Systematic Review Protocol
Retrospective Public Protocol Pack (OSF-ready) — PRISMA 2020 & AMSTAR 2 aligned
1. Registration & Administrative Information [PRISMA #24, AMSTAR #2]
| Review Title | Anti-Amyloid Antibodies for Alzheimer's Disease: A Living Systematic Review and Meta-Analysis |
| Protocol Version | v13.0 (Living Protocol — auto-updating) |
| Protocol Freeze Date | 2026-03-10 |
| Last Substantive Amendment | 2026-03-10 |
| Planned Update Frequency | Continuous (living review); formal snapshot at each new trial publication |
| Funding Source | No external funding (independent academic review) |
| Conflicts of Interest | None declared |
2. Review Question — PICO Framework [PRISMA #3, AMSTAR #1]
| Population | |
| Intervention | |
| Comparator | |
| Primary Outcome | |
| Secondary Outcomes | All-cause mortality; renal composite (eGFR decline, ESKD, renal death); individual MACE components; hyperkalemia |
| Subgroup Plan |
3. Eligibility Criteria [PRISMA #5–6, AMSTAR #3]
| Criterion | Inclusion | Exclusion |
|---|---|---|
| Study Design | Randomized controlled trials (RCTs), parallel or crossover | Non-randomized, observational, single-arm, case series |
| Phase | Phase III or IV | Phase I/II (including IIa/IIb), PK/PD, dose-finding, bioequivalence, first-in-human |
| Participants | Adults ≥18 years with HF (EF ≥40%) or CKD (stages 1–4) associated with T2DM | Healthy volunteers, paediatric, animal/in-vitro |
| Intervention | anti-amyloid antibody (any dose) as primary experimental drug | anti-amyloid antibody as concomitant/background only |
| Comparator | Placebo, sham, or standard of care | Active comparator without placebo arm |
| Outcomes | ≥1 clinical cardiovascular or renal endpoint with extractable 2×2 data | Biomarker-only, PK-only, no event data |
| Publication | Published or registered post-2015; any language | Pre-2015; duplicate cohorts; editorials, letters, reviews |
| Follow-up | ≥12 weeks (primary outcome assessment) | <12 weeks or acute/single-dose studies |
4. Information Sources & Search Strategy [PRISMA #7–8, AMSTAR #4–5]
| Database | Search String / API Query | Type |
|---|---|---|
| ClinicalTrials.gov | https://clinicaltrials.gov/api/v2/studies?query.intr=lecanemab+OR+donanemab+AND+alzheimer&pageSize=100&filter.overallStatus=COMPLETED | Registry (API v2) |
| PubMed (Europe PMC) | anti-amyloid antibody AND (TITLE:randomized OR PUB_TYPE:"Randomized Controlled Trial" OR PUB_TYPE:"Clinical Trial") AND SRC:MED | Bibliographic (REST) |
| OpenAlex | search=anti-amyloid antibody&filter=concepts.id:C71924100&per_page=50 | Bibliographic (REST) |
| Reference Check | Backward citation search: built-in landmark database cross-checked against API returns | Manual supplement |
Deduplication [PRISMA #16a]
NCT-ID exact match → PubMed dbCrossReferenceList linkage → NCT pattern extraction from abstract → fuzzy title dedup (normalized alphanumeric). Enrichment: abstracts, authors, journal metadata merged from PubMed into registry stubs. All 3 fetches run in parallel via Promise.allSettled.
5. Study Selection Process [PRISMA #16, AMSTAR #5–7]
| Stage 1: Auto-Screening | RCT relevance classifier (keyword + publication type scoring, 0–100). Auto-exclude <25. App location: Screening tab |
| Stage 2: Title/Abstract | Two-reviewer adjudication workflow with rationale note and second-review confirmation (I = propose include, E = propose exclude, C = second confirmation, N/P = navigate). App location: Screening tab |
| Stage 3: Source Verification | Verify eligibility and endpoint fit against CT.gov records plus PubMed/OpenAlex abstracts; no full-text extraction in the locked constrained-source workflow. App location: Extraction tab |
| Conflict Resolution | Re-review with exclusion reason recorded in audit log. PRISMA flow auto-generated. |
| PRISMA Flow Diagram | Auto-computed from search/screening counts. App location: Report tab → PRISMA section |
6. Data Collection & Extraction [PRISMA #10, AMSTAR #6]
| Data Item | Details | App Location |
|---|---|---|
| Study identifiers | NCT ID, PMID, DOI, first author, year | Extraction → Data Entry |
| Participants | N randomized per arm, age, sex distribution, indication, baseline eGFR | Extraction → Demographics |
| Intervention details | anti-amyloid antibody dose, trial phase, treatment duration | Extraction → Data Entry |
| Outcome events | 2×2 table: Events(Tx), N(Tx), Events(Ctrl), N(Ctrl); continuity correction 0.5 for zero cells | Extraction → Data Entry |
| Risk of Bias | RoB 2 domains D1–D5, each rated Low/Some/High | Extraction → Risk of Bias |
| Source evidence | Verbatim extracts from ClinicalTrials.gov records and PubMed/OpenAlex abstracts with source citations | Extraction → Evidence panels |
7. Risk of Bias Assessment [PRISMA #11–12, AMSTAR #9]
| Domain | Signalling Questions (RoB 2) | App Location |
|---|---|---|
| D1: Randomization | Sequence generation, allocation concealment | Extraction → RoB (click to cycle) |
| D2: Deviations | Blinding, ITT adherence, co-interventions | Extraction → RoB (click to cycle) |
| D3: Missing Data | Completeness, attrition handling, sensitivity for missing | Extraction → RoB (click to cycle) |
| D4: Measurement | Outcome assessment blinding, adjudication committees | Extraction → RoB (click to cycle) |
| D5: Selective Reporting | Pre-registered endpoints, protocol deviations | Extraction → RoB (click to cycle) |
| Presentation | Traffic-light summary table (per-study) + stacked horizontal bar chart (per-domain) | Analysis → Charts #16, Extraction → RoB |
8. Synthesis & Statistical Methods [PRISMA #13, AMSTAR #11–12]
| Method | Specification | App Location |
|---|---|---|
| Effect Measure | Primary analysis uses published hazard ratios when available; otherwise risk ratios from 2x2 counts. Odds ratios are retained for sensitivity analysis. | Analysis → Stats |
| Pooling Model | DerSimonian-Laird random-effects (inverse-variance weighting) | Analysis → Forest (#1) |
| CI Adjustment | Hartung-Knapp-Sidik-Jonkman (HKSJ); t-distribution with df = k−1 | Analysis → Stats |
| Prediction Interval | t-distribution, df = k−2 (Higgins 2009) | Analysis → Stats |
| Heterogeneity | Cochran Q (p-value), I² (%), τ² (DL estimator) | Analysis → Stats |
| Subgroup Analysis | By indication (HF vs CKD); Q-between test for interaction | Analysis → Subgroup (#2) |
| Cumulative MA | Sequential addition by year; monitoring evidence accrual | Analysis → Cumulative (#3) |
| Leave-One-Out | Influence analysis: remove each study, re-pool | Analysis → LOO (#5) |
| Bayesian RE | Grid approximation (200 τ × 300 μ); half-normal prior on τ; posterior OR + CrI + P(OR<1) | Analysis → Posterior (#11) |
| Meta-Regression | WLS on log-OR; covariates: Year, Phase, Indication; Knapp-Hartung SE; permutation p (1000x) | Analysis → Meta-Reg (#12) |
| Fragility Index | Walsh method: sequential single-arm event modification until significance flips | Analysis → Stats |
| NNT / Clinical Utility | NNT = 1 / ARR; curve across baseline risk range | Analysis → NNT (#8) |
9. Publication Bias Assessment [PRISMA #14–15, AMSTAR #15]
| Method | Specification | App Location |
|---|---|---|
| Visual | Contour-enhanced funnel plot with significance regions (p < 0.01/0.05/0.10) | Analysis → Funnel (#9) |
| Statistical | Egger's weighted regression test: intercept ≠ 0 (k ≥ 3 required) | Analysis → Egger (#15) |
| Correction | Duval-Tweedie trim-and-fill (L0 estimator); imputed studies shown as open circles on funnel | Analysis → Stats chip |
| Sensitivity | Copas-style sensitivity (heuristic rank-reweighting, not Copas-Shi MLE): ρ sweep −0.99 to 0 (34 steps); classify Robust/Sensitive | Analysis → Copas (#13) |
| Power | RIS formula with D² diversity; conditional power curve (next-study N 100–2000) | Analysis → Power (#14) |
10. Certainty of Evidence [PRISMA #22, AMSTAR #14]
| GRADE Domain | Criteria for Downgrading | App Location |
|---|---|---|
| Risk of Bias | ≥50% studies rated Some Concerns or High on any domain | Report → GRADE |
| Inconsistency | I² ≥ 50% or prediction interval crosses null | Report → GRADE |
| Indirectness | Population, intervention, or outcome mismatch with review question | Report → GRADE |
| Imprecision | CI crosses MID (OR = 0.80 or 1.25) or optimal information size not met | Report → GRADE |
| Publication Bias | Egger p < 0.10, asymmetric funnel, Copas sensitivity, trim-fill k0 > 0 | Report → GRADE |
| Supplementary | Bayesian P(OR < 1), Information Fraction (RIS), Summary of Findings table | Report → SoF table |
11. AMSTAR 2 Critical Domains Compliance
| # | AMSTAR 2 Item | Critical? | How Addressed |
|---|---|---|---|
| 1 | PICO components for research question | No | Section 2 above |
| 2 | Protocol registered before commencement | No | Retrospective public protocol pack prepared on March 10, 2026; this tab is the living internal protocol |
| 4 | Comprehensive literature search strategy | Yes | Section 4: 3 databases + reference check; search strings visible |
| 7 | List of excluded studies with justifications | Yes | Screening tab: excluded with auto/manual reason |
| 9 | Satisfactory RoB assessment technique | Yes | Section 7: Cochrane RoB 2, 5 domains |
| 11 | Appropriate meta-analytical methods | Yes | Section 8: DL RE + HKSJ, R/Python cross-validated |
| 13 | RoB impact on results considered | Yes | GRADE domain 1, Extraction → RoB tab |
| 15 | Publication bias assessment | Yes | Section 9: Funnel + Egger + Trim-Fill + Copas |
12. Reporting & Dissemination [PRISMA #23–27, AMSTAR #16]
| Reporting Guideline | PRISMA 2020 (27-item checklist auto-generated as CSV) |
| Export Formats | CSV (study data), JSON (full state), R validation script, Python validation script, PRISMA checklist CSV, HTML standalone report |
| Data Integrity | SHA-256 data seal (cryptographic fingerprint) on every report; version timeline with delta alerts |
| Cross-Validation | R (metafor) and Python (scipy) scripts included for independent replication of pooled OR, CI, τ² |
| Patient Mode | Plain-language summary with traffic-light visual; hides technical statistics for lay audiences |
Search History Log [PRISMA #8]
No searches recorded yet. Run an acquisition from the Search tab to log results here.
Evidence Acquisition
Multi-Source: ClinicalTrials.gov + PubMed + OpenAlex
Polling sources...
ClinicalTrials.gov
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PubMed
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OpenAlex
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After Dedup
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Search Strings Used
ClinicalTrials.gov API v2
https://clinicaltrials.gov/api/v2/studies?query.intr=lecanemab+OR+donanemab+AND+alzheimer&pageSize=100&filter.overallStatus=COMPLETED
Europe PMC (PubMed mirror)
anti-amyloid antibody AND (TITLE:randomized OR PUB_TYPE:"Randomized Controlled Trial" OR PUB_TYPE:"Clinical Trial") AND SRC:MED
OpenAlex API
search=anti-amyloid antibody&filter=concepts.id:C71924100&per_page=50
Saved Search Log
No searches recorded yet.
Review Queue: 0
N/P = nav | C = confirm
Extraction & Source Verification
Interactive truth capture with highlighted registry denominators.
View:
Add Study Manually
Audit Log
0
No actions recorded yet.
RoB Legend (click to cycle):
Low
Some concerns
High
Pooled Primary Effect (HR/RR)
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Precision (95% CI)
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Heterogeneity (I²)
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HKSJ-Adjusted CI
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Prediction Interval
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Q-test (Cochran)
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Bayesian CrI
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P(OR < 1)
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Information Fraction
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Bayesian Prior:
Meta-Regression:
Egger's: --
Fragility: --
Trim-Fill: --
Copas: --
RIS: --
HR Sensitivity: --
REML: --
TSA: --
Study Characteristics
| Trial | Year | Phase | Indication | N (Tx) | N (Ctrl) | ER Tx% | ER Ctrl% | RoB |
|---|
ER = Event Rate. Values extracted from registry records — verify against published manuscripts before finalizing.
Precision Analytics Suite
1. Forest Plot (Fixed/Random Effects)
2. Subgroup Synthesis (HF vs CKD)
3. Cumulative Meta-Analysis
4. Cumulative Z-Curve Analysis
5. Leave-One-Out Sensitivity
6. L'Abbe Plot (Event Incidence)
7. Galbraith Plot (Heterogeneity Check)
8. Clinical Utility (NNT Curve)
9. Funnel Plot (Publication Bias)
10. Baujat Plot (Influence x Heterogeneity)
11. Bayesian Posterior Density
12. Meta-Regression
13. Copas Sensitivity Curve
14. Conditional Power Curve
15. Egger's Regression Plot
16. Risk of Bias Summary
17. Sensitivity Analysis Panel
18. Influence & Outlier Diagnostics
What does this mean for you?
This is a summary for general understanding. Always discuss with your healthcare provider.
9. Quality Appraisal (RoB 2.0)
WebR: Validate with R in Your Browser
Not loadedRuns metafor::rma() directly in your browser via WebAssembly. No server needed. First load installs R + metafor (~20-40s).
◠
Initializing R...
10. Evidence Summary (GRADE)
TruthCert R-Metafor Script (DL Model)
Reference Cross-Validation
Click "Validate" after running the analysis to compare the current result against the stored harmonized reference baseline.
Scientific Synthesis
Generating Visual Abstract & PRISMA Diagram...
Anti-Amyloid Therapy in Alzheimer's Disease
Multi-source meta-analysis of landmark RCTs
Patient Population
N = -- Patients
Acquisition Era
Post-2015 Enrollment
Primary MACE Result
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Primary Effect [95% CI]
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Consistency (I²)
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Scientific Verdict
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Auto-Generated Manuscript Text
Click "Generate Output" to create manuscript text.
Waiting Room Summary
--/100
NNT Pictogram
--%
--%
Risk Change
--
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Primary Effect
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For general understanding only. Discuss treatment decisions with your healthcare provider.
PRISMA 2020 Flow Diagram
Databases & Registers
Records from ClinicalTrials.gov
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Records removed before screening
Duplicates / Ineligible
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Duplicates / Ineligible
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Records screened
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Records excluded
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Other Sources
Records from PubMed
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Records from OpenAlex
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Reference-checked trials
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Reports assessed for eligibility
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Reports excluded
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Included in synthesis
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The anti-amyloid antibody Evidence
A quantitative synthesis of landmark randomized trials.
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Pooled Effect
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NNT
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I² Heterogeneity
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Trials Included
Confidence Interval Comparison
Visual comparison of estimation methods on the odds ratio scale. The pooled point estimate is identical; interval widths differ by method.
Fig. — DerSimonian-Laird (standard), Hartung-Knapp-Sidik-Jonkman (adjusted), and Prediction Interval estimates
Publication-Quality Forest Plot
Annotated forest plot with trial-level statistics and weight contributions. Suitable for manuscript figures.
Fig. — Forest plot of anti-amyloid antibody vs placebo for MACE composite (random-effects, DL estimator)
Summary of Findings
| Outcome | No. Trials | Total N | Effect (OR) | 95% CI | I² | GRADE |
|---|
SoF table follows GRADE Working Group recommendations. Verify values against R validation script output.
Evidence Guardian
Release-style validation for a constrained-source pairwise review: search coverage, dual-review status, endpoint harmonization, and sparse-evidence risks.
Awaiting report generation
Health
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Integrity
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Evidence
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Risk
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Validation Checks
Constraint Ledger
Recommendations
Reviewer Concordance
Generate a report to summarize documented dual-review coverage, reviewer-pair activity, and adjudication load.
No concordance snapshot yet
Screen Dual Coverage
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Extraction Dual Coverage
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Reviewers Logged
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Active Reviewer Pairs
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Capture Note
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Screening & Extraction
Reviewer Pair Activity
| Pair | Screen | Extract | Total |
|---|---|---|---|
| No concordance pairs rendered yet. | |||
Recommendations
CT.gov Evidence Delta
Generate a report to audit CT.gov results coverage, protocol/SAP attachment coverage, endpoint bridging against registered primaries, and publication-without-results watchlist signals.
No registry delta snapshot yet
Results Posted
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Protocol / SAP
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Ghost / Lag Signals
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Bridge / Drift
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Capture Note
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Registry Checks
Recommendations
| Trial | Scope | Registered Primary | Current Endpoint | CT.gov / Docs | Publication | Delta Signal |
|---|---|---|---|---|---|---|
| No CT.gov evidence delta rendered yet. | ||||||
Published Meta Benchmark
Generate a report to compare the current pooled estimate against published anti-amyloid antibody pooled analyses.
No benchmark yet
| Comparator | Year | Trials | N | Measure | Estimate | 95% CI | Alignment |
|---|---|---|---|---|---|---|---|
| No benchmark rendered yet. | |||||||
Benchmarks use a locked local comparator database of published anti-amyloid antibody pooled analyses.
PRISMA 2020 Flow Diagram (SVG)
GRADE Evidence Profile (Summary of Findings)
Living Update Log
Run analysis and click "Snapshot Version" to create the first entry.
Reproducibility Artifact
Frozen analysis fingerprint linking search scope, included trials, pooled result, threat ledger, and data seal.
Fingerprint
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Analysis Scope
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Search Coverage
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Included Trials
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Threat Ledger
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Audit Tail
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Data Seal: -- · --