Gadoxetic Acid Disodium (Primovist, BAY86-4873)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients between 18 and 75 years of age inclusive. Patients (men or women) with at least one focal liver lesion, either identified or suspected by ultrasound (US), Computed Tomography (CT)/spiral-CT, conventional angiography, CT-angiography (CTA), CT-arterioportography (CTAP) or unenhanced / contrast-enhanced MRI* within 2 months before entering the study For reference, the following pathologies will meet the definition of 'focal liver lesions': Hepatocellular carcinoma Cholangiole carcinoma Metastasis Focal lymphoma Adenoma Focal nodular hyperplasia Hemangioma Abscess Focal liver fibrosis Regenerative nodules Focal fatty infiltration Hydatid cyst Liver cyst Focal sparing in fatty liver Others Patients willing to undergo study procedures including safety follow-up Patients who have undergone or who are scheduled to undergo the defined procedure for SOR within one month before or after the study MRI Women of child-bearing potential with negative urine pregnancy test result within 24 hours before contrast medium (CM) injection Patients who are fully informed about the study and have signed the informed consent form Exclusion Criteria: Patients who have previously entered this study Patients who have received any contrast material within 24 hours before injection with study drug, or who are scheduled to receive any contrast material within 24 hours after injection Patients who are, or suspected to be, nursing Patients who require emergency treatment Patients with severely impaired hepatic or renal functions (e.g. serum glutamic-pyruvic transaminase (SGPT) twice the upper limit of reference range, acute renal failure) Patients who are clinically unstable and whose clinical course during the observation period is unpredictable (e.g. due to previous surgery, acute myocardial infarction) Patients with any physical or mental status that interferes with the signing of informed consent Patients with known anaphylactoid or anaphylactic reaction to any contrast media or hypersensitivity to any allergen including drugs Patients with a contraindication for MRI Patients who are scheduled for liver biopsy/surgery or other surgeries within 24 hours after injection with contrast media, or who would have a biopsy within 24 hours before planned injection with contrast media Patients who are likely to have any therapy or change in therapy between the study MRI and the procedures for the SOR

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gadoxetic Acid Disodium (Primovist, BAY86-4873)<br>Bolus injection of 0.025 mmol/kg body weight (0.1 ml/kg BW) of Gadoxetic Acid Disodium (Primovist, BAY86-4873). Single i.v. injection during MRI procedure, with one contrast-enhanced MRI procedure per patient | Drug: Gadoxetic Acid Disodium (Primovist, BAY86-4873)<br>* Bolus injection of 0.025 mmol/kg body weight (0.1 ml/kg BW) of Gadoxetic Acid Disodium (Primovist, BAY86-4873). Single i.v. injection during MRI procedure, with one contrast-enhanced MRI procedure per patient<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in Sensitivity of Lesion Detection in MRI Images (Post-contrast MRI Minus Pre-contrast MRI) Measured as Percentage Points | Three Blinded Readers performed lesion detection in pre- and post-contrast MRI image sets. Per Blinded Reader/image set combination, sensitivity of lesion detection was calculated, as: (number of lesions detected in the reader/image set combination)/(number of lesions in Standard of Reference)*100%. Then, difference in sensitivity of lesion detection for post- minus pre-contrast MRI images (in percentage points) was calculated for each Blinded Reader. | Post administration assessment of study images (i.e. on the same day of treatment by the investigators and at the end of patient enrollment of the study from 29 September to 18 November 2008 by the Blinded Readers). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in Sensitivity of Lesion Detection in MRI Images (Post-contrast MRI Minus Pre-contrast MRI) Assessed by Investigators Measured in Percentage Points | The on-site investigators performed lesion detection in pre- and post-contrast MRI image sets. Per image set, sensitivity of lesion detection was calculated, as: (number of lesions detected in image set)/(number of lesions in Standard of Reference)*100%. Then, difference in sensitivity of lesion detection for post- minus pre-contrast MRI (in percentage points) was calculated. | Post administration assessment of study images (i.e. on the same day of treatment by the investigators and at the end of patient enrollment of the study from 29 September to 18 November 2008 by the Blinded Readers). | 
| Difference in Precision of Lesion Characterization (Combined Pre- and Post-contrast Minus Pre-contrast MRI) Measured in Percentage Points | Three Blinded Reader performed lesion characterization in pre- and combined pre-/post-contrast MRI image set. Per Blinded Reader/image set combination, precision of lesion characterization was calculated: (number of unique Standard of Reference-matched characterizations detected for the Reader/image set combination)/(number of unique lesion characterizations in Standard of Reference)*100%. Then, difference in precision of lesion characterization for post- minus combined pre-/post-contrast MRI (in percentage points) was calculated for each Blinded Reader. | Post administration assessment of study images (i.e. on the same day of treatment by the investigators and at the end of patient enrollment of the study from 29 September to 18 November 2008 by the Blinded Readers). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Primovist, Chinese patients, Liver MRI