TRUTH: Comparison of Prohance® With Gadovist®/Gadavist™ in Magnetic Resonance Imaging (MRI) of the Brain

• Sponsor: Bracco Diagnostics, Inc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01613417
• Collaborator: (none)
• Enrollment: 229
• Location: 1
• Arms: 2
• Duration (Months): 20
• Patients Per Site Per Month: 11.5

Study Details

Study Description

Brief Summary

This study aims at a direct comparison between ProHance (0.1 mmol/kg) and a validated comparator Gadovist/Gadavist (0.1 mmol/kg) in a crossover intra-individual design in subjects with brain tumors to confirm the identical overall technical and diagnostic performance of the two MR contrast agents.

Condition or Disease	Intervention/Treatment	Phase
Brain Disease	Drug: gadoteridol; Drug: gadobutrol	Phase 4

Detailed Description

Adult patients were given two MRI exams, one after injection of ProHance (0.1 mmol/kg) and one after injection of Gadovist/Gadavist (0.1 mmol/kg). The exams were performed with identical equipment and imaging parameters with the order of the two exams randomized and 2-14 days between the first and the second MRI exam. Image data was evaluated by 3 expert neuroradiologist blinded to the agent administered and patient clinical data.

Study Design

• Study Type: Interventional
• Actual Enrollment: 229 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Diagnostic
• Official Title: Phase IV, Double-blind, Multi-center, Randomized, Crossover Study to Compare 0.1 mmol/kg of Prohance® With 0.1 mmol/kg of Gadovist®/Gadavist™ in Magnetic Resonance Imaging (MRI) of the Brain (TRUTH)
• Study Start Date: Aug 1, 2012
• Actual Primary Completion Date: Apr 1, 2014
• Actual Study Completion Date: Apr 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: MRI with Gadoteridol MRI after 0.1 mmol/kg IV ProHance, then with 0.1 mmol/kg Gadovist/Gadavist. MRI performed after both agents with identical sequences.	Drug: gadoteridol; ProHance 0.1 mmol/kg; Other Names: ProHance ; Drug: gadobutrol; Gadovist/Gadavist 0.1 mmol/kg; Other Names: Gadovist, Gadavist
Active Comparator: MRI with Gadobutrol MRI after 0.1 mmol/kg IV Gadovist/Gadavist, then with 0.1 mmol/kg ProHance. MRI performed after both agents with identical sequences.	Drug: gadoteridol; ProHance 0.1 mmol/kg; Other Names: ProHance ; Drug: gadobutrol; Gadovist/Gadavist 0.1 mmol/kg; Other Names: Gadovist, Gadavist

Outcome Measures

Primary Outcome Measures

1. Global Diagnostic Preference Between the Two Exams [Comparison of image sets obtained within 2 to 14 days]

   Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance and Gadovist/Gadavist. Readers assessed whether images with ProHance were preferred or images with Gadovist/Gadavist were preferred, or whether images after both exams were considered equal.

Secondary Outcome Measures

1. Lesion Border Delineation [Comparison of image sets obtained within 2 to 14 days]

   Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance and Gadovist/Gadavist. Readers assessed whether images with ProHance were preferred or images with Gadovist/Gadavist were preferred, or whether images after both exams were considered equal.

2. Lesion Internal Morphology [Comparison of image sets obtained within 2 to 14 days]

   Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance and Gadovist/Gadavist. Readers assessed whether images with ProHance were preferred or images with Gadovist/Gadavist were preferred, or whether images after both exams were considered equal.

3. Extent of Disease [Comparison of image sets obtained within 2 to 14 days]

   Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance and Gadovist/Gadavist. Readers assessed whether images with ProHance were preferred or images with Gadovist/Gadavist were preferred, or whether images after both exams were considered equal.

4. Lesion Contrast Enhancement [Comparison of image sets obtained within 2 to 14 days]

   Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance and Gadovist/Gadavist. Readers assessed whether images with ProHance were preferred or images with Gadovist/Gadavist were preferred, or whether images after both exams were considered equal.

5. Lesion to Background Ratio on Post T1-weighed Spin Echo Images [5-10 minutes Postdose]

   Mean of difference in signal intensity postdose (ProHance - Gadovist/Gadavist)

6. Percentage Signal Intensity Enhancement on Postdose Images [5-10 minutes Postdose]

   Mean difference in percentage signal intensity enhancement on postdose T1-weighted SE/FSE images (ProHance - Gadovist/Gadavist)

7. Lesion Detection [5-10 minutes Postdose]

   Lesion detection rate by contrast agent and reader

8. Accuracy for Tumor Characterization [5-10 minutes Postdose]

   Blinded reader assessment of accuracy of tumor characterization (benign/malignant) - patient level assessment

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Are scheduled to undergo MRI

• Are willing to undergo two MRI procedures within 14 days

• Have confirmed or are highly suspected of brain disease likely to enhance as determined by the following:

• Clinical/neurological symptomatology;

• Diagnostic testing, such as CT or previous MRI examinations; or

• Have had previous brain surgery and are to be evaluated for recurrence.

Exclusion Criteria:

• Are pregnant or lactating females. Exclude the possibility of pregnancy:

• by testing on site at the institution within 24 hours prior to the start of each investigational product administration; or

• by history (i.e., tubal ligation or hysterectomy); or

• post menopausal with a minimum of 1 year without menses

• Have any known allergy to one or more of the ingredients in the investigational products, or have a history of hypersensitivity to any metals

• Have congestive heart failure (class IV according to the classification of the New York Heart Association; see Appendix A)

• Have suffered a stroke within a year

• Have received or are scheduled to receive any other contrast medium in the 24 hours preceding through the 24 hours following Exam 1, and in the 24 hours preceding through the 24 hours following Exam 2

• Have received or are scheduled to receive an investigational compound and/or medical device within 30 days before admission into the present study, through the 24 hours post-administration of the second investigational product.

• Have moderate-to-severe renal impairment, defined as a GFR/eGFR < 45 mL/min.

• Have been previously entered into this study

• Have received or are scheduled for one of the following:

• Surgery within three weeks prior to the first examination or between the two examinations

• Initiation of steroid therapy between the two examinations

• Radiosurgery between the two examinations

• Have any contraindications to MRI such as a pace-maker, magnetic material (i.e., surgical clips) or any other conditions that would preclude proximity to a strong magnetic field.

• Are suffering from severe claustrophobia

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Holy Name Medical Center	Teaneck	New Jersey	United States	07666

Sponsors and Collaborators

• Bracco Diagnostics, Inc

Investigators

• Study Director: Gianpaolo Pirovano, MD, Bracco Diagnostics, Inc

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Bracco Diagnostics, Inc
• ClinicalTrials.gov Identifier: NCT01613417
• Other Study ID Numbers: PH-107
• First Posted: Jun 7, 2012
• Last Update Posted: Jul 1, 2015
• Last Verified: Jun 1, 2015

• Keywords provided by Bracco Diagnostics, Inc: Have confirmed or are highly suspected of brain disease
• Additional relevant MeSH terms: Brain Diseases

Study Results

Participant Flow

Recruitment Details	A total of 229 patients were recruited from September 2012 through November 2013 at 19 clinical trial sites. Off-site assessment of the images was performed between 21 January and 3 April 2014 by 3 board-certified neuroradiologists blinded as to which contrast agent was used, patient clinical information, and the results of other imaging studies.
Pre-assignment Detail	229 patients were enrolled and signed informed consent. Each enrolled patient was randomized and dosed with at least one contrast agent.

Arm/Group Title	Sequence 1 (ProHance Then Gadovist/Gadavist)	Sequence 2 (Gadovist/Gadavist Then ProHance)
Arm/Group Description	Patients randomized to receive ProHance first	Patients randomized to receive Gadovist/Gadavist first
Period Title: First Injection
STARTED	113	116
COMPLETED	113	116
NOT COMPLETED	0	0
Period Title: First Injection
STARTED	113	116
COMPLETED	100	109
NOT COMPLETED	13	7
Period Title: First Injection
STARTED	100	109
COMPLETED	100	109
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	ProHance Then Gadovist/Gadavist	Gadovist/Gadavist Then ProHance	Total
Arm/Group Description	Per Protocol=patients who completed both exams, had global paired image data available, and had no major protocol violations	Per Protocol=patients who completed both exams, had global paired image data available, and had no major protocol violations	Total of all reporting groups
Overall Participants	93	105	198
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	70 75.3%	70 66.7%	140 70.7%
>=65 years	23 24.7%	35 33.3%	58 29.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.5 (14.27)	55.9 (14.29)	55.2 (14.31)
Sex: Female, Male (Count of Participants)
Female	50 53.8%	58 55.2%	108 54.5%
Male	43 46.2%	47 44.8%	90 45.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	3 3.2%	1 1%	4 2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	2 1.9%	2 1%
White	88 94.6%	102 97.1%	190 96%
More than one race	2 2.2%	0 0%	2 1%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	46 49.5%	46 43.8%	92 46.5%
Europe	39 41.9%	51 48.6%	90 45.5%
Canada	8 8.6%	8 7.6%	16 8.1%

Outcome Measures

1. Primary Outcome

Title	Global Diagnostic Preference Between the Two Exams
Description	Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance and Gadovist/Gadavist. Readers assessed whether images with ProHance were preferred or images with Gadovist/Gadavist were preferred, or whether images after both exams were considered equal.
Time Frame	Comparison of image sets obtained within 2 to 14 days

Outcome Measure Data

Analysis Population Description

Per Protocol=patients who completed both exams, had global paired image data available, and had no major protocol violations

Arm/Group Title	Reader 1	Reader 2	Reader 3
Arm/Group Description	Paired exams reviewed by Reader 1	Paired exams reviewed by Reader 2	Paired exams reviewed by Reader 3
Measure Participants	198	194	196
Measure Patient Exams	198	194	196
ProHance Preferred	14	7	1
Contrast Agents Equal	171	180	195
Gadovist/Gadavist Preferred	13	7	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reader 1
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Power calculation was based on primary endpoint. 185 patients were deemed necessary for the lower limit of the observed 2-sided 95% confidence interval for the difference to exceed -5% with 85% power.
Statistical Test of Hypothesis	p-Value	0.8516
	Comments	P-value from Wilcoxon signed-rank test
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Percentage PH better minus GV better
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; -4.6 to 5.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in percentage ProHance better minus percentage Gadovist/Gadavist better (%)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reader 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Power calculation was based on primary endpoint. 185 patients were deemed necessary for the lower limit of the observed 2-sided 95% confidence interval for the difference to exceed -5% with 85% power.
Statistical Test of Hypothesis	p-Value	1.0
	Comments	P-value from Wilcoxon signed-rank test
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Percentage PH better minus GV better
	Estimated Value	0
	Confidence Interval	(2-Sided) 95%; -3.8 to 3.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in percentage ProHance better minus percentage Gadovist/Gadavist better (%)

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reader 3
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Power calculation was based on primary endpoint. 185 patients were deemed necessary for the lower limit of the observed 2-sided 95% confidence interval for the difference to exceed -5% with 85% power.
Statistical Test of Hypothesis	p-Value	1.0
	Comments	P-value from Wilcoxon signed-rank test
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Percentage PH better minus GV better
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; -0.5 to 1.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in percentage ProHance better minus percentage Gadovist/Gadavist better (%)

2. Secondary Outcome

Title	Lesion Border Delineation
Description	Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance and Gadovist/Gadavist. Readers assessed whether images with ProHance were preferred or images with Gadovist/Gadavist were preferred, or whether images after both exams were considered equal.
Time Frame	Comparison of image sets obtained within 2 to 14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Reader 1	Reader 2	Reader 3
Arm/Group Description	Paired exams reviewed by Reader 1	Paired exams reviewed by Reader 2	Paired exams reviewed by Reader 3
Measure Participants	198	194	196
Measure Patient Exams	198	194	196
ProHance Better	8	2	1
No Difference between Prohance and Gadovist/Gadavi	181	189	195
Gadovist/Gadavist Better	9	3	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reader 1
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments	P-value from Wilcoxon signed-rank test
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reader 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments	P-value from Wilcoxon signed-rank test
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reader 3
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments	P-value from Wilcoxon signed-rank test
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Lesion Internal Morphology
Description	Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance and Gadovist/Gadavist. Readers assessed whether images with ProHance were preferred or images with Gadovist/Gadavist were preferred, or whether images after both exams were considered equal.
Time Frame	Comparison of image sets obtained within 2 to 14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Reader 1	Reader 2	Reader 3
Arm/Group Description	Paired exams reviewed by Reader 1	Paired exams reviewed by Reader 2	Paired exams reviewed by Reader 3
Measure Participants	198	198	198
Measure Patient Exams	198	194	196
ProHance better	2	2	1
No Difference Between ProHance and Gadovist/Gadavi	195	188	195
Gadovist/Gadavist betterB	1	4	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reader 1
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments	P-value from Wilcoxon signed-rank test
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reader 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6875
	Comments	P-value from Wilcoxon signed-rank test
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reader 3
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments	P-value from Wilcoxon signed-rank test
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. Secondary Outcome

Title	Extent of Disease
Description	Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance and Gadovist/Gadavist. Readers assessed whether images with ProHance were preferred or images with Gadovist/Gadavist were preferred, or whether images after both exams were considered equal.
Time Frame	Comparison of image sets obtained within 2 to 14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Reader 1	Reader 2	Reader 3
Arm/Group Description	Paired exams reviewed by Reader 1	Paired exams reviewed by Reader 2	Paired exams reviewed by Reader 3
Measure Participants	198	198	198
Measure Patient Exams	198	194	196
ProHance Better	1	2	1
No Difference between ProHance and Gadovist/Gadavi	196	190	195
Gadovist/Gadavist Better	1	2	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reader 1
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments	P-value from Wilcoxon signed-rank test
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reader 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments	P-value from Wilcoxon signed-rank test
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reader 3
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments	P-value from Wilcoxon signed-rank test
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Lesion Contrast Enhancement
Description	Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance and Gadovist/Gadavist. Readers assessed whether images with ProHance were preferred or images with Gadovist/Gadavist were preferred, or whether images after both exams were considered equal.
Time Frame	Comparison of image sets obtained within 2 to 14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Reader 1	Reader 2	Reader 3
Arm/Group Description	Paired exams reviewed by Reader 1	Paired exams reviewed by Reader 2	Paired exams reviewed by Reader 3
Measure Participants	198	198	198
Measure Patient Exams	198	194	196
ProHance Better	14	10	2
No Difference between ProHance and Gadovist/Gadavi	170	174	193
Gadovist/Gadavist Better	14	10	1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reader 1
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments	P-value from Wilcoxon signed-rank test
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reader 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments	P-value from Wilcoxon signed-rank test
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reader 3
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments	P-value from Wilcoxon signed-rank test
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Secondary Outcome

Title	Lesion to Background Ratio on Post T1-weighed Spin Echo Images
Description	Mean of difference in signal intensity postdose (ProHance - Gadovist/Gadavist)
Time Frame	5-10 minutes Postdose

Outcome Measure Data

Analysis Population Description

Per-protocol population

Arm/Group Title	Reader 1	Reader 2	Reader 3
Arm/Group Description	Lesions reviewed by Reader 1	Lesions reviewed by Reader 2	Lesions reviewed by Reader 3
Measure Participants	198	194	196
Measure Lesions	194	137	162
Mean (Standard Deviation) [signal intensity]	-0.02 (0.17)	-0.16 (1.12)	-0.01 (0.18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reader 1
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2758
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effect model with period, sequence, and IP and fixed effect and subject nested within sequence as random effect

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reader 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0676
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effect model with period, sequence, and IP and fixed effect and subject nested within sequence as random effect

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reader 3
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5267
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effect model with period, sequence, and IP and fixed effect and subject nested within sequence as random effect

7. Secondary Outcome

Title	Percentage Signal Intensity Enhancement on Postdose Images
Description	Mean difference in percentage signal intensity enhancement on postdose T1-weighted SE/FSE images (ProHance - Gadovist/Gadavist)
Time Frame	5-10 minutes Postdose

Outcome Measure Data

Analysis Population Description

Per-protocol population

Arm/Group Title	Reader 1	Reader 2	Reader 3
Arm/Group Description	Lesions reviewed by Reader 1	Lesions reviewed by Reader 2	Lesions reviewed by Reader 3
Measure Participants	198	194	196
Measure Lesions	191	133	159
Mean (Standard Deviation) [percentage signal intensity enhancement]	1.06 (28.61)	-2.09 (29.06)	-1.59 (29.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reader 1
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6201
	Comments
	Method	Mixed Models Analysis
	Comments	Investigation product (IP) effect from mixed model with period, sequence, and IP as fixed effects and subject nested within sequence as random effect.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reader 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4514
	Comments
	Method	Mixed Models Analysis
	Comments	Investigation product (IP) effect from mixed model with period, sequence, and IP as fixed effects and subject nested within sequence as random effect.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reader 3
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7722
	Comments
	Method	Mixed Models Analysis
	Comments	Investigation product (IP) effect from mixed model with period, sequence, and IP as fixed effects and subject nested within sequence as random effect.

8. Secondary Outcome

Title	Lesion Detection
Description	Lesion detection rate by contrast agent and reader
Time Frame	5-10 minutes Postdose

Outcome Measure Data

Analysis Population Description

Per protocol patients with histologically confirmed lesions

Arm/Group Title	Reader 1 - ProHance	Reader 1 - Gadovist/Gadavist	Reader 2 - ProHance	Reader 2 - Gadovist/Gadavist	Reader 3 - ProHance	Reader 3 - Gadovist/Gadavist
Arm/Group Description	MRI after ProHance 0.1 mmol/kg	MRI after Gadovist/Gadavist 0.1 mmol/kg	MRI after ProHance 0.1 mmol/kg	MRI after Gadovist/Gadavist 0.1 mmol/kg	MRI after ProHance 0.1 mmol/kg	MRI after Gadovist/Gadavist 0.1 mmol/kg
Measure Participants	139	139	139	139	139	139
True Positive (Patients)	133	135	137	136	136	132
False Negative (Pa	6	4	2	3	3	7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reader 1, Reader 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3173
	Comments
	Method	McNemar
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reader 3, Reader 2 - Gadovist/Gadavist
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5637
	Comments
	Method	McNemar
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reader 3 - ProHance, Reader 3 - Gadovist/Gadavist
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0455
	Comments
	Method	McNemar
	Comments

9. Secondary Outcome

Title	Accuracy for Tumor Characterization
Description	Blinded reader assessment of accuracy of tumor characterization (benign/malignant) - patient level assessment
Time Frame	5-10 minutes Postdose

Outcome Measure Data

Analysis Population Description

Subjects with histologically confirmed lesions

Arm/Group Title	Reader 1 - ProHance	Reader 1 - Gadovist/Gadavist	Reader 2 - ProHance	Reader 2 - Gadovist/Gadavist	Reader 3 - ProHance	Reader 3 - Gadovist/Gadavist
Arm/Group Description	MRI after ProHance 0.1 mmol/kg	MRI after Gadovist/Gadavist 0.1 mmol/kg	MRI after ProHance 0.1 mmol/kg	MRI after Gadovist/Gadavist 0.1 mmol/kg	MRI after ProHance 0.1 mmol/kg	MRI after Gadovist/Gadavist 0.1 mmol/kg
Measure Participants	128	128	128	128	128	128
Patients with Tumors Correctly Categorized	94 101.1%	96 91.4%	106 53.5%	101 NaN	93 NaN	83 NaN
Patients with Tumors Incorrectly Categorized	34 36.6%	32 30.5%	22 11.1%	27 NaN	35 NaN	45 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reader 1, Reader 2
	Comments	McNemar test of difference (ProHance minus Gadovist/Gadavist) in accuracy for tumor characterization
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6949
	Comments
	Method	McNemar
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Reader 3, Reader 2 - Gadovist/Gadavist
	Comments	McNemar test of difference (ProHance minus Gadovist/Gadavist) in accuracy for tumor characterization
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1317
	Comments
	Method	McNemar
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Reader 3 - ProHance, Reader 3 - Gadovist/Gadavist
	Comments	McNemar test of difference (ProHance minus Gadovist/Gadavist) in accuracy for tumor characterization
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0124
	Comments
	Method	McNemar
	Comments

Adverse Events

Time Frame	Up to 24 hours after contrast media injection
Adverse Event Reporting Description	All adverse events collected were categorized using MedDRA 16.1 and tabulated
Arm/Group Title	Safety Population (ProHance)		Safety Population (Gadovist/Gadavist)
Arm/Group Description	All enrolled patients who received a randomized injection of ProHance		All enrolled patients who received a randomized injection of Gadovist/Gadavist
All Cause Mortality
	Safety Population (ProHance)		Safety Population (Gadovist/Gadavist)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Safety Population (ProHance)		Safety Population (Gadovist/Gadavist)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/222 (0%)		0/216 (0%)
Other (Not Including Serious) Adverse Events
	Safety Population (ProHance)		Safety Population (Gadovist/Gadavist)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/222 (6.8%)		8/216 (3.7%)
Gastrointestinal disorders
Diarrhea	1/222 (0.5%)		0/216 (0%)
Nausea	4/222 (1.8%)		1/216 (0.5%)
Vomiting	1/222 (0.5%)		1/216 (0.5%)
Fatigue	0/222 (0%)		1/216 (0.5%)
General disorders
Feeling hot	1/222 (0.5%)		0/216 (0%)
Nervous system disorders
Convulsion	0/222 (0%)		1/216 (0.5%)
Dizziness	1/222 (0.5%)		1/216 (0.5%)
Dysgeusia	4/222 (1.8%)		1/216 (0.5%)
Headache	2/222 (0.9%)		1/216 (0.5%)
Lethargy	1/222 (0.5%)		0/216 (0%)
Migraine	1/222 (0.5%)		0/216 (0%)
Paresthesia	0/222 (0%)		1/216 (0.5%)
Psychiatric disorders
Anxiety	0/222 (0%)		1/216 (0.5%)
Mood altered	0/222 (0%)		1/216 (0.5%)
Respiratory, thoracic and mediastinal disorders
Cough	2/222 (0.9%)		0/216 (0%)
Dyspnea	1/222 (0.5%)		0/216 (0%)
Orophanyngeal pain	0/222 (0%)		1/216 (0.5%)
Skin and subcutaneous tissue disorders
Pruritus	1/222 (0.5%)		0/216 (0%)
Rash	1/222 (0.5%)		0/216 (0%)
Urticaria	1/222 (0.5%)		0/216 (0%)
Vascular disorders
Vascular rupture	1/222 (0.5%)		0/216 (0%)

Limitations/Caveats

Histologic confirmation of disease available for only 139/198 patients in the PP analysis. Of these, 128 patients had confirmed brain tumors and were available for the analyses of diagnostic performance (tumor detection and tumor characterization).

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Study results may be presented at scientific symposia or published in a peer-review journal after review by sponsor in accordance with the guidelines set forth in the applicable publication or financial agreement