Ignite Creation Date:
2024-05-06 @ 8:28 PM
Last Modification Date:
2024-10-26 @ 3:28 PM
Study NCT ID:
NCT06392815
Status:
RECRUITING
Last Update Posted:
2024-05-21
First Post:
2024-04-25
Brief Title:
64Cu-DOTATATE-PET for Lyme Neuroborreliosis
Sponsor:
Rigshospitalet Denmark
Organization:
Rigshospitalet Denmark
Study Overview
Official Title:
64Cu-DOTATATE-PET Imaging for Lyme Neuroborreliosis
Status:
RECRUITING
Status Verified Date:
2024-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
DOTA-LYME
Brief Summary:
The aim of the study is to investigate the applicability and performance of 64Cu-DOTATATE PETCTMR for diagnosis in patients with Lyme neuroborreliosis LNB
In this prospective observational cohort study with 64Cu-DOTATATE the investigators wish to include a total of 50 patients clinically suspected of LNB The investigators will investigate the diagnostic value of 64Cu-DOTATATE-PET comparing clinically suspected and CSF verified LNB patients with clinically suspected patients without CSF verification
The investigators hypothesize that the information obtained from 64Cu-DOTATATE PETCTMRI can improve the diagnostics of LNB as well as that 64Cu-DOTATATE PETCTMRI will be able to contribute to the follow-up of patients by adding prognostic information and the risk of persistent symptoms The application of 64Cu-DOTATATE PETCTMRI in the diagnostic work-up of LNB would thus expectedly lead to a more precise diagnosis and risk assessment
In this prospective observational cohort study with 64Cu-DOTATATE the investigators wish to include a total of 50 patients clinically suspected of LNB The investigators will investigate the diagnostic value of 64Cu-DOTATATE-PET comparing clinically suspected and CSF verified LNB patients with clinically suspected patients without CSF verification
The investigators hypothesize that the information obtained from 64Cu-DOTATATE PETCTMRI can improve the diagnostics of LNB as well as that 64Cu-DOTATATE PETCTMRI will be able to contribute to the follow-up of patients by adding prognostic information and the risk of persistent symptoms The application of 64Cu-DOTATATE PETCTMRI in the diagnostic work-up of LNB would thus expectedly lead to a more precise diagnosis and risk assessment
Detailed Description:
Background
Imaging of neuroinfections is well documented however with several restrictions due to the heterogeneity of pathogens Lyme neuroborreliosis LNB is a tick-borne infection caused by Borrelia burgdorferi sensu lato complex Bb and among the most prevalent bacterial infections of the nervous system Due to climatic and environmental changes the incidence of tickborne diseases is increasing throughout Europe in Denmark the annual incidence is estimated to 3-4100000 Adults mainly manifests as a self-limiting subacute painful meningoradiculitis lymphocytic meningitis andor cranial nerve palsy symptoms of CNS involvement such as acute encephalitis and myelitis are rare Over time most cases of Bb infection is thought to be self-resolving however antibiotics accelerate the process by eradicating the pathogen and reduces the risk of disseminated late infection and persistent symptoms The response to antibiotics can be slow but the majority of patients report marked improvement in symptoms after treatment a proportion of patients do however report to experience persistent residual symptoms including fatigue pain or cognitive disturbances and studies have suggested that late diagnosis and the burden of symptoms at time of treatment initiation increases the risk of these symptoms
If antibiotic treatment is initiated as early as possible LNB has a very good prognosis early diagnosis and treatment initiation are therefore of paramount interest
As no markers in plasma can be used to diagnose or follow LNB the diagnosis of LNB is based on clinical symptoms in combination with elevated white blood cell count in cerebrospinal fluid CSF and the detection of specific Bb intrathecal antibody production However Bb serology has several disadvantages in the ability to confirm active disease and monitor disease activity and response to antibiotic treatment Bb antibodies in CSF are first detectable weeks after onset of the neuroinfection and they may persist for years even after the disease has been well-treated In addition symptoms can be unspecific evolving over time and even mimic other neurological diseases potentially resulting in misdiagnosis diagnostic delay and reduced patient outcome The investigators recently reported a median duration of neurological symptoms before first hospital contact of 21 days in a Danish nationwide prospective cohort study of 194 LNB patients included between 2015-2018 Currently the only way to monitor disease activity - although not ideal - is to to perform a re-lumbar puncture which is an invasive procedure not always possible or successful and with risk of post lumbar puncture headache which develops in 10-20 of the patients
Improving diagnosis ideally non-invasively is therefore of great interest and new methods to confirm active disease and monitor the effect of treatment an important field of research which might promote a shift from empirical treatment to personalized medicine with expected improvement in patient outcome
Non-invasive imaging seems an obvious solution The investigators have retrospectively studied the value of CT and MRI in diagnosis of LNB and found no value of computerized tomography CT-head and limited value of magnetic resonance imaging MRI-BrainSpine Regarding use of positron emission tomography PET the most commonly used ligand for infection and inflammation imaging is the radiolabeled glucose analogue fluorine-18-fluorodeoxyglucose 18F-FDG However 18F-FDG has major limitations including low specificity as it is taken up by any cell with increased glucose metabolism including but not restricted to leukocytes macrophages monocytes lymphocytes and giant cells In addition as the normal brain has high glucose consumption it is difficult impossible to obtain sufficient contrast in LNB as inflammation is primarily in the meninges Indeed the investigators have confirmed from cases of LNB that had 18F-FDG-PET could not be used Due to these limitations there is an unmet need for other more specific targeted radioligands to improve imaging of infectious diseases eg LNB and the adjacent inflammatory response
Macrophages is a potential and promising target for the diagnosing of more specific infections and in particular LNB Macrophages have anti-inflammatory properties with high phagocytic activity and they are not only involved in the early immune response but present as long as the infection is active Macrophage activation can be monitored by the circulating biomarker soluble CD163 the intrathecal inflammation in LNB does not lead to any or only very subtle peripheral measurable changes of normal infectious parameters even with highly active but localized infection as in LNB As activated macrophages overexpresses somatostatin receptor subtype 2 sstr2 the activity of macrophages can be visualized by PET imaging targeting sstr2 using the ligand 14710-tetraazacyclododecane-NNNN-tetraacetic acid-d-Phe1Tyr3-octreotate DOTATATE At Rigshospitalet the investigators recently developed 64Cu-DOTATATE with a physical half-life of 127 hours vs 1 hour and a 4-fold better theoretical positron range spatial resolution compared to existing 68Ga-labeled tracers These characteristics are a prerequisite Accordingly the investigators found in a pre-clinical trial that 64Cu-DOTATATE was able to non-invasively detect and monitor Lyme borreliosis in a murine model of Lyme arthritis and that delayed imaging later than 3 h and ideally 24 h post injection was necessary to obtain good target-to-background ratios in images of Bb infection
In humans the investigators previously demonstrated that 64Cu-DOTATATE-PET could visualize macrophages in vivo in atherosclerotic carotid plaques prior to endarterectomy Gene expression analysis on the excised plagues demonstrated at close correlation between CD163 gene expression and PET tracer uptake confirming that it was indeed macrophages that were visualized
In this prospective observational cohort study with 64Cu-DOTATATE the investigators wish to include a total of 50 patients clinically suspected of LNB The investigators will investigate the diagnostic value of 64Cu-DOTATATE-PET comparing clinically suspected and CSF verified LNB patients with clinically suspected patients without CSF verification The investigators further wish to explore if the biomarkers sCD163 NfL and Tau may contribute to the diagnostics of LNB and if 64Cu-DOTATATE PECTMRI have a prognostic value by including a follow-up visit 6 months after treatment comparing patients with persistent symptoms to patients without persistent symptoms The investigators hypothesize that the information obtained from 64Cu-DOTATATE PETCTMRI and the biomarkers sCD163 and NfL can improve the diagnostics of LNB The investigators also hypothesize that 64Cu-DOTATATE PETCTMRI will be able to contribute to the follow-up of patients by adding prognostic information and the risk of persistent symptoms The application of 64Cu-DOTATATE PETCTMRI in the diagnostic work-up of LNB would thus expectedly lead to a more precise diagnosis and risk assessment
Imaging of neuroinfections is well documented however with several restrictions due to the heterogeneity of pathogens Lyme neuroborreliosis LNB is a tick-borne infection caused by Borrelia burgdorferi sensu lato complex Bb and among the most prevalent bacterial infections of the nervous system Due to climatic and environmental changes the incidence of tickborne diseases is increasing throughout Europe in Denmark the annual incidence is estimated to 3-4100000 Adults mainly manifests as a self-limiting subacute painful meningoradiculitis lymphocytic meningitis andor cranial nerve palsy symptoms of CNS involvement such as acute encephalitis and myelitis are rare Over time most cases of Bb infection is thought to be self-resolving however antibiotics accelerate the process by eradicating the pathogen and reduces the risk of disseminated late infection and persistent symptoms The response to antibiotics can be slow but the majority of patients report marked improvement in symptoms after treatment a proportion of patients do however report to experience persistent residual symptoms including fatigue pain or cognitive disturbances and studies have suggested that late diagnosis and the burden of symptoms at time of treatment initiation increases the risk of these symptoms
If antibiotic treatment is initiated as early as possible LNB has a very good prognosis early diagnosis and treatment initiation are therefore of paramount interest
As no markers in plasma can be used to diagnose or follow LNB the diagnosis of LNB is based on clinical symptoms in combination with elevated white blood cell count in cerebrospinal fluid CSF and the detection of specific Bb intrathecal antibody production However Bb serology has several disadvantages in the ability to confirm active disease and monitor disease activity and response to antibiotic treatment Bb antibodies in CSF are first detectable weeks after onset of the neuroinfection and they may persist for years even after the disease has been well-treated In addition symptoms can be unspecific evolving over time and even mimic other neurological diseases potentially resulting in misdiagnosis diagnostic delay and reduced patient outcome The investigators recently reported a median duration of neurological symptoms before first hospital contact of 21 days in a Danish nationwide prospective cohort study of 194 LNB patients included between 2015-2018 Currently the only way to monitor disease activity - although not ideal - is to to perform a re-lumbar puncture which is an invasive procedure not always possible or successful and with risk of post lumbar puncture headache which develops in 10-20 of the patients
Improving diagnosis ideally non-invasively is therefore of great interest and new methods to confirm active disease and monitor the effect of treatment an important field of research which might promote a shift from empirical treatment to personalized medicine with expected improvement in patient outcome
Non-invasive imaging seems an obvious solution The investigators have retrospectively studied the value of CT and MRI in diagnosis of LNB and found no value of computerized tomography CT-head and limited value of magnetic resonance imaging MRI-BrainSpine Regarding use of positron emission tomography PET the most commonly used ligand for infection and inflammation imaging is the radiolabeled glucose analogue fluorine-18-fluorodeoxyglucose 18F-FDG However 18F-FDG has major limitations including low specificity as it is taken up by any cell with increased glucose metabolism including but not restricted to leukocytes macrophages monocytes lymphocytes and giant cells In addition as the normal brain has high glucose consumption it is difficult impossible to obtain sufficient contrast in LNB as inflammation is primarily in the meninges Indeed the investigators have confirmed from cases of LNB that had 18F-FDG-PET could not be used Due to these limitations there is an unmet need for other more specific targeted radioligands to improve imaging of infectious diseases eg LNB and the adjacent inflammatory response
Macrophages is a potential and promising target for the diagnosing of more specific infections and in particular LNB Macrophages have anti-inflammatory properties with high phagocytic activity and they are not only involved in the early immune response but present as long as the infection is active Macrophage activation can be monitored by the circulating biomarker soluble CD163 the intrathecal inflammation in LNB does not lead to any or only very subtle peripheral measurable changes of normal infectious parameters even with highly active but localized infection as in LNB As activated macrophages overexpresses somatostatin receptor subtype 2 sstr2 the activity of macrophages can be visualized by PET imaging targeting sstr2 using the ligand 14710-tetraazacyclododecane-NNNN-tetraacetic acid-d-Phe1Tyr3-octreotate DOTATATE At Rigshospitalet the investigators recently developed 64Cu-DOTATATE with a physical half-life of 127 hours vs 1 hour and a 4-fold better theoretical positron range spatial resolution compared to existing 68Ga-labeled tracers These characteristics are a prerequisite Accordingly the investigators found in a pre-clinical trial that 64Cu-DOTATATE was able to non-invasively detect and monitor Lyme borreliosis in a murine model of Lyme arthritis and that delayed imaging later than 3 h and ideally 24 h post injection was necessary to obtain good target-to-background ratios in images of Bb infection
In humans the investigators previously demonstrated that 64Cu-DOTATATE-PET could visualize macrophages in vivo in atherosclerotic carotid plaques prior to endarterectomy Gene expression analysis on the excised plagues demonstrated at close correlation between CD163 gene expression and PET tracer uptake confirming that it was indeed macrophages that were visualized
In this prospective observational cohort study with 64Cu-DOTATATE the investigators wish to include a total of 50 patients clinically suspected of LNB The investigators will investigate the diagnostic value of 64Cu-DOTATATE-PET comparing clinically suspected and CSF verified LNB patients with clinically suspected patients without CSF verification The investigators further wish to explore if the biomarkers sCD163 NfL and Tau may contribute to the diagnostics of LNB and if 64Cu-DOTATATE PECTMRI have a prognostic value by including a follow-up visit 6 months after treatment comparing patients with persistent symptoms to patients without persistent symptoms The investigators hypothesize that the information obtained from 64Cu-DOTATATE PETCTMRI and the biomarkers sCD163 and NfL can improve the diagnostics of LNB The investigators also hypothesize that 64Cu-DOTATATE PETCTMRI will be able to contribute to the follow-up of patients by adding prognostic information and the risk of persistent symptoms The application of 64Cu-DOTATATE PETCTMRI in the diagnostic work-up of LNB would thus expectedly lead to a more precise diagnosis and risk assessment
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None