Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Sustained effect of prasinezumab on Parkinson's disease motor progression in the open-label extension of the PASADENA trial.

Name: Kaimen Rigor review — Sustained effect of prasinezumab on Parkinson's disease motor progression in the open-label extension of the PASADENA trial.
Item: Sustained effect of prasinezumab on Parkinson's disease motor progression in the open-label extension of the PASADENA trial.
Rating: 96
Author: Alpha1

Pagano G, Monnet A, Reyes A, Ribba B, Svoboda H, Kustermann T, Simuni T, Postuma RB, Pavese N, Stocchi F, Brockmann K, Smigorski K, Gerbaldo V, Fontoura P, Doody R, Kerchner GA, Brundin P, Marek K, Bonni A, Nikolcheva T, PASADENA Investigators, Prasinezumab Study Group

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Kaimen Rigor review — 2★ (Weak), 0 critical, 4 high issues for “Sustained effect of prasinezumab on Parkinson's disease motor progression in the open-label extension of the PASADENA trial.”

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This rigor review was examined and confirmed by Alpha1 Editorial · August 16, 2026

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Sustained effect of prasinezumab on Parkinson's disease motor progression in the open-label extension of the PASADENA trial.

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DOI

10.1038/s41591-024-03270-6

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Sustained effect of prasinezumab on Parkinson's disease motor progression in the open-label extension of the PASADENA trial.

Paper source

Sustained effect of prasinezumab on Parkinson's disease motor progression in the open-label extension of the PASADENA trial.

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Links back to this Kaimen Rigor review.

Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 16, 2026

Kaimen Rigor review

Kaimen Rigor reviewed

2 / 5

Weak — serious problems found

Observational Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×2−1★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
LinksDead data/code link ×2−0.5★
ReportingStudy design partially met−0.25★
CitationsUnresolved reference−0.25★

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Not verified in this report

No reported statistical tests were found to recompute.
The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 10 reported means were read, and their group size is not stated where the values are printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy claim is based on MDS-UPDRS Part III and Part II scores, which are clinical rating scales, not biomarkers. However, the study uses an external comparator (PPMI) rather than a placebo control, and the analysis is exploratory. The paper does not demonstrate target engagement at the tested dose (e.g., PK/PD) nor cite validated evidence linking MDS-UPDRS changes to long-term clinical outcomes beyond the scale itself. The claim of sustained motor progression slowing relies on a surrogate endpoint (MDS-UPDRS) without establishing a validated link to hard clinical outcomes.
“The primary endpoints of this analysis were: change from baseline to year 4 in the severity of motor progression ... as measured by change in MDS–UPDRS Parts II and III in both ON and OFF state”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The reported effect sizes are relative differences in MDS-UPDRS scores (e.g., -51%, -65%, -94%, -118%) and absolute differences (e.g., -5.73, -7.26 points). While the paper mentions a within-patient worsening threshold of 5 points for MDS-UPDRS Part III OFF, the observed differences are presented as group differences and the clinical meaningfulness is not robustly anchored. The study is exploratory and lacks a placebo control, and the effect sizes are not explicitly compared to a minimal clinically important difference (MCID) for all endpoints.
“A within-patient worsening threshold of 5 points has been identified for MDS–UPDRS Part III OFF ... and thus the observed differences in change scores are meaningful.”
Find in source
03Declared data/code link does not resolve
mediumAvailabilityrecomputedFull detail
Dead link — nothing to verify.
“https://www.ppmi-info.org/access-dataspecimens/download-data”
Find in source
04Declared data/code link does not resolve
mediumAvailabilityrecomputedFull detail
Dead link — nothing to verify.
“http://www.ppmi-info.org/access-dataspecimens/download-data”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 302OverreachOverstated conclusions 103AuthenticityData authenticity concerns 104DisclosureReporting gaps 205AvailabilityBroken references and links 06Copyedit4 minor suggestions

This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.

The paper is a well-conducted observational comparison of an open-label extension with an external comparator, with strong reporting of methods, ethics, and data availability. The main weaknesses are the lack of a pre-specified analysis plan, no power analysis, and incomplete reporting of outlier handling and code sharing.

The reviewers disagreed on study type (observational vs. interventional); I adopted 'observational' because the primary analysis is a comparison of an OLE cohort with an external observational cohort, not a randomized intervention. The statistics verification component found no recomputable tests, so statistical correctness is not fully confirmed.

Numerical inconsistencies

1 finding · worst low

Values that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.

Internal contradictions in the reported numbersAssessed

Overstated conclusions

3 findings · worst high

Conclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.

Efficacy rests on an unvalidated surrogate endpointAssessed
Treatment effect not shown to be clinically meaningfulAssessed
Conclusions only partially backed by the presented evidenceAssessed

9 major claims checked against the paper's own evidence: 5 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.

Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.

Data authenticity concerns

1 finding · worst low

An adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.

Methods and results do not matchAssessed

2 integrity concerns flagged (0 high).

Reporting gaps

1 finding · worst medium

Required detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.

Study-design details incomplete (controls, blinding, power)Assessed

Eight Dimensions7 pass · 1 warn

The introduction cites prior studies on α-synuclein aggregation and the development of prasinezumab, including the PASADENA Phase II trial. It acknowledges that the primary endpoint was not met in the double-blind period but that motor progression was reduced. The rationale linking the premise to the study objectives is logical: to evaluate whether the effect on motor progression is sustained long-term. Limitations of prior research (e.g., lack of long-term data, placebo arm in OLE) are addressed in the discussion.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific premise based on prior work on alpha-synuclein and prasinezumab, and provides a logical rationale for the study.

Evidence

paraphrase[Introduction, paragraph 1]

“Prasinezumab is a humanized monoclonal antibody designed to bind aggregated α-synuclein and inhibit the intercellular spread of pathogenic α-synuclein, thus potentially protecting neurons and slowing Parkinson’s disease (PD) progression.”

paraphrase[Introduction, paragraph 2]

“The PPMI was used to put into context the rates of disease progression seen in the OLE of PASADENA, in the absence of a placebo group beyond PASADENA Part 1.”

paraphrase[Discussion, paragraph 2]

“Using a well-established method of propensity score balancing of baseline characteristics, we matched the trial and comparator groups.”

PASSReviewer 2· 95% conf

The paper clearly establishes the scientific premise by citing prior work on α-synuclein aggregation in Parkinson's disease and the rationale for immunotherapy, and acknowledges limitations of prior research.

Evidence

Introduction ¶1Find in source

paraphrase[Introduction, paragraph 2]

“In the double-blind study period (Part 1), the primary endpoint was not met (Movement Disorders Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS–UPDRS) sum of Parts I, II and III). However, prasinezumab-treated individuals (both low- and high-dose) showed less motor progression in MDS–UPDRS Part III than placebo-treated individuals.”

“A major limitation of the OLE is the lack of a placebo arm, and, for this reason, it is not possible to fully rule out a potential placebo effect as an explanation for the differences in progression between PASADENA participants and the PPMI cohort.”

Discussion ¶2Find in source

The original PASADENA trial was randomized and double-blind for Part 1, but the OLE is open-label. The present analysis uses an external comparator from PPMI, not a concurrent placebo group. Randomization method and unit are reported for the original trial but not for the OLE analysis. Blinding levels are not applicable for the OLE. No a priori power analysis is reported for this exploratory analysis. Inclusion/exclusion criteria are reported for both PASADENA and PPMI. Outlier handling is not explicitly described. Controls are not applicable as this is not a bench study. Independent replication is not reported.

Sub-criteria

controlsN/A

power analysisNOT REPORTED

blinding levelsN/A

outlier handlingNOT REPORTED

randomization unitINADEQUATE

inclusion exclusionADEQUATE

randomization methodINADEQUATE

replicate distinctionN/A

independent replicationNOT REPORTED

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 80% conf

The study design is appropriate for an observational comparison, but lacks a pre-specified analysis plan and has limitations in blinding and replication.

Evidence

“In PASADENA, key inclusion criteria included idiopathic PD with bradykinesia and one of the other cardinal signs of PD (resting tremor, rigidity) and no other known or suspected cause of PD; age 40‒80 years; dopamine transporter imaging with DaT–SPECT consistent with PD; diagnosis of PD for 2 years or less at screening; modified H&Y stage 1 or 2; and either treatment naive or on a stable dose of an MAO-B inhibitor for at least 90 days at baseline.”

MethodsFind in source

“Missing values were considered events (26 records in PPMI, 12 in PASADENA).”

MethodsFind in source

paraphrase[Discussion, paragraph 10]

“The PADOVA study ( NCT04777331 ) is an ongoing Phase IIb, multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of intravenous prasinezumab versus placebo in participants with early-stage PD.”

WARNReviewer 2· 85% conf

The study design is a secondary analysis of an open-label extension with an external comparator, lacking randomization and blinding for the OLE period. Power analysis is not reported, and the external comparator introduces potential biases.

Evidence

paraphrase[Methods, Study design]

“PASADENA (ClinicalTrials.gov identifier no. NCT03100149) is a randomized controlled trial evaluating prasinezumab in participants with early-stage PD”

absence[Methods]

No power analysis is reported for this exploratory analysis.

MethodsFind in source

Sex is reported as a baseline characteristic (Table 1). Age and health status (MDS-UPDRS scores, H&Y stage) are reported. Demographics including age, sex, education, and cognitive assessment are provided. Species/strain and housing conditions are not applicable for a human clinical trial.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Biological variables are adequately reported for this human observational study, including sex, age, and disease characteristics.

Evidence

paraphrase[Methods, Study population]

“Sex (male versus female) was considered in the study design as a baseline characteristic and was included as a variable in the covariate adjustment.”

“Age (years), mean (s.d.) | 59.98 (9.00) | 62.11 (8.53) | 0.243 | 59.98 (9.00) | 61.20 (9.28) | 0.133”

Table 1Find in source

“Years of education ≥12, n (%) | 244 (90.0) | 279 (92.1) | 0.072 | 244.0 (90.0) | 236.2 (87.5) | 0.080”

Table 1Find in source

PASSReviewer 2· 95% conf

Biological variables are adequately reported: sex, age, health status, and demographics are provided for both cohorts. Species/strain and housing conditions are not applicable as this is a human study.

Evidence

“Male sex, n (%) | 188 (69.4) | 202 (66.7) | 0.058 | 188.0 (69.4) | 189.3 (70.1) | 0.017”

Table 1Find in source

“Age (years), mean (s.d.) | 59.98 (9.00) | 62.11 (8.53) | 0.243 | 59.98 (9.00) | 61.20 (9.28) | 0.133”

Table 1Find in source

“Years of education ≥12, n (%) | 244 (90.0) | 279 (92.1) | 0.072 | 244.0 (90.0) | 236.2 (87.5) | 0.080”

Table 1Find in source

The paper states that the PASADENA protocol was approved by institutional review boards or ethics committees at each study site, and the trial was conducted according to the Declaration of Helsinki and Good Clinical Practice. All participants provided written informed consent. Similarly, the PPMI study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice with local ethics committee approval and informed consent.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Ethical approvals and consent are adequately reported for both PASADENA and PPMI studies.

Evidence

paraphrase[Methods, Ethics statement]

“In PASADENA, the protocol and recruitment materials used were approved by the institutional review boards or ethics committees at each study site.”

paraphrase[Methods, Ethics statement]

“All participants provided written informed consent before participation and for secondary data use.”

“The trial was conducted according to the principles of the Declaration of Helsinki and Good Clinical Practice guidelines.”

EthicsFind in source

PASSReviewer 2· 95% conf

Ethical approvals are adequately reported: both PASADENA and PPMI studies have ethics committee approval, informed consent, and regulatory compliance statements.

Evidence

paraphrase[Methods, Ethics statement]

“In PASADENA, the protocol and recruitment materials used were approved by the institutional review boards or ethics committees at each study site. The trial was conducted according to the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. All participants provided written informed consent before participation and for secondary data use.”

paraphrase[Methods, Ethics statement]

“Similarly, the PPMI study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines following approval by the local ethics committees of the participating sites, and all participants provided informed consent.”

Prasinezumab is identified as a humanized monoclonal antibody, and the manufacturer is implied (Roche). Statistical software is identified with versions. No antibodies, cell lines, or organisms are used in this clinical study.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Key resources are adequately identified, including the investigational product prasinezumab and statistical software.

Evidence

paraphrase[Introduction, paragraph 1]

“Prasinezumab is a humanized monoclonal antibody designed to bind aggregated α-synuclein.”

“All analyses were performed using SAS software v.9.04 and R v.4.0.3.”

MethodsFind in source

PASSReviewer 2· 90% conf

Key resources are adequately identified: the investigational product (prasinezumab) is named with manufacturer and dose, and software tools are identified with versions. Other resource types are not applicable.

Evidence

“Prasinezumab is a humanized monoclonal antibody designed to bind aggregated α-synuclein”

Introduction ¶1Find in source

“All analyses were performed using SAS software v.9.04 and R v.4.0.3.”

MethodsFind in source

“intravenous prasinezumab administered every 4 weeks in early-stage PD”

Introduction ¶2Find in source

The paper names statistical tests (MMRM, logistic regression, propensity score weighting). Effect sizes with 80% confidence intervals are reported throughout. Software is identified (SAS v.9.04, R v.4.0.3). Data presentation includes figures with error bars and per-group n. Assumptions verification is not explicitly reported but the use of MMRM with unstructured covariance handles some assumptions. Exact p-values are not reported; instead, the analysis uses estimation with confidence intervals, which is appropriate. Mathematical plausibility checks are not applicable for these continuous outcomes with large N.

Sub-criteria

tests namedADEQUATE

exact p valuesN/A

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedINADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 80% conf

Statistical methods are well described, with named tests, effect sizes with confidence intervals, and software identified.

Evidence

“A mixed model for repeated measures (MMRM) was used for the longitudinal endpoints including covariates: age, sex, education, bilateral putamen at baseline, the visit (as a categorical factor), a group-by-visit interaction and the baseline endpoint.”

MethodsFind in source

“with a −51% relative difference (mean (80% confidence interval (CI)), −5.73 (−7.33 to −4.14) points) for the delayed-start group”

Results ¶2Find in source

“All analyses were performed using SAS software v.9.04 and R v.4.0.3.”

MethodsFind in source

PASSReviewer 2· 90% conf

Statistical analysis is rigorous: tests are named, effect sizes with confidence intervals are reported, software is identified, and data presentation is adequate. Assumptions verification is handled by design, and exact p-values are not applicable as the analysis uses estimation with CIs.

Evidence

MethodsFind in source

“with a −51% relative difference (mean (80% confidence interval (CI)), −5.73 (−7.33 to −4.14) points) for the delayed-start group”

Results ¶1Find in source

“All analyses were performed using SAS software v.9.04 and R v.4.0.3.”

MethodsFind in source

The paper provides a data availability statement with concrete access routes: PASADENA data via Vivli platform, PPMI data via the PPMI database, and a figshare dataset (DOI provided). This meets the criteria for adequate reporting. Repository deposit and accession numbers are not applicable for patient-level clinical trial data. Code sharing is not reported, but the paper does not describe custom code beyond standard statistical software.

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositADEQUATE

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Data availability is well documented with a clear access route for PASADENA data and a figshare deposit for generated datasets.

Evidence

“Qualified researchers may request access to individual patient-level data through the clinical study data request platform ( https://vivli.org/ ).”

Data availabilityFind in source

paraphrase[Data availability]

“The datasets generated and analyzed that support the conclusions of this study are available via figshare at 10.6084/m9.figshare.25541221.”

paraphrase[Data availability]

“PPMI data used in the preparation of this article were obtained (in September 2022) from the PPMI database ( www.ppmi-info.org/access-dataspecimens/download-data ).”

PASSReviewer 2· 95% conf

Data availability is adequately reported: PASADENA data are available via a managed-access platform (Vivli), PPMI data are publicly accessible, and a figshare dataset is provided. Code sharing is not applicable as no custom code is mentioned.

Evidence

paraphrase[Data availability]

“Qualified researchers may request access to individual patient-level data through the clinical study data request platform (https://vivli.org/).”

paraphrase[Data availability]

“PPMI data used in the preparation of this article were obtained (in September 2022) from the PPMI database (www.ppmi-info.org/access-dataspecimens/download-data), RRID:SCR 006431.”

“The datasets generated and analyzed that support the conclusions of this study are available via figshare at 10.6084/m9.figshare.25541221”

Data availabilityFind in source

Methods are detailed enough for replication. The trial is registered (NCT03100149). A reporting summary is linked. All outcomes are reported, including null results (e.g., DaT-SPECT, MDS-UPDRS Part IV). Limitations are extensively discussed. Conclusions are proportional, noting the exploratory nature and need for confirmation. Funding sources and competing interests are disclosed.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Reporting is transparent with a detailed methods section, limitations discussed, and funding/COI statements provided.

Evidence

“PASADENA ClinicalTrials.gov no. NCT03100149”

AbstractFind in source

“We identified several limitations in this exploratory analysis.”

Discussion ¶9Find in source

“The study is sponsored by F. Hoffmann-La Roche Ltd.”

AcknowledgementsFind in source

PASSReviewer 2· 95% conf

Reporting transparency is high: methods are detailed, the trial is registered, limitations are discussed, conclusions are proportional, and funding/COI are disclosed. A reporting guideline is referenced.

Evidence

paraphrase[Abstract]

“PASADENA ClinicalTrials.gov no. NCT03100149 (https://clinicaltrials.gov/ct2/show/NCT03100149).”

“We identified several limitations in this exploratory analysis. Some of these are related to potential differences between the external observational PPMI cohort and PASADENA participants.”

Discussion ¶8Find in source

“This exploratory analysis, which requires confirmation in future studies, suggested that the effect of prasinezumab in slowing motor progression in PD may be sustained long term.”

AbstractFind in source

Registered (2 IDs: ClinicalTrials.gov). No reporting guideline cited.

Broken references and links

2 findings · worst medium

References checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.

Dead data/code linksRecomputed
References not resolvable to a published paperRecomputed

Checked 29 references by DOI: 25 verified — 1 DOI unresolved, 3 no DOI (shown, not verified).

7 data/code links checked; 5 live, 2 dead.

Copyediting

4 minor

Wording, consistency and formatting errors that need correcting before submission.

No major wording or formatting errors. 4 minor suggestions below.

4 copyedit issues flagged: mostly typo, consistency.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust in its reporting and transparency, but readers should weigh the lack of a pre-specified analysis plan and the potential for residual confounding in the external comparator design. The minor copyedit issues and dead links should be corrected in any revision or erratum.

1.
HIGHrigor
Add a pre-specified statistical analysis plan (SAP) to the Methods, including a power analysis or justification for not performing one.
The absence of a pre-specified plan and power analysis weakens the study design and could be a reviewer concern.
2.
HIGHrigor
Explicitly describe outlier handling procedures in the Methods, including criteria for defining outliers and sensitivity analyses excluding them.
Outlier handling is not reported, which is a gap in the analysis description.
3.
HIGHdata code
Add a statement on code availability, including scripts for propensity score weighting and disease modeling, in a public repository.
Code sharing is not reported, which limits reproducibility.
4.
HIGHdata code
Fix the two dead links identified in the reproducibility check (in the Data availability section).
Dead links undermine the data availability statement and could prevent readers from accessing the data.
5.
MEDIUMreporting
Clarify the handling of missing data for all endpoints, not just the H&Y analysis, and describe imputation methods if used.
Missing data handling is only described for one endpoint, which is incomplete.
6.
MEDIUMrigor
Discuss the potential for unmeasured confounding in the external comparator design and how propensity score weighting addresses it.
The external comparator design is prone to residual confounding, and this should be explicitly addressed.
7.
MEDIUMrigor
Include a sensitivity analysis using alternative propensity score methods (e.g., matching) to confirm robustness.
Sensitivity analyses would strengthen the conclusions.
8.
MEDIUMreporting
Report the number of participants with complete data for each endpoint to assess potential attrition bias.
Attrition bias is a concern in longitudinal studies, and reporting completeness would help assess it.
9.
MEDIUMstatistics
Add a brief statement on assumptions verification for the MMRM (e.g., normality of residuals, homoscedasticity) in the Methods.
Assumptions verification is not explicitly reported, which is a minor gap.
10.
MEDIUMreporting
Clarify the definition of 'OFF state' for MDS-UPDRS Part III assessments in both cohorts to ensure comparability.
Inconsistent definitions could affect the comparability of the cohorts.
11.
LOWcopyedit
Fix the typo 'Pakinson’s' to 'Parkinson’s' in the Introduction (two occurrences).
Typos in the expansion of PASADENA are minor but should be corrected.
12.
LOWcopyedit
Clarify the R version used in the Methods: the paper mentions both v.4.0.3 and v.4.2.2.
Inconsistent software versions could confuse readers about the exact analysis environment.

Full text (55,251 chars)Analyzed: Aug 16, 2026

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Sustained effect of prasinezumab on Parkinson's disease motor progression in the open-label extension of the PASADENA trial.

Read full text (PMC)

DOI

10.1038/s41591-024-03270-6

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Record fingerprint

ba8168836d2b1892ec2f2416ae3de7c281da39126d8a6bd1c97a16d4c083ba48

Verify via API

Issued Aug 16, 2026Engine 7.39.0

Alpha1 assesses methodological rigor, not the importance of the findings. See how we calibrate →

Kaimen Rigor review

Kaimen Rigor reviewed

2 / 5

Weak — serious problems found

Observational Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×2−1★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
LinksDead data/code link ×2−0.5★
ReportingStudy design partially met−0.25★
CitationsUnresolved reference−0.25★

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Not verified in this report

No reported statistical tests were found to recompute.
The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 10 reported means were read, and their group size is not stated where the values are printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy claim is based on MDS-UPDRS Part III and Part II scores, which are clinical rating scales, not biomarkers. However, the study uses an external comparator (PPMI) rather than a placebo control, and the analysis is exploratory. The paper does not demonstrate target engagement at the tested dose (e.g., PK/PD) nor cite validated evidence linking MDS-UPDRS changes to long-term clinical outcomes beyond the scale itself. The claim of sustained motor progression slowing relies on a surrogate endpoint (MDS-UPDRS) without establishing a validated link to hard clinical outcomes.
“The primary endpoints of this analysis were: change from baseline to year 4 in the severity of motor progression ... as measured by change in MDS–UPDRS Parts II and III in both ON and OFF state”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The reported effect sizes are relative differences in MDS-UPDRS scores (e.g., -51%, -65%, -94%, -118%) and absolute differences (e.g., -5.73, -7.26 points). While the paper mentions a within-patient worsening threshold of 5 points for MDS-UPDRS Part III OFF, the observed differences are presented as group differences and the clinical meaningfulness is not robustly anchored. The study is exploratory and lacks a placebo control, and the effect sizes are not explicitly compared to a minimal clinically important difference (MCID) for all endpoints.
“A within-patient worsening threshold of 5 points has been identified for MDS–UPDRS Part III OFF ... and thus the observed differences in change scores are meaningful.”
Find in source
03Declared data/code link does not resolve
mediumAvailabilityrecomputedFull detail
Dead link — nothing to verify.
“https://www.ppmi-info.org/access-dataspecimens/download-data”
Find in source
04Declared data/code link does not resolve
mediumAvailabilityrecomputedFull detail
Dead link — nothing to verify.
“http://www.ppmi-info.org/access-dataspecimens/download-data”
Find in source

Findings by category

Numerical inconsistencies

1 finding · worst low

Internal contradictions in the reported numbersAssessed

Overstated conclusions

3 findings · worst high

Efficacy rests on an unvalidated surrogate endpointAssessed
Treatment effect not shown to be clinically meaningfulAssessed
Conclusions only partially backed by the presented evidenceAssessed

9 major claims checked against the paper's own evidence: 5 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.

Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.

Data authenticity concerns

1 finding · worst low

Methods and results do not matchAssessed

2 integrity concerns flagged (0 high).

Reporting gaps

1 finding · worst medium

Study-design details incomplete (controls, blinding, power)Assessed

Eight Dimensions7 pass · 1 warn

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific premise based on prior work on alpha-synuclein and prasinezumab, and provides a logical rationale for the study.

Evidence

paraphrase[Introduction, paragraph 1]

paraphrase[Introduction, paragraph 2]

“The PPMI was used to put into context the rates of disease progression seen in the OLE of PASADENA, in the absence of a placebo group beyond PASADENA Part 1.”

paraphrase[Discussion, paragraph 2]

“Using a well-established method of propensity score balancing of baseline characteristics, we matched the trial and comparator groups.”

PASSReviewer 2· 95% conf

Evidence

Introduction ¶1Find in source

paraphrase[Introduction, paragraph 2]

Discussion ¶2Find in source

Sub-criteria

controlsN/A

power analysisNOT REPORTED

blinding levelsN/A

outlier handlingNOT REPORTED

randomization unitINADEQUATE

inclusion exclusionADEQUATE

randomization methodINADEQUATE

replicate distinctionN/A

independent replicationNOT REPORTED

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 80% conf

The study design is appropriate for an observational comparison, but lacks a pre-specified analysis plan and has limitations in blinding and replication.

Evidence

MethodsFind in source

“Missing values were considered events (26 records in PPMI, 12 in PASADENA).”

MethodsFind in source

paraphrase[Discussion, paragraph 10]

WARNReviewer 2· 85% conf

Evidence

paraphrase[Methods, Study design]

“PASADENA (ClinicalTrials.gov identifier no. NCT03100149) is a randomized controlled trial evaluating prasinezumab in participants with early-stage PD”

absence[Methods]

No power analysis is reported for this exploratory analysis.

MethodsFind in source

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Biological variables are adequately reported for this human observational study, including sex, age, and disease characteristics.

Evidence

paraphrase[Methods, Study population]

“Sex (male versus female) was considered in the study design as a baseline characteristic and was included as a variable in the covariate adjustment.”

“Age (years), mean (s.d.) | 59.98 (9.00) | 62.11 (8.53) | 0.243 | 59.98 (9.00) | 61.20 (9.28) | 0.133”

Table 1Find in source

“Years of education ≥12, n (%) | 244 (90.0) | 279 (92.1) | 0.072 | 244.0 (90.0) | 236.2 (87.5) | 0.080”

Table 1Find in source

PASSReviewer 2· 95% conf

Evidence

“Male sex, n (%) | 188 (69.4) | 202 (66.7) | 0.058 | 188.0 (69.4) | 189.3 (70.1) | 0.017”

Table 1Find in source

“Age (years), mean (s.d.) | 59.98 (9.00) | 62.11 (8.53) | 0.243 | 59.98 (9.00) | 61.20 (9.28) | 0.133”

Table 1Find in source

“Years of education ≥12, n (%) | 244 (90.0) | 279 (92.1) | 0.072 | 244.0 (90.0) | 236.2 (87.5) | 0.080”

Table 1Find in source

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Ethical approvals and consent are adequately reported for both PASADENA and PPMI studies.

Evidence

paraphrase[Methods, Ethics statement]

“In PASADENA, the protocol and recruitment materials used were approved by the institutional review boards or ethics committees at each study site.”

paraphrase[Methods, Ethics statement]

“All participants provided written informed consent before participation and for secondary data use.”

“The trial was conducted according to the principles of the Declaration of Helsinki and Good Clinical Practice guidelines.”

EthicsFind in source

PASSReviewer 2· 95% conf

Ethical approvals are adequately reported: both PASADENA and PPMI studies have ethics committee approval, informed consent, and regulatory compliance statements.

Evidence

paraphrase[Methods, Ethics statement]

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Key resources are adequately identified, including the investigational product prasinezumab and statistical software.

Evidence

paraphrase[Introduction, paragraph 1]

“Prasinezumab is a humanized monoclonal antibody designed to bind aggregated α-synuclein.”

“All analyses were performed using SAS software v.9.04 and R v.4.0.3.”

MethodsFind in source

PASSReviewer 2· 90% conf

Evidence

“Prasinezumab is a humanized monoclonal antibody designed to bind aggregated α-synuclein”

Introduction ¶1Find in source

“All analyses were performed using SAS software v.9.04 and R v.4.0.3.”

MethodsFind in source

“intravenous prasinezumab administered every 4 weeks in early-stage PD”

Introduction ¶2Find in source

Sub-criteria

tests namedADEQUATE

exact p valuesN/A

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedINADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 80% conf

Statistical methods are well described, with named tests, effect sizes with confidence intervals, and software identified.

Evidence

MethodsFind in source

“with a −51% relative difference (mean (80% confidence interval (CI)), −5.73 (−7.33 to −4.14) points) for the delayed-start group”

Results ¶2Find in source

“All analyses were performed using SAS software v.9.04 and R v.4.0.3.”

MethodsFind in source

PASSReviewer 2· 90% conf

Evidence

MethodsFind in source

“with a −51% relative difference (mean (80% confidence interval (CI)), −5.73 (−7.33 to −4.14) points) for the delayed-start group”

Results ¶1Find in source

“All analyses were performed using SAS software v.9.04 and R v.4.0.3.”

MethodsFind in source

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositADEQUATE

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Data availability is well documented with a clear access route for PASADENA data and a figshare deposit for generated datasets.

Evidence

“Qualified researchers may request access to individual patient-level data through the clinical study data request platform ( https://vivli.org/ ).”

Data availabilityFind in source

paraphrase[Data availability]

“The datasets generated and analyzed that support the conclusions of this study are available via figshare at 10.6084/m9.figshare.25541221.”

paraphrase[Data availability]

“PPMI data used in the preparation of this article were obtained (in September 2022) from the PPMI database ( www.ppmi-info.org/access-dataspecimens/download-data ).”

PASSReviewer 2· 95% conf

Evidence

paraphrase[Data availability]

“Qualified researchers may request access to individual patient-level data through the clinical study data request platform (https://vivli.org/).”

paraphrase[Data availability]

“PPMI data used in the preparation of this article were obtained (in September 2022) from the PPMI database (www.ppmi-info.org/access-dataspecimens/download-data), RRID:SCR 006431.”

“The datasets generated and analyzed that support the conclusions of this study are available via figshare at 10.6084/m9.figshare.25541221”

Data availabilityFind in source

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Reporting is transparent with a detailed methods section, limitations discussed, and funding/COI statements provided.

Evidence

“PASADENA ClinicalTrials.gov no. NCT03100149”

AbstractFind in source

“We identified several limitations in this exploratory analysis.”

Discussion ¶9Find in source

“The study is sponsored by F. Hoffmann-La Roche Ltd.”

AcknowledgementsFind in source

PASSReviewer 2· 95% conf

Evidence

paraphrase[Abstract]

“PASADENA ClinicalTrials.gov no. NCT03100149 (https://clinicaltrials.gov/ct2/show/NCT03100149).”

“We identified several limitations in this exploratory analysis. Some of these are related to potential differences between the external observational PPMI cohort and PASADENA participants.”

Discussion ¶8Find in source

“This exploratory analysis, which requires confirmation in future studies, suggested that the effect of prasinezumab in slowing motor progression in PD may be sustained long term.”

AbstractFind in source

Registered (2 IDs: ClinicalTrials.gov). No reporting guideline cited.

Broken references and links

2 findings · worst medium

References checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.

Dead data/code linksRecomputed
References not resolvable to a published paperRecomputed

Checked 29 references by DOI: 25 verified — 1 DOI unresolved, 3 no DOI (shown, not verified).

7 data/code links checked; 5 live, 2 dead.

Copyediting

4 minor

Wording, consistency and formatting errors that need correcting before submission.

No major wording or formatting errors. 4 minor suggestions below.

4 copyedit issues flagged: mostly typo, consistency.

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHrigor
Add a pre-specified statistical analysis plan (SAP) to the Methods, including a power analysis or justification for not performing one.
The absence of a pre-specified plan and power analysis weakens the study design and could be a reviewer concern.
2.
HIGHrigor
Explicitly describe outlier handling procedures in the Methods, including criteria for defining outliers and sensitivity analyses excluding them.
Outlier handling is not reported, which is a gap in the analysis description.
3.
HIGHdata code
Add a statement on code availability, including scripts for propensity score weighting and disease modeling, in a public repository.
Code sharing is not reported, which limits reproducibility.
4.
HIGHdata code
Fix the two dead links identified in the reproducibility check (in the Data availability section).
Dead links undermine the data availability statement and could prevent readers from accessing the data.
5.
MEDIUMreporting
Clarify the handling of missing data for all endpoints, not just the H&Y analysis, and describe imputation methods if used.
Missing data handling is only described for one endpoint, which is incomplete.
6.
MEDIUMrigor
Discuss the potential for unmeasured confounding in the external comparator design and how propensity score weighting addresses it.
The external comparator design is prone to residual confounding, and this should be explicitly addressed.
7.
MEDIUMrigor
Include a sensitivity analysis using alternative propensity score methods (e.g., matching) to confirm robustness.
Sensitivity analyses would strengthen the conclusions.
8.
MEDIUMreporting
Report the number of participants with complete data for each endpoint to assess potential attrition bias.
Attrition bias is a concern in longitudinal studies, and reporting completeness would help assess it.
9.
MEDIUMstatistics
Add a brief statement on assumptions verification for the MMRM (e.g., normality of residuals, homoscedasticity) in the Methods.
Assumptions verification is not explicitly reported, which is a minor gap.
10.
MEDIUMreporting
Clarify the definition of 'OFF state' for MDS-UPDRS Part III assessments in both cohorts to ensure comparability.
Inconsistent definitions could affect the comparability of the cohorts.
11.
LOWcopyedit
Fix the typo 'Pakinson’s' to 'Parkinson’s' in the Introduction (two occurrences).
Typos in the expansion of PASADENA are minor but should be corrected.
12.
LOWcopyedit
Clarify the R version used in the Methods: the paper mentions both v.4.0.3 and v.4.2.2.
Inconsistent software versions could confuse readers about the exact analysis environment.

Full text (55,251 chars)Analyzed: Aug 16, 2026