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The Influence of [18F]PMPBB3 and [18F]THK5351 PET Distribution Patterns on Post-stroke Cognitive Impairment

Primary Purpose

Post-stroke Cognitive Impairment, Neuroinflammation

Status
Recruiting
Phase
Phase 2
Locations
Taiwan
Study Type
Interventional
Intervention
PMPBB3
THK5351
Sponsored by
Chang Gung Memorial Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Post-stroke Cognitive Impairment focused on measuring Post-stroke cognitive impairment, PET, MRI, neuroinflammation, tau protein

Eligibility Criteria

20 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  1. Inclusion criteria for acute stroke/TIA patients (Group A, n=50)

    • Males or females with age >= 20 years old.
    • Having acute cerebral stroke or transient ischemic attack in recent 1 month.
    • Female subjects of childbearing potential must practice effective contraception during the - Provision of signed informed consent from the subject and the subject's legally
    • The subject has an appropriate caregiver capable of accompanying the subject, if necessary.

  2. Inclusion criteria for healthy controls (Group B, n = 30)

    • Males or females with age >= 20 years old
    • Without history of cerebral stroke or transient ischemic attack
    • Without history of mild cognitive impairment or dementia
    • Ability to participate in cognitive and neuroimaging assessments
    • Female subjects of childbearing potential must practice effective contraception during the study and be willing and able to continue contraception after the final study
    • Provision of signed informed consent

Exclusion Criteria:

  1. Exclusion criteria for acute stroke/TIA patients (Group A, n = 50)

    • Presence of dementia diagnosis before the index stroke or at the initial screening
    • History of vascular MCI (VaMCI)
    • The Chinese version of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) score >=104 at the initial screening 45.
    • Life expectancy less than 1 year.
    • Clinically significant abnormal laboratory values.
    • Clinically significant or unstable medical or psychiatric illness.
    • Epilepsy history.
    • Cognitive impairment resulting from trauma or brain damage.
    • Substance abuse or alcoholism in the past 3 months.
    • General MRI, and / or PET exclusion criteria.
    • Pregnant or becoming pregnant during the study (as documented by pregnancy testing at screening or at any date during the study according to the PI discretion) or current breast feeding.
    • History of allergy to 18F-labelled radionucleic agents, such as [18F]PMPBB3 or [18F]THK5351.
    • Subjects having high risks for the study according to the PI discretion.

  2. Exclusion criteria for healthy controls (Group B, n = 30)

    • The Chinese version of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) score >=104 at the initial screening 45.
    • Life expectancy less than 1 year.
    • Clinically significant abnormal laboratory values.
    • Clinically significant or unstable medical or psychiatric illness.
    • Epilepsy history.
    • Cognitive impairment resulting from trauma or brain damage.
    • Substance abuse or alcoholism in the past 3 months.
    • General MRI, and / or PET exclusion criteria.
    • Pregnant or becoming pregnant during the study (as documented by pregnancy testing at screening or at any date during the study according to the PI discretion) or current breast feeding.
    • History of allergy to 18F-labelled radionucleic agents, such as [18F]PMPBB3 or [18F]THK5351.
    • Subjects having high risks for the study according to the PI discretion.

Sites / Locations

  • Department of Neurology, Chang-Gung memorial HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Other

Arm Label

PMPBB3

THK

Arm Description

Name: [18F] PMPBB3，[18F]1-Fluoro-3-((2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dien-1-yl)ben Dosage form: intravenous injection Dose(s): 7mCi Dosing schedule: Visit 2 Mechanism of action (if known): high affinity radiotracer for the tau protein Pharmacological category：Radio pharmaceutical

Name: [18F]THK5351，(S)-6-[(3-Fluoro-2-hydroxy)propoxy]-2-(2-Methylaminopyrid-5-yl)-quinoline Dosage form: intravenous injection Dose(s): 10mCi Dosing schedule: Visit 2 Mechanism of action (if known): high affinity radiotracer for the tau protein Pharmacological category：Radio pharmaceutical

Outcomes

Primary Outcome Measures

CDR score of cognition deteriorating group and stable group
The CDR is a 5-point scale (0、0.5、1、2、3) used to characterize six domains of cognitive and functional performance applicable to Alzheimer disease and related dementias: Memory, Orientation, Judgment & Problem Solving, Community Affairs, Home & Hobbies, and Personal Care. The necessary information to make each rating is obtained through a semi-structured interview of the patient and a reliable informant or collateral source (e.g., family member). Global score 0 = Normal、0.5 = Very Mild Dementia、1 = Mild Dementia、2 = Moderate Dementia、3 = Severe Dementia. The cognition deteriorating group is defined as CDR score declines from 0 or 0.5 at Month 3 to >=1 at Month 12. The cognition stable group is defined as CDR score remains at 0 or 0.5 at Month 12.
PET imaging positive and negative conditions
PET images are visually assessed by independent raters, who are nuclear medicine doctors and blinded to all clinical and diagnostic information. The raters classify each scan as 0-1 (no significant uptake)、2 (suspicious uptake)、3-4 (significant uptake). The score >= 2 is deemed as positive condition.
Correlation between Neuroimaging factors and CDR-SB condition
Neuroimaging continuous variables will be first examined for their collinearity, determined as variance inflation factor (VIF) of 2 or more. The approach suggested by Zuur et al is to calculate VIFs for each parameter in the model, and if they are larger than some cutoff, sequentially drop the predictor with the largest VIF, recalculate, and repeat until all values are below the cutoff of 2^68. Variables showing moderate to significant inter-group difference (P < 0.10) will be selected for the logistic regression analysis (CDR-SB increase > 1 and conversion to dementia as the dependent variables).

Secondary Outcome Measures

Full Information

First Posted
March 10, 2020
Last Updated
April 28, 2023
Sponsor
Chang Gung Memorial Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT04318626
Brief Title
The Influence of [18F]PMPBB3 and [18F]THK5351 PET Distribution Patterns on Post-stroke Cognitive Impairment
Official Title
The Influence of [18F]PMPBB3 and [18F]THK5351 PET Distribution Patterns on Post-stroke Cognitive Impairment
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 1, 2020 (Actual)
Primary Completion Date
July 31, 2023 (Anticipated)
Study Completion Date
July 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Chang Gung Memorial Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
Background and objects： Neuroinflammation is an active process detectable in the earliest stages of the neurodegeneration pathway. On the other hand, significant neuroinflammation, such as reactive astrocytosis, can also be observed after cerebral ischemic injury. [18F]THK5351 can monitor the neuroinflammatory process due to its high affinity to astrogliosis, and [18F]PMPBB3 is the novel tau protein radiotracer without significant off-target binding to MAO-B. The investigators hypothesize that the neuroinflammation after acute stroke may induce the tau protein accumulation. In the current proposal, our aims are to 1) explore the interaction between neuroinflammation and tau protein accumulation in acute stroke patients by applying both the [18F]PMPBB3 and [18F]THK5351 PET images and 2) determine their influence on the longterm stroke outcome and cognitive performance. Method： The prospective project plans to recruit 2 groups of participants: one is patients with first-ever acute stroke (Group A, n=50), and the other is healthy people as the control group (Group B, n=30). Within 3 weeks of stroke, [18F]THK5351 and [18F]PMPBB3 PET will be done for imaging cerebral neuroinflammation and tau protein distribution. Brain MRI for obtaining structural and functional information will be done within 3 weeks and 3 months after stroke. Clinical and cognitive outcome will be evaluated at week 3 and months 3 and 12. In addition, APOE genotyping and carotid ultrasound will be performed as well. By obtaining the neuroimaging information, such as severity of white matter change and infarction, cortical and hippocampal atrophy, and SUVRs of [18F]THK5351 and [18F]PMPBB3 PET, the study will be able to investigate the complex interaction between neuroinflammation and tau protein accumulation after stroke, and also evaluate their influence on structural changes, stroke outcome and cognitive performance. Group comparisons will be performed using the Chi-square test, independent t test, Mann-Whitney U test, and multiple linear regression, where appropriate. Anticipation： In this project, the investigators will be able to identify the distribution patterns of neuroinflammation and tau protein accumulation after actue stroke. Secondly, the investigators expect that the presence of neuroinflammation and tau protein accumulation will interfere with the functional connectivity. Finally, the investigators expect that the extent of neuroinflammation and tau protein is correlated with stroke outcome and post-stroke cognitive impairment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Post-stroke Cognitive Impairment, Neuroinflammation
Keywords
Post-stroke cognitive impairment, PET, MRI, neuroinflammation, tau protein

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
A. Group A: Patients with acute stroke/TIA, n=50. B. Group B: Normal control, n=30.
Masking
Investigator
Allocation
Non-Randomized
Enrollment
80 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
PMPBB3
Arm Type
Other
Arm Description
Name: [18F] PMPBB3，[18F]1-Fluoro-3-((2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dien-1-yl)ben Dosage form: intravenous injection Dose(s): 7mCi Dosing schedule: Visit 2 Mechanism of action (if known): high affinity radiotracer for the tau protein Pharmacological category：Radio pharmaceutical
Arm Title
THK
Arm Type
Other
Arm Description
Name: [18F]THK5351，(S)-6-[(3-Fluoro-2-hydroxy)propoxy]-2-(2-Methylaminopyrid-5-yl)-quinoline Dosage form: intravenous injection Dose(s): 10mCi Dosing schedule: Visit 2 Mechanism of action (if known): high affinity radiotracer for the tau protein Pharmacological category：Radio pharmaceutical
Intervention Type
Drug
Intervention Name(s)
PMPBB3
Intervention Description
F-18 PMPBB3 PET Imaging
Intervention Type
Drug
Intervention Name(s)
THK5351
Intervention Description
F-18 THK5351 PET Imaging
Primary Outcome Measure Information:
Title
CDR score of cognition deteriorating group and stable group
Description
The CDR is a 5-point scale (0、0.5、1、2、3) used to characterize six domains of cognitive and functional performance applicable to Alzheimer disease and related dementias: Memory, Orientation, Judgment & Problem Solving, Community Affairs, Home & Hobbies, and Personal Care. The necessary information to make each rating is obtained through a semi-structured interview of the patient and a reliable informant or collateral source (e.g., family member). Global score 0 = Normal、0.5 = Very Mild Dementia、1 = Mild Dementia、2 = Moderate Dementia、3 = Severe Dementia. The cognition deteriorating group is defined as CDR score declines from 0 or 0.5 at Month 3 to >=1 at Month 12. The cognition stable group is defined as CDR score remains at 0 or 0.5 at Month 12.
Time Frame
through study completion, an average of 1 year
Title
PET imaging positive and negative conditions
Description
PET images are visually assessed by independent raters, who are nuclear medicine doctors and blinded to all clinical and diagnostic information. The raters classify each scan as 0-1 (no significant uptake)、2 (suspicious uptake)、3-4 (significant uptake). The score >= 2 is deemed as positive condition.
Time Frame
through study completion, an average of 1 year
Title
Correlation between Neuroimaging factors and CDR-SB condition
Description
Neuroimaging continuous variables will be first examined for their collinearity, determined as variance inflation factor (VIF) of 2 or more. The approach suggested by Zuur et al is to calculate VIFs for each parameter in the model, and if they are larger than some cutoff, sequentially drop the predictor with the largest VIF, recalculate, and repeat until all values are below the cutoff of 2^68. Variables showing moderate to significant inter-group difference (P < 0.10) will be selected for the logistic regression analysis (CDR-SB increase > 1 and conversion to dementia as the dependent variables).
Time Frame
through study completion, an average of 1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
20 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Inclusion criteria for acute stroke/TIA patients (Group A, n=50) Males or females with age >= 20 years old. Having acute cerebral stroke or transient ischemic attack in recent 1 month. Female subjects of childbearing potential must practice effective contraception during the - Provision of signed informed consent from the subject and the subject's legally The subject has an appropriate caregiver capable of accompanying the subject, if necessary. Inclusion criteria for healthy controls (Group B, n = 30) Males or females with age >= 20 years old Without history of cerebral stroke or transient ischemic attack Without history of mild cognitive impairment or dementia Ability to participate in cognitive and neuroimaging assessments Female subjects of childbearing potential must practice effective contraception during the study and be willing and able to continue contraception after the final study Provision of signed informed consent Exclusion Criteria: Exclusion criteria for acute stroke/TIA patients (Group A, n = 50) Presence of dementia diagnosis before the index stroke or at the initial screening History of vascular MCI (VaMCI) The Chinese version of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) score >=104 at the initial screening 45. Life expectancy less than 1 year. Clinically significant abnormal laboratory values. Clinically significant or unstable medical or psychiatric illness. Epilepsy history. Cognitive impairment resulting from trauma or brain damage. Substance abuse or alcoholism in the past 3 months. General MRI, and / or PET exclusion criteria. Pregnant or becoming pregnant during the study (as documented by pregnancy testing at screening or at any date during the study according to the PI discretion) or current breast feeding. History of allergy to 18F-labelled radionucleic agents, such as [18F]PMPBB3 or [18F]THK5351. Subjects having high risks for the study according to the PI discretion. Exclusion criteria for healthy controls (Group B, n = 30) The Chinese version of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) score >=104 at the initial screening 45. Life expectancy less than 1 year. Clinically significant abnormal laboratory values. Clinically significant or unstable medical or psychiatric illness. Epilepsy history. Cognitive impairment resulting from trauma or brain damage. Substance abuse or alcoholism in the past 3 months. General MRI, and / or PET exclusion criteria. Pregnant or becoming pregnant during the study (as documented by pregnancy testing at screening or at any date during the study according to the PI discretion) or current breast feeding. History of allergy to 18F-labelled radionucleic agents, such as [18F]PMPBB3 or [18F]THK5351. Subjects having high risks for the study according to the PI discretion.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Huang Kuo-Lun, M.D.
Phone
+886-3-3281200
Ext
8340
Email
drkuolun@cgmh.org.tw
First Name & Middle Initial & Last Name or Official Title & Degree
Chen Jing-Fang
Phone
+886-3-3281200
Ext
8413
Email
tp6tp6fg@gmail.com
Facility Information:
Facility Name
Department of Neurology, Chang-Gung memorial Hospital
City
Taoyuan
State/Province
Guishan
ZIP/Postal Code
333
Country
Taiwan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Huang Kuo-Lun, M.D.
Phone
+886-3-3281200
Ext
8340
Email
drkuolun@cgmh.org.tw
First Name & Middle Initial & Last Name & Degree
Chen Jing-Fang
Phone
+886-3-3281200
Ext
8413
Email
tp6tp6fg@gmail.com

12. IPD Sharing Statement

Learn more about this trial

The Influence of [18F]PMPBB3 and [18F]THK5351 PET Distribution Patterns on Post-stroke Cognitive Impairment

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