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P2‐003: Clinical Trial Design of Cread: A Randomized, Double‐Blind, Placebo‐Controlled, Parallel‐Group Phase 3 Study to Evaluate Crenezumab Treatment in Patients with Prodromal‐To‐Mild Alzheimer’s Disease
Thomas Blaettler, Janice Smith, Jillian P. Smith, Robert H. Paul, Veronica Asnaghi, Reina N. Fuji, Angelica Linnea Quartino, Lee A. Honigberg et al.. Alzheimer s & Dementia, 2016-07-01
Topic: Drug trials: efficacy and safety
Crenezumab is a humanized anti-amyloid-beta (Aβ) monoclonal IgG4 antibody in development for the treatment of Alzheimer’s disease (AD). Crenezumab binds monomeric and aggregated Aβ species and may reduce their neurotoxicity and accumulation. Its IgG4 backbone confers reduced effector function, with the intent to reduce inflammation at sites of Aβ engagement, which may provide a safer passive immunotherapeutic alternative for AD. Crenezumab has been evaluated in Phase 2 studies in over 500 patients with mild-to-moderate AD treated for 18 months. Although the co-primary endpoints (ADAS-Cog12 and CDR-SB) were not met, pre-planned exploratory analyses suggest that treatment with crenezumab compared with placebo leads to increasing benefit on both endpoints in progressively milder subsets of AD patients at the higher dose (15 mg/kg IV q4w). In Phase 2, only a single case of asymptomatic ARIA-E was reported. These data suggest that further dose increases in patients at an earlier disease stage may yield greater clinical efficacy. Therefore, a randomized, double-blind, placebo-controlled, parallel-group Phase 3 study is testing the efficacy and safety of a higher dose of crenezumab in patients with prodromal-to-mild AD. This study is being conducted in approximately 200 centers across 30 countries, with approximately 750 patients randomized 1:1 to placebo or crenezumab 60 mg/kg q4w IV treatment arms. Eligible patients are 50–85 years old, have a clinical diagnosis of probable or prodromal AD according to the NIA-AA diagnostic criteria, an MMSE score of ≥22, a CDR-global score of 0.5 or 1, and confirmed evidence of cerebral amyloid pathology. The primary endpoint of this study is change in the CDR-SB score at 2 years. Substudies will explore treatment effects on cerebrospinal fluid biomarkers and amyloid-PET, and examine their concordance. MRI examinations will monitor safety and measure volumetric changes. Building on key learnings from Phase 2, this Phase 3 study has been designed to investigate the clinical efficacy of a higher dose of crenezumab in patients with prodromal-to-mild AD, and to test whether efficacy can be obtained without the associated increase in safety findings that have been described with other passive immunotherapies in AD.
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APA 7th
Blaettler, T., Smith, J., Smith, J. P., Paul, R. H., Asnaghi, V., Fuji, R. N., et al. (2016). P2‐003: Clinical Trial Design of Cread: A Randomized, Double‐Blind, Placebo‐Controlled, Parallel‐Group Phase 3 Study to Evaluate Crenezumab Treatment in Patients with Prodromal‐To‐Mild Alzheimer’s Disease. Alzheimer s & Dementia. https://doi.org/10.1016/j.jalz.2016.06.1207
Vancouver
Blaettler T, Smith J, Smith JP, Paul RH, Asnaghi V, Fuji RN, et al. P2‐003: Clinical Trial Design of Cread: A Randomized, Double‐Blind, Placebo‐Controlled, Parallel‐Group Phase 3 Study to Evaluate Crenezumab Treatment in Patients with Prodromal‐To‐Mild Alzheimer’s Disease. Alzheimer s & Dementia. 2016. doi:10.1016/j.jalz.2016.06.1207.
BibTeX
@article{blaettler2016-916a25c5,
author = {Blaettler, Thomas and Smith, Janice and Smith, Jillian P. and Paul, Robert H. and Asnaghi, Veronica and Fuji, Reina N. and Quartino, Angelica Linnea and Honigberg, Lee A. and others},
title = {{P2‐003: Clinical Trial Design of Cread: A Randomized, Double‐Blind, Placebo‐Controlled, Parallel‐Group Phase 3 Study to Evaluate Crenezumab Treatment in Patients with Prodromal‐To‐Mild Alzheimer’s Disease}},
journal = {Alzheimer s \& Dementia},
year = {2016},
doi = {10.1016/j.jalz.2016.06.1207},
url = {https://doi.org/10.1016/j.jalz.2016.06.1207}
}
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Key findings
- Although the co-primary endpoints (ADAS-Cog12 and CDR-SB) were not met, pre-planned exploratory analyses suggest that treatment with crenezumab compared with placebo leads to increasing benefit on both endpoints in progressively milder subsets of AD patients at the higher dose (15 mg/kg IV q4w).
- These data suggest that further dose increases in patients at an earlier disease stage may yield greater clinical efficacy.
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Study details
- Study designclinical trial
- Participants500
- Evidence strengthHigh
How this study scored 52/100
Published in a peer-reviewed journal. Scored zero for study design and effect reported because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 30 of the 58 points we could judge it on, which is 52 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Alzheimer s & Dementia) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | Design recorded as “clinical trial”, which our rubric does not rank (not stated in the record — scored 0) |
| Strength of evidence | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2016 — within 20 year(s) of the newest study here |
| Sample size | 2 / 4 | 500 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 1 / 2 | Randomised (as stated in the record) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 30 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 30 of the 58 points we could judge it on is 52 out of 100. |
| Total | 52 / 100 | — |
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