Dose Finding Study of Gadavist in Central Nervous System (CNS) Magnetic Resonance Imaging (MRI)

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

Bayer

ClinicalTrials.gov Identifier:

NCT00862459

First received: November 26, 2008

Last updated: December 11, 2013

Last verified: December 2013

History of Changes

Results First Received: September 14, 2011

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double Blind (Participant, Investigator, Outcomes Assessor); Primary Purpose: Diagnostic
Conditions:	Brain Diseases Spinal Cord Diseases
Interventions:	Drug: Gadobutrol~0.03 mmol/kg BW (Gadavist, Gadovist, BAY86-4875) Drug: Gadobutrol~0.1 mmol/kg BW (Gadavist, Gadovist, BAY86-4875) Drug: Gadobutrol~0.3 mmol/kg BW (Gadavist, Gadovist, BAY86-4875) Drug: OptiMARK~0.1 mmol/kg BW

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
The date of the first participant's first visit was 27 August 2005. The date of the last participant's last visit was 26 March 2007.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
242 participants were screened: 5 were screening failures (withdrew consent, did not meet study criteria, other). The remaining 237 were randomized to the 0.3, 0.1, or 0.03 millimole per kilogram (mmol/kg) group.

Reporting Groups

	Description
Gadobutrol~0.03 mmol/kg BW (Gadavist, BAY86-4875)	Participant received one dose of 0.03 mmol/kg body weight (BW) of Gadobutrol and one dose of 0.1 mmol/kg BW of OptiMARK. The order in which the participants received Gadobutrol and OptiMARK was randomized. Gadobutrol was administered via a power injector at a rate of 5 milliliter per second (mL/s) followed by a 20 mL 0.9% saline flush at the same rate.
Gadobutrol~0.1 mmol/kg BW (Gadavist, BAY86-4875)	Participant received one dose of 0.1 mmol/kg BW of Gadobutrol and one dose of 0.1 mmol/kg BW of OptiMARK. The order in which the participants received Gadobutrol and OptiMARK was randomized. Gadobutrol was administered via a power injector at a rate of 5 mL/s followed by a 20 mL 0.9% saline flush at the same rate.
Gadobutrol~0.3 mmol/kg BW (Gadavist, BAY86-4875)	Participant received one dose of 0.3 mmol/kg BW of Gadobutrol and one dose of 0.1 mmol/kg BW of OptiMARK. The order in which the participants received Gadobutrol and OptiMARK was randomized. Gadobutrol was administered via a power injector at a rate of 5 mL/s followed by a 20 mL 0.9% saline flush at the same rate.

Participant Flow: Overall Study

	Gadobutrol~0.03 mmol/kg BW (Gadavist, BAY86-4875)	Gadobutrol~0.1 mmol/kg BW (Gadavist, BAY86-4875)	Gadobutrol~0.3 mmol/kg BW (Gadavist, BAY86-4875)
STARTED	72	93	72
Participants Received Treatment	70 ^[1]	90 ^[2]	69 ^[3]
COMPLETED	66	85	66
NOT COMPLETED	6	8	6
Lost to Follow-up	1	2	2
Protocol Violation	1	0	0
Withdrawal by Subject	1	1	3
Adverse Event	0	1	0
Personal reasons	1	0	0
Operation	1	1	0
Intravenous (IV) site problems	1	0	1
Unable to hold still for imaging	0	1	0
Inclusion/exclusion criteria not met	0	1	0
Administrative problems	0	1	0

^[1]	Number reflects all treated participants of whom 67 received Gadobutrol and 70 received OptiMARK
^[2]	Number reflects all treated participants of whom 90 received Gadobutrol and 88 received OptiMARK
^[3]	Number reflects all treated participants of whom 68 received Gadobutrol and 69 received OptiMARK

Baseline Characteristics

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Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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Reporting Groups

	Description
Gadobutrol~0.03 mmol/kg BW (Gadavist, BAY86-4875)	Participant received one dose of 0.03 millimole per kilogram of body weight (mmol/kg BW) of Gadobutrol and one dose of 0.1 mmol/kg BW of OptiMARK. The order in which the participants received Gadobutrol and OptiMARK was randomized. Gadobutrol was administered via a power injector at a rate of 5 milliliter per second (mL/s) followed by a 20 mL 0.9% saline flush at the same rate.
Gadobutrol~0.1 mmol/kg BW (Gadavist, BAY86-4875)	Participant received one dose of 0.1 mmol/kg BW of Gadobutrol and one dose of 0.1 mmol/kg BW of OptiMARK. The order in which the participants received Gadobutrol and OptiMARK was randomized. Gadobutrol was administered via a power injector at a rate of 5 mL/s followed by a 20 mL 0.9% saline flush at the same rate.
Gadobutrol~0.3 mmol/kg BW (Gadavist, BAY86-4875)	Participant received one dose of 0.3 mmol/kg BW of Gadobutrol and one dose of 0.1 mmol/kg BW of OptiMARK. The order in which the participants received Gadobutrol and OptiMARK was randomized. Gadobutrol was administered via a power injector at a rate of 5 mL/s followed by a 20 mL 0.9% saline flush at the same rate.
Total	Total of all reporting groups

Baseline Measures

	Gadobutrol~0.03 mmol/kg BW (Gadavist, BAY86-4875)	Gadobutrol~0.1 mmol/kg BW (Gadavist, BAY86-4875)	Gadobutrol~0.3 mmol/kg BW (Gadavist, BAY86-4875)	Total
Overall Participants Analyzed [Units: Participants]	70	90	69	229

Age, Customized [Units: Years]
<45 years	36	42	29	107
45-64 years	24	39	28	91
>=65 years	10	9	12	31

Gender [Units: Participants]
Female	33	58	38	129
Male	37	32	31	100

Race/Ethnicity, Customized [Units: Participants]
Caucasian	30	45	29	104
Black	7	8	3	18
Hispanic	3	6	3	12
Asian	1	1	0	2
Other	29	30	34	93

Outcome Measures

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1. Primary:

Categorical Visualization Score (CVS) [ Time Frame: up to 2 hours after the injection of study medication ]

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2. Primary:

Difference in Number of Lesions Detected in Pre-contrast and Combined Pre-/Post-contrast MRI. [ Time Frame: up to 2 hours after the injection of study medication ]

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3. Primary:

Assessment of Lesion Contrast Enhancement [ Time Frame: up to 2 hours after the injection of study medication ]

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4. Primary:

Assessment of Border Delineation [ Time Frame: up to 2 hours after the injection of study medication ]

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5. Primary:

Assessment of Internal Morphology [ Time Frame: up to 2 hours after the injection of study medication ]

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6. Primary:

Contrast to Noise Ratio (CNR) Between White and Gray Matter With Gadobutrol Perfusion MRI [ Time Frame: up to 2 hours after the injection of study medication ]

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7. Secondary:

Accuracy Comparison of Gadobutrol Doses – Detection of Matched Lesions: Blinded Reader 1 [ Time Frame: up to 2 hours after the injection of study medication ]

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8. Secondary:

Accuracy Comparison of Gadobutrol Doses – Detection of Matched Lesions: Blinded Reader 2 [ Time Frame: up to 2 hours after the injection of study medication ]

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9. Secondary:

Accuracy Comparison of Gadobutrol Doses – Detection of Matched Lesions: Blinded Reader 3 [ Time Frame: up to 2 hours after the injection of study medication ]

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10. Secondary:

Accuracy Comparison of Gadobutrol Doses – Detection of Matched Enhanced Lesions: Blinded Reader 1 [ Time Frame: up to 2 hours after the injection of study medication ]

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11. Secondary:

Accuracy Comparison of Gadobutrol Doses – Detection of Matched Enhanced Lesions: Blinded Reader 2 [ Time Frame: up to 2 hours after the injection of study medication ]

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12. Secondary:

Accuracy Comparison of Gadobutrol Doses – Detection of Matched Enhanced Lesions: Blinded Reader 3 [ Time Frame: up to 2 hours after the injection of study medication ]

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13. Secondary:

Evaluation of the Correct Diagnosis Following Gadobutrol-enhanced and Unenhanced MRI [ Time Frame: up to 2 hours after the injection of study medication ]

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14. Secondary:

Evaluation of the Diagnostic Confidence Based on Unenhanced MRI and Combined Unenhanced and Enhanced MRI [ Time Frame: up to 2 hours after the injection of study medication ]

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15. Secondary:

Evaluation of Perfusion Map Quality (Uncorrected Cerebral Blood Volume [CBV]) – Blinded Reader 1 [ Time Frame: up to 2 hours after the injection of study medication ]

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16. Secondary:

Evaluation of Perfusion Map Quality (Uncorrected Cerebral Blood Volume (CBV)) – Blinded Reader 2 [ Time Frame: up to 2 hours after the injection of study medication ]

Show Outcome Measure 16

17. Secondary:

Evaluation of Perfusion Map Quality (Uncorrected Cerebral Blood Volume (CBV)) – Blinded Reader 3 [ Time Frame: up to 2 hours after the injection of study medication ]

Show Outcome Measure 17

18. Secondary:

Evaluation of Perfusion Map Quality (Corrected Cerebral Blood Volume (CBV)) – Blinded Reader 1 [ Time Frame: up to 2 hours after the injection of study medication ]

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19. Secondary:

Evaluation of Perfusion Map Quality (Corrected Cerebral Blood Volume (CBV)) – Blinded Reader 2 [ Time Frame: up to 2 hours after the injection of study medication ]

Show Outcome Measure 19

20. Secondary:

Evaluation of Perfusion Map Quality (Corrected Cerebral Blood Volume (CBV)) – Blinded Reader 3 [ Time Frame: up to 2 hours after the injection of study medication ]

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21. Secondary:

Evaluation of Perfusion Map Quality (Cerebral Blood Flow (CBF)) – Blinded Reader 1 [ Time Frame: up to 2 hours after the injection of study medication ]

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22. Secondary:

Evaluation of Perfusion Map Quality (Cerebral Blood Flow (CBF)) – Blinded Reader 2 [ Time Frame: up to 2 hours after the injection of study medication ]

Show Outcome Measure 22

23. Secondary:

Evaluation of Perfusion Map Quality (Cerebral Blood Flow (CBF)) – Blinded Reader 3 [ Time Frame: up to 2 hours after the injection of study medication ]

Show Outcome Measure 23

24. Secondary:

Evaluation of Perfusion Map Quality (Time to Peak (TTP)) – Blinded Reader 1 [ Time Frame: up to 2 hours after the injection of study medication ]

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25. Secondary:

Evaluation of Perfusion Map Quality (Time to Peak (TTP)) – Blinded Reader 2 [ Time Frame: up to 2 hours after the injection of study medication ]

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26. Secondary:

Evaluation of Perfusion Map Quality (Time to Peak (TTP)) – Blinded Reader 3 [ Time Frame: up to 2 hours after the injection of study medication ]

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27. Secondary:

Evaluation of Perfusion Map Quality (Mean Transit Time (MTT)) – Blinded Reader 1 [ Time Frame: up to 2 hours after the injection of study medication ]

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28. Secondary:

Evaluation of Perfusion Map Quality (Mean Transit Time (MTT)) – Blinded Reader 2 [ Time Frame: up to 2 hours after the injection of study medication ]

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29. Secondary:

Evaluation of Perfusion Map Quality (Mean Transit Time (MTT)) – Blinded Reader 3 [ Time Frame: up to 2 hours after the injection of study medication ]

Show Outcome Measure 29

30. Secondary:

Evaluation of Perfusion Map Quality (Permeability Factor (PF) – Blinded Reader 1 [ Time Frame: up to 2 hours after the injection of study medication ]

Show Outcome Measure 30

31. Secondary:

Evaluation of Perfusion Map Quality (Permeability Factor (PF) – Blinded Reader 2 [ Time Frame: up to 2 hours after the injection of study medication ]

Show Outcome Measure 31

32. Secondary:

Evaluation of Perfusion Map Quality (Permeability Factor (PF)) – Blinded Reader 3 [ Time Frame: up to 2 hours after the injection of study medication ]

Show Outcome Measure 32

33. Secondary:

Evaluation of Perfusion Map Parameter Value (Uncorrected Cerebral Blood Volume (CBV)) – Independent Radiologist [ Time Frame: up to 2 hours after the injection of study medication ]

Show Outcome Measure 33

34. Secondary:

Evaluation of Perfusion Map Parameter Value (Corrected Cerebral Blood Volume (CBV)) – Independent Radiologist [ Time Frame: up to 2 hours after the injection of study medication ]

Show Outcome Measure 34

35. Secondary:

Evaluation of Perfusion Map Parameter Value (Cerebral Blood Flow (CBF)) – Independent Radiologist [ Time Frame: up to 2 hours after the injection of study medication ]

Show Outcome Measure 35

36. Secondary:

Evaluation of Perfusion Map Parameter Value (Time to Peak (TTP)) – Independent Radiologist [ Time Frame: up to 2 hours after the injection of study medication ]

Show Outcome Measure 36

37. Secondary:

Evaluation of Perfusion Map Parameter Value (Mean Transit Time (MTT)) – Independent Radiologist [ Time Frame: up to 2 hours after the injection of study medication ]

Show Outcome Measure 37

38. Secondary:

Evaluation of Perfusion Map Parameter Value (Permeability Factor (PF)) – Independent Radiologist [ Time Frame: up to 2 hours after the injection of study medication ]

Show Outcome Measure 38

39. Secondary:

Evaluation of Perfusion Map Artifacts (Uncorrected Cerebral Blood Volume (CBV)) – Blinded Reader [ Time Frame: up to 2 hours after the injection of study medication ]

Show Outcome Measure 39

40. Secondary:

Evaluation of Perfusion Map Artifacts (Corrected Cerebral Blood Volume (CBV)) – Blinded Reader [ Time Frame: up to 2 hours after the injection of study medication ]

Show Outcome Measure 40

41. Secondary:

Evaluation of Perfusion Map Artifacts (Cerebral Blood Flow (CBF)) – Blinded Reader [ Time Frame: up to 2 hours after the injection of study medication ]

Show Outcome Measure 41

42. Secondary:

Evaluation of Perfusion Map Artifacts (Time to Peak (TTP)) – Blinded Reader [ Time Frame: up to 2 hours after the injection of study medication ]

Show Outcome Measure 42

43. Secondary:

Evaluation of Perfusion Map Artifacts (Mean Transit Time (MTT)) – Blinded Reader [ Time Frame: up to 2 hours after the injection of study medication ]

Show Outcome Measure 43

44. Secondary:

Evaluation of Perfusion Map Artifacts (Permeability Factor (PF)) – Blinded Reader [ Time Frame: up to 2 hours after the injection of study medication ]

Show Outcome Measure 44

45. Secondary:

Evaluation of MRI Tumor Grade Agreement With Biopsy Results by Dose Group [ Time Frame: up to 2 hours after the injection of study medication ]

Show Outcome Measure 45

46. Secondary:

Contrast to Noise Ratio (CNR) of Lesion/Gray Matter and Lesion/White Matter [ Time Frame: up to 2 hours after the injection of study medication ]

Show Outcome Measure 46

Serious Adverse Events

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Other Adverse Events

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Limitations and Caveats

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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
OptiMARK was used as a standard of reference in this study. A formal comparison of the efficacy of gadobutrol and OptiMARK was not specified prospectively in the statistical analysis plan. For completeness, the safety data of OptiMARK is presented.

More Information

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Certain Agreements:

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Publication of results will be a group publication. Sites with recruitment of >= 6 valid patients will contribute. There will be one author from each site having contributed >= 6 valid patients. Authorship listed according to recruitment. Sponsor will appoint up to 3 persons as co-authors. Main author of publication may be announced by site with most valid patients enrolled. In case more than 1 center reaches maximum patient No., main author will be from the center with fastest recruitment

Results Point of Contact:

Name/Title: Therapeutic Area Head
Organization: BAYER
e-mail: clinical-trials-contact@bayerhealthcare.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Breuer J, Gutierrez J, Latchaw R, Lehr R, Sorensen AG. Gadobutrol in the central nervous system at three doses: results from a phase II, randomized, multicenter trial. J Magn Reson Imaging. 2014 Feb;39(2):410-8. doi: 10.1002/jmri.24180. Epub 2013 May 16.

Responsible Party:	Bayer
ClinicalTrials.gov Identifier:	NCT00862459 History of Changes
Other Study ID Numbers:	91400 308200 ( Other Identifier: company internal )
Study First Received:	November 26, 2008
Results First Received:	September 14, 2011
Last Updated:	December 11, 2013

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