Phase III Study of the Correlation Between Florbetapir F18 PET Imaging and Amyloid Pathology in the Brain

• Sponsor: Avid Radiopharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00857415
• Collaborator: (none)
• Enrollment: 226
• Locations: 25
• Arms: 2
• Duration (Months): 17
• Patients Per Site: 9
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The study is designed to test the relationship between measurements of brain amyloid using florbetapir F 18 PET imaging and true levels of amyloid by dissection of the brain at autopsy. Amyloid in the brain is a key feature of Alzheimer's Disease (AD).

Condition or Disease	Intervention/Treatment	Phase
Alzheimer's Disease	Drug: florbetapir F 18	Phase 3

Detailed Description

There will be two primary analyses:

• The first primary analysis will evaluate the correlation between the blinded readers' rating of amyloid plaque density on the PET scan and the cortical amyloid plaque density at autopsy.

• The second primary analysis will evaluate the specificity of the blinded readers' rating of presence or absence of amyloid plaque density on the PET scan

For the autopsy population, subjects will be enrolled from various end-of-life (e.g. hospice / hospital / nursing home) and late-life (longitudinal studies of aging) populations. Enrollment will include subjects with various levels of cognitive status, ranging from cognitively normal through dementia. It is expected that amyloid plaque density in this elderly population will range from very low (normal aging) through moderate (e.g. cognitively normal subjects with asymptomatic amyloid deposits or mild cognitive impairment (MCI) subjects with intermediate levels of amyloid deposits) to very high (subjects with AD). The study will also enroll younger healthy subjects presumably devoid of amyloid in the specificity cohort.

Screening assessments may take place over several days and will include collection of demographic information, diagnostic interview, and safety assessments. At the time of screening, subjects or caregivers will be asked to provide consent for brain donation if they are not already enrolled in a brain donation program affiliated with this study, in addition to providing informed consent for the screening and imaging procedures in the study.

Subjects who qualify for the study will have a catheter placed for intravenous (i.v.) administration of florbetapir F 18. Subjects will receive a single i.v. bolus of 370 MBq (10 mCi) of florbetapir F 18 followed by brain PET imaging for 10 minutes duration, beginning approximately 50 minutes post-injection. Vital signs and safety labs will be obtained prior to the administration of florbetapir F 18 and at the completion of the imaging session. Adverse events will be continuously monitored during the imaging session. Subjects who experience an adverse event will not be discharged until the event has been resolved or stabilized.

Study Design

• Study Type: Interventional
• Actual Enrollment: 226 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Diagnostic
• Official Title: A Phase III Study of the Correlation Between Florbetapir F 18 (18F-AV-45) PET Imaging and Amyloid Pathology
• Study Start Date: Dec 1, 2008
• Actual Primary Completion Date: Mar 1, 2010
• Actual Study Completion Date: May 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Autopsy Cohort End-of-life subjects (life expectancy < 6 months) consenting to brain donation at autopsy.	Drug: florbetapir F 18; Single i.v. bolus injection of 370MBq (10 mCi) followed by saline flush, 50 minutes prior to imaging, 10 minute image duration; Other Names: 18F-AV-45 AV-45 Amyvid
Experimental: Specificity Cohort Younger healthy controls presumed to be devoid of beta-amyloid plaques.	Drug: florbetapir F 18; Single i.v. bolus injection of 370MBq (10 mCi) followed by saline flush, 50 minutes prior to imaging, 10 minute image duration; Other Names: 18F-AV-45 AV-45 Amyvid

Outcome Measures

Primary Outcome Measures

1. Correlation of Florbetapir-PET Image and Amyloid Plaque Density [at autopsy up to 12 months post-scan]

   Spearman's rank order correlation of the median semi-quantitative visual read of the florbetapir-PET image and the amyloid plaque density assessed post-mortem by quantitative immunohistochemistry (IHC) averaged across 6 brain regions (precuneus, parietal cortex, frontal cortex, temporal cortex, posterior cingulate, anterior cingulate). Spearman's rank order correlation ranges from -1 to +1. A value of -1 indicates perfect negative correlation, and a value of +1 indicates a perfect positive correlation.

2. Specificity Analysis [50-60 min after injection]

   Specificity of florbetapir-PET scan in younger healthy controls presumed to be negative for amyloid. Specificity results are reported as the number of subjects who had a negative scan based on majority of 3 blinded readers.

Secondary Outcome Measures

1. Regional Correlation Analysis [at autopsy up to 12 months post-scan]

   Spearman's rank order correlation of median visual read of the florbetapir-PET image vs. amyloid plaque density assessed post-mortem by quantitative IHC of six individual brain regions (precuneus, parietal cortex, frontal cortex, temporal cortex, posterior cingulate, anterior cingulate). Spearman's rank order correlation ranges from -1 to +1. A value of -1 indicates perfect negative correlation, and a value of +1 indicates a perfect positive correlation.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria (autopsy cohort):

• Have a projected life expectancy of ≤ 6 months as determined by the principal investigator (e.g. terminal medical condition) or are already enrolled in a longitudinal study of aging with an autopsy component;

• Can tolerate a 10 minute PET scan; and

• Give informed consent for study procedures and brain donation consistent with the legal requirements of the State in which they are enrolled and the State in which they die.

Inclusion Criteria (specificity cohort):

• Cognitively and neurologically healthy males and females 18 to 40 years of age;

• Who had no known risk factors for AD, including:

• Known genetic risk factors for AD, including an ApoE ε4 allele (note: ApoE genotype was determined after enrollment and was not disclosed to healthy control subjects). Scans from subjects carrying an ApoE ε4 allele were not included in the primary specificity analysis, but were included in an exploratory analysis;

• First degree relative with a known progressive dementing disorder;

• History of cognitive decline;

• History of neurologic, neurodegenerative, or psychiatric disease;

• History of head trauma; or

• Evidence of brain abnormality on a MRI scan;

• Who performed in an age-appropriate normal range on the Wechsler Logical Memory I & II, story A;

• Who could tolerate a 10-minute PET scan; and

• Who provided informed consent before any study procedures were performed.

Exclusion Criteria:

• Have primary brain tumor, known metastases to the brain, central nervous system (CNS) lymphoma;

• Have any major, focal structural loss of brain matter;

• Are aggressively being treated with life sustaining measures (e.g. currently on respirator; receiving high dose chemotherapy);

• Have a clinically significant infectious disease, including Acquired Immune Deficiency Syndrome (AIDS), Human Immunodeficiency Virus (HIV) infection, previous positive test for hepatitis or HIV or Creutzfeldt-Jakob disease (CJD);

• Are receiving any investigational medications, or have participated in a trial with investigational medications within the last 30 days;

• Have ever participated in an experimental study with an amyloid targeting agent (e.g. anti-amyloid immunotherapy, secretase inhibitor);

• Have had a radiopharmaceutical imaging or treatment procedure within 7 days prior to the study imaging session; or

• Are females of childbearing potential who are pregnant or not using adequate contraception.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Phoenix	Arizona	United States	85006
2	Research Site	Scottsdale	Arizona	United States	85258
3	Research Site	Sun City	Arizona	United States	85351
4	Research Site	Little Rock	Arkansas	United States	72211
5	Research Site	Irvine	California	United States	92697
6	Research Site	San Francisco	California	United States	94109
7	Research Site	Fort Myers	Florida	United States	33912
8	Research Site	Miami Beach	Florida	United States	33140
9	Research Site	Miami Springs	Florida	United States	33166
10	Research Site	Miami	Florida	United States	33137
11	Research Site	Orlando	Florida	United States	32835
12	Research Site	Sarasota	Florida	United States	34231
13	Research Site	St. Petersburg	Florida	United States	33709
14	Research Site	West Palm Beach	Florida	United States	33407
15	Research Site	Baltimore	Maryland	United States	21221
16	Research Site	Hattiesburg	Mississippi	United States	39401
17	Research Site	St. Louis	Missouri	United States	63141
18	Research Site	Albany	New York	United States	12208
19	Research Site	New Hyde Park	New York	United States	11040
20	Research Site	Durham	North Carolina	United States	27710
21	Research Site	Centerville	Ohio	United States	45459
22	Research Site	Oklahoma City	Oklahoma	United States	73112
23	Research Site	Charleston	South Carolina	United States	29425
24	Research Site	Johnson City	Tennessee	United States	37614
25	Research Site	Bennington	Vermont	United States	05201

Sponsors and Collaborators

• Avid Radiopharmaceuticals

Investigators

• Study Director: Chief Medical Officer, Avid Radiopharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Avid Radiopharmaceuticals
• ClinicalTrials.gov Identifier: NCT00857415
• Other Study ID Numbers: 18F-AV-45-A07
• First Posted: Mar 6, 2009
• Last Update Posted: May 22, 2012
• Last Verified: May 1, 2012

• Keywords provided by Avid Radiopharmaceuticals: florbetapir F 18 PET; amyloid imaging; Amyloid pathology in the brain
• Additional relevant MeSH terms: Alzheimer Disease; Amyloidosis

Study Results

Participant Flow

Arm/Group Title	Autopsy Cohort	Specificity Cohort
Arm/Group Description	End-of-life subjects consenting to brain donation at autopsy. Subjects received a single intravenous injection of 370 MBq florbetapir followed by a 10-minute PET scan 50 minutes post-injection.	Younger healthy controls presumed to be devoid of beta-amyloid plaques. Subjects received a single intravenous injection of 370 MBq florbetapir followed by a 10-minute PET scan 50 minutes post-injection.
Period Title: Overall Study
STARTED	152	74
Deceased Within One Year of AV-45 Scan	37	0
COMPLETED	35	74
NOT COMPLETED	117	0

Baseline Characteristics

Arm/Group Title	Autopsy Cohort	Specificity Cohort	Total
Arm/Group Description	End-of-life subjects consenting to brain donation at autopsy. Subjects received a single intravenous injection of 370 MBq florbetapir followed by a 10-minute PET scan 50 minutes post-injection.	Younger healthy controls presumed to be devoid of beta-amyloid plaques. Subjects received a single intravenous injection of 370 MBq florbetapir followed by a 10-minute PET scan 50 minutes post-injection.	Total of all reporting groups
Overall Participants	152	74	226
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	78.1 (13.35)	26.6 (6.50)	61.3 (26.84)
Sex: Female, Male (Count of Participants)
Female	81 53.3%	26 35.1%	107 47.3%
Male	71 46.7%	48 64.9%	119 52.7%
Region of Enrollment (participants) [Number]
United States	152 100%	74 100%	226 100%

Outcome Measures

1. Primary Outcome

Title	Correlation of Florbetapir-PET Image and Amyloid Plaque Density
Description	Spearman's rank order correlation of the median semi-quantitative visual read of the florbetapir-PET image and the amyloid plaque density assessed post-mortem by quantitative immunohistochemistry (IHC) averaged across 6 brain regions (precuneus, parietal cortex, frontal cortex, temporal cortex, posterior cingulate, anterior cingulate). Spearman's rank order correlation ranges from -1 to +1. A value of -1 indicates perfect negative correlation, and a value of +1 indicates a perfect positive correlation.
Time Frame	at autopsy up to 12 months post-scan

Outcome Measure Data

Analysis Population Description

All subjects with a valid image who came to autopsy within 1 year of scan, minus 6 subjects who served as front-runners

Arm/Group Title	Autopsy Cohort
Arm/Group Description	End-of-life subjects consenting to brain donation at autopsy
Measure Participants	29
Number (95% Confidence Interval) [Correlation coefficient]	0.78

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Autopsy Cohort
	Comments	Spearman's Rank Order Correlation of the median semiquantitative read (three readers) and the quantitative IHC measurement of cortical amyloid plaque density averaged across six brain regions.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	A one-sided test (rho > 0) was performed with a significance level of alpha=0.05 to assess a significant correlation.
	Method	Spearman's Rank Correlation test
	Comments
Method of Estimation	Estimation Parameter	Correlation coefficient
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95%; 0.58 to 0.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.194
	Estimation Comments	Asymptotic standard error and 95 percent CI used Fisher z-transformation.

2. Primary Outcome

Title	Specificity Analysis
Description	Specificity of florbetapir-PET scan in younger healthy controls presumed to be negative for amyloid. Specificity results are reported as the number of subjects who had a negative scan based on majority of 3 blinded readers.
Time Frame	50-60 min after injection

Outcome Measure Data

Analysis Population Description

Per protocol, 27 subjects who were genetic carriers for ApoE e4 or whose genetic status was unknown were excluded from the analysis

Arm/Group Title	Specificity Cohort
Arm/Group Description	Younger healthy controls presumed to be devoid of beta-amyloid plaques
Measure Participants	47
Positive for amyloid	0 0%
Negative for amyloid	47 30.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Autopsy Cohort
	Comments	Proportion of subjects who had a negative scan based on majority of 3 blinded readers
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Specificity
	Estimated Value	100
	Confidence Interval	(2-Sided) 95%; 91 to 100
	Parameter Dispersion	Type: Value:
	Estimation Comments	95% CI calculated by Wilson score method

3. Secondary Outcome

Title	Regional Correlation Analysis
Description	Spearman's rank order correlation of median visual read of the florbetapir-PET image vs. amyloid plaque density assessed post-mortem by quantitative IHC of six individual brain regions (precuneus, parietal cortex, frontal cortex, temporal cortex, posterior cingulate, anterior cingulate). Spearman's rank order correlation ranges from -1 to +1. A value of -1 indicates perfect negative correlation, and a value of +1 indicates a perfect positive correlation.
Time Frame	at autopsy up to 12 months post-scan

Outcome Measure Data

Analysis Population Description

All subjects with a valid image who came to autopsy within 1 year of scan, minus 6 subjects who served as front-runners

Arm/Group Title	Autopsy Cohort
Arm/Group Description	End-of-life subjects consenting to brain donation at autopsy
Measure Participants	29
Precuneus	0.75
Parietal cortex	0.77
Frontal cortex	0.69
Temporal cortex	0.68
Posterior cingulate	0.70
Anterior cingulate	0.74

Adverse Events

Time Frame	AEs were collected up to 48 hours after injection. SAEs were collected up to 30 days after injection.
Arm/Group Title	Autopsy Cohort		Specificity Cohort
Arm/Group Description	End-of-life subjects consenting to brain donation at autopsy. Subjects received a single intravenous injection of 370 MBq florbetapir followed by a 10-minute PET scan 50 minutes post-injection.		Younger healthy controls presumed to be devoid of beta-amyloid plaques. Subjects received a single intravenous injection of 370 MBq florbetapir followed by a 10-minute PET scan 50 minutes post-injection.
All Cause Mortality
	Autopsy Cohort		Specificity Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Autopsy Cohort		Specificity Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/152 (0.7%)		0/74 (0%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure	1/152 (0.7%)	152	0/74 (0%)	0
Other (Not Including Serious) Adverse Events
	Autopsy Cohort		Specificity Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/152 (2%)		2/74 (2.7%)
Nervous system disorders
Headache	3/152 (2%)	3	2/74 (2.7%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.