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

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ClinicalTrials.gov Identifier: NCT04318626
Recruitment Status : Not yet recruiting
First Posted : March 24, 2020
Last Update Posted : July 22, 2020
Sponsor:
Information provided by (Responsible Party):
Chang Gung Memorial Hospital

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.


Condition or disease Intervention/treatment Phase
Post-stroke Cognitive Impairment Neuroinflammation Drug: PMPBB3 Drug: THK5351 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: A. Group A: Patients with acute stroke/TIA, n=50. B. Group B: Normal control, n=30.
Masking: Single (Investigator)
Primary Purpose: Diagnostic
Official Title: The Influence of [18F]PMPBB3 and [18F]THK5351 PET Distribution Patterns on Post-stroke Cognitive Impairment
Estimated Study Start Date : October 1, 2020
Estimated Primary Completion Date : January 15, 2021
Estimated Study Completion Date : January 15, 2022

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

Drug: THK5351
F-18 THK5351 PET Imaging

THK
  1. Name: [18F]THK5351,(S)-6-[(3-Fluoro-2-hydroxy)propoxy]-2-(2-Methylaminopyrid-5-yl)-quinoline
  2. Dosage form: intravenous injection
  3. Dose(s): 10mCi
  4. Dosing schedule: Visit 2
  5. Mechanism of action (if known): high affinity radiotracer for the tau protein
  6. Pharmacological category:Radio pharmaceutical
Drug: PMPBB3
F-18 PMPBB3 PET Imaging

Drug: THK5351
F-18 THK5351 PET Imaging




Primary Outcome Measures :
  1. CDR score of cognition deteriorating group and stable group [ Time Frame: through study completion, an average of 1 year ]

    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.


  2. PET imaging positive and negative conditions [ Time Frame: through study completion, an average of 1 year ]
    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.

  3. Correlation between Neuroimaging factors and CDR-SB condition [ Time Frame: through study completion, an average of 1 year ]
    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).



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Ages Eligible for Study:   20 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04318626


Contacts
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Contact: Huang Kuo-Lun, M.D. +886-3-3281200 ext 8340 drkuolun@cgmh.org.tw
Contact: Tseng Yu-Hui +886-3-3281200 ext 7901 julie031422@gmail.com

Locations
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Taiwan
Department of Neurology, Chang-Gung memorial Hospital
Taoyuan, Guishan, Taiwan, 333
Contact: Huang Kuo-Lun, M.D.    +886-3-3281200 ext 8340    drkuolun@cgmh.org.tw   
Contact: Tseng Yu-Hui    +886-3-3281200 ext 7901    julie031422@gmail.com   
Sponsors and Collaborators
Chang Gung Memorial Hospital
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Responsible Party: Chang Gung Memorial Hospital
ClinicalTrials.gov Identifier: NCT04318626    
Other Study ID Numbers: 201802299A0
First Posted: March 24, 2020    Key Record Dates
Last Update Posted: July 22, 2020
Last Verified: March 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Chang Gung Memorial Hospital:
Post-stroke cognitive impairment
PET
MRI
neuroinflammation
tau protein
Additional relevant MeSH terms:
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Stroke
Cognitive Dysfunction
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Cognition Disorders
Neurocognitive Disorders
Mental Disorders