SH L 562BB Phase II/III Dose Justification and Gadoteridol-controlled Comparative Study

NCT00522951 — Phase 3, Completed, 165 participants, Bayer

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Multi-center, Randomized, Controlled, Single-blind, Intra-individual Comparisons of 2 Dose of Gadobutrol 1.0 Molar and Gadoteridol (ProHance) Crossover Studies With Corresponding Blinded Image Evaluation Following Multiple Injections of 0.1 mmol/kg bw of Gadobutrol and Gadoteridol in Patients With Known or Suspected Brain Metastasis

Registry	NCT00522951
Status	Completed
Phase	Phase 3
Study type	Interventional; randomized, crossover, masking: single, diagnostic
Enrollment	165 (Actual)
Sponsor	Bayer (Industry)
Conditions	Brain Metastases
Interventions	Gadobutrol (Gadavist, Gadovist, BAY86-4875), ProHance (Drug)
Dates	start 2007-08-01, primary completion 2008-08-01, completion 2008-08-01, first posted 2007-08-30, last updated 2017-08-28
Locations	20 sites in Japan

-Summary

This study is conducted to compare the contrast effect and safety of SH L562BB with ProHance, which has already been approved as a pharmaceutical product of similar indication.

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+Arms and interventions

Arm	Type	Interventions	Description
Gadobutrol 0.1 mmol/kg bw	Experimental	Drug: Gadobutrol (Gadavist, Gadovist, BAY86-4875)	Participants received first injection (intravenous \[i.v.\]) of gadobutrol 0.1 mmol/kg body weight (bw), corresponding to a dose of 0.1 mmol/kg bw
Gadobutrol 0.2 mmol/kg bw	Experimental	Drug: Gadobutrol (Gadavist, Gadovist, BAY86-4875)	Participants received second injection (i.v.) of gadobutrol 0.1 mmol/kg bw, corresponding to a total dose of 0.2 mmol/kg bw. The interval of two bolus injections is 13-15 min
Gadoteridol (ProHance)	Experimental	Drug: ProHance	Participants received two injections (i.v.) of gadoteridol 0.1 mmol/kg bw, corresponding to a total dose of 0.2 mmol/kg bw. The interval of two bolus injections is 13-15 min

Gadobutrol (Gadavist, Gadovist, BAY86-4875) (Drug): Gadobutrol enhanced MRI (first injection of gadobutrol 0.1 mmol/kg bw, corresponding to a dose of 0.1 mmol/kg bw)
Gadobutrol (Gadavist, Gadovist, BAY86-4875) (Drug): Gadobutrol enhanced MRI (second injection of gadobutrol 0.1 mmol/kg bw, corresponding to a total dose of 0.2 mmol/kg bw)
ProHance (Drug): ProHance enhanced MRI (two injections of gadoteridol 0.1 mmol/kg bw, corresponding to a total dose of 0.2 mmol/kg bw)

+Outcome measures

Primary outcomes

Number of Lesions Detected by Blinded Readers (BR) and Investigator [one day]: Number of metastatic lesions (unenhanced and enhanced) per participant detected on postcontrast Magnetic resonance (MR) images by averaged blinded reader and investigator

Secondary outcomes

Score of Visibility Assessment - Degree of Lesion Contrast Enhancement by Blinded Reader [one day]: Degree of contrast enhancement for each lesion on postcontrast MR images using the 4-point scale by averaged blinded reader (Score 1=No, 2=Moderate, 3=Good, 4=Excellent)
Score of Visibility Assessment - Degree of Lesion Contrast Enhancement by Investigator [one day]: Degree of contrast enhancement for each lesion on postcontrast MR images using the 4-point scale by investigator (Score 1=No, 2=Moderate, 3=Good, 4=Excellent)
Score of Visibility Assessment - Border Delineation by Blinded Reader [one day]: Border delineation for each lesion on postcontrast MR images using the 4-point scale by averaged blinded reader (Score 1=None, 2=Moderate, 3=Good, 4=Excellent)
Score of Visibility Assessment - Border Delineation by Investigator [one day]: Border delineation for each lesion on postcontrast MR images using the 4-point scale by investigator (Score 1=None, 2=Moderate, 3=Good, 4=Excellent)
Treatment Planning Confidence - Gadobutrol 0.1 mmol/kg bw vs. Gadoteridol (ProHance) 0.2 mmol/kg bw by Treatment Planning Experts (TPE) [one day]: Treatment planning confidence evaluated separately for each image set (gadobutrol \[Gado-\] 0.1 mmol/kg bw and gadoteridol \[Pro-\] 0.2 mmol/kg) by TPE (category: not confident, confident, and not assessable)
Treatment Planning Confidence - Gadobutrol 0.1 mmol/kg bw vs. Gadoteridol (ProHance) 0.2 mmol/kg bw by Investigator [one day]: Treatment planning confidence evaluated separately for each image set (gadobutrol 0.1 mmol/kg bw and gadoteridol 0.2 mmol/kg) by investigator (category: not confident, confident, and not assessable)
Treatment Planning Confidence - Gadobutrol 0.2 mmol/kg bw vs. Gadoteridol (ProHance) 0.2 mmol/kg bw by TPE [one day]: Treatment planning confidence evaluated separately for each image set (gadobutrol 0.2 mmol/kg bw and gadoteridol 0.2 mmol/kg) by TPE (category: not confident, confident, and not assessable)
Treatment Planning Confidence - Gadobutrol 0.2 mmol/kg bw vs. Gadoteridol (ProHance) 0.2 mmol/kg bw by Investigator [one day]: Treatment planning confidence evaluated separately for each image set (gadobutrol 0.2 mmol/kg bw and gadoteridol 0.2 mmol/kg) by investigator (category: not confident, confident, and not assessable)
Number of Participants With Performance in Stereotactic Radiosurgery (SRS) Planning by TPE [one day]: Comparison of overall image quality for SRS treatment planning between gadobutrol and gadoteridol by TPE
Number of Participants With Performance in Stereotactic Radiosurgery (SRS) Planning by Investigator [one day]: Comparison of overall image quality for SRS treatment planning between gadobutrol and gadoteridol by investigator
Number of Participants With Reasons for Performance in SRS Planning by TPE [one day]: Reasons for comparison results of overall image quality for SRS treatment planning between gadobutrol and gadoteridol by investigator (multiple answers applicable)
Number of Participants With Reasons for Performance in SRS Planning by Investigator [one day]: Reasons for comparison results of overall image quality for SRS treatment planning between gadobutrol and gadoteridol by investigator (multiple answers applicable)
Lesion Size Evaluated by Independent Radiologist [one day]: Size of each lesion on postcontrast MR images evaluated by independent radiologist (mean and standard deviation of 603 lesions)
Contrast Noise Ratio (CNR) of Lesions Evaluated by Independent Radiologist [one day]: CNR of lesion/normal white matter based on the signal intensity of MR images evaluated by independent radiologist (mean and standard deviation of 306 lesions)
Intraclass Correlation Coefficient (ICC) Among 3 Blinded Readers on the Number of Detected Lesions [one day]: ICC among 3 blinded readers calculated for number of detected lesions using the statistical model with two random effects, i.e., blinded readers and individual patients.

+Eligibility

Sex: All, ages: 20 Years to any

Inclusion Criteria:

* Japanese patients at least 20 years of age
* Patients with diagnosed primary cancer
* Patients with metastatic lesions by CT/MRI

Exclusion Criteria:

* Patients who have contraindication to the MRI examinations
* Patients who have severe renal disorder
* Patients in extremely serious general condition

+Posted results

Participant flow

Milestone	Gadobutrol Then Gadoteridol	Gadoteridol Then Gadobutrol
Started	86	79
Received treatment	86	78
Completed	86	78
Not completed	0	1

Outcome results

Number of Lesions Detected by Blinded Readers (BR) and Investigator (Primary), Mean, lesions: Gadobutrol 0.1 mmol/kg bw 6.28 +/- 8.31; Gadobutrol 0.2 mmol/kg bw 6.92 +/- 8.69; Gadoteridol (ProHance) 0.2mmol/kg bw 6.87 +/- 8.65
Score of Visibility Assessment - Degree of Lesion Contrast Enhancement by Blinded Reader (Secondary), Mean, scores on a scale: Gadobutrol 0.1 mmol/kg bw 3.44 +/- 0.42; Gadobutrol 0.2 mmol/kg bw 3.54 +/- 0.44; Gadoteridol (ProHance) 0.2mmol/kg bw 3.51 +/- 0.49
Score of Visibility Assessment - Degree of Lesion Contrast Enhancement by Investigator (Secondary), Mean, scores on a scale: Gadobutrol 0.1 mmol/kg bw 3.16 +/- 0.63; Gadobutrol 0.2 mmol/kg bw 3.46 +/- 0.55; Gadoteridol (ProHance) 0.2mmol/kg bw 3.31 +/- 0.63
Score of Visibility Assessment - Border Delineation by Blinded Reader (Secondary), Mean, scores on a scale: Gadobutrol 0.1 mmol/kg bw 3.30 +/- 0.46; Gadobutrol 0.2 mmol/kg bw 3.45 +/- 0.48; Gadoteridol (ProHance) 0.2mmol/kg bw 3.36 +/- 0.56
Score of Visibility Assessment - Border Delineation by Investigator (Secondary), Mean, scores on a scale: Gadobutrol 0.1 mmol/kg bw 3.10 +/- 0.70; Gadobutrol 0.2 mmol/kg bw 3.38 +/- 0.61; Gadoteridol (ProHance) 0.2mmol/kg bw 3.22 +/- 0.68
Treatment Planning Confidence - Gadobutrol 0.1 mmol/kg bw vs. Gadoteridol (ProHance) 0.2 mmol/kg bw by Treatment Planning Experts (TPE) (Secondary), Number, participants: Gadobutrol 0.1 mmol/kg bw vs. ProHance 0.2 mmol/kg bw 0
Treatment Planning Confidence - Gadobutrol 0.1 mmol/kg bw vs. Gadoteridol (ProHance) 0.2 mmol/kg bw by Investigator (Secondary), Number, participants: Gadobutrol 0.1 mmol/kg bw vs. ProHance 0.2 mmol/kg bw 1
Treatment Planning Confidence - Gadobutrol 0.2 mmol/kg bw vs. Gadoteridol (ProHance) 0.2 mmol/kg bw by TPE (Secondary), Number, participants: Gadobutrol 0.2 mmol/kg bw vs. ProHance 0.2 mmol/kg bw 0
Treatment Planning Confidence - Gadobutrol 0.2 mmol/kg bw vs. Gadoteridol (ProHance) 0.2 mmol/kg bw by Investigator (Secondary), Number, participants: Gadobutrol 0.2 mmol/kg bw vs. ProHance 0.2 mmol/kg bw 1
Number of Participants With Performance in Stereotactic Radiosurgery (SRS) Planning by TPE (Secondary), Number, participants: Gadobutrol 0.1 mmol/kg bw vs. ProHance 0.2 mmol/kg bw 26; Gadobutrol 0.2 mmol/kg bw vs. ProHance 0.2 mmol/kg bw 22
Number of Participants With Performance in Stereotactic Radiosurgery (SRS) Planning by Investigator (Secondary), Number, participants: Gadobutrol 0.1 mmol/kg bw vs. ProHance 0.2 mmol/kg bw 9; Gadobutrol 0.2 mmol/kg bw vs. ProHance 0.2 mmol/kg bw 24
Number of Participants With Reasons for Performance in SRS Planning by TPE (Secondary), Number, participants: Gadobutrol 0.1 mmol/kg bw vs. ProHance 0.2 mmol/kg bw 2; Gadobutrol 0.2 mmol/kg bw vs. ProHance 0.2 mmol/kg bw 5
Number of Participants With Reasons for Performance in SRS Planning by Investigator (Secondary), Number, participants: Gadobutrol 0.1 mmol/kg bw vs. ProHance 0.2 mmol/kg bw 2; Gadobutrol 0.2 mmol/kg bw vs. ProHance 0.2 mmol/kg bw 8
Lesion Size Evaluated by Independent Radiologist (Secondary), Mean, mm: Gadobutrol 0.1 mmol/kg bw 8.79 +/- 8.06; Gadobutrol 0.2 mmol/kg bw 9.07 +/- 8.19; Gadoteridol (ProHance) 0.2mmol/kg bw 8.83 +/- 8.02
Contrast Noise Ratio (CNR) of Lesions Evaluated by Independent Radiologist (Secondary), Mean, CNR: Gadobutrol 0.1 mmol/kg bw 36.74 +/- 47.82; Gadobutrol 0.2 mmol/kg bw 60.09 +/- 67.40; Gadoteridol (ProHance) 0.2mmol/kg bw 53.01 +/- 56.20
Intraclass Correlation Coefficient (ICC) Among 3 Blinded Readers on the Number of Detected Lesions (Secondary), Number, ICC: Gadobutrol 0.1 mmol/kg bw 0.963; Gadobutrol 0.2 mmol/kg bw 0.955; Gadoteridol (ProHance) 0.2mmol/kg bw 0.949

Adverse events

Arm	Deaths	Serious adverse events	Other adverse events
Gadobutrol Period	0	0/161 (0.0%)	2/161 (1.2%)
ProHance Period	0	2/162 (1.2%)	9/162 (5.6%)

Serious adverse events by term

Term	Organ system	Gadobutrol Period	ProHance Period
General physical health deterioration	General disorders	0/161	1/162
Bile duct stone	Hepatobiliary disorders	0/161	1/162

Other adverse events by term

Term	Organ system	Gadobutrol Period	ProHance Period
Nausea	Gastrointestinal disorders	0/161	2/162
Vomiting	Gastrointestinal disorders	1/161	2/162
Glucose urine present	Investigations	0/161	2/162
Headache	Nervous system disorders	0/161	2/162
Rash	Skin and subcutaneous tissue disorders	1/161	2/162

+Locations (20)

Facility	City	Country	Status
	Nagoya, Aichi-ken	Japan
	Matsuyama, Ehime	Japan
	Kitakyushu, Fukuoka	Japan
	Sapporo, Hokkaido	Japan
	Kobe, Hyōgo	Japan
	Sagamihara, Kanagawa	Japan
	Yokohama, Kanagawa	Japan
	Habikino, Osaka	Japan
	Habikino, Osaka	Japan
	Sayama, Osaka	Japan
	Hamamatsu, Shizuoka	Japan
	Sunto, Shizuoka	Japan
	Bunkyo-ku, Tokyo	Japan
	Bunkyo-ku, Tokyo	Japan
	Chuo-ku, Tokyo	Japan
	Mitaka, Tokyo	Japan
	Shinagawa-ku, Tokyo	Japan
	Yonago, Tottori	Japan
	Fukuoka	Japan
	Osaka	Japan

+Publications

Results publication: Katakami N, Inaba Y, Sugata S, Tsurusaki M, Itoh T, Machida T, Tanaka H, Nakayama T, Morikawa T, Breuer J, Aitoku Y. Magnetic resonance evaluation of brain metastases from systemic malignances with two doses of gadobutrol 1.0 m compared with gadoteridol: a multicenter, phase ii/iii study in patients with known or suspected brain metastases. Invest Radiol. 2011 Jul;46(7):411-8. doi: 10.1097/RLI.0b013e3182145a6c. PMID 21467949

+Investigators

Bayer Study Director, Study director, Bayer

My Notes

Public

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