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I2PETPG - Imidazoline2 Binding Sites in a Group of Participants Diagnosed With AD (I2PETPG)

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ClinicalTrials.gov Identifier: NCT02874820
Recruitment Status : Terminated (Patient recruitment issues.)
First Posted : August 22, 2016
Last Update Posted : August 27, 2020
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
Imperial College London

Brief Summary:

The imdazoline2 binding site (I2BS) is known to reside inside astrocytes. Changes in the numbers of I2BS in post mortem tissue has implicated them in a range of psychiatric conditions such as depression and addiction, along with neurodegenerative disorders such as Alzheimer's disease and Huntington's chorea. Preclinical studies have also demonstrated functional interactions with the opioid system, where I2BS ligands have been shown to affect tolerance to morphine and alleviate some of the morphine withdrawal syndrome in rats. Recently the I2BS and I2BS ligands have been shown to have some interesting analgesic effects in different models of pain.

The location of I2BS on astrocytic glial cells and the possibility that they may in some way regulate glial fibrillary acidic protein have led to increased interest into the role of I2BS and I2BS ligands in conditions characterised by marked gliosis. The number of I2BS has been shown to increase in Alzheimer's disease post mortem, and it has also been suggested that I2BS may be a marker for the severity and malignancy of human glioblastomas.

The lack of suitable imaging tools for the I2BS has meant that information regarding the number and distribution of I2BS in the brain has come from preclinical species and in vitro post-mortem studies. The recent development of [11C]BU99008 as a suitable PET ligand to quantify I2BS in vivo, enables the direct quantification of I2BS availability and regional distribution in the living human brain. In this study the investigators plan to utilise [11C]BU99008 to quantify the regional brain availability of I2BS in the human brain in vivo using PET.


Condition or disease Intervention/treatment Phase
Alzheimer Disease Radiation: [11C]BU99008 Drug: Idazoxan Early Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: I2PETPG - Quantification and Localisation of Imidazoline2 Binding Sites in a Group of Participants Diagnosed With Alzheimer's Disease Using 11C-BU99008: a Positron Emission Tomography Study
Study Start Date : July 2016
Actual Primary Completion Date : March 2017
Actual Study Completion Date : July 2017

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Arm Intervention/treatment
Experimental: Patient Group
Baseline PET scan followed by a blocked PET scan
Radiation: [11C]BU99008
Baseline and blocked scans

Drug: Idazoxan
Idazoxan dose up to 80mg




Primary Outcome Measures :
  1. Density and distribution of Imidazoline 2 binding sites using either Total Volume of Distribution (VT) or Binding Potential (BP) [ Time Frame: 1 year ]
    The primary outcome of this study will be the determination of the regional density and distribution of the I2BS in human brain of participants with a diagnosis of early AD. The output parameter used to determine this will be derived from the most appropriate PET pharmacokinetic model for this ligand in human. However, from our current study of this ligand in healthy volunteers this will probably be the Volume of distribution (Vt) derived from the 2 tissue compartment model (2TCM).



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Ages Eligible for Study:   50 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male aged 50 to 80 years
  • Subjects who meet the NIA-AA core clinical criteria for probable Alzheimer's disease dementia
  • Clinical Dementia Rating (CDR) score of 0.5 or more and MMSE ≥ 17
  • Subjects on acetylcholinesterase inhibitor or memantine therapy for Alzheimer's disease must be on a stable dose prior to baseline
  • Subjects must have partners/caregivers able to accompany them during the study visits, as well as monitor for, and report, any adverse events to the study team in the week after scanning
  • Non-smoker
  • Willing to comply with protocol and lifestyle restrictions
  • Excellent understanding of English (for questionnaires)
  • Participant is ambulant and capable of attending a PET scan visit as an outpatient.
  • Participants with female partners of child-bearing potential must agree to use one of the contraception methods listed in Section 7.5.1. This criterion must be followed from after the first PET Scan until after the follow-up contact.
  • Adequate collateral flow to the radial and ulnar arteries in both hands as determined by an Allen's test.
  • Body weight ≥50 kg.

Exclusion Criteria:

  • Current or past history of major psychiatric disorder
  • Current or past history of substance use disorder
  • Clinically significant brain injury or abnormality
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • History of or suffers from claustrophobia or subject feels unable to lie flat and still on their back for a period of up to 2 hours in the PET/CT scanner.
  • Previous inclusion in a research and/or medical protocol involving nuclear medicine, PET or radiological investigations or occupational exposure resulting in radiation exposure greater than 10 mSv over the past 3 years or greater than 10 mSv in a single year including the proposed study. Clinical exposure from which the subject receives a direct benefit is not included in these calculations.
  • Previous inclusion in a research and/or medical protocol involving study medication within the last 3 months
  • In the opinion of the study team they are unlikely to comply with the study protocol and restrictions that it imposes.
  • Contraindications for subjects undergoing an MR scan (including but not limited to metal implants pacemakers, etc.)

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): NCT02874820


Locations
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United Kingdom
Centre for Neuropsychopharmacology; Division of Brain Sciences; Imperial College London; Burlington Danes Building; Hammersmith Hospital campus; 160 Du Cane Road
London, United Kingdom, W12 0NN
Sponsors and Collaborators
Imperial College London
GlaxoSmithKline
Investigators
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Principal Investigator: David J Nutt, MD Director of Centre for Neuropsychopharmacology, Imperial College London
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Responsible Party: Imperial College London
ClinicalTrials.gov Identifier: NCT02874820    
Other Study ID Numbers: 16HH3243
MR/L01307X/1 ( Other Grant/Funding Number: MRC )
First Posted: August 22, 2016    Key Record Dates
Last Update Posted: August 27, 2020
Last Verified: August 2020
Keywords provided by Imperial College London:
Imidazoline Receptor 2
(4,5-dihydro-1H-imidazol-2-yl)-1-methyl-1H-indole
BU99008
[11C]-BU99008
Radionuclide Imaging
Molecular Imaging
Additional relevant MeSH terms:
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Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Idazoxan
Adrenergic alpha-2 Receptor Antagonists
Adrenergic alpha-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs