Clinical Trial Results:
Diagnostic accuracy of neuroblastoma patient imaging with 18F-mFBG PET-CT compared to 123I-mIBG scanning
Summary
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EudraCT number |
2019-003713-33 |
Trial protocol |
NL |
Global end of trial date |
01 Sep 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
07 Jun 2022
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First version publication date |
07 Jun 2022
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
70903
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Dutch Trial Register: NL8152 | ||
Sponsors
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Sponsor organisation name |
Princess Máxima Center for pediatric oncology
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Sponsor organisation address |
Heidelberglaan 25, Utrecht, Netherlands, 3584CS
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Public contact |
Dr. G.A.M. Tytgat, Princess Máxima Center for Pediatric Oncology, G.A.M.Tytgat@prinsesmaximacentrum.nl
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Scientific contact |
Dr. B. de Keizer, Princess Máxima Center for Pediatric Oncology, B.deKeizer@prinsesmaximacentrum.nl
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
02 Aug 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
21 Jun 2021
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Global end of trial reached? |
Yes
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Global end of trial date |
01 Sep 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To perform 18F-MFBG PET-CT imaging in neuroblastoma patients and compare results with the current standard of imaging, 123I-MIBG imaging, using the SIOPEN score for skeletal lesions and the number of detected soft tissue lesions as endpoints.
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Protection of trial subjects |
- The final 18F-MFBG drug product batches underwent quality control testing, before batch release for patient administration.
- Adverse events were not expected. However, patients were monitored after injection for 180 minutes. Furthermore, 3–7 days after the procedure a medical doctor conducted a telephone consultation to check for adverse events up to 72 hours after injection.
- Monitors of the trial ensured that the clinical trial is conducted, recorded, and reported in accordance with the protocol, ICH-GCP, and the applicable regulatory requirement(s).
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Background therapy |
Recently, meta-18F-fluorobenzylguanidine (18F-mFBG), was developed to overcome the 123I-mIBG-associated disadvantages. As an analogue of mIBG, 18F-mFBG also targets the norepinephrine transporter, only 18F-MFBG is labelled with a positron-emitting radioisotope, fluorine-18, enabling imaging by positron emission tomography (PET) scanning. Compared to scintigraphy/SPECT, PET is a superior imaging technique that offers high resolution imaging, more accurate quantification of tracer uptake (using SUV measurements), whole-body 3D PET-CT range, a shorter acquisition time (10min) with less procedural sedation needed. In addition, the use of 18F-mFBG allows for a single-day protocol (possible to scan ≤2h after injection), and no need for thyroid-blocking medication. To date, there is only in-human study studying 18F-mFBG including five patients with neuroblastoma, with no adverse reaction in any of the patients. 18F-mFBG has a similar distribution as 123I-mIBG, with similar lesion uptake, but much faster uptake of the more hydrophilic 18F-MFBG enabling high-contrast visualisation of lesions as early as one hour after injection. In this small study, 18F-mFBG PET-CT detected more lesions 123I-mIBG scanning (122 vs. 63 lesions, respectively). Although 18F-mFBG is a promising tracer, there is limited experience of the use of 18F-mFBG imaging in neuroblastoma. Safety, optimal imaging time and diagnostic accuracy of 18F-mFBG scanning are yet to be established. | ||
Evidence for comparator |
meta-123I-iodobenzylguanidine (123I-mIBG) scanning is currently the first-line nuclear imaging technique that is routinely used for diagnosis, staging, and follow-up of neuroblastoma. MIBG is a norepinephrine analogue that can specifically detect tumours expressing the norepinephrine transporter, including neuroblastoma. 123I-mIBG uptake in the primary tumour and metastatic lesions is then visualized with gamma camera imaging. The addition of single-photon emission computed tomography with computed tomography (SPECT-CT) to planar whole-body scintigraphy has become standard in gamma camera imaging to increase certainty of interpretation and anatomical localization. Although worldwide 123I-mIBG scanning is the standard of care, it has several disadvantages. Scintigraphy and SPECT have limited image resolution (associated with gamma-camera imaging), resulting in no clear anatomical imaging. As the 3D SPECT-CT has a limited field-of-view and can only image about 40 cm, this requires a predefined area of interest, often only primary tumour. Another disadvantage is the long scan time (acquisition time of ~90 min) requiring sedation in young patients. Lastly, the use of iodine-123 also requires a two-day scanning protocol (scanning 24h after radiopharmaceutical injection) and thyroid blocking medication to prevent accumulation of free radioactive iodide. | ||
Actual start date of recruitment |
12 Jul 2020
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 25
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Worldwide total number of subjects |
25
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EEA total number of subjects |
25
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
7
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Children (2-11 years) |
15
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Adolescents (12-17 years) |
3
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
A prospective pilot study was conducted at the Princess Máxima Centre for Paediatric Oncology, Utrecht, the Netherlands, between July 2020 and July 2021. Paediatric patients with confirmed (or clinical suspicion of) neuroblastoma referred for standard 123I-mIBG scanning were prospectively recruited. | ||||||||||||||
Pre-assignment
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Screening details |
Paediatric patients with confirmed (or clinical suspicion of) neuroblastoma referred for standard MIBG scanning. Exclusion criteria were age ≥18 years, pregnancy, critical clinical condition (Lansky scale ≤20, organ failure, sepsis, hypoxia), and/or logistic planning reasons (if the MFBG scan could not be planned <2 weeks of MIBG scan). | ||||||||||||||
Pre-assignment period milestones
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Number of subjects started |
25 | ||||||||||||||
Number of subjects completed |
25 | ||||||||||||||
Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||
Arms
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Arm title
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Patient intended to undergo paired MIBG and MFBG scanning | ||||||||||||||
Arm description |
Single arm study | ||||||||||||||
Arm type |
Active comparator | ||||||||||||||
Investigational medicinal product name |
18F-meta-fluorobenzylguanidine
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Investigational medicinal product code |
not available
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Other name |
18F-mFBG
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Bolus of 2 MBq/kg body weight
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
Included patients to be scanned. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Patients who underwent MIBG scanning
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Patients who underwent MIBG scanning (as part of regular clinical care)
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Subject analysis set title |
Patients who underwent MFBG 1h scanning
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Patients who underwent the 1h post-injection MFBG scan
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Subject analysis set title |
Patients who underwent MFBG 2h scanning
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Patients who underwent the 2h post-injection MFBG scan
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End points reporting groups
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Reporting group title |
Patient intended to undergo paired MIBG and MFBG scanning
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Reporting group description |
Single arm study | ||
Subject analysis set title |
Patients who underwent MIBG scanning
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Patients who underwent MIBG scanning (as part of regular clinical care)
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Subject analysis set title |
Patients who underwent MFBG 1h scanning
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Patients who underwent the 1h post-injection MFBG scan
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Subject analysis set title |
Patients who underwent MFBG 2h scanning
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Patients who underwent the 2h post-injection MFBG scan
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End point title |
Detection of skeletal lesions | ||||||||||||||||
End point description |
SIOPEN score for skeletal lesions
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End point type |
Primary
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End point timeframe |
Maximum of 2 weeks between the paired MIBG and MFBG scan
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Statistical analysis title |
SIOPEN score MIBG vs. MFBG 1h scan | ||||||||||||||||
Comparison groups |
Patients who underwent MIBG scanning v Patients who underwent MFBG 1h scanning
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Number of subjects included in analysis |
40
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Analysis specification |
Pre-specified
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Analysis type |
other [1] | ||||||||||||||||
P-value |
= 0.003 | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
6.3
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
3.2 | ||||||||||||||||
upper limit |
9.4 | ||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
1.6
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Notes [1] - pilot |
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End point title |
Detection of soft tissue lesions | ||||||||||||||||
End point description |
Absolute number of soft tissue lesions
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End point type |
Primary
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End point timeframe |
Maximum of 2 weeks between the MFBG and MIBG scan
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Statistical analysis title |
Number of soft tissue lesions MIBG vs. MFBG 1h | ||||||||||||||||
Comparison groups |
Patients who underwent MIBG scanning v Patients who underwent MFBG 1h scanning
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Number of subjects included in analysis |
40
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Analysis specification |
Pre-specified
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Analysis type |
other [2] | ||||||||||||||||
P-value |
= 0.017 | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
1.7
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.4 | ||||||||||||||||
upper limit |
3.5 | ||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.8
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Notes [2] - pilot |
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Adverse events information [1]
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Timeframe for reporting adverse events |
Follow-up was up to 72 hours after the MFBG scan.
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Adverse event reporting additional description |
Serious adverse events that occured within 72 hours were reported within one week to the sponsor. The patient was followed up untill SAE resolved.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
CTCAE | ||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
5.0
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Reporting groups
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Reporting group title |
Patient intended to undergo MFBG scanning
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||
Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: For this pilot study there were no non serious adverse events observed / reported |
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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05 Mar 2021 |
Version 2.1, with the following content:
1) Clarification of section "Safety Reporting" in the protocol
2) Adding possibility of procedural sedation when scanning younger children.
3) Administrative corrections, updates and clarifications.
4) Update of the Investigator’s Brochure on [18F]MFBG
5) Adjustment of the informed consent form due to above-mentioned changes.
6) Annual progress report
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
Six out of 14 patients were included twice in the study. |