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STUDY PROTOCOL
Asia Pac J Clin Trials Nerv Syst Dis 2017,  2:23

Diagnostic performance of 68Ga-NOTA-Aca-BBN(7-14) positron emission tomography/computed tomography in patients with brain gliomas: study protocol for an open-label single-arm clinical trial


PET Center, Department of Nuclear Medicine and Beijing Key Laboratory of Nuclear Medicine in Molecular Targeted Diagnosis and Therapy, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China

Date of Web Publication30-Jan-2017

Correspondence Address:
Zhao-hui Zhu
PET Center, Department of Nuclear Medicine and Beijing Key Laboratory of Nuclear Medicine in Molecular Targeted Diagnosis and Therapy, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing
China
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Source of Support: This study was supported by the Peking Union Medical College Scholar Project, China., Conflict of Interest: None


DOI: 10.4103/2542-3932.198959

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  Abstract 

Background: Gastrin-releasing peptide receptor is particularly expressed in gliomas, while the peptide bombesin [BBN(7-14)] has the complete C-terminal structure of human gastrin-releasing peptide. Glioma-specific imaging agents can therefore be constructed from BBN, for example 68Ga-NOTA-Aca-BBN(7-14). For consideration of the clinical translation of 68Ga-NOTA-Aca-BBN(7-14), an open-label dynamic whole-body positron emission tomography/computed tomography (PET/CT) study was designed to investigate the diagnostic effectiveness and safety of 68Ga-NOTA-Aca-BBN(7-14) in patients with brain gliomas.
Methods/Design: This is an open-label single-arm clinical trial that will be conducted at Peking Union Medical College Hospital in Beijing, China. Thirty patients in suspicion of brain gliomas scheduled for surgical treatment will be recruited and subjected to PET/CT via intravenous injection of 68Ga-NOTA-Aca-BBN(7-14). The primary outcome measure will be the standardized uptake value of 68Ga-NOTA-Aca-BBN(7-14) in brain glioma at 30 minutes after injection. Secondary outcomes include the diagnostic accuracy rate of 68Ga-NOTA-Aca-BBN(7-14) PET/CT, and adverse events after injection.
Discussion: Diagnostic performance and safety assessment of 68Ga-NOTA-Aca-BBN(7-14) in brain gliomas will provide new insights into the specific PET/CT diagnosis of brain gliomas.
Trial registration: ClinicalTrials.gov identifier: NCT02520882, registered on 2 August 2015.
Ethics: This study protocol has been approved by the Ethics Committee of Peking Union Medical College Hospital in China (approval No. S-714), and will be performed in accordance with the Declaration of Helsinki, formulated by the World Medical Association.
Informed consent: An informed consent will be obtained from each patient or his/her guardian prior to participation in the study.

Keywords: clinical trial; 68Ga-NOTA-Aca-BBN(7-14); PET/CT; brain glioma; imaging agent; diagnosis; open-label clinical trial


How to cite this article:
Zang J, Wang H, Zhang Jj, Zhu Zh. Diagnostic performance of 68Ga-NOTA-Aca-BBN(7-14) positron emission tomography/computed tomography in patients with brain gliomas: study protocol for an open-label single-arm clinical trial. Asia Pac J Clin Trials Nerv Syst Dis 2017;2:23-9

How to cite this URL:
Zang J, Wang H, Zhang Jj, Zhu Zh. Diagnostic performance of 68Ga-NOTA-Aca-BBN(7-14) positron emission tomography/computed tomography in patients with brain gliomas: study protocol for an open-label single-arm clinical trial. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2017 [cited 2018 Dec 16];2:23-9. Available from: http://www.actnjournal.com/text.asp?2017/2/1/23/198959


  Introduction Top


History and current studies

Gliomas arise from glial cells and are the most common primary tumor in the central nervous system (Mamelak and Jacoby, 2007; Brat et al., 2008), accounting for 27% of all central nervous system tumors and 80% of all malignant brain tumors (Goodenberger and Jenkins, 2012; Ostrom et al., 2015). The main clinical manifestations of gliomas are increased intracranial pressure and neurological deficit, and there may be a difficulty in distinguishing them from inflammation, demyelinating diseases, or leukoencephalopathy. Pathological evaluation is considered to be the gold standard for the diagnosis of glioma, but it is an invasive method, and moreover, the sites for pathological biopsies need to be previously determined using other methods. Therefore, noninvasive imaging has become the preferred clinical method for the diagnosis of glioma. Computed tomography (CT) and magnetic resonance imaging (MRI) are commonly used to diagnose intracranial lesions (Götz et al., 2012), but both of them have limitations in the assessment of benign and malignant tumors, and the biological behaviors of such tumors. Positron emission tomography (PET)/CT is an imaging method that combines structural imaging and functional imaging within a single procedure, and has demonstrated considerable advantages in the diagnosis of tumors. 18F-fluorodeoxyglucose (FDG) is the most widely used radioactive imaging agent in the PET/CT diagnosis of brain tumors; however, its usage is limited by the excessively high background concentration in brain tissue, non-specificity between inflammation and tumor uptake, and the blood glucose effect on 18F-FDG uptake (Dunet et al., 2012). There is therefore a considerable requirement for a new imaging agent suitable for the diagnosis of glioma.

Studies have shown that gastrin-releasing peptide receptor (GRPR) is distributed not only in glioma cell lines (Sharif et al., 1997; Farias et al., 2008), but also in glioma tissue sections from glioma patients (Flores et al., 2010). Various GRPR targeting imaging probes have therefore been developed as imaging agents for gliomas (Chen et al., 2004; Garrison et al., 2007; Carlucci et al., 2015). Bombesin (BBN) is an amphibian homolog of mammalian gastrin-releasing peptide (GRP) (Reubi et al., 2005; Zhang et al., 2006), and BBN(7-14), with an amino acid sequence of Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 has been extensively used for the development of molecular probes for the imaging of GRPR, after being labeled with various radionuclides (Chen et al., 2004; Smith et al., 2005; Prasanphanich et al., 2007; Mansi et al., 2011; Carlucci et al., 2015; Pourghiasian et al., 2015). Multiple preclinical studies have demonstrated receptor-specific accumulation of BBN imaging agents in GRPR positive tumors (Kunstler et al., 2007; Chatalic et al., 2014), and some of these imaging agents have been used in early clinical trials (Van de Wiele et al., 2001, 2008; Berthold and Theodosia, 2012; Ananias et al., 2013).

Main objective

We aim to assess the diagnostic effectiveness and safety of 68Ga-NOTA-Aca-BBN(7-14) PET/CT in brain gliomas.

Novelty of this study

Most clinical imaging agent studies are based on 99mTc labeling and single photon emission computed tomography (SPECT) (Van de Wiele et al., 2000, 2001; Scopinaro et al., 2002a, b). In comparison with such techniques, PET imaging is characterized by higher sensitivity and spatial resolution. To date, PET imaging agents such as FDG, amino acid derivatives, thymidine analogues, and transporter targeting probes have been used in brain tumor imaging ([Table 1] and [Table 2]). BBN-based PET imaging agents are known to be useful for GRPR-targeted tumor imaging, and in this study we will examine the use of the GRPR specific imaging agent 68Ga-NOTA-Aca-BBN(7-14) for the diagnosis of brain gliomas.
Table 1: Characteristics of existing clinical trials on PET/CT diagnosis of brain gliomas


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Table 2: Clinical trials registered at ClinicalTrials.gov addressing biomarker and imaging analysis in traumatic brain injury


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  Methods/Design Top


Study design

This open-label clinical trial, which includes recruitment, detection, and data analysis, will be conducted at Peking Union Medical College Hospital, Beijing, China.

Study procedure

Thirty patients in suspicion of brain gliomas scheduled for tumor resection will be recruited at Peking Union Medical College Hospital in China. PET/CT examination will be performed by intravenous injection of 68Ga-NOTA-Aca-BBN(7-14). The primary outcome measure will be the standardized uptake value (SUV) of 68Ga-NOTA-Aca-BBN(7-14) in brain gliomas, and the secondary outcome measures will include the diagnostic accuracy of 68Ga-NOTA-Aca-BBN(7-14) PET/CT in brain gliomas and adverse reactions within 1 week after imaging agent injection.

The study protocol is outlined in [Figure 1].
Figure 1: Flow chart of this trial.

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Participants

Patients who are highly suspected to have brain glioma and who are scheduled for tumor resection at Peking Union Medical College Hospital will be enrolled into this study.

Inclusion criteria

Patients will be eligible for this trial if they meet all of the following conditions:

  • Brain glioma as confirmed by MRI (Louis et al., 2007; Drafting Group for the China's Diagnosis and Treatment Guidelines for Gliomas in the Central Nervous System, 2016; the specific contents of which are shown in Additional file 1 [Additional file 1])
  • Glioma resection and pathological examination
  • An age of 30-70 years


Exclusion criteria

Patients who meet any one of the following criteria will be excluded from the trial:

  • Allergy or sensitivity to type IV imaging agent
  • Inability to complete PET/CT scan due to cough and/or pain
  • Inability to complete various examinations due to claustrophobia and radiation phobia
  • Pregnant women or those at risk of pregnancy


Withdrawal criteria

Participants will be withdrawn from the trial if one of the following occurs:

  • It is not possible to make an accurate therapeutic and safety judgment due to complications
  • The patient is unable to complete a 1-year follow-up visit


Sample size

In accordance with previous reports (Idema et al., 2012; Schwarzenberg et al., 2012; Karunanithi et al., 2013), a suitable sample size for this trial was identified as n = 30, which will be determined following the intention-to-treat principle.

Recruitment

The recruitment of patients who are highly suspected to have brain glioma and are scheduled for surgical treatment is ongoing at Peking Union Medical College Hospital. Patients or guardians who are interested in participation in the trial can contact the sponsor via telephone, e-mail, or WeChat. After providing written informed consent, patients will be screened according to the inclusion and exclusion criteria.

Baseline data

Baseline data, including demographical data, are shown in [Table 3].
Table 3: Baseline data of recruited patients


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PET/CT examination

Patients will be intravenously injected with 111-148 Mega-Becquerel (MBq)/kg 68Ga-NOTA-Aca-BBN(7-14) (provided by the Molecular Imaging and Nanomedicine Laboratory, National Institute of Health/National Institute of Biomedical Imaging and Bioengineering, USA), and low-dose CT (Siemens Medical Solutions, Erlangen, Germany) scans with parameters of 120 kV, 35 mA, 3-mm slice thickness, 512 × 512 matrix, and 70-cm field of view will be performed first, with whole-body PET (Siemens Medical Solutions) being performed 30 minutes after the administration of 68Ga-NOTA-Aca-BBN(7-14). Regions of interest will be drawn by two experienced nuclear medicine specialists, and the mean and maximum SUVs will be calculated from these regions of interest (Zhang et al., 2016).

Primary outcomes

The primary outcomes will be the mean and maximum SUVs of 68Ga-NOTA-Aca-BBN(7-14) in brain gliomas at 30 minutes after injection, with the SUV value being defined as the radioactivity concentration of the imaging agent in the lesions per unit volume/injected dose/body mass.

Secondary outcomes

  • Diagnostic accuracy of 68Ga-NOTA-Aca-BBN(7-14) PET/CT in brain gliomas: from a comparison of the diagnostic findings of 68Ga-NOTA-Aca-BBN(7-14) PET/CT with pathological results.
  • Incidence of adverse reactions within 1 week after injection.


The time schedule for outcome assessments is shown in [Table 4].
Table 4: Schedule for outcome assessments


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Data management

Medical data will be collected and recorded in a case report form, both manually and electronically. Any alteration or correction will be recorded in detail.

Only authorized persons have the right to query the clinical data, in order to ensure security and confidentiality. All data relevant to this clinical trial will be preserved by Peking Union Medical College Hospital. Patient information will not be disclosed unless required by law. Research findings will be published for scientific purposes without disclosing the patient's identity, and published data will be released at http://www.figshare.com.

Statistical analysis

Measurement data will be expressed as the mean ± SD, and enumeration data expressed as percent.


  Trial Status Top


Recruitment is ongoing at the time of submission.

Pre-test results from Zhao-hui Zhu's team addressing different imaging agents in the PET/CT diagnosis of gliomas are shown in [Table 5].
Table 5: Research findings concerning different imaging agents in the PET/CT diagnosis of gliomas published by Zhao-hui Zhu's team


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  Discussion Top


Significance of this study

Unspecific imaging agents, such as 18F-thymidine, have been used in most existing studies addressing the PET diagnosis of gliomas. The current study will attempt to observe the effect of 68Ga-NOTA-Aca-BBN(7-14), a GRPR-specific imaging agent, in the PET diagnosis of brain glioma. Studies have shown the presence of GRPR in brain glioma, but not in normal brain tissues, and moreover, GRPR antagonists are pathologically confirmed to inhibit glioma (Pinski et al., 1994; Kiaris et al., 1999; de Oliveira et al., 2009). On the basis of this knowledge, the non-invasive imaging evaluation of GRPR expression will be of great help in drug development, patient stratification, and therapeutic response monitoring.

Limitations

Outcome evaluation will be limited by the small sample size, lack of a comparison with other metastatic tumors similar to brain glioma and non-neoplastic lesions, and the lack of a comparison with other imaging agents. Therefore, further studies will be needed to determine the application value of 68Ga-NOTA-Aca-BBN(7-14) PET/CT in gliomas.

Contribution to future studies

Through the 1-year follow-up, our outcomes concerning the diagnostic safety and effectiveness of PET/CT in brain glioma patients will provide new insights into glioma-specific PET/CT diagnosis.

Additional file

Additional file 1: MRI diagnostic criteria for gliomas (Louis et al., 2007; Drafting Group for the China's Diagnosis and Treatment Guidelines for Gliomas in the Central Nervous System, 2016).[43]

 
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Declaration of patient consent
The authors certify that they will obtain all appropriate patient consent forms. In the form the patients will give their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Conflicts of interest
None declared.
Author contributions
JZ and HW will implement the trial. JJZ will be responsible for coordination and assistance. ZHZ will be responsible for study design, analysis and summarization. All authors have approved the final version of the paper.
Plagiarism check
This paper was screened twice using CrossCheck to verify originality before publication.
Peer review
This paper was double-blinded and stringently reviewed by international expert reviewers.


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    Tables

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