Evaluation of [123I]CLINDE and SPECT as a Marker of Inflammation in Subjects With PD or AD and in Healthy Subjects

NCT ID: NCT00612872

Last Updated: 2019-04-03

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 46 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-01-31
• Study Completion Date: 2009-11-01

Brief Summary

To assess the dynamic uptake and washout of 123-I CLINDE, a potential imaging biomarker for inflammatory changes in brain, using single photon emission computed tomography (SPECT) in similarly aged healthy controls and subjects with Alzheimer (AD) or Parkinson disease (PD).

To perform blood metabolite characterization of 123-I CLINDE in healthy and subjects with AD or PD to determine the nature of metabolites in assessment of 123-I CLINDE as a single photon computed tomography (SPECT) brain imaging agent.

Evaluate the test/retest reproducibility of 123-I CLINDE, and SPECT in AD and PD subjects and healthy controls

Detailed Description

When microglia become activated they express peripheral benzodiazepine receptors (PBR) or binding sites on their mitochondrial membrane. PBRs are functionally and structurally distinct from central benzodiazepine receptors associated with y-aminiobutric acid (GABA)-regulated chloride channels. PBRs are found in abundance in peripheral organs and hematologic cells, but are present at only very low levels in the normal central nervous system (Banati, 2002). CLINDE is a phenylimidazopyridine and appears to bind selectively to the PBR. In the absence of excessive blood in the CNS an increase CLINDE binding to PBR is a potential marker of microglial activation in the CNS. The increase in CLINDE binding may be an indicator of the transition of microglia from a resting to an activated state. When labeled with 123-I and used as a SPECT radiotracer, CLINDE may serve as an in vivo marker of microglial activation in Alzheimer disease and Parkinson disease.

The 123-I radioactive tag offers distinct advantages for large-scale clinical imaging studies of anti-inflammatory targeted treatments as a marker of microglial activation and efficacy of therapeutic intervention. The half-life (13.1 h) of 123-I permits imaging in multiple subjects in a single research-dedicated imaging center, with multiple research subjects per day. This minimizes variability introduced in multi-center quantitative imaging trials where different cameras, image processing methods, and QA procedures all conspire to increase the variance imaging biomarkers. Using this model, our group pioneered a method to evaluate the loss of dopamine function in Parkinson's disease using a radioactive drug 123-I β-CIT which binds directly to dopamine nerve terminals.

The adaptation of imaging agents like 123-I CLINDE as a biomarker of microglial activation in neurodegenerative diseases requires human validation studies. Expanding upon our previous work with b-amyloid ligands (123I-IMPY, 123-I MNI-187) for AD and dopamine transporter ligands (123-I B-CIT, Altropane) for PD, we desire to develop and characterize 123-I CLINDE as a potential marker for microglial activation in association with neuronal damage that may be applicable to multiple neurodegenerative diseases. Ultimately a marker of microglial activation could be used for large-scale quantitative brain imaging trials in AD or PD, specifically to investigate the agent as an objective biomarker in treatments aimed at reducing inflammatory changes in these conditions. The significance of this work lies in applying state-of-art quantitative neuroimaging tools to develop a relevant biomarker in individuals with neurodegenerative diseases with the intention of using this efficiently in large clinical imaging trials.

Conditions

Parkinson Disease; Alzheimer Disease; Healthy Controls; Multiple Sclerosis

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

Assess [123-I]CLINDE and brain imaging

Subjects will be injected with up to 5 mCi and not to exceed 5.5 (not \>10% of 5 mCi limit) of 123-I CLINDE followed by serial SPECT imaging.

Group Type: EXPERIMENTAL

[123I]CLINDE

Intervention Type: DRUG

Subjects will be injected with up to 5 mCi and not to exceed 5.5 (not \>10% of 5 mCi limit) of 123-I CLINDE followed by serial SPECT imaging.

Interventions

[123I]CLINDE

Subjects will be injected with up to 5 mCi and not to exceed 5.5 (not \>10% of 5 mCi limit) of 123-I CLINDE followed by serial SPECT imaging.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

Alzheimer's Subject Selection. Subjects who have a clinical diagnosis of mild to moderate Alzheimer's disease will be recruited for this study. The following criteria will be met for inclusion of AD subjects in this study:

• The participant is 50 years or older.
• Written informed consent is obtained.
• Participants have a clinical diagnosis of probable Alzheimer's disease based on National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria.
• Mini-Mental Status Exam score < 25.
• Modified Hachinski Ischemia Scale score of ≤ 4.
• Geriatric Depression Scales (GDS) ≤ 10.
• For females, non-child bearing potential a negative urine or blood pregnancy test on day of 123-I CLINDE injection.

Parkinson's Subject Selection. Subjects who have a clinical diagnosis of mild to moderate Parkinson disease will be recruited for this study. The following criteria will be met for inclusion of PD subjects in this study:

• The participant is 30 years or older.
• Written informed consent is obtained.
• Participants have a clinical diagnosis of Parkinson disease (at least two of the three cardinal symptoms: resting tremor, rigidity, bradykinesia).
• Geriatric Depression Scales (GDS) ≤ 10.
• Hoehn and Yahr ≤4.
• For females, non-child bearing potential a negative urine or blood pregnancy test on day of 123-I CLINDE injection.

Healthy Control Subject Selection. Healthy control subjects who have no neurological disease will be recruited for this study. The following criteria will be met for inclusion of healthy control subjects in this study:

• The participant is 30 years or older.
• Written informed consent is obtained.
• Negative history of neurological or psychiatric illness based on evaluation by a research physician.
• Mini-Mental Status Exam score ≥28.
• For females, non-child bearing potential a negative urine or blood pregnancy test on day of 123-I CLINDE injection.

Exclusion Criteria

Alzheimer's subjects will be excluded from participation for the following reasons:

• The subject has a history of significant cerebrovascular disease.
• The subject has a clinically significant abnormal laboratory value and/or clinically significant unstable medical or psychiatric illness
• The subject has evidence of clinically significant gastrointestinal, cardiovascular, hepatic, renal, hematological, neoplastic, endocrine, neurological, immunodeficiency, pulmonary, or other disorder or disease.
• Pregnancy
• Positive urine drug test.

Parkinson's subjects will be excluded from participation for the following reasons:

• The subject has a clinically significant abnormal laboratory value and/or clinically significant unstable medical or psychiatric illness
• The subject has evidence of clinically significant gastrointestinal, cardiovascular, hepatic, renal, hematological, neoplastic, endocrine, neurological, immunodeficiency, pulmonary, or other disorder or disease.
• Pregnancy
• Positive urine drug test.

Healthy control subjects will be excluded from participation for the following reasons:

• The subject has a clinically significant abnormal laboratory value and/or clinically significant unstable medical or psychiatric illness.
• The subject has evidence of clinically significant gastrointestinal, cardiovascular, hepatic, renal, hematological, neoplastic, endocrine, neurological, immunodeficiency, pulmonary, or other disorder or disease.
• Pregnancy
• Positive urine drug test.

• Minimum Eligible Age: 30 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Institute for Neurodegenerative Disorders

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Danna L Jennings, M.D.

Role: PRINCIPAL_INVESTIGATOR

Institute for Neurodegenerative Disorders

Locations

Institute for Neurodegenerative Disorders

New Haven, Connecticut, United States

Countries

United States

References

Aktas O, Ullrich O, Infante-Duarte C, Nitsch R, Zipp F. Neuronal damage in brain inflammation. Arch Neurol. 2007 Feb;64(2):185-9. doi: 10.1001/archneur.64.2.185.

Reference Type: BACKGROUND

PMID: 17296833 (View on PubMed)

Nomenclature and research case definitions for neurologic manifestations of human immunodeficiency virus-type 1 (HIV-1) infection. Report of a Working Group of the American Academy of Neurology AIDS Task Force. Neurology. 1991 Jun;41(6):778-85. doi: 10.1212/wnl.41.6.778. No abstract available.

Reference Type: BACKGROUND

PMID: 2046917 (View on PubMed)

Related Links

http://www.indd.org

IND web page

Other Identifiers

IND 100,863

Identifier Type: OTHER

Identifier Source: secondary_id

CLINDE 001

Identifier Type: -

Identifier Source: org_study_id