Efficacy and Safety of Gadopiclenol for Central Nervous System (CNS) Magnetic Resonance Imaging (MRI)

The purpose of this trial was to evaluate a new gadolinium-based contrast agent (GBCA) gadopiclenol injection for Central Nervous System (CNS) lesion detection and visualization by conventional steady-state CNS imaging.

This is a multi-center, international, prospective, double-blind, randomized, controlled, cross-over with comparator trial in male and female patients presenting with known or highly suspected CNS lesion(s) with focal areas of disrupted Blood Brain Barrier (BBB) (e.g., primary and secondary tumors) who are scheduled to undergo a routine contrast-enhanced Magnetic Resonance Imaging (MRI) of the CNS.

This trial was conducted in 33 centers worldwide.

During the course of the trial, two MRIs were obtained from each patient: one unenhanced and gadopiclenol-enhanced MRI; and one unenhanced and gadobutrol-enhanced MRI. MRI evaluations were performed by on-site investigators and three independent off-site blinded readers.

• gadopiclenol (Drug): single intravenous (IV) bolus injection at a rate of 2ml/second
• Gadobutrol 1Mmol/mL Solution for Injection Vial (Drug): single intravenous (IV) bolus injection at a rate of 2ml/second

Primary outcomes

• Lesion Visualization Comparing Gadopiclenol-enhanced MRI to Unenhanced MRI [At first MRI examination (gadopiclenol-enhanced MRI) for patients of Arm 1. At second MRI examination (gadopiclenol-enhanced MRI) for patients of Arm 2, performed 2-14 days after gadobutrol-enhanced MRI.]: The lesion visualization (per patient) was based on 3 co-primary criteria on marching lesions: border delineation, internal morphology and degree of contrast enhancement, assessed on the images acquired during the MRI performed with gadopiclenol by 3 independent readers. The independent blinded reader recorded each of the 3 co-primary criteria for up to 3 most representative lesions, using a 4-point scale (1 = poor \[internal morphology\] or none \[border delineation, contrast enhancement\], 2 = moderate, 3 = good, 4 = excellent). The mean of scores for each patient and for each co-criterion was calculated as follows: Mean of scores = score of lesion 1 + score of lesion 2 (if any) + score of lesion 3 (if any) divided by the number of lesions, ranged from 1 to 4. The difference in mean scores on matching lesions between Paired \[unenhanced and contrast-enhanced\] images and Pre-contrast \[unenhanced\] images was calculated for each of the 3 co-primary criteria and for each reader.

Secondary outcomes

• Lesion Visualization Comparing Gadopiclenol-enhanced MRI to Gadobutrol-enhanced MRI [At each of two MRI examinations with an interval of 2-14 days between 2 MRI examinations]: The lesion visualization (per patient) was based on 3 co-primary criteria: border delineation, internal morphology and degree of contrast enhancement, assessed on the images performed with gadopiclenol and images performed with gadobutrol by 3 independent readers. The independent blinded reader recorded each of the 3 co-primary criteria for up to 3 most representative lesions, using a 4-point scale (1 = poor \[internal morphology\] or none \[border delineation, contrast enhancement\], 2 = moderate, 3 = good, 4 = excellent). The mean of scores for each patient and for each of the 3 lesion visualization co-criteria was calculated as follows: Mean of scores = score of lesion 1 + score of lesion 2 (if any) + score of lesion 3 (if any) divided by the number of lesions, ranged from 1 to 4. The difference in mean scores on matching lesions between gadopiclenol scores mean and gadobutrol scores mean was calculated for each of the 3 co-primary criteria and for each reader.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Patient presenting with known or highly suspected CNS lesion(s) with focal areas of disrupted Blood Brain Barrier (BBB) (e.g., primary and secondary tumors) based on results of a previous imaging procedure such as Computed Tomography (CT) or MRI, which should have been performed within 12 months prior to ICF signature.

Exclusion Criteria:

* Patient presenting with acute or chronic renal insufficiency, defined as an estimated Glomerular Filtration Rate (eGFR) < 30 mL/min/1.73 m² assessed within 1 day prior to each contrast agent injection
* Patient presenting extra cranial lesions and/or extra-dural lesions.

Participant flow

Outcome results

• Lesion Visualization Comparing Gadopiclenol-enhanced MRI to Unenhanced MRI (Primary), Least squares mean, mean of a score (on a scale) per patient: Patients With Gadopiclenol Paired Images 3.90 +/- 0.02; Patients With Gadopiclenol Pre Images 2.08 +/- 0.02 (p <.0001)
• Lesion Visualization Comparing Gadopiclenol-enhanced MRI to Gadobutrol-enhanced MRI (Secondary), Least squares mean, mean of a score (on a scale) per patient: Patients With Gadopiclenol Paired Images 3.91 +/- 0.02; Patients With Gadobutrol Paired Images 3.93 +/- 0.02 (p <0.0001)

Adverse events

Time frame: Adverse events were recorded from informed consent signature up to one day after the second MRI (i.e., minimum of 4 days and a maximum of 23 days)

Serious adverse events by term

Other adverse events by term

• Results publication: Loevner LA, Kolumban B, Hutoczki G, Dziadziuszko K, Bereczki D, Bago A, Pichiecchio A. Efficacy and Safety of Gadopiclenol for Contrast-Enhanced MRI of the Central Nervous System: The PICTURE Randomized Clinical Trial. Invest Radiol. 2023 May 1;58(5):307-313. doi: 10.1097/RLI.0000000000000944. Epub 2022 Dec 19. PMID 36729404

• Study Protocol (PDF, 2018-12-20)
• Statistical Analysis Plan (PDF, 2020-11-09)

• Lorie Loevner, MD, Principal investigator, University of Pennsylvania