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Multicrossover Randomized Controlled Trial Designs in Alzheimer Disease
Steven E Arnold, Rebecca A Betensky. Annals of neurology, 2018-08-29
Topic: Drug trials: efficacy and safety
Conventional parallel group randomized controlled clinical trials (RCT) in Alzheimer’s disease (AD) are too large, long, expensive and insensitive to clinical change to meet the urgent need for an effective treatment. While providing good evidence for a treatment’s benefit, parallel group RCTs in AD must have very large samples and broad measures of change to accommodate the marked heterogeneity of demographics, genetics, symptoms, pathophysiologies, comorbidities and rates of progression. Multi-crossover, placebo-controlled, double-blind RCTs, including those with sample sizes as small as a single subject (“N-of-1”), are robust designs wherein subjects serve as their own controls in repeated blocks of randomly sequenced crossover treatments. Heterogeneities are inherently controlled and the sensitivity, specificity and clinical relevance of outcomes can be enhanced further by including personalized outcome measures for each individual. Multi-crossover N-of-1 RCTs enable unbiased estimation of efficacy for single subjects, and joint analysis of multiple N-of-1 trials enables estimation of efficacy for populations with much smaller sample sizes than those needed in conventional parallel group studies. It is important to identify carryover effects and natural history time trends to achieve unbiased estimation and testing of the treatment effect. We assert that in AD, multi-crossover RCTs offer many advantages over standard parallel group trials for drugs or other treatments with suitable mechanisms of action, pharmacokinetics and pharmacodynamics; despite the fact that they are almost never conducted. They may be especially useful for therapies directed at symptomatic improvement of cognitive and neuropsychiatric symptoms, but also can be used in early phase studies of disease modifying treatments with biomarker outcome measures.
Key findings
- Heterogeneities are inherently controlled and the sensitivity, specificity and clinical relevance of outcomes can be enhanced further by including personalized outcome measures for each individual.
- Multi-crossover N-of-1 RCTs enable unbiased estimation of efficacy for single subjects, and joint analysis of multiple N-of-1 trials enables estimation of efficacy for populations with much smaller sample sizes than those needed in conventional parallel group studies.
- It is important to identify carryover effects and natural history time trends to achieve unbiased estimation and testing of the treatment effect.
- We assert that in AD, multi-crossover RCTs offer many advantages over standard parallel group trials for drugs or other treatments with suitable mechanisms of action, pharmacokinetics and pharmacodynamics; despite the fact that they are almost never conducted.
- They may be especially useful for therapies directed at symptomatic improvement of cognitive and neuropsychiatric symptoms, but also can be used in early phase studies of disease modifying treatments with biomarker outcome measures.
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Study details
- Evidence strengthHigh
How this study scored 52/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported and studied in people 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, multi-centre collaboration and free to read, so those were left out: it earned 29 of the 56 points we could judge it on, which is 52 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Annals of neurology) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (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 | 2 / 5 | 2018 — within 10 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| 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 | 2 / 2 | Indexed in PubMed (PMID 30014506) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 29 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 29 of the 56 points we could judge it on is 52 out of 100. |
| Total | 52 / 100 | — |
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Arnold, S. E., & Betensky, R. A. (2018). Multicrossover Randomized Controlled Trial Designs in Alzheimer Disease. Annals of neurology. https://doi.org/10.1002/ana.25280
Vancouver
Arnold SE, Betensky RA. Multicrossover Randomized Controlled Trial Designs in Alzheimer Disease. Annals of neurology. 2018. doi:10.1002/ana.25280. PMID: 30014506.
BibTeX
@article{arnold2018-30014506,
author = {Arnold, Steven E and Betensky, Rebecca A},
title = {{Multicrossover Randomized Controlled Trial Designs in Alzheimer Disease}},
journal = {Annals of neurology},
year = {2018},
doi = {10.1002/ana.25280},
pmid = {30014506},
url = {https://doi.org/10.1002/ana.25280}
}