A Prospective Study to Evaluate the Efficacy and Safety of a Single Intravenous Injection of 0.1 mmol/kg Body Weight of Viv-Butrol for Contrast Enhancement MRI of Various Organs

Introduction: Magnetic Resonance Imaging (MRI) is the diagnostic technique preferred for tissue imaging in conditions like neurological and other abnormalities, as the procedure is able to generate images providing subtle differences between pathological and normal tissues. MRI works with a high-strength magnetic field, radio waves, and computer to generate images and has not been reported to produce any tissue damage or any other side effects. To improve the imaging of tissues, better iodinated and gadolinium-based contrast agents are used. Hypersensitivity reactions to contrast media are generally sporadic and unpredictable. The incidences of mild to moderate reactions are more common for iodinated contrast media than gadolinium-based chelates.

Aims and Objectives: To determine the efficacy and safety of a single intravenous injection of 0.1 mmol/kg Body Weight of Viv-Butrol in patients referred for contrast enhancement MRI of various organs, including the brain, spinal cord, breast, liver, and kidney.

Materials and Methods: A prospective, single-arm, open-label, multi-center, post-marketing surveillance study with a sample size of 100 was conducted for nine months. The study was conducted at three study centers: Bangalore Medical College and Research Institute, Department of Radio Diagnosis Bengaluru, ESIC Medical College & Hospital, Department of Radiology, Hyderabad, and Rajiv Gandhi Institute of Medical Sciences (RIMS), Srikakulam.

Results: It was observed that there was a statistically significant difference (p < 0.05) in Contrast Enhancement, Border Delineation, Internal Mor- phology, and Total Mean Score post-administration of Viv-Butrol. Conclusion: For several years, Gadolinium agents have been used worldwide for Contrast MRI. MRI with gadolinium contrasts is relatively much safer than iodinated contrast media, while establishing the efficacy of Gadobutrol and establishing the safety parameters also becomes essential. The study result shows that Viv-Butrol-enhanced MRI has been established to have much better efficacy when compared to its unenhanced/plain MRI with minimal Adverse reactions.

Introduction

Radio contrast media (RCM) are medical drugs which are utilized to enhance the visibility of internal organs and structures in various imaging techniques. These Contrast media can cause various side effects ranging from itching to a life-threatening emergency, known as contrast-induced nephropathy (CIN) [1]. Advances in the field of medical imaging over last few decades, have been associated with increased use of contrast media (CM) for magnetic resonances imaging (MRI) and multi-detector computed tomography (MDCT). In general, both iodinated and gadolinium-based contrast media are safe drugs with very low incidence of adverse reactions. Hypersensitivity reactions to contrast media are mostly sporadic and unpredictable and the incidences of contrast media reactions are common for iodinated contrast media than gadolinium-based chelates [2].

Contrast media are generally safe, their adverse reactions though mild needs observation and patient reassurance as it may also cause potential life-threatening conditions. These probable side effect imposes challenge for radiologists and allied medical staff at different levels of radiology practices. Hence, medical personnel involved in contrast media administration have to be oriented to the justifications for their use and stratification of risk factors [2].

The term Contrast basically refers to the difference in brightness between an area of interest and the surroundings. Greater the difference, greater is the contrast enhancing property of contrast media. MRI gadolinium contrasts are relatively much safer than iodinated contrast media but can sometimes cause tolerable side effects or serious side effects like nephrogenic systemic fibrosis, hence along with the efficacy, establishing the safety of a contrast media also becomes important [3].

A study conducted by Francesco Sardanelli et al on breast cancer, gadobutrol- enhanced breast MRI had demonstrated high levels of sensitivity and specificity [4]. Similarly in a Phase II, multi-center, double-blind, parallel-group controlled study done by Josy Breuer et al on 229 subjects showed that the 0.1 mmol/kg body weight dose of gadobutrol was effective and well tolerated for contrast- enhanced MRI of CNS [5]. In another prospective on MRI of CNS, multi-center, double-blind, crossover trial by Gutierrez et al. 2015 in patients who underwent unenhanced MRI followed by enhanced imaging with gadobutrol or gadoteridol proved that Gadobutrol was an effective and well-tolerated macrocyclic contrast agent for MRI of the CNS [6]. Accoding to Study by Rajiv Mahajan et al. 2019 Gadolinium-containing MRI contrast agents are most commonly used for the enhancement of vessels in MR angiography or for brain tumor enhancement associated with the degradation of the blood–brain barrier. There are studies available to determine the efficacy of gadobutrol in patients referred for contrast enhancement MRI of various organs including brain, spinal cord, breast, liver and kidney. Assessment of Safety parameters also becomes important. Hence, this study is designed to assess the safety and efficacy of gadobutrol in patients referred for contrast enhancement MRI of various organs including brain, spinal cord, breast, liver and kidney.

Aims and Objectives

The objective of this study is to determine the Efficacy and Safety of a Single Intravenous Injection of 0.1 mmol/kg Body Weight of Viv-Butrol in patients referred for contrast enhancement MRI of various organs including brain, spinal cord, breast, liver and kidney.

Materials and Methods

In this prospective, single-arm, open-label multi-center, post-marketing surveillance study conducted at three study centers, Bangalore Medical College and Research Institute, Department of Radio Diagnosis Bengaluru, ESIC Medical College & Hospital, Department of Radiology, Hyderabad and Rajiv Gandhi Institute of Medical Sciences (RIMS), Srikakulam.

Institutional Ethics Committees of the study site reviewed all the study-related documents, Bangalore Medical College and Research Institute (Approved on February 06, 2021), Institutional Ethics Committee Medical College & Government General Hospital (Approved on June 23, 2021), Institutional Ethics Committee -ESIC Medical College & Hospital (Approved on June 8, 2021). The study was conducted following the ethical standard of the Helsinki Declaration of 1975. The study was registered under CTRI with the CTRI no CTRI/2021/03/032302 [Registered on: 25/03/2021]. Eligible subjects were enrolled in the study only after obtaining their written consent. The study was initiated on March 30, 2021, where subjects who were referred for contrast enhancement MRI of various organs, including the brain, spinal cord, breast, liver, and kidney, were screened, out of which 100 were enrolled, and 20 subjects who were not fulfilling the eligibility criteria were considered as screen failures. There was no stratification /blinding /randomization based on any factors.

Study Drug

Single Intravenous Injection of 0.1 mmol/kg Body Weight of Viv-Butrol (Gadobutrol). Gadobutrol is a paramagnetic macrocyclic contrast agent administered for magnetic resonance imaging. In MRI, visualization of normal and pathological tissue depends in part on variations in the radio frequency signal intensity that occur with:

– Differences in proton density,

– Differences in the spin-lattice or longitudinal relaxation times (T1),

– Differences in the spin-spin or transverse relaxation time (T2).

Methodology

The study was conducted outpatient, and the trial participants were reviewed before the procedure. Potential participants for the study were enrolled after signing an informed consent form. The participants were subjected to an Unenhanced/Plain MRI scan. The Trial drug, a Single Intravenous Injection of 0.1 mmol/kg Body Weight of Viv-Butrol (Gadobutrol), was administered to the study participant, and a contrast MRI scan procedure was conducted. Laboratory tests for safety parameters such as CBC, LFT, RFT, and ECG were conducted before and after the MRI. The enrolled participants were followed up for six months. The total duration of the trial was approximately nine months.

Inclusion and Exclusion Criteria

The inclusion criteria adopted were as follows:

1) Males and females of age 18 and older,

2) Requiring gadolinium contrast-enhanced MRI for organs including brain, spinal cord, breast, liver, and kidney,

3) Ability to understand study procedures and to comply with them for the entire length of the study,

a) Lab Eligibility parameters (for contrast scans within 4 weeks of gadolinium injection),

b) Creatinine below the upper normal limit,

4) eGFR greater than or equal to 60 mL/min/1.73 m²,

5) Able to understand and sign informed consent,

6) Willing to follow up telephonically for 6 months,

7) No MRI scan with gadolinium injection in the last 6 months.

The exclusion criteria adopted were as follows:

1) Is a female patient who is pregnant or lactating,

2) Has any contraindication to the MRI examination (e.g., metal implants). Implanted metal clips or wires may concentrate radiofrequency fields or cause tissue damage from twisting in a Magnetic field. Examples: (Aneurysm clip, implanted neural stimulator, Implanted cardiac pacemaker, defibrillator, or certain other implanted electrical or metallic devices, Cochlear implant, ocular foreign body (metal shavings), Any implanted device (pumps, infusion devices, etc.), Shrapnel injuries, History of metal in head or eyes or other parts of the body,

3) Morbid obesity/or a body circumference that prevents the study subject from lying flat in the scanner

4) Untreatable claustrophobia otherwise requiring anesthesia,

5) Has received any contrast agent within 24 hours prior to the study, or is scheduled to receive any contrast agent within 24 hours after the study,

6) GBCA (gadolinium-based contrast agents) with an MRI scan in the last six months. This includes scans performed with GBCA at any outside institution and/or at the clinical center,

7) Has severe cardiovascular disease (e.g., known long QT syndrome, acute myocardial infarction [<14 days], unstable angina, congestive heart failure New York Heart Association class IV) or acute stroke (<48 hours),

8) Has acute renal insufficiency of any severity due to hepato-renal syndrome or in the peri-operative liver transplantation period or who has acute or chronic moderate or severe renal insufficiency (glomerular filtration rate <60 mL/min/1.73 m²),

9) Is scheduled or likely to require surgery and/or biopsy in the period up to 24 hours following study drug application,

10) Contraindications to the administration of gadobutrol (depending on local product label),

11) History of severe allergic or anaphylactic/anaphylactoid reaction to any allergen, including drugs and contrast agents,

12) History of allergic asthma,

13) Individuals with a history of liver transplant or severe liver disease,

14) Individuals with hemoglobinopathies,

15) Surgery of uncertain type, as per the investigator’s opinion,

16) Considered clinically unstable as per the investigator’s opinion,

17) Any contraindications the investigator identifies from the subject and/or History and Physical findings for MRI examination and/or gadobutrol.

Assessment Criteria

All the basic tests were conducted before and after the study procedure, and the subjects were telephonically followed up for any adverse effects to confirm their safety.

a) Efficacy Endpoint

A comparison of the sum of lesion visualization parameters between Viv-Butrol enhanced MRI v/s unenhanced (plain) MRI was considered as an endpoint efficacy. In addition, the parameters assessed on the visualization scoring system, border delineation, contrast enhancement, and internal morphology, were also considered for endpoint efficacy assessment.

b) Safety Endpoint

For the safety endpoint assessment, laboratory parameters such as CBC, LFT, RFT, and ECG were performed before and after the study procedure.

Statistical Assessment

A total of 120 patients were screened, and 100 patients were enrolled to meet the primary objectives of the study. The sample size determination was based on the following:

1) Assuming a dropout rate of 10%,

2) Power estimates were made assuming a two-sided test with an alpha (type I) of 0.05,

3) The common standard deviation of 0.075.

Based on these assumptions, a sample size of a total of 100 patients was sufficient to give 91% power to the study to detect a treatment difference of 0.080.

The individual Case Report Forms data were compared between screening and baseline day values (pre- and post) as dependent variables. Intervention as a fixed effect and VISIT 0 (Baseline) as a covariate for continuous data. All two-sided statistical tests were conducted at the 5% significance level unless otherwise specified. Two-sided t-tests were used to assume data normality and identify the significant differences between means for change from baseline in TSS. Student t-test was conducted to analyze efficacy evaluations and objective assessment values, while p < 0.05 was considered statistically significant for the study.

Results

During the study period of 9 months, about 120 patients referred for contrast-enhanced MRI were screened, and the 100 patients fulfilling the inclusion criteria were enrolled in the study. The mean age of the study participants was 36.85 years, with a minimum age of 21 years and a maximum of 50 years. The majority of the study participants were females, 60% of whom were female, and the remaining 40% were male subjects.

Baseline General Physical Examination

The General Physical Examination during the baseline for the parameters such as height, weight, temperature, pulse rate, respiratory rate, SBP, DBP, and systemic examination found that all the study participants were within normal limits, which is summarized in Table I.

Table I. Baseline General Physical Examination

Parameter	Mean	Minimum	Maximum	SD
Height (cm)	164.37	140	181	5.74
Weight (Kg)	63.28	48	82	8.02
Temperature (F)	98.43	97.6	98.8	0.32
Pulse rate (beats/min)	77.5	64	87	5.43
Respiratory rate (cycles/min)	17.5	16	20	1.32
SBP (mmHg)	126	120	144	4.14
DBP (mmHg)	82.1	70	92	4.71

Body Part Analysis

Among the 100 enrolled study patients, it was found that patients were most commonly referred for MRI of the brain and PNS (30%), closely followed by the brain (21%), spine (11%), abdomen or pelvis (10%) among others (28%). Fig. 1 depicts the analysis results.

Fig. 1. Results of the body part analysis for referral to MRI.

Differences in Contrast Enhancement, Border Delineation, and Internal Morphology between Before and After the Administration of Viv-Butrol

It was observed that there was a statistically significant difference (p < 0.05) in the parameters of contrast enhancement, border delineation, internal morphology, and their total score. The summarized statistical values are provided in Table II.

Table II. Statistical Values of Various Efficacy Parameters

Parameter	Mean ± SD before	Mean ± SD after	p
Contrast enhancement	2.22 ± 0.63	3.20 ± 0.70	<0.001
Border delineation	2.32 ± 0.75	3.22 ± 0.69	<0.001
Internal morphology	2.04 ± 0.75	2.88 ± 0.61	<0.001
Total score	6.56 ± 1.39	9.24 ± 0.92	<0.001

Safety Parameters

The safety of Viv-Butrol was assessed by immediate adverse events and a comparison of laboratory parameters before and after the administration of Viv-Butrol. A total of 7 adverse events occurred among the 100 enrolled subjects. The details of the severity of the adverse events are described in Table III.

Table III. Details of Severity of Adverse Events

Severity level	Frequency
Mild	7
Moderate	0
Severe	0
Serious	0

At each contact with the patient, the Investigator sought information on adverse events by specific questioning and, as appropriate, by examination. Information on all adverse events was recorded immediately in the appropriate adverse event module of the CRF. To elaborate, there were 7 mild ADRs, such as headache (n = 3), nausea (n = 2), palpitations (n = 1), and Pain at the injection site (n = 1), most frequently among others that were reported immediately post-administration.

Laboratory parameters were analyzed pre- and post-administration of Viv-Butrol, and no significant change was observed. The details of Laboratory parameters are described in Table IV.

Table IV. Details of Laboratory Parameters

Parameter	Mean before	Mean after
RBC (mill/cumm)	4.85 ± 0.54	4.82 ± 0.44
PLT (lakhs/cumm)	2.39 ± 0.69	2.37 ± 0.69
WBC (cells/cumm)	7.13 ± 1.52	7.12 ± 1.52
SGOT (U/L)	35.22 ± 10	35.24 ± 10
SGPT (U/L)	24.08 ± 12.13	24.09 ± 12.13
Total bilirubin (mg/dl)	0.62 ± 0.18	0.61 ± 0.18
Total cholesterol (mg/dl)	209.35 ± 29.03	209 ± 29.03
TGs (mg/dl)	145.89 ± 37.50	145.88 ± 37.50
LDL (mg/dl)	68.60 ± 12.5	68.90 ± 12.7

Discussion

MRI is a non-invasive imaging technology that provides detailed three-dimensional images of anatomical structures. It is used for diagnostic and treatment monitoring purposes. It works on the technology that detects the change in the direction of the rotational axis of protons found in water that make up living tissues. It is more useful than CT when soft tissues of the body are to be studied and analyzed. Using contrast to enhance MRI images is often preferred because it causes strategic contrast localization in the desired area, thereby aiding the treating physician [7]. Gadolinium-based compounds are commonly used as contrast media in MRI, and Viv-Butrol is one such compound. No other contrast agent is chosen as a comparator, as the trial aims at safety and efficacy.

The efficacy of Gadabutrol was assessed with three parameters: Contrast Enhancement, Border Delineation, and Internal Morphology in the Visual Scoring Scale. These scores were then summated to a total highest of 11. Viv-Butrol shortens the T1 and T2 relaxation times when placed in a magnetic field. The extent of decrease of T1 and T2 relaxation times, and therefore the amount of signal enhancement obtained from Viv-Butrol, is based upon several factors, including the concentration of Viv-Butrol in the tissue, the field strength of the MRI system, and the relative ratio of the longitudinal and transverse relaxation times. The T1 shortening effect is observed with the greatest sensitivity in T1-weighted magnetic resonance sequences; similarly, in T2^*—weighted sequences, the induction of local magnetic field in homogeneities by the large magnetic moment of gadolinium. Viv-Butrol leads to a distinct shortening of relaxation times, even in low concentrations. At pH 7, 37 °C and 1.5 T, the relaxivity (r1)—determined from the influence on the relaxation times (T1) of protons in plasma—is 5.2 L/(mmol·sec) and the relaxivity (r2)—determined from the influence on the relaxation times (T2)—is 6.1 L/(mmol·sec). These relaxivities prove to be slightly dependent on the strength of the magnetic field. The shortening effect of T1 with paramagnetic contrast agents depends on concentration and R1 relaxivity. This may improve tissue visualization. Compared to 0.5 molar gadolinium-based contrast agents, the higher concentration of Viv-Butrol results in half the administration volume and a more compact contrast bolus. Viv-Butrol is a highly water-soluble, extremely hydrophilic compound with a partition coefficient between n-butanol and buffer at pH 7.6 of about 0.006. (FDA).

It was found that post-administration of Viv-Butrol, the mean scores of Contrast Enhancement, Border Delineation, Internal Morphology, and Total scores all increased, and there was a significant difference between pre and post-Viv Butrol scores (p < 0.001). The probable reason for Gadobutrol’s good efficacy could be that it successfully shortens T1 and T2 relaxation time. Greater signal enhancement is achieved when there is increased T1 and T2 shortening.

The spontaneous reporting method was adopted immediately after administering IV gadobutrol to assess its safety. Mild ADRS, such as headache and nausea, was reported as a known side effect. Routine Laboratory parameters like CBC, LFT, Lipid Profile, and ECG were done before and after administration of Viv-Butrol to observe if there were any marked deviations of the parameters from the normal range. It was observed that Viv-Butrol did not cause any significant change in any of the assessed laboratory parameters, and no long-term ADRs were reported during the follow-up period of 6 months.

Conclusion

The phase IV, open-label, multi-center trial demonstrated that Viv-Butrol (Gadobutrol) at a dose of 0.1 mmol/kg body weight is an effective and safe contrast agent for contrast enhancement MRI. Viv-Butrol-enhanced imaging significantly improved contrast-enhancement, border delineation, and internal morphology, v/s unenhanced imaging. It must be noted that Viv-Butrol demonstrated good efficacy results as assessed through the visualization scoring system (VSS); their average values were much higher and better than the pre-administration values of Viv-Butrol. The product’s safety has been well established, along with all the basic hematology. Thus, Viv-Butrol-enhanced MRI has been established to have much better efficacy when compared to its unenhanced/plain MRI. It exhibited an excellent safety profile as it had minimal ADRs of mild severity with no long-term adverse effects. This concludes that Gadobutrol (Viv-Butrol) is an efficient, safe contrast media for MRI of various organs, including the brain, spinal cord, breast, liver, and kidney.