Alzheimer Disease
Conditions
Brief summary
This substudy will evaluate the effect of crenezumab on the longitudinal tau burden in a subgroup of preclinical Presenilin1 (PSEN1) E280A mutation carriers and non-carriers, who were enrolled in study NCT01998841 (GN28352). Participants will receive up to three intravenous (IV) injections of \[\^18F\] Genentech Tau Probe 1 (GTP1) and will undergo a tau positron emission tomography (PET) scan after each IV injection of \[18\^F\]GTP1. The purpose of this substudy is to increase the understanding of disease progression in the preclinical stage of familial Alzheimer's Disease (AD).
Interventions
DRUGCrenezumab
Crenezumab will be administered subcutaneously (every 2 weeks) or IV (every 4 weeks) for at least 260 weeks.
DRUGPlacebo
Placebo matched to crenezumab will be administered subcutaneously (every 2 weeks) or IV (every 4 weeks) for at least 260 weeks.
OTHER[^18F]GTP1
IV \[\^18F\]GTP1 will be administered up to three times. The first primary \[\^18F\]GTP1 tau PET scan will occur during any visit in the main protocol NCT01998841 (GN28352) from Week 130 to Week 224 and the second \[\^18F\]GTP1 tau PET scan from Week 248 to Week 260. The third and optional \[\^18F\]GTP1 tau PET scan will supplement the two primary scans.
Sponsors
Banner Alzheimer's Institute
National Institute on Aging (NIA)
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
\- Enrolled in main Study NCT01998841 (GN28352).
Exclusion criteria
\- Contraindication to PET scan procedures, possibly including, but not limited to current, past, or planned participation in studies involving radioactive agents, including the main Study NCT01998841 (GN28352) and this Tau PET substudy, such that the total research-related radiation dose to the participant in any given year would exceed the limits set forth in the U.S. Code of Federal Regulations (CFR) Title 21 Section 361.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Rate of Change in Tau Burden | Baseline up to Week 149 | Tau is a protein that accumulates in Alzheimer's disease and damages brain cells including those essential for learning and memory. The effect of crenezumab on tau burden was assessed using \[18F\]GTP1 Tau PET. The annualized rate of change in tau burden from the first \[18F\]GTP1 scan of the standardized uptake ratio (SUVR) in the entorhinal cortex (Braak Stage 1) with an inferior cerebellum reference region was analyzed using a random coefficient regression model (RCRM). Braak staging classifies the degree of pathology in Alzheimer's disease. Braak stages 1 and 2 are used when neurofibrillary tangle involvement is confined mainly to the transentorhinal region of the brain, stages 3 and 4 when there is also involvement of limbic regions such as the hippocampus, and 5 and 6 when there is extensive neocortical involvement. |
Countries
Colombia
Participant flow
Recruitment details
This sub-study enrolled participants from the main study: NCT01998841, who consented to participate in it. Participants took part in this sub-study from 10 Jun 2019 to 19 Apr 2022.
Pre-assignment details
114 participants enrolled in this sub-study.
Participants by arm
| Arm | Count |
|---|---|
| Crenezumab - Mutation Carriers Participants who were PSEN1 E280A mutation carriers and were administered crenezumab, 720 mg, SC, Q2W, or 60 mg/kg, IV, Q4W in the main study (NCT01998841) received up to three IV injections of \[\^18F\]GTP1 and underwent a tau PET scan after each IV injection of \[\^18F\]GTP1. | 44 |
| Placebo - Mutation Carriers Participants who were PSEN1 E280A mutation carriers and were administered crenezumab matching placebo SC, Q2W or IV, Q4W in the main study (NCT01998841) received up to three IV injections of \[\^18F\]GTP1 and underwent a tau PET scan after each IV injection of \[\^18F\]GTP1. | 39 |
| Placebo - Non-Carriers of Mutation Participants who were non-carriers of PSEN1 E280A mutation and were administered crenezumab matching placebo SC, Q2W or IV, Q4W in the main study (NCT01998841) received up to three IV injections of \[\^18F\]GTP1 and underwent a tau PET scan after each IV injection of \[\^18F\]GTP1. | 31 |
| Total | 114 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Reason not disclosed to prevent genetic unblinding | 2 | 0 | 4 |
Baseline characteristics
| Characteristic | Placebo - Non-Carriers of Mutation | Total | Crenezumab - Mutation Carriers | Placebo - Mutation Carriers |
|---|---|---|---|---|
| Age, Continuous | 41.8 years STANDARD_DEVIATION 8 | 37.8 years STANDARD_DEVIATION 7.2 | 36.0 years STANDARD_DEVIATION 5.5 | 36.7 years STANDARD_DEVIATION 7.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 31 Participants | 114 Participants | 44 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 5 Participants | 13 Participants | 5 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Black or African American | 0 Participants | 3 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Multiple | 12 Participants | 35 Participants | 15 Participants | 8 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants | 10 Participants | 4 Participants | 6 Participants |
| Race/Ethnicity, Customized Race Unknown | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race White | 14 Participants | 53 Participants | 17 Participants | 22 Participants |
| Sex: Female, Male Female | 23 Participants | 73 Participants | 21 Participants | 29 Participants |
| Sex: Female, Male Male | 8 Participants | 41 Participants | 23 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 0 / 70 | 0 / 114 |
| other Total, other adverse events | 43 / 44 | 67 / 70 | 110 / 114 |
| serious Total, serious adverse events | 4 / 44 | 5 / 70 | 9 / 114 |
Outcome results
Primary
Annualized Rate of Change in Tau Burden
Tau is a protein that accumulates in Alzheimer's disease and damages brain cells including those essential for learning and memory. The effect of crenezumab on tau burden was assessed using \[18F\]GTP1 Tau PET. The annualized rate of change in tau burden from the first \[18F\]GTP1 scan of the standardized uptake ratio (SUVR) in the entorhinal cortex (Braak Stage 1) with an inferior cerebellum reference region was analyzed using a random coefficient regression model (RCRM). Braak staging classifies the degree of pathology in Alzheimer's disease. Braak stages 1 and 2 are used when neurofibrillary tangle involvement is confined mainly to the transentorhinal region of the brain, stages 3 and 4 when there is also involvement of limbic regions such as the hippocampus, and 5 and 6 when there is extensive neocortical involvement.
Time frame: Baseline up to Week 149
Population: Modified Intent-to-Treat (mITT) population included all mutation carrier participants randomized in Study GN28352 (NCT01998841) and consented to the tau PET substudy who had received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Crenezumab - Mutation Carriers | Annualized Rate of Change in Tau Burden | 0.0124 SUVR per year | Standard Error 0.00752 |
| Placebo - Mutation Carriers | Annualized Rate of Change in Tau Burden | 0.0254 SUVR per year | Standard Error 0.00768 |
Comparison: Analysis was based on RCRM using unstructured covariance matrix: GTP1 PET = Treatment \* Analysis Year + Interactive Voice or Web Response System (IxRS) defined Age Group + IxRS defined Education History + IxRS defined apolipoprotein (APOE4) Carrier Status + IxRS defined Clinical Dementia Rating Global Score.p-value: 0.195395% CI: [-0.0327, 0.0068]RCRM