E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subject presenting, at the time of inclusion, with known or highly suspected focal areas of disrupted Blood Brain Barrier (BBB) (e.g., primary and secondary tumors, focal inflammatory or demyelinating disorders) including at least one expected enhancing lesion of minimum 5 mm (long axis) |
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E.1.1.1 | Medical condition in easily understood language |
lesion of the brain or spine |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10067294 |
E.1.2 | Term | Brain lesion |
E.1.2 | System Organ Class | 100000004852 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10041552 |
E.1.2 | Term | Spinal cord injury |
E.1.2 | System Organ Class | 10022117 - Injury, poisoning and procedural complications |
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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 |
To determine a safe and effective dose of P03277 based on a comparison of Contrast to Noise Ratio (CNR) between several doses, 0.025, 0.05, 0.1, 0.2 mmol/kg, of P03277 and MultiHance® at 0.1 mmol/kg. |
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E.2.2 | Secondary objectives of the trial |
•To assess technical adequacy of images •To evaluate capacity of lesion detection: number, size and location of lesions detected •To evaluate diagnostic information using lesion visualization variables (lesion border delineation, internal morphology and degree of contrast enhancement) •To evaluate diagnostic confidence •To compare overall diagnostic preference between P03277 and MultiHance® •To assess P03277 dose / response relationship for CNR and lesion visualization variables •To evaluate the impact of P03277 and MultiHance®-enhanced MRI on subject treatment plan •To assess the safety profile of P03277 as compared to MultiHance® after intravenous administration
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Female or male adult subject (subject having reached legal majority age). 2.Subject presenting, at the time of inclusion, with known or highly suspected focal areas of disrupted Blood Brain Barrier (BBB) (e.g., primary and secondary tumors, focal inflammatory disorders) including at least one expected enhancing lesion of minimum 5 mm (long axis). This lesion must have been detected on a previous imaging procedure (computerized Tomography (CT) or MRI). 3.Subject scheduled for a routine CNS contrast-enhanced MRI examination for clinical reasons and agreeing to have a second contrast-enhanced MRI examination for the purpose of the study. 4.Subject able and willing to participate to the study. 5.Subject having read the information and having provided his/her consent to participate in writing by dating and signing the informed consent prior to any study related procedure being conducted. 6.Subject affiliated to national health insurance according to local regulatory requirements.
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E.4 | Principal exclusion criteria |
1.Subject presenting with acute or chronic Grade III (at least) renal insufficiency, defined as an estimated Glomerular Filtration Rate (eGFR) <60 mL/min/1.73 m² based on one eGFR assessment performed the day of the MRI prior to the first contrast agent injection. 2.Subject presenting with known class III/IV congestive heart failure according to the New York Heart Association classification (NYHA). 3.Pregnant or breast-feeding female subject (a female subject of childbearing potential or with amenorrhea for less than 12 months must have a negative urine or serum pregnancy test within 24 hours prior to study MRI and must be using a medically approved contraception method* until the last study visit). 4.Subject having received any investigational medicinal product within 30 days prior to study entry. 5.Subject previously enrolled in this study. 6.Subject presenting with any contraindication to MRI examinations. 7.Subject with known contra-indication(s) to the use or with known sensitivity to one of the products under investigation or other GBCAs. 8.Subject having received any contrast agent (MRI or CT) within 3 days prior to study products administration, or scheduled to receive any contrast agent during the course of the study or within 24 hours after the second study product administration. 9.Subject having received any treatment or medical procedure (e.g. chemotherapy, radiotherapy, biopsy or surgery etc…) within 7 days prior to the first MRI or is expected/ scheduled to have a change in any treatment or medical procedure (e.g. chemotherapy, radiotherapy, biopsy or surgery etc…) in-between the 2 MRI examinations. 10.Subject with anticipated, current or past condition (medical, psychological, social or geographical) that would compromise the subject’s safety or her/his ability to participate in the study. 11.Subject unlikely to comply with the protocol, e.g. uncooperative attitude, inability to return for follow-up visits and/or unlikelihood of completing the study. 12.Subject related to the Investigator or any other study staff or relative directly involved in the study conduct. 13. Subject presenting with acute relapse of multiple sclerosis. * medically approved contraception methods include: female sterilization, barrier methods of contraception (condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository), use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception, placement of an Intrauterine Device (IUD) or Intrauterine System (IUS).
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E.5 End points |
E.5.1 | Primary end point(s) |
Contrast to Noise Ratio (CNR) for maximum 3 enhanced lesions. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Only lesions detected by both MRIs after lesion tracking will be used. Image evaluations will be done for each MRI (from V2 and V3). |
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E.5.2 | Secondary end point(s) |
1.Technical adequacy of images (on-site and off-site reads) Images will be evaluated as adequate or not. Images are considered technically inadequate if artifacts completely compromise image interpretability. 2.Lesion detection capacity (on-site and off-site reads): Number, size and location of lesions detected, and the presence or absence of enhancement will be recorded. 3.Diagnostic information using lesion visualization variables (on-site and off-site reads): Three variables (lesion border delineation, internal morphology and degree of contrast enhancement) will be assessed on combined unenhanced and enhanced MRI on a 4-point scale. 4.Diagnostic confidence (on-site and off-site reads): Diagnosis and diagnostic confidence will be recorded for each subject. 5 Overall diagnostic preference in a global matched-pairs fashion (off-site read). 6.P03277 dose / response relationship for CNR and lesion visualization variables. 7.Impact of contrast agent-enhanced MRI on subject treatment plan (on-site read). 8.Safety assessments: vital signs, 12-lead ECGs, injection site tolerance, clinical laboratory parameters (blood and urine) and adverse events (AEs) monitoring
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Image evaluations will be done for each MRI (from V2 and V 4). • ECG and vital signs - prior to each injection (V2 and V4), 45mins plus/minus 15 mins, 2-4 hr and 1 day after (V3 and V5). • Injection site reactions - during each injection (V2 and V4), 45mins plus/minus 15 mins, 2-4 hr and 1 day after (V3 and V5). • AEs – V1-V5 • Clinical labs – V2-V5
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
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 |
Belgium |
Czech Republic |
Hungary |
Italy |
Mexico |
Poland |
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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The study will be considered as completed once all the images collected for all the subjects will have been reviewed by all the independent blinded readers. |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 2 |