Microglial Activation Positron Emission Tomography (PET) Brain Imaging in Multiple Sclerosis and Alzheimer's Disease (MAPET)

• ClinicalTrials.gov Identifier: NCT02649985
• Recruitment Status: Unknown
• First Posted: January 8, 2016
• Last Update Posted: December 11, 2020
• Sponsor: Brigham and Women's Hospital
• Information provided by (Responsible Party): TARUN SINGHAL, Brigham and Women's Hospital

Tracking Information

• First Submitted Date: January 6, 2016
• First Posted Date: January 8, 2016
• Last Update Posted Date: December 11, 2020
• Actual Study Start Date: May 2, 2016
• Estimated Primary Completion Date: December 31, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 6, 2016)

Tissue Volume of Distribution [ Time Frame: 1 month ]

PET imaging measurement

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 9, 2020)

Standardized uptake values (SUV)/Standardized uptake value Ratios (SUVR) [ Time Frame: 1 month ]

PET imaging measurement

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Microglial Activation Positron Emission Tomography (PET) Brain Imaging in Multiple Sclerosis and Alzheimer's Disease
• Official Title: Microglial Activation Positron Emission Tomography (PET) Brain Imaging in Multiple Sclerosis and Alzheimer's Disease

Brief Summary

The specific aims of the study are:

Primary: To determine the presence and regional distribution of microglial activation, as assessed by Fluorine-18 (18F) labeled "Peripheral Benzodiazepine Receptor 06" (PBR06) -PET, in subjects with active Relapsing Remitting Multiple Sclerosis (RRMS), Secondary Progressive Multiple Sclerosis (SPMS), and Alzheimer's Disease (AD) as compared to healthy controls

Secondary:

1. To assess the relationship between microglial activation and clinical variables including disease severity and comorbidities (such as pain, fatigue and/or depression), as well as clinical MRI findings (such as lesions and atrophy)
2. A pilot substudy aims to establish the non-inferiority of [F-18]PBR06 as compared with Carbon-11 [C-11] labeled "Peripheral Benzodiazepine Receptor 28" (PBR28) PET in patients with RRMS.

Hypothesis: The working hypothesis is that there is microglial activation in multiple sclerosis and Alzheimer's disease as compared to healthy controls and that the pattern/ regional distribution of microglial activation is different in Multiple Sclerosis (MS) versus AD and correlates with disease severity and comorbidities.

In addition, the investigators hypothesize that [F-18]PBR06-PET scans will be at least as good as [C-11]PBR28-PET scans, the current gold standard.

Detailed Description

Four groups of subjects will be recruited:

1. Subjects meeting the definition for RRMS by the International Panel Criteria, who are active, as defined by at least one MS relapse in the past 12 months, or at least one gadolinium enhancing lesion on Magnetic Resonance Imaging (MRI) within 3 months of enrollment.
2. Subjects meeting the definition for SPMS by International Panel Criteria and who have demonstrated deterioration in Expanded Disability Status Scale (EDSS) score in last 1 year
3. Subjects meeting the definition for probable AD based on National Institute of Neurological and Communicable Diseases-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria. In terms of severity of disease, we will select subjects with mild AD, as defined by Mini-Mental Status Examination (MMSE) score of 20-26.
4. Healthy Controls

The study will be performed in two phases. In the early pilot phase, 8 subjects with RRMS will undergo both [C-11]PBR28 PET scan and [F-18]PBR06 PET scan. At the end of this phase, a formal interim analysis will be performed and if imaging characteristics of [F-18]PBR06 are found non-inferior to or better than [C-11]PBR28, rest of the study will be completed using [F-18]PBR06. All subjects will also undergo 3-Tesla (3T) MRI of the brain.

The goal sample size is 30 subjects including 6 healthy controls, 8 subjects with relapsing remitting MS, 8 subjects with secondary progressive MS (SPMS), and 8 subjects with AD.

Subjects will be recruited by the PI, one of the other co-investigators, or a staff member listed on the protocol at the Partners MS Center and the Behavioral Neurology Clinic of Brigham and Women's Hospital.

Side Effects Monitoring:

No side effects from the radiopharmaceuticals are expected. The dose of radiopharmaceutical being administered in this study is below that at which we would expect any effect, including physical dependence and addiction. Subjects will be exposed to a small amount of radiation. The radiotracer will be prepared in such a way as to ensure that it is sterile and pyrogen free, and its radiochemical purity (RCP) will be determined using Silica Gel-Instant Thin Layer Chromatography and/or high pressure liquid chromatography (HPLC). In addition, because both [F-18]PBR06 and [C-11]PBR28 are non-FDA approved radioligands, their use for this study will be reviewed by Radioactive Drugs Research Committee.

Subject Safety:

Subject monitoring during MRI and PET scans will be performed using a 2-way intercom system between the scanner operator and subject and by visual monitoring of the subject through the window into the scan room (the subject is visible to the operator at all times).

Subjects will need to lie still in the PET camera for period of 120 min, and subjects may find it uncomfortable to remain still over this time. Therefore, as mentioned above, subjects will be given the opportunity to take a break for up to 20 minutes after 70 minutes of PET scanning, following which the last 30 minutes of scanning will be completed. A standard head-support device will be used to make the subjects comfortable during the scanning.

If subjects find an intravenous catheter or duration of scanning too uncomfortable, they are free to withdraw from the study at any time.

The MRI scans take place in a confined space that makes some people claustrophobic. Claustrophobic individuals will be excluded from the study. Also during the scan the subject will hear loud banging noises and will therefore wear ear plugs to reduce this noise.

Recruitment Process:

Physicians at the Partners MS Center and the Brigham and Women's Hospital (BWH) Behavioral Neurology clinic may present the study to a subject during a regular scheduled clinic visit. If the subject is interested in the study, a copy of the consent form will be given. At the time of the subject's initial screening visit, a licensed physician investigator will answer any questions the subject may have regarding the study and subsequently obtain informed consent. In accordance with NIH guidelines, efforts will be made to attain a mix of study participants, in terms of gender and racial/ethnic representation.

Consent Process:

Informed consent will be obtained from the subjects by a licensed physician investigator on the study protocol. If the investigator is a clinician from the MS Center or Behavioral Neurology clinic, they will not be allowed to obtain consent from their own patients. Existing MS Center or Behavioral Neurology clinic subjects may be sent a letter describing the study and a copy of the consent document. Interested subjects are directed to contact research staff via a telephone number provided in the letter inviting participation in the study to set up a screening visit. They will have the opportunity to discuss the study with research study staff prior to giving consent as outlined above. Subjects approached for participation in the study during a routine clinical visit will have the opportunity to participate in the study at that time or they may choose to return for participation at another time in the future. All subjects will be informed that they are free to withdraw consent from the study at any time without affecting the quality or type of care that they receive at BWH. Subjects will be informed that they may not qualify for the study if their genetic analysis reveals that they are low affinity binders for translocator protein (TSPO).

Monitoring and Quality Assurance:

During the study period, subjects will be followed by their clinical neurologists for adverse events and disease progression. If problems are reported to their physicians, they will receive care as is normally performed. In addition, the Principal Investigator (PI) will review all laboratory results of tests undergone by the subjects during the study period and help co-ordinate any necessary care with patient's primary providers.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Diagnostic

Condition

• Multiple Sclerosis
• Alzheimer's Disease

Intervention

• Drug: [F-18]PBR06
  PET radiopharmaceutical
  Other Name: [F-18] PBR06
• Drug: [C-11]PBR28
  PET radiopharmaceutical
  Other Name: [C-11] PBR28

Study Arms

• Experimental: Relapsing-Remitting Multiple Sclerosis

  Subjects meeting the definition for RRMS by the International Panel Criteria, who are active, as defined by at least one MS relapse in the past 12 months, at least one gadolinium enhancing lesion on a MRI within 12 months of enrollment, or at least one new FLAIR bright lesion on MRI within 6 months of enrollment.

  The study will be performed in two phases. In the early pilot phase, 8 subjects with multiple sclerosis will undergo both [C-11]PBR28 PET scan and [F-18]PBR06 PET scan. At the end of this phase, a formal interim analysis will be performed and if imaging characteristics of [F-18]PBR06 are found non-inferior to or better than [C-11]PBR28, the rest of the study will be completed using [F-18]PBR06. On the other hand, if [F-18]PBR06 is found to be inferior to [C-11]PBR28, the rest of the study will be pursued using [C-11]PBR28.

  Interventions:

  • Drug: [F-18]PBR06
  • Drug: [C-11]PBR28
• Experimental: Progressive Multiple Sclerosis
  Subjects meeting the definition for SPMS/PPMS (Primary Progressive Multiple Sclerosis) by International Panel Criteria and who have demonstrated deterioration in EDSS score in last 1 year.
  Intervention: Drug: [F-18]PBR06
• Active Comparator: Alzheimer's Disease
  Subjects meeting the definition for probable AD based on NINDS-ADRDA criteria. In terms of severity of disease, the investigators will select subjects with mild AD, as defined by Mini-Mental Status Examination (MMSE) score of 20-26.
  Intervention: Drug: [F-18]PBR06
• Healthy Control
  This group will serve as non disease population.
  Intervention: Drug: [F-18]PBR06
• Experimental: Multiple Sclerosis Ocrelizumab

  Subjects who have been prescribed Ocrelizumab by their treating MS neurologist but have not yet started the first Ocrelizumab infusion.

  Subjects will undergo two separate visits for [F-18]PBR06 PET scans, once before starting Ocrelizumab and the second visit 3 months after completion of the initial Ocrelizumab doses.

  Intervention: Drug: [F-18]PBR06

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: December 9, 2020): 105
• Original Estimated Enrollment (submitted: January 6, 2016): 50
• Estimated Study Completion Date: December 31, 2021
• Estimated Primary Completion Date: December 31, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Male and female subjects age 18 to 70 years. For Alzheimer's Disease patients and healthy controls, the age range is going to be 18 to 85 years.
2. For RRMS, it needs to be active, which is defined as at least one relapse in the past 12 months, at least one gadolinium enhancing lesion on MRI within 12 months of enrollment or at least one new FLAIR bright lesion on MRI within 6 months of enrollment.
3. For SPMS, deterioration in EDSS score in the last year is required.
4. For the subjects in the Ocrelizumab arm, only the subjects who have already been prescribed Ocrelizumab by their treating MS neurologist but have not yet started the first infusion, will be included.
5. AD subjects with MMSE score of 20-26.
6. Subjects willing to undergo PET and MRI imaging
7. Subjects willing and able to give informed consent

Exclusion Criteria:

1. Individuals with a known alternate neurologic disorder, previous head injury, or substance abuse.
2. Individuals with bipolar disease and schizophrenia
3. Concurrent medical conditions that contraindicate study procedures.
4. Women who are pregnant or nursing. Also, any woman who is seeking to become pregnant or suspects she is pregnant will be excluded from enrollment.
5. Claustrophobia
6. Non-MRI compatible implanted devices
7. For the Ocrelizumab arm, subjects already on Ocrelizumab will be excluded. For the Alemtuzumab arm, subjects already on Alemtuzumab will be excluded.
8. For the Ocrelizumab arm and the Alemtuzumab arm, subjects with abnormal serum creatinine will be excluded.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02649985
• Other Study ID Numbers: 2015P002329
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: TARUN SINGHAL, Brigham and Women's Hospital
• Original Responsible Party: Tarun Singhal, Brigham and Women's Hospital, Associate Neurologist
• Current Study Sponsor: Brigham and Women's Hospital
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Tarun Singhal, MD; Brigham and Women's Hospital

• PRS Account: Brigham and Women's Hospital
• Verification Date: December 2020