E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects with known or suspected renal artery disease |
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E.1.1.1 | Medical condition in easily understood language |
Known or suspected renal artery disease |
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E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Diagnosis [E01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10038378 |
E.1.2 | Term | Renal artery stenosis |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to evaluate the efficacy of gadobutrol-enhanced MRA over 2D-ToF MRA in subjects with known or suspected renal artery disease, as verified by
- superiority for structural delineation,
- non-inferiority for the detection of clinically significant vascular disease,
- non-inferiority for the exclusion of clinically significant vascular disease,
- minimum performance for gadobutrol detection of clinically significant vascular disease, and
- minimum performance for gadobutrol exclusion of clinically significant vascular disease
using CTA as the SoR excluding the first objective, structural delineation.
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E.2.2 | Secondary objectives of the trial |
A further objective of this study is to confirm the safety profile of gadobutrol for this indication.
Secondary efficacy assessments will include:
- minimum diameter of the segment
- location and length of stenotic segment with ≥50 % stenosis
- aneurysmal dilatation
- artifacts by type
- diagnostic confidence (segmental)
- additional imaging studies recommended (example: non contrast MRA, computed tomography, ultrasound, nuclear medicine study). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The following inclusion criteria must be met at the time of screening unless otherwise specified.
1. Male or female subjects, aged ≥ 18 years
2. Known or suspected renal artery disease based on any of the following:
a. Referred for evaluation of the renal arteries for clinically significant stenosis. In Germany, only subjects who undergo a CTA within 60 days prior to consent or subjects who clinically require a CTA which is ordered by the referring physician as part of the standard clinical routine will be included. Once the German Radiation Protection Authority has approved the conduct of a study-specific CTA, subjects without prior CTA or referral for a clinically indicated CTA can be included and undergo a CTA as part of the study.
b. follow-up for a metallic stent in a renal artery
c. prior imaging study (CTA) showing ≥ 50% renal artery stenosis (within 60 days prior to consent)
If there is inadequate enrollment of subjects with clinically significant disease (based on CTA interpretation made by the investigators) then the enrollment may be restricted to subjects who underwent a CTA (within 60 days prior to consent) or clinically indicated and ordered by the referring physician as part of the standard clinical routine (within 7 days prior to the MRA) showing at least moderate disease (≥ 50%). Once the German Radiation Protection Authority has approved the conduct of a study-specific CTA, subjects without prior CTA or referral for clinically indicated CTA can be included and undergo a CTA as part of the study. This would meet the protocol guidelines as described in Section 8.6.2.
Note: Any CTA must meet the specifications provided in Section 7.3.4 and will be used as the SoR for this study. If the CTA does not meet the specifications, then the CTA has to be repeated as part of the study or the subject cannot be enrolled.
3. Willingness to undergo the routine CE MRA examinations with gadobutrol
4. Willingness and ability to follow directions and complete all study procedures specified in the protocol
5. Females of childbearing potential only: Negative pregnancy test on the day of the MRA prior to administration of study drug
6. Written informed consent, including information about the provisions of the Health Insurance Portability and Accountability Act as applicable |
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E.4 | Principal exclusion criteria |
Subjects who meet any of the following criteria at the time of screening will be excluded:
1. Pregnant or nursing (including pumping for storage and feeding)
2. Received any other investigational product or participation in any other clinical trial within 30 days prior to enrollment in this study
3. Previous enrollment into this study or any other Bayer sponsored study using gadobutrol
4. Contraindication to the MRI examination (e.g. inability to hold breath; severe arrhythmias; very low cardiac output, severe claustrophobia, defibrillators, or other metallic devices not approved for MRI)
5. Contraindications to the use of Gd-containing contrast agents (including subjects who are suspected for or known to have NSF)
6. History of severe (as judged by the investigator, taking into account the intensity of the event) allergic or anaphylactoid reaction to any allergen including drugs and contrast agents
7. Received any contrast agent within 72 hours prior to the study MRA, or is scheduled to receive any contrast agent within 72 hours after the study MRA
(Note: This applies also to a CTA potentially scheduled during the course of the study)
8. Estimated glomerular filtration rate (eGFR) value < 30 mL/min/1.73 m² derived from a serum creatinine result within 2 weeks prior to gadobutrol injection. Any subject on hemodialysis or peritoneal dialysis is excluded from enrollment.
(Note: If there are multiple creatinine values, the values obtained prior to and closest to the time of the MRA should be used. The core lab value should not be used if not available prior to the MRA/CTA).
9. Acute renal insufficiency of any intensity, either due to hepato-renal syndrome or occurring in the perioperative liver transplantation period.
10. Known history of severe cardiovascular disease (e.g., acute myocardial infarction [< 14 days], unstable angina, congestive heart failure [New York Heart Association Class IV]) or known long QT syndrome
11. Suspected clinical instability or unpredictability of the clinical course during the study period (e.g., due to previous surgery or acute stroke)
12. Scheduled or potentially expected for the period between the CTA and gadobutrol MRA:
a. any procedure that may alter the MRA or CTA interpretation, or
b. any interventional or surgical procedure involving the renal or abdominal aorta
In Germany, the investigators additionally have to adhere to guidelines given in the country specific package insert. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The following five co-primary endpoints are based on the proportion of assessable vascular segments, and the sensitivity and specificity of clinically significant disease:
• Superiority in the proportion of assessable segments with gadobutrol-enhanced MRA compared to non-contrast MRA
• Non-inferior diagnosis of clinically significant disease based on the sensitivity [≥ 50% stenosis] on a segmental basis
• Non-inferior diagnosis of clinically significant disease based on the specificity [≥ 50% stenosis] on a segmental basis
• The two minimum gadobutrol performance criteria (both sensitivity and specificity should exceed 50%)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Approximately 15 months after LPLV |
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E.5.2 | Secondary end point(s) |
The following secondary efficacy variables will be summarized:
- Length of the right and left renal arteries
- Narrowest diameter of a segment
- Location of stenoses in the proximal segments
- Artifacts by type (segmental)
- Accessory (duplicate) renal arteries
- Aneurysmal dilatation (segmental)
- Diagnosis (subject): FMP vs. arteriosclerosis
- Diagnostic confidence (segmental)
- Additional imaging studies recommended (subject) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Approximately 15 months after LPLV |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Austria |
Brazil |
China |
Colombia |
Czech Republic |
France |
Germany |
Korea, Republic of |
Poland |
Switzerland |
Taiwan |
Turkey |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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For each participating EU country, the end of the study according to the EU Clinical Trial Directive will be reached when the last visit of the last subject for all centers in the respective country has occurred.
As for this study, the primary outcome will be collected after last patient (subject) last visit (LPLV) and the end of the study as a whole will be the date when the clean data base is available. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 5 |