| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Long term potential effect of repeated exposure to either a linear or a macrocyclic gadolinium-based contrast agent (GBCA) on change from baseline to Year 5 in motor and cognitive function among neurologically normal adults in comparison to a matched non-GBCA–exposed control group effects regarding |
Mogelijke langetermijneffect van herhaalde blootstelling aan een lineair of een macrocyclisch gadoliniumgebaseerd contrastmiddel (GBCA) op de verandering van baseline tot jaar 5 in motorische en cognitieve functie bij neurologisch normale volwassenen in vergelijking met een gematchte controlegroep zonder blootstelling aan GBCA.
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| E.1.1.1 | Medical condition in easily understood language |
| Prospective evaluation of potential effects of repeated gadolinium-based contrast agent administrations |
| Prospectieve beoordeling van mogelijke effecten van herhaalde toediening van hetzelfde gadolinium-gebaseerde contrastmiddel (GBCA) |
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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 | PT |
| E.1.2 | Classification code | 10070999 |
| E.1.2 | Term | Intraductal papillary mucinous neoplasm |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008953 |
| E.1.2 | Term | Chronic liver disease |
| E.1.2 | System Organ Class | 100000004871 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061451 |
| E.1.2 | Term | Colorectal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060862 |
| E.1.2 | Term | Prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 prospectively assess the potential effect of repeated exposure to either a linear or a macrocyclic gadolinium-based contrast agent (GBCA) on change from baseline to Year 5 in motor and cognitive function among neurologically normal adults in comparison to a matched non-GBCA–exposed control group. |
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| E.2.2 | Secondary objectives of the trial |
• To assess the change from baseline in the composite endpoints (motor and cognitive) at each of the post-baseline time points (Years 1 to 4) in GBCA-exposed participants as compared to controls.
• To assess the change from baseline for each of the individual tests (motor and cognitive) at each of the post-baseline time points (Years 1 to 5) in GBCA-exposed participants as compared to controls.
• To evaluate safety through collection of adverse events.
• To assess total Gd concentrations (as measured in a central laboratory) in blood and urine samples taken from exposed and control participants at the time of annual visit.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participant must be an adult having reached legal majority age and less than 65 years old.
2. Participant must be neurologically normal, defined as free of unstable neurologic and psychiatric disease as confirmed by a normal neurologic examination at screening.
3. Participant agrees to be tested as per protocol for 5 consecutive years
4. Participant (GBCA-exposed or controls) agrees to undergo unenhanced magnetic resonance imaging (UE-MRI) of the brain at enrollment and at the end of the observation period (5 years).
5. Patient affiliated to national health insurance according to local regulatory requirements, where applicable.
6. Participants should have at least 1 of the following indications:
• Medium to high risk for breast cancer or dense breasts undergoing breast cancer screening with MRI.
• Elevated prostate-specific antigen (PSA) and under active diagnostic surveillance for prostate cancer.
• Chronic liver disease (eg, liver cirrhosis limited to Child class A, post-hepatitis chronic hepatopathy, or primary sclerosing cholangitis) for surveillance of hepatocellular carcinoma development.
• Low-grade colorectal cancer or neuroendocrine tumor undergoing screening for liver metastases.
• Branch-duct intraductal papillary mucinous neoplasm (IPMN) of the pancreas (maximum size ≤2 cm) undergoing imaging surveillance.
In addition, for participants in the GBCA Arms only:
7. Each participant should be likely to undergo ≥5 GBCA-enhanced MR examinations with the same GBCA at least annually throughout the 5-year study duration.
8. Prospective participants with up to 3 well-documented GBCA administrations prior to study screening are acceptable, provided that the imaging was performed with the same GBCA as the one to be prospectively used in the study. If the GBCA used cannot be identified, he/she cannot be enrolled.
For the Control Arm:
9. Participants who never had and are not likely to receive any GBCA injection during the course of the study.
10. Each control participant must be willing to undergo UE-MRI of the brain at baseline and at Year 5. In Years 1 to 4, the control participants will undergo their clinically indicated UE-MRIs, computed tomography (CT), ultrasound, or X-ray procedures.
11. Participants matched with the population characteristics of the 2 GBCA study arms, including clinical indication for imaging, geographic region, and age-group. Additional potential risk factors (education level and sex) will be recorded and adjusted for as appropriate at the statistical analysis stage.
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| E.4 | Principal exclusion criteria |
Patients are excluded from the study if any of the following criteria apply:
1. As evidenced by history or determined in the neurologic exam at screening, concurrent neurological and/or psychiatric disease (or treatments) that could influence the results of the study’s motor and cognitive tests. Examples include but are not limited to:
• Cerebrovascular disease.
• Multiple sclerosis.
• Neurodegenerative disease.
• Malignant disease other than listed in indications.
• Carcinoid tumors.
• Epilepsy.
• Prior neurosurgery.
• Psychotic disorders or any prior psychotic episode not otherwise specified (NOS)—any documented prior history of chronic schizophrenia.
• Remittent or current medically confirmed major depressive disorder or bipolar disorder.
• History of long-term major depression or bipolar affective disorder with an active episode in the past 2 to 5 years.
• Neurodevelopmental disorders (eg, trisomy 21).
• Uncontrolled severe migraine.
• Uncontrolled or controlled anxiety or depression within 6 months before enrollment.
• Screening scores of ≤24 on the MMSE and/or ≥11 on the Hospital Anxiety and Depression Scale (HADS).
2. Prior, planned, or ongoing chemotherapy or brain irradiation
3. Use of concomitant medication(s) affecting neuro-cognitive or motor function (an authorized exception is a single intake before the study MRI because of anxiety if administered after the motor and cognitive test evaluation):
• Regular use of benzodiazepines or non-benzodiazepine hypnotics. Long-acting benzodiazepines (eg, diazepam) should not be administered within 24 hours prior to cognitive testing.
• Short/medium-acting benzodiazepines (eg, alprazolam, lorazepam, oxazepam, temazepam), except if used chronically for sleep and on a stable dose for 8 weeks prior to Screening Visit 1 or 12 hours prior to cognitive testing.
• Regular use of anticholinergic drugs (anticholinergics for bladder control with limited cognitive effects are permitted).
• Long-term use of corticosteroids or methotrexate, cladribine.
• Regular use of antidepressants (eg, anticholinergic, tricyclic, monoamine oxidase inhibitors (MAOIs), norepinephrine–dopamine reuptake inhibitors (NDRIs) selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), or lithium, anti-epileptics and/or antipsychotic drugs: Use of antidepressants is allowed if at stable doses for 8 weeks prior to Screening Visit. Antipsychotics used on a regular basis, except for low doses of atypical antipsychotics (e.g., risperidone, aripiprazole, or quetiapine), anticonvulsants with limited cognitive effects, such as lamotrigine, pregabalin, levetiracetam for treatment of pain, and other non-epilepsy indications, are allowed as-needed basis or if used at a stable dose for 8 weeks prior to Screening Visit
• CNS stimulants (eg, for attention-deficit/hyperactivity disorder [ADHD])
4. Substance or alcohol abuse as determined by the investigator.
5. Alcoholic cirrhosis.
6. Any history or presence of other relevant chronic disease that prevents participation in the study or that may confound neurofunction testing.
7. Renal disease, defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, calculated by using the Modification of Diet in Renal Disease (MDRD) formula or the Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
8. History of environmental/occupational/other exposure to one or more chemicals that may affect cognitive and/or motor function, including, but not limited to, heavy metals (arsenic [As], cadmium [Cd], lead [Pb], manganese [Mn], and mercury [Hg]), pesticides, solvents, or carbon monoxide.
9. Anticipated, current, or past conditions (medical, psychological, social, or geographical) that, in the opinion of the investigator, would compromise the participant’s safety or her/his ability to participate in the study (eg, clinically significant vitamin B12 deficiency, folic acid deficiency, uncontrolled thyroid dysfunction from medical history).
10. Clinical indications requiring >1 contrast-enhanced magnetic resonance imaging (CE-MRI) every 6 months.
11. Receipt of any investigational product or participation in any other clinical trial within 30 days prior to enrolling in this study or while enrolled in this trial.
12. Previous enrollment in this study.
13. Pregnant or nursing (lactating) women.
14. Presence of any metal-containing joint implants/prostheses.
In addition, for participants in either of the GBCA Arms only:
15. Any contraindication to GBCA-enhanced MRI examinations.
16. Receipt of a GBCA or generic prior to study entry other than the specific GBCA to be administered during the course of the study.
In addition, for participants in the Control Arm only:
17. Participants with any previous exposure to a GBCA.
18. Participants with any contraindication to UE-MRI examinations. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The co-primary endpoints are the change from baseline to Year 5 in motor function and in cognitive function as expressed by the composite z score, defined as the weighted sum of the z scores of the individual tests. Since each of these tests is considered equally important, each test will be assigned an equal weight. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
• Changes from baseline in the composite endpoint (years 1 to 4) and in each individual test of motor and cognitive function (years 1 to 5) will be assessed.
Additional secondary endpoints include:
• Evaluation of adverse events. The recording of adverse events (AEs) that occur after the signing of the ICF at Screening, will be done at baseline and at each annual visit. Signs/symptoms, onset date/time, severity, causality, seriousness, treatment and outcome, will be recorded.
• Total gadolinium concentrations in blood plasma and urine samples collected at baseline and at each annual visit will be determined. If the CE-MRI is obtained at the same visit, the blood and urine samples will be obtained prior to imaging. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
change from baseline in the composite endpoints (motor and cognitive) at each of the post-baseline time points (Years 1 to 4) in GBCA-exposed participants as compared to controls.
the change from baseline for each of the individual tests (motor and cognitive) at each of the post-baseline time points (Years 1 to 5) in GBCA-exposed participants as compared to controls. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| no exposure to GBCA and not expected to receive over 5 consecutive years |
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| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 77 |
| 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 |
| Brazil |
| Canada |
| China |
| Korea, Republic of |
| Russian Federation |
| United States |
| Austria |
| France |
| Germany |
| Italy |
| Netherlands |
| Switzerland |
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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 end of the study is the completion of the last participant’s last visit (LPLV) |
| Het einde van de study is de afronding van de laatste visite van de laatste participant. |
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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