Efficacy and Safety of Gadopiclenol for Contrast-Enhanced MRI of the Central Nervous System: The PICTURE Randomized Clinical Trial.

OBJECTIVES: Developing new high relaxivity gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI) allowing dose reduction while maintaining similar diagnostic efficacy is needed, especially in the context of gadolinium retention in tissues. This study aimed to demonstrate that contrast-enhanced MRI of the central nervous system (CNS) with gadopiclenol at 0.05 mmol/kg is not inferior to gadobutrol at 0.1 mmol/kg, and superior to unenhanced MRI. MATERIALS AND METHODS: PICTURE is an international, randomized, double-blinded, controlled, cross-over, phase III study, conducted between June 2019 and September 2020. Adult patients with CNS lesions were randomized to undergo 2 MRIs (interval, 2-14 days) with gadopiclenol (0.05 mmol/kg) then gadobutrol (0.1 mmol/kg) or vice versa. The primary criterion was lesion visualization based on 3 parameters (border delineation, internal morphology, and contrast enhancement), assessed by 3 off-site blinded readers. Key secondary outcomes included lesion-to-background ratio, enhancement percentage, contrast-to-noise ratio, overall diagnostic preference, and adverse events. RESULTS: Of the 256 randomized patients, 250 received at least 1 GBCA administration (mean [SD] age, 57.2 [13.8] years; 53.6% women). The statistical noninferiority of gadopiclenol (0.05 mmol/kg) to gadobutrol (0.1 mmol/kg) was achieved for all parameters and all readers (n = 236, lower limit 95% confidence interval of the difference ≥-0.06, above the noninferiority margin [-0.35], P < 0.0001), as well as its statistical superiority over unenhanced images (n = 239, lower limit 95% confidence interval of the difference ≥1.29, P < 0.0001).Enhancement percentage and lesion-to-background ratio were higher with gadopiclenol for all readers ( P < 0.0001), and contrast-to-noise ratio was higher for 2 readers ( P = 0.02 and P < 0.0001). Three blinded readers preferred images with gadopiclenol for 44.8%, 54.4%, and 57.3% of evaluations, reported no preference for 40.7%, 21.6%, and 23.2%, and preferred images with gadobutrol for 14.5%, 24.1%, and 19.5% ( P < 0.001).Adverse events reported after MRI were similar for gadopiclenol (14.6% of patients) and gadobutrol (17.6%). Adverse events considered related to gadopiclenol (4.9%) and gadobutrol (6.9%) were mainly injection site reactions, and none was serious. CONCLUSIONS: Gadopiclenol at 0.05 mmol/kg is not inferior to gadobutrol at 0.1 mmol/kg for MRI of the CNS, confirming that gadopiclenol can be used at half the gadolinium dose used for other GBCAs to achieve similar clinical efficacy.

Plasma Somatostatin Levels Increase during Scoliosis Surgery, but Not Herniated Disc Operations: Results of a Pilot Study.

Somatostatin (SST) released from capsaicin-sensitive sensory nerves in response to stimulation exerts systemic anti-inflammatory, analgesic actions. Its elevation correlates with the extent of tissue injury. We measured plasma SST alterations during spine operations (scoliosis and herniated disc) to determine whether its release might be a general protective mechanism during painful conditions. Sampling timepoints were baseline (1), after: soft tissue retraction (2), osteotomy (3), skin closure (4), the following morning (5). Plasma SST-like immunoreactivity (SST-LI) determined by radioimmunoassay was correlated with pain intensity and the correction angle (Cobb angle). In scoliosis surgery, postoperative pain intensity (VAS 2.) 1 day after surgery significantly increased (from 1.44 SEM ± 0.68 to 6.77 SEM ± 0.82, p = 0.0028) and positively correlated with the Cobb angle (p = 0.0235). The baseline Cobb degree negatively correlated (p = 0.0459) with the preoperative SST-LI. The plasma SST-LI significantly increased in fraction 3 compared to the baseline (p < 0.05), and significantly decreased thereafter (p < 0.001). In contrast, in herniated disc operations no SST-LI changes were observed in either group. The VAS decreased after surgery both in the traditional (mean 6.83 to 2.29, p = 0.0005) and microdiscectomy groups (mean 7.22 to 2.11, p = 0.0009). More extensive and destructive scoliosis surgery might cause greater tissue damage with greater pain (inflammation), which results in a significant SST release into the plasma from the sensory nerves. SST is suggested to be involved in an endogenous postoperative analgesic (anti-inflammatory) mechanism.

Dose Finding Study of Gadopiclenol, a New Macrocyclic Contrast Agent, in MRI of Central Nervous System.

OBJECTIVES: The aim of this study was to determine a safe and effective dose of gadopiclenol, a new high relaxivity macrocyclic gadolinium-based contrast agent. Based on the contrast-to-noise ratio (CNR) as primary criterion, this new agent was compared with gadobenate dimeglumine in patients with contrast-enhancing central nervous system lesions. METHODS AND MATERIALS: This phase IIb international, multicenter, double-blind, randomized, controlled, parallel dose groups, and cross-over study included adult patients with known or highly suspected lesions with disrupted blood-brain barrier. Patients were randomized to 1 of 4 doses of gadopiclenol (0.025, 0.05, 0.1, 0.2 mmol/kg) and to 1 series of 2 magnetic resonance imaging scans: gadopiclenol then gadobenate dimeglumine at 0.1 mmol/kg or vice versa. The qualitative and quantitative efficacy evaluations were performed by 3 independent off-site blinded readers. Adverse events were monitored up to 1 day after second magnetic resonance imaging. RESULTS: The study population included 272 patients (58.5% females) with a mean (SD) age of 53.8 (13.6) years. The superiority of gadopiclenol over gadobenate dimeglumine was statistically demonstrated at 0.2 and 0.1 mmol/kg for all readers with an increase in CNR of more than 30% (P ≤ 0.0007). At 0.05 mmol/kg, gadopiclenol showed a CNR of similar magnitude as gadobenate dimeglumine at 0.1 mmol/kg, with no statistically significant difference. Similar results were obtained for lesion-to-brain ratio and contrast enhancement percentage, as secondary criteria. The relationship between CNR and dose of gadopiclenol was linear for all readers. Mean scores for lesion visualization variables, particularly lesion contrast enhancement, tended to be higher with gadopiclenol at 0.1 and 0.2 mmol/kg compared with gadobenate dimeglumine. All 3 readers mainly expressed an overall diagnostic preference for images with gadopiclenol at 0.1 mmol/kg (45.3%, 50.9%, or 86.8% of images) or expressed no preference (49.1%, 49.1%, or 9.4%, respectively), whereas preference for images with gadobenate dimeglumine was reported by 2 readers for 3.8% and 5.7% of the images. Predominantly, no preference was expressed when comparing images with gadopiclenol at 0.05 mmol/kg to those with gadobenate dimeglumine.Rates of adverse reactions were comparable for gadopiclenol (11.7%) and gadobenate dimeglumine (12.1%). Changes from baseline of more than 25% in serum creatinine and estimated glomerular filtration rate occurred in less than 2% of patients equally for gadopiclenol and gadobenate dimeglumine. Changes from baseline for the values of blood urea nitrogen and cystatin C were also similar between gadopiclenol and gadobenate dimeglumine. No safety concerns were detected on centralized electrocardiography readings. CONCLUSIONS: Between the doses of 0.025 and 0.2 mmol/kg of gadopiclenol, the increase in CNR is linear. Compared with gadobenate dimeglumine at 0.1 mmol/kg, the doses of 0.05 and 0.1 mmol/kg of gadopiclenol gave similar or significantly greater contrast enhancement, respectively, and thus both doses can be considered for future phase III studies.