Multimodal Imaging Outcome Measures for ALS (Image ALS)

Sponsor

University of Pennsylvania (Other)

Overall Status

Terminated

CT.gov ID

NCT04490096

Collaborator

Biogen (Industry), University of Miami (Other), University of Kansas (Other)

Enrollment

Location

Arm

12.6

Actual Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary aim of this study is to determine whether longitudinal neuroimaging acquired across multiple research and clinical centers is a feasible biomarker to use as an outcome measure for clinical trials in amyotrophic lateral sclerosis (ALS)

Condition or Disease	Intervention/Treatment	Phase
ALS	Drug: [11C]-PBR28	Phase 1

Detailed Description

ALS is a progressive neurodegenerative disorder that manifests with extensive clinical heterogeneity, including variable degrees of upper motor neuron (UMN) and lower motor neuron (LMN) impairment. While ALS is classically defined as a neuromuscular disorder, approximately 15% of individuals also develop cognitive and/or behavioral dysfunction of the frontotemporal variety, ranging in severity from ALS with cognitive or behavior impairment to a frank form of dementia consistent with FTD2

Recent consensus criteria capture this heterogeneity by defining these conditions together as amyotrophic lateral sclerosis frontotemporal spectrum disorder (ALS-FTSD)3
There are emerging and in-progress interventional clinical trials underway that aim to arrest ALS and/or FTD disease progression; however, there are limited objective and quantitative biomarkers to directly track disease progression during life. Multi-modal neuroimaging provides an ideal candidate biomarker for clinical trials because ALS-FTSD affects a distributed neuroanatomic network and we can reliably measure neurodegeneration of grey matter (GM) and arterial spin labeling based perfusion MRI (pMRI) measurements of cerebral blood flow (CBF). However, there are many unaddressed technical challenges associated with measuring disease progression using neuroimaging techniques in a multi-center setting. The overall aim of this protocol is to leverage a team science approach to develop disease-specific candidate neuroimaging outcome measures for ALS-FTSD clinical trials.

Study Design

Study Type:

Interventional

Actual Enrollment :

2 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Diagnostic

Official Title:

Multimodal Imaging Outcome Measures for ALS (Image ALS)

Actual Study Start Date :

Feb 25, 2021

Actual Primary Completion Date :

Mar 17, 2022

Actual Study Completion Date :

Mar 17, 2022

Arms and Interventions

Arm	Intervention/Treatment
Other: [11C]-PBR28 ALS Neuroinflammatory pathways have been implicated in a variety of neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), but the vast majority of this evidence is from animal or ex vivo human studies. In vivo measurement of the 18 kDa translocator protein (TSPO) has become possible with [11C]-PBR28 PET imaging. Briefly, TSPO expression is increased when microglial are activated. Cross-sectional studies have demonstrated that [11C]-PBR28 uptake is elevated in ALS compared to controls, is correlated with upper motor neuron severity, and that microglial activation is associated with more severe upper motor neuron disease and faster disease progression. We are only aware of a single 6-month study of 10 patients evaluating longitudinal change of [11C]-PBR28 in ALS. We hypothesize that we will observe increased [11C]-PBR28 uptake over a 6-month period in motor cortex and prefrontal cortex in ALS. This portion of the study will be performed at UPenn only.	Drug: [11C]-PBR28 A dose of ≤ 20 mCi (approximate range for most studies is anticipated to be 5-20 mCi) of [11C]-PBR28 will be administered by IV injection to the patient under the direct supervision of a Nuclear Medicine Authorized User. A lesser activity may be injected if, in the opinion of a nuclear medicine authorized user complete imaging data could be generated. Subjects will undergo an approximately 90 minute dynamic PET/CT scan over the brain starting at approximately the same time as the [11C]-PBR-28 injection. Scans will be acquired using a Philips PET/CT time-of-flight Ingenuity scanner (Philips Healthcare, Cleveland, OH, USA). At the end of the dynamic imaging the participant will be allowed to get off the scanner.

Arm

Intervention/Treatment

Other: [11C]-PBR28 ALS

Neuroinflammatory pathways have been implicated in a variety of neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), but the vast majority of this evidence is from animal or ex vivo human studies. In vivo measurement of the 18 kDa translocator protein (TSPO) has become possible with [11C]-PBR28 PET imaging. Briefly, TSPO expression is increased when microglial are activated. Cross-sectional studies have demonstrated that [11C]-PBR28 uptake is elevated in ALS compared to controls, is correlated with upper motor neuron severity, and that microglial activation is associated with more severe upper motor neuron disease and faster disease progression. We are only aware of a single 6-month study of 10 patients evaluating longitudinal change of [11C]-PBR28 in ALS. We hypothesize that we will observe increased [11C]-PBR28 uptake over a 6-month period in motor cortex and prefrontal cortex in ALS. This portion of the study will be performed at UPenn only.

Drug: [11C]-PBR28

A dose of ≤ 20 mCi (approximate range for most studies is anticipated to be 5-20 mCi) of [11C]-PBR28 will be administered by IV injection to the patient under the direct supervision of a Nuclear Medicine Authorized User. A lesser activity may be injected if, in the opinion of a nuclear medicine authorized user complete imaging data could be generated. Subjects will undergo an approximately 90 minute dynamic PET/CT scan over the brain starting at approximately the same time as the [11C]-PBR-28 injection. Scans will be acquired using a Philips PET/CT time-of-flight Ingenuity scanner (Philips Healthcare, Cleveland, OH, USA). At the end of the dynamic imaging the participant will be allowed to get off the scanner.

Outcome Measures

Primary Outcome Measures

Volume measurement (cubic mm) of brain regions using MRI [Change from baseline volume measurement (cubic mm) at 6 months]
Volume measurement (cubic mm) of brain regions using MRI for ALS patients and healthy controls.
Volume measurement (cubic mm) of brain regions using MRI [Change from baseline volume measurement (cubic mm) at 12 months]
Volume measurement (cubic mm) of brain regions using MRI for ALS patients and healthy controls.
Thickness measurement (mm) of brain regions using MRI [Change from baseline thickness measurement (mm) at 6 months]
Thickness measurement (mm) of brain regions using MRI in ALS patients and healthy controls.
Thickness measurement (mm) of brain regions using MRI [Change from baseline thickness measurement (mm) at 12 months]
Thickness measurement (mm) of brain regions using MRI in ALS patients and healthy controls.
Cerebral blood flow measurement (mL of blood/100g per minute) of brain regions using MRI [Change from baseline cerebral blood flow measurement (mL of blood/100g per minute) at 6 months]
Determine whether MRI is a feasible for measuring longitudinal change comparing ALS patients relative to healthy controls. ALS will have increased rate of hyperperfusion, reflected by reduced cerebral blood flow (mL of blood/100g per minute), in the motor cortex and frontal cortex brain regions relative to healthy controls.
Cerebral blood flow measurement (mL of blood/100g per minute) of brain regions using MRI [Change from baseline cerebral blood flow measurement (mL of blood/100g per minute at 12 months]
Determine whether MRI is a feasible for measuring longitudinal change comparing ALS patients relative to healthy controls. ALS will have increased rate of hyperperfusion, reflected by reduced cerebral blood flow (mL of blood/100g per minute), in the motor cortex and frontal cortex brain regions relative to healthy controls.

Secondary Outcome Measures

[18F]-FDG signal measurement (standard uptake volume or SUV) in brain regions using PET scan [Change from baseline [18F]-FDG signal measurement (standard uptake volume or SUV) at 3 months]
[18F]-FDG signal measurement (Standard Uptake Value or SUV) of [18F]-FDG PET for ALS patients at PENN only.
[18F]-FDG signal measurement (standard uptake volume or SUV) in brain regions using PET scan [Change from baseline [18F]-FDG signal measurement (standard uptake volume or SUV) at 6 months]
[18F]-FDG signal measurement (Standard Uptake Value or SUV) of [18F]-FDG PET for ALS patients at PENN only.
[11C]-PBR28 signal measurement (standard uptake volume or SUV) in brain regions using PET scan [Change from baseline [11C]-PBR28 signal measurement (standard uptake volume or SUV) at 3 months]
[11C]-PBR28 signal measurement (Standard Uptake Value or SUV) of [11C]-PBR28 PET for ALS patients at PENN only.
[11C]-PBR28 signal measurement (standard uptake volume or SUV) in brain regions using PET scan [Change from baseline [11C]-PBR28 signal measurement (standard uptake volume or SUV) at 6 months]
[11C]-PBR28 signal measurement (Standard Uptake Value or SUV) of [11C]-PBR28 PET for ALS patients at PENN only.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria for participants in PET sub-study (Penn Only):

Enrolled in the MRI study at Penn.
Willing to participate in a 30 minute [18F]-FDG and 1.5 hour [11C]-PBR28 PET scan within 15 days baseline and longitudinally at the 3-month and 6-month follow-up visits, if able.

Exclusion criteria for PET sub-study participants:

Females who are pregnant at the time of study visits will not be eligible for the PET sub-study; urine or serum pregnancy test will be performed in women of child-bearing potential at each of the baseline, 3-month, and 6-month study visit.
Homozygous genotype for the threonine-associated substitution allele (A) in the rs6971 polymorphism.
Blood glucose less than or equal to 250 mg/dl, or at the discretion of the authorized user

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

University of Pennsylvania
Biogen
University of Miami
University of Kansas

Investigators

Principal Investigator: Corey McMillan, PhD, University of Pennsylvania

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

University of Pennsylvania

ClinicalTrials.gov Identifier:

NCT04490096

Other Study ID Numbers:

834366

First Posted:

Jul 28, 2020

Last Update Posted:

Apr 12, 2022

Last Verified:

Apr 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Study Results

No Results Posted as of Apr 12, 2022