| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Retention of gadolinium/traces of metals/minerals to be determined in bone/skin specimens and evaluation of signs of nephrogenic systemic fibrosis in skin. |
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| E.1.1.1 | Medical condition in easily understood language |
| Retention of gadolinium, traces of minerals/metals in bone/skin and assessment of nephrogenic systemic fibrosis in skin. |
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| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Diagnosis [E01] |
| MedDRA Classification |
| 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 |
The main objective is to prospectively explore the potential for long-term retention of Gd in bones in patients who have received a single dose of GdCA or multiple doses of the same GdCA, with moderate or severe renal impairment or stable normal renal function (eGFR > 60 ml/min/1.73 m2) at the time of GdCA injection.
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are
- to evaluate skin samples for concentration of Gd,
- to evaluate bone and skin samples for concentrations of calcium, phosphorus, sodium, iron, zinc and potassium
- to evaluate skin samples for any dermatopathological changes that may be associated with Nephrogenic Systemic Fibrosis (NSF)
- to describe potential co-factors for NSF, susceptibility factors and drug treatments with potential impact on bone metabolism |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient must be at least 18 years of age (or older if required by local regulations)
2. Patient scheduled for an orthopaedic surgical procedure provided that the required amount of trans-operatory collection of bone and skin as defined per-protocol in section 5.1.3 is feasible and all inclusion and no exclusion criteria are met.
3. Patient is scheduled to have sufficient bone removed during the orthopaedic surgical procedure and sufficient non-scarred skin tissue from the edge of the surgical incision or amputated part to permit sample collection, in the investigator’s medical opinion
4. Patient agreed to have bone and skin samples collected at the time of the surgical procedure(s)
5. Patient’s surgical procedure and subsequent remission will not be altered by study-specific skin biopsies, in the investigator’s medical opinion
6. Patient is fully informed about the study and has signed the informed consent form
Patients having received GdCA:
7. Patient belongs to one of the following subgroups with respect to the number of GdCA doses received and the status of their renal function:
a) patient (total to enrol = 5) has stable impaired renal function (at least moderate impairment, eGFR ≤ 60 ml/min/1.73 m2) and has received one GdCA injection at the standard dose (0.025 mmol per kg body weight for Gadoxetic acid and 0.1 mmol per kg body weight for all other agents)
or
b) Up to 5 patients with stable impaired renal function (at least moderate impairment, eGFR ≤ 60 ml/min/1.73 m2) and has received more than one injection of the same GdCA.
• Gadodiamide, Gadopentetic acid, Gadoversetamide, and Gadoxetic acid groups: no target number. Patients should be recruited to this subgroup throughout the study duration, but there is no requirement to reach a specific number of patients in this subgroup to achieve study completion.
• Gadobutrol and Gadoteric acid groups: at least 3 patients. If the target of 3 patients is reached, but the study has not yet completed, then recruitment to this group should be continued during the remaining study time.
or
c) patient (total to enrol = 5) has stable normal renal function (eGFR > 60 ml/min /1.73 m2) and has received one GdCA injection at the standard dose (0.025 mmol per kg body weight for Gadoxetic acid and 0.1 mmol per kg body weight for all other agents)
or
d) patient (total to enrol = 3 to 5) with stable normal renal function (eGFR > 60 ml/min/1.73 m2) who have received more than one injection of the same GdCA. If the target of 3 patients is reached, but the study has not yet been completed, then recruitment to this subgroup should be continued during the remaining study time, stopping when 5 patients have been recruited to this subgroup, or when all other subgroups have reached their minimum target for recruitment, whichever comes first.
8. A minimum of 1 month have elapsed between GdCA dose and the scheduled orthopaedic surgical procedure.
9. Patient GdCA history, including dose(s), date(s), and product(s) administered is com-plete and accurate.
GdCA naïve patients (control group):
10. Patient has never received GdCA before the scheduled orthopaedic surgical procedure.
11. Patient belongs to one of the following renal function categories:
e) patient (total to enrol = 5) has stable severe renal impairment (eGFR < 30 ml/ min/1.73 m2);
f) patient (total to enrol = 5) has stable moderate renal impairment (eGFR within the range 30 to 60 ml/min/1.73 m2);
g) patient (total to enrol = 5) has stable normal renal function (eGFR > 60 ml/min /1.73 m2).
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| E.4 | Principal exclusion criteria |
1. Patient has received different GdCAs.
2. Patient has received intra-articular GdCA or per any other non-i.v. route.
3. Patient has received or is scheduled to receive GdCA within 1 month prior to the date of the scheduled orthopaedic surgical and study sample collection procedures.
4. Patient has received any investigational product or has participated in any other clini-cal trial within 30 days prior to enrolling in this study.
5. Patient suspected of, or diagnosed with, tumour of the skeletal system (i.e. tumour, metastatic bone, and bone marrow disease in the region from where the skin and bone will be harvested).
Note: Patients shall not be excluded for other bone diseases with the exception of those with bone cancer as specified in exclusion criterion 5.
6. Patient has diagnosed or suspected NSF at time of enrolment.
Note: Patients shall not be excluded for diagnosis of NSF subsequent to enrolment.
7. Patient presents with scarring in the region(s) of the scheduled surgical procedure(s) or of the skin sampling location, to the extent that collection of an unscarred skin sample is not feasible.
8. Patient has a close affiliation with the investigational site; e.g., a relative of the investi-gator, dependent person (e.g., employee or student of the investigational site).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Evaluation of Gadolinium concentration in trabecular and cortical bone after orthopaedic surgery.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After all samples have been collected and evaluated in the respective laboratory. |
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| E.5.2 | Secondary end point(s) |
Secondary variable(s)
• Concentration of total Gd in skin tissue samples (determined by ICP-MS), collected at the time of the scheduled orthopaedic surgical procedure, from a biopsy from the edge of the surgical wound or the amputated part.
• Concentrations of calcium, phosphorus, sodium, iron, zinc and potassium in bone (both trabecular and cortical) and skin tissue samples (determined by ICP-MS or al-ternatively ICP-AES if the feasibility evaluation of ICP-MS does not show reliable re-sults).
• Histopathological evaluation of skin samples with regard to the possibility of findings associated with NSF (determined by an experienced dermatopathologist).
• Description of potential co-factors for NSF, susceptibility factors and drug treatments with potential impact on bone metabolism. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After all samples have been collected and evaluated in the respective laboratory. |
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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 | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Retrospective evaluation, if there is a potential of Gadolinium in the bones after having received a Gadolinium based contrast agent. |
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| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
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| 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 | No |
| 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 | 30 |
| 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 |
| Germany |
| India |
| Italy |
| Japan |
| Korea, Republic of |
| Poland |
| Spain |
| Turkey |
| 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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| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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