Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Intracerebroventricular anaerobic dopamine in Parkinson's disease with L-dopa-related complications: a phase 1/2 randomized-controlled trial.

Name: Kaimen Rigor review — Intracerebroventricular anaerobic dopamine in Parkinson's disease with L-dopa-related complications: a phase 1/2 randomized-controlled trial.
Item: Intracerebroventricular anaerobic dopamine in Parkinson's disease with L-dopa-related complications: a phase 1/2 randomized-controlled trial.
Rating: 59
Author: Alpha1

Moreau C, Odou P, Labreuche J, Demailly A, Touzet G, Reyns N, Gouges B, Duhamel A, Barthelemy C, Lannoy D, Carta N, Palas B, Vasseur M, Marchand F, Ollivier T, Leclercq C, Potey C, Ouk T, Baigne S, Dujardin K, Carton L, Rolland AS, Devedjian JC, Foutel V, Deplanque D, Fisichella M, Devos D

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Kaimen Rigor review — 1.75★ (Critical), 0 critical, 5 high issues for “Intracerebroventricular anaerobic dopamine in Parkinson's disease with L-dopa-related complications: a phase 1/2 randomized-controlled trial.”

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

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Intracerebroventricular anaerobic dopamine in Parkinson's disease with L-dopa-related complications: a phase 1/2 randomized-controlled trial.

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DOI

10.1038/s41591-024-03428-2

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Intracerebroventricular anaerobic dopamine in Parkinson's disease with L-dopa-related complications: a phase 1/2 randomized-controlled trial.

Paper source

Intracerebroventricular anaerobic dopamine in Parkinson's disease with L-dopa-related complications: a phase 1/2 randomized-controlled trial.

Read full text (PMC)

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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

1.75 / 5

Critical — serious problems across many checks

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×3−1.5★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
ReportingStudy design partially met−0.25★
ReportingStatistical analysis partially met−0.25★
ReportingData & code availability partially met−0.25★

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

Not verified in this report

Statistics were not checked: no recomputable values were found in this text — no test statistic reported with its degrees of freedom, no effect estimate printed with both a 95% CI and a p-value, and no percentage printed with both its count and its denominator.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy endpoint is the percentage over total target (time with dyskinesia or bradykinesia) recorded by actimetry, which is a surrogate/behavioral proxy for clinical benefit. The paper does not provide evidence of target engagement at the tested dose (e.g., PK/PD or dose-exposure relationship) nor does it cite validated evidence linking this actimetry-based surrogate to a hard clinical outcome. The claim of efficacy rests on this surrogate without such validation.
“The primary endpoint, a blinded assessment of the percentage over target (that is, time with dyskinesia or bradykinesia), recorded by home actimetry using a wristwatch, was significantly reduced on A-dopamine compared with that on oral treatment alone ( P =…”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The primary effect size is a median within-patient difference of -10.4 percentage points (Hedge's g = -0.62), which is presented without an anchor to a minimal clinically important difference or to clinical meaningfulness. The paper acknowledges that the clinical interpretation of the primary endpoint is not obvious, and the effect is not explicitly anchored as clinically material.
“with a median within-patient difference of −10.4 (Hedge g = −0.62 (95% confidence interval: −1.43, −0.08))”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 302OverreachOverstated conclusions 103AuthenticityData authenticity concerns 304DisclosureReporting gaps 05AvailabilityNone found 06Copyedit5 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 phase 1/2 crossover trial with a clear scientific premise, strong ethical approvals, and transparent reporting. The main weaknesses are the revised sample size without formal recalculation, partial blinding, vague data/code availability, and minor statistical reporting issues.

Both reviewers classified the study as interventional and agreed on all dimension statuses; no divergence to reconcile. The statistics component could not verify any tests due to lack of test statistics/df, and the GRIM/GRIMMER checks were not applicable to continuous data.

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: 2 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

3 integrity concerns flagged (0 high).

Reporting gaps

3 findings · worst high

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.

Statistical reporting gaps (tests, assumptions, effect sizes)Assessed
Data/code availability incompleteAssessed
Study-design details incomplete (controls, blinding, power)Assessed

Eight Dimensions5 pass · 3 warn

The introduction cites prior studies on dopamine deficiency in PD, limitations of current treatments, and previous attempts at i.c.v. dopamine administration. It acknowledges the strengths and weaknesses of prior work, including the historical failure due to dopamine oxidation. The rationale for A-dopamine is logically derived from these limitations, and the study objectives follow directly.

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 with extensive prior work cited and a logical rationale for the study.

Evidence

paraphrase[Introduction, paragraph 1]

“A loss of dopamine in the striatum, as a result of progressive neuronal degeneration in the substantia nigra pars compacta (SNpc), is the primary neurotransmitter marker of Parkinson’s disease (PD).”

“To meet the challenge of dopamine biodistribution and oxidation, a novel concept of continuous i.c.v. administration of an anaerobic dopamine formulation (A-dopamine) has been developed”

Introduction ¶3Find in source

paraphrase[Introduction, paragraph 2]

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise with extensive prior work and a logical rationale for the study.

Evidence

paraphrase[Introduction, paragraph 2]

“In the 1980s, a pilot preclinical study on two rat and monkey PD models and two independent clinical cases, showed that intracerebroventricular (i.c.v.) administration of dopamine improved motor symptoms, but also resulted in tachyphylaxia, possibly owing to dopamine oxidation despite the use of a preservative solution (sodium metabisulfite), precluding the therapeutic development of this concept.”

paraphrase[Introduction, paragraph 3]

“To meet the challenge of dopamine biodistribution and oxidation, a novel concept of continuous i.c.v. administration of an anaerobic dopamine formulation (A-dopamine) has been developed using a telemetry-controlled subcutaneous abdominal pump connected to a subcutaneous catheter implanted in the third ventricle, near the striatum.”

paraphrase[Introduction, paragraph 2]

“A-dopamine has been shown to be safe and effective in two rodent models of PD and in a chronic non-human primate model of PD.”

Randomization method is described (SAS-generated random numbers, concealed allocation). Blinding is partial: primary endpoint analysis blinded, but other outcomes open-label. Power analysis was initially for 20 patients but revised to 12 without a formal recalculation. Inclusion/exclusion criteria are detailed. Outlier handling is addressed through per-protocol analysis excluding non-compliant weeks. Controls are inherent in the crossover design (oral treatment). Independent replication is not applicable for a single trial.

Sub-criteria

controlsADEQUATE

power analysisINADEQUATE

blinding levelsINADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 85% conf

The study design is a randomized crossover trial with adequate randomization and blinding of the primary endpoint, but lacks a pre-specified power analysis for the revised sample size and has incomplete reporting of inclusion/exclusion criteria.

Evidence

“Randomization sequence was created using a random number generated by the SAS 9.4 software in the Lille University Hospital biostatistics department.”

MethodsFind in source

“The analysis of actimetry parameters, and in particular the primary endpoint, was blinded to patients and investigators.”

MethodsFind in source

“The sample size was revised on 23 February 2023 following an amendment regarding the ability of the central pharmacy of Lille University Hospital to ensure the weekly production of A-dopamine under safe conditions for a maximum of 12 patients.”

MethodsFind in source

WARNReviewer 2· 85% conf

The study design is a randomized crossover trial with adequate randomization and blinding of the primary endpoint, but the sample size was revised downward and the open-label design for secondary endpoints is a limitation.

Evidence

“Randomization sequence was created using a random number generated by the SAS 9.4 software in the Lille University Hospital biostatistics department.”

MethodsFind in source

“The analysis of actimetry parameters, and in particular the primary endpoint, was blinded to patients and investigators. Other parameters were analyzed openly for patients and investigators.”

MethodsFind in source

Sex is reported (9 male, 3 female). Age and health status are reported in baseline characteristics. Demographics include age, sex, and disease-related measures. Species/strain and housing conditions are not applicable for a human 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 well reported for a human trial, including sex, age, disease duration, and other clinical characteristics.

Evidence

“The median age was 60.8 years (range: 53–69 years) and 9 patients were male (75.0%).”

ResultsFind in source

“Since diagnosis, the median (range) duration of the disease, motor fluctuations and dyskinesia was 7.9 years (3.7–12.2 years), 4.3 years (1.2–8.3 years) and 2.4 years (0.2–5.3 years), respectively”

ResultsFind in source

PASSReviewer 2· 90% conf

Biological variables are well reported for this human study, including sex, age, and detailed clinical characteristics.

Evidence

“The median age was 60.8 years (range: 53–69 years) and 9 patients were male (75.0%).”

Table 1Find in source

paraphrase[Table 1]

“Body mass index (kg m−2) | 20 | 30 | 26 | 21 | 25 | 18 | 23 | 26 | 24 | 28 | 24 | 28 | 24.4 | 24.7 (18; 29.9)”

The study was approved by a named ethics committee (French Ethics Committee of Amiens) with protocol numbers. Written informed consent was obtained from all participants. Compliance with ICH-GCP and Declaration of Helsinki is stated.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approvals and consent are adequately reported.

Evidence

“The study was approved by the local independent ethics committee in 2020 (trial registration: protocol identifier: 2018_49; French Ethics Committee of Amiens: 2020-000155-12; French Drug Agency: MEDAECPP-2020-04-00002; ClinicalTrials.gov identifier: NCT04332276”

MethodsFind in source

“All participants provided written informed consent before screening”

MethodsFind in source

“The trial was conducted in accordance with the International Council for Harmonization Good Clinical Practice guidelines and the ethical principles of the Declaration of Helsinki.”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approvals and consent are clearly documented with named bodies and protocol numbers.

Evidence

MethodsFind in source

“All participants provided written informed consent before screening, including knowledge of the plan to withhold dopaminergic medication unless necessary.”

MethodsFind in source

“The trial was conducted in accordance with the International Council for Harmonization Good Clinical Practice guidelines and the ethical principles of the Declaration of Helsinki.”

MethodsFind in source

The investigational product (A-dopamine) is described with formulation details. The pump (Prometra II Flowonix) and catheter are named with manufacturers. Software used for randomization and analysis is identified. Antibodies, cell lines, and mycoplasma testing are not applicable.

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· 85% conf

Key resources, including the investigational product and devices, are adequately identified.

Evidence

“A-dopamine was formulated as a solution of dopamine hydrochloride (2, 10, 50 and 100 mg ml −1 ) dissolved in sodium chloride (0.9%) and sterile water for injection in a sterile anaerobic isolator”

MethodsFind in source

“The catheter (Flowonix) implantation procedure through the right frontal horn into the third ventricle was performed by the neurosurgical team, with stereotactic placement of the catheter guided by Renishaw’s Neuro Mate robot.”

MethodsFind in source

“All data were analyzed using the SAS software package, release 9.4 (SAS Institute), or using R software (R version 4.1.2).”

Statistical analysisFind in source

PASSReviewer 2· 85% conf

Key resources, including the investigational product and devices, are adequately identified.

Evidence

paraphrase[Methods, A-dopamine preparation]

“A-dopamine was formulated as a solution of dopamine hydrochloride (2, 10, 50 and 100 mg ml−1) dissolved in sodium chloride (0.9%) and sterile water for injection in a sterile anaerobic isolator”

MethodsFind in source

“All data were analyzed using the SAS software package, release 9.4 (SAS Institute), or using R software (R version 4.1.2).”

Statistical analysisFind in source

The primary test (Wilcoxon signed-rank) is named. Effect sizes with CIs are reported for primary and secondary outcomes. However, many secondary outcomes report only effect sizes and CIs without p-values, which is acceptable per estimation approach, but some p-values are reported as thresholds (e.g., P = 0.027 is exact). Software is identified. Data presentation includes individual data in extended tables. Mathematical plausibility checks were not fully verifiable due to limited raw data.

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedINADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 80% conf

Statistical methods are generally sound, but there are issues with exact p-value reporting and some effect sizes lack p-values.

Evidence

“The primary outcome was compared between the two treatments using a paired Wilcoxon signed-rank test (performed on the intra-patient differences).”

Statistical analysisFind in source

“The A-dopamine effect size (standardized difference) was medium (Hedge’s g = −0.62 (95% confidence interval (CI): −1.43, −0.08)).”

ResultsFind in source

“No statistical tests of comparisons were done for secondary and exploratory outcomes; only a descriptive analysis and an estimation of effect sizes are reported.”

Statistical analysisFind in source

WARNReviewer 2· 80% conf

Statistical methods are appropriate and well-described, but the primary analysis excluded ~30% of evaluation weeks, and some p-values are reported as thresholds.

Evidence

“The primary outcome was compared between the two treatments using a paired Wilcoxon signed-rank test (performed on the intra-patient differences).”

Statistical analysisFind in source

paraphrase[Results, Efficacy outcomes]

“the percentage over total target ... was significantly reduced under A-dopamine when compared with oral treatment alone (P = 0.027)”

paraphrase[Table 3]

“Hedge’s g = −0.62 (95% CI: −1.43, −0.08)”

The data availability statement says data will be available on reasonable request with a review committee, but lacks specific conditions and timeframe. No repository deposit or accession numbers are provided. Code availability is not mentioned.

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositNOT REPORTED

data availability statementINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 85% conf

Data availability is stated but the access route is vague; code availability is not reported.

Evidence

“The data supporting the results will also be available on reasonable request from the corresponding author and C.M. (caroline.moreau@chu-lille.fr).”

Data availabilityFind in source

“Statistical analyses were carried out independently by A. Duhamel and J.L. at the Lille University Hospital Biostatistics Department.”

Data availabilityFind in source

WARNReviewer 2· 80% conf

Data availability is stated with a managed-access procedure, but no code is shared and the statement is somewhat vague.

Evidence

“The data supporting the results will also be available on reasonable request from the corresponding author and C.M. (caroline.moreau@chu-lille.fr). Researchers should submit a request for access to pseudoanonymous patient-level clinical data, aggregated clinical data or anonymized clinical study documents.”

Data availabilityFind in source

“Statistical analyses were carried out independently by A. Duhamel and J.L. at the Lille University Hospital Biostatistics Department.”

Data availabilityFind in source

The trial is registered (NCT04332276). Methods are detailed. Limitations are discussed extensively. Conclusions are proportional. Funding and COI are disclosed. Reporting guideline (SPIRIT) is mentioned for the protocol.

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 trial registration, detailed methods, and discussion of limitations.

Evidence

“ClinicalTrials.gov registration: NCT04332276”

AbstractFind in source

“However, this is a proof-of-concept study with several limitations that need to be discussed.”

Discussion ¶4Find in source

“The study was funded by InBrain Pharma, France, a spin-off of the research academic team UMR-S 1172”

AcknowledgementsFind in source

PASSReviewer 2· 90% conf

The manuscript is transparent with detailed methods, trial registration, and discussion of limitations.

Evidence

“ClinicalTrials.gov registration: NCT04332276”

AbstractFind in source

“However, this is a proof-of-concept study with several limitations that need to be discussed. Firstly, the number of patients involved was limited.”

Discussion ¶4Find in source

“The study was funded by InBrain Pharma, France, a spin-off of the research academic team UMR-S 1172 (University of Lille, INSERM, University Hospital of Lille), which delegated the promotion of the study to the University Hospital of Lille, France.”

AcknowledgementsFind in source

Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.

Broken references and links

None found

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.

Checked — nothing surfaced.

Checked 34 references by DOI: 34 verified.

2 data/code links checked; 2 live.

Copyediting

5 minor

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

No major wording or formatting errors. 5 minor suggestions below.

5 copyedit issues flagged: mostly consistency, typo, clarity.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is methodologically sound but has several reporting gaps that an informed reader should weigh: the sample size revision without recalculation, partial blinding, and vague data/code availability. These do not invalidate the findings but warrant caution and would benefit from a correction or clarification.

1.
HIGHrigor
Add a formal sample size recalculation for the revised 12-patient target, including assumptions for effect size and power, in the Methods section.
The sample size was revised without a formal recalculation, which is a major methodological gap that could affect the interpretation of the primary endpoint.
2.
HIGHreporting
Clarify the blinding status for secondary outcomes and justify the open-label design for those measures in the Methods.
The open-label design for secondary outcomes is a potential source of bias that should be explicitly acknowledged and justified.
3.
HIGHstatistics
Report exact p-values for all secondary outcomes where hypothesis tests are performed, or explicitly state that only effect sizes are reported.
Threshold-only p-values and missing p-values for secondary outcomes reduce transparency and hinder interpretation.
4.
HIGHdata code
Enhance the data availability statement to include a specific access mechanism, conditions, and expected timeframe for data requests.
The current 'on reasonable request' statement is vague and does not meet modern data-sharing expectations.
5.
HIGHdata code
Add a code availability statement, even if stating that no custom code was used, in the Code availability section.
Lack of code sharing hinders reproducibility and is a common reviewer concern.
6.
MEDIUMstatistics
Include a statement on whether assumptions for the Wilcoxon test (e.g., symmetry of differences) were checked, in the Statistical analyses section.
Verifying assumptions strengthens the statistical analysis and addresses a reviewer concern.
7.
MEDIUMreporting
Consider depositing de-identified individual patient data in a repository like Vivli or YODA to improve data accessibility.
Repository deposit would significantly improve data availability and reproducibility.
8.
MEDIUMreporting
Mention the reporting guideline used for the results (e.g., CONSORT) in the Methods or Reporting summary.
Explicitly stating the reporting guideline improves transparency and completeness.
9.
MEDIUMreporting
Provide a CONSORT flow diagram in the main text to improve transparency of patient flow.
A flow diagram clarifies patient disposition and is a standard requirement for clinical trials.
10.
MEDIUMreporting
Include a statement on whether any patients were excluded from the safety analysis and why.
Clarifying exclusions from safety analysis is important for completeness.
11.
MEDIUMreporting
Specify the version of the Flowonix pump and catheter used, and any relevant lot numbers.
Detailed device identification is important for reproducibility and safety assessment.
12.
MEDIUMreporting
Add a note on the generalizability of the results given the small sample size and single-center design.
Acknowledging limitations in generalizability is important for balanced interpretation.
13.
MEDIUMcopyedit
Fix the typo 'Univeristy of Lille' to 'University of Lille' in the author affiliations.
Correcting typos in affiliations is a basic copyedit requirement.
14.
MEDIUMcopyedit
Verify the arithmetic in Table 4 LEDD reduction row; the mean of the listed values appears to be 43.75, not 42.
An internal inconsistency in reported summary statistics could undermine data credibility.
15.
MEDIUMcopyedit
Verify the arithmetic in Table 2 LEDD reduction row; the mean and median appear inconsistent with the listed values.
Similar arithmetic inconsistency in another table suggests a potential data entry error.
16.
LOWcopyedit
Clarify whether the washout period is included in the 4-week treatment period or additional in the Methods, Phase 2.
Ambiguity in the crossover design description could confuse readers about the study timeline.

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Intracerebroventricular anaerobic dopamine in Parkinson's disease with L-dopa-related complications: a phase 1/2 randomized-controlled trial.

Read full text (PMC)

DOI

10.1038/s41591-024-03428-2

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Record fingerprint

569ab1591c87b8bc7893b07d7315a576c063f6071aafdc55a90c1b8ad8c8465f

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

1.75 / 5

Critical — serious problems across many checks

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×3−1.5★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
ReportingStudy design partially met−0.25★
ReportingStatistical analysis partially met−0.25★
ReportingData & code availability partially met−0.25★

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

Not verified in this report

Statistics were not checked: no recomputable values were found in this text — no test statistic reported with its degrees of freedom, no effect estimate printed with both a 95% CI and a p-value, and no percentage printed with both its count and its denominator.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy endpoint is the percentage over total target (time with dyskinesia or bradykinesia) recorded by actimetry, which is a surrogate/behavioral proxy for clinical benefit. The paper does not provide evidence of target engagement at the tested dose (e.g., PK/PD or dose-exposure relationship) nor does it cite validated evidence linking this actimetry-based surrogate to a hard clinical outcome. The claim of efficacy rests on this surrogate without such validation.
“The primary endpoint, a blinded assessment of the percentage over target (that is, time with dyskinesia or bradykinesia), recorded by home actimetry using a wristwatch, was significantly reduced on A-dopamine compared with that on oral treatment alone ( P =…”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The primary effect size is a median within-patient difference of -10.4 percentage points (Hedge's g = -0.62), which is presented without an anchor to a minimal clinically important difference or to clinical meaningfulness. The paper acknowledges that the clinical interpretation of the primary endpoint is not obvious, and the effect is not explicitly anchored as clinically material.
“with a median within-patient difference of −10.4 (Hedge g = −0.62 (95% confidence interval: −1.43, −0.08))”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 302OverreachOverstated conclusions 103AuthenticityData authenticity concerns 304DisclosureReporting gaps 05AvailabilityNone found 06Copyedit5 minor suggestions

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: 2 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

3 integrity concerns flagged (0 high).

Reporting gaps

3 findings · worst high

Statistical reporting gaps (tests, assumptions, effect sizes)Assessed
Data/code availability incompleteAssessed
Study-design details incomplete (controls, blinding, power)Assessed

Eight Dimensions5 pass · 3 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 with extensive prior work cited and a logical rationale for the study.

Evidence

paraphrase[Introduction, paragraph 1]

“To meet the challenge of dopamine biodistribution and oxidation, a novel concept of continuous i.c.v. administration of an anaerobic dopamine formulation (A-dopamine) has been developed”

Introduction ¶3Find in source

paraphrase[Introduction, paragraph 2]

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise with extensive prior work and a logical rationale for the study.

Evidence

paraphrase[Introduction, paragraph 2]

paraphrase[Introduction, paragraph 3]

paraphrase[Introduction, paragraph 2]

“A-dopamine has been shown to be safe and effective in two rodent models of PD and in a chronic non-human primate model of PD.”

Sub-criteria

controlsADEQUATE

power analysisINADEQUATE

blinding levelsINADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 85% conf

Evidence

“Randomization sequence was created using a random number generated by the SAS 9.4 software in the Lille University Hospital biostatistics department.”

MethodsFind in source

“The analysis of actimetry parameters, and in particular the primary endpoint, was blinded to patients and investigators.”

MethodsFind in source

WARNReviewer 2· 85% conf

Evidence

“Randomization sequence was created using a random number generated by the SAS 9.4 software in the Lille University Hospital biostatistics department.”

MethodsFind in source

“The analysis of actimetry parameters, and in particular the primary endpoint, was blinded to patients and investigators. Other parameters were analyzed openly for patients and investigators.”

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 well reported for a human trial, including sex, age, disease duration, and other clinical characteristics.

Evidence

“The median age was 60.8 years (range: 53–69 years) and 9 patients were male (75.0%).”

ResultsFind in source

PASSReviewer 2· 90% conf

Biological variables are well reported for this human study, including sex, age, and detailed clinical characteristics.

Evidence

“The median age was 60.8 years (range: 53–69 years) and 9 patients were male (75.0%).”

Table 1Find in source

paraphrase[Table 1]

“Body mass index (kg m−2) | 20 | 30 | 26 | 21 | 25 | 18 | 23 | 26 | 24 | 28 | 24 | 28 | 24.4 | 24.7 (18; 29.9)”

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approvals and consent are adequately reported.

Evidence

MethodsFind in source

“All participants provided written informed consent before screening”

MethodsFind in source

“The trial was conducted in accordance with the International Council for Harmonization Good Clinical Practice guidelines and the ethical principles of the Declaration of Helsinki.”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approvals and consent are clearly documented with named bodies and protocol numbers.

Evidence

MethodsFind in source

“All participants provided written informed consent before screening, including knowledge of the plan to withhold dopaminergic medication unless necessary.”

MethodsFind in source

“The trial was conducted in accordance with the International Council for Harmonization Good Clinical Practice guidelines and the ethical principles of the Declaration of Helsinki.”

MethodsFind in source

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· 85% conf

Key resources, including the investigational product and devices, are adequately identified.

Evidence

MethodsFind in source

“All data were analyzed using the SAS software package, release 9.4 (SAS Institute), or using R software (R version 4.1.2).”

Statistical analysisFind in source

PASSReviewer 2· 85% conf

Key resources, including the investigational product and devices, are adequately identified.

Evidence

paraphrase[Methods, A-dopamine preparation]

“A-dopamine was formulated as a solution of dopamine hydrochloride (2, 10, 50 and 100 mg ml−1) dissolved in sodium chloride (0.9%) and sterile water for injection in a sterile anaerobic isolator”

MethodsFind in source

“All data were analyzed using the SAS software package, release 9.4 (SAS Institute), or using R software (R version 4.1.2).”

Statistical analysisFind in source

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedINADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 80% conf

Statistical methods are generally sound, but there are issues with exact p-value reporting and some effect sizes lack p-values.

Evidence

“The primary outcome was compared between the two treatments using a paired Wilcoxon signed-rank test (performed on the intra-patient differences).”

Statistical analysisFind in source

“The A-dopamine effect size (standardized difference) was medium (Hedge’s g = −0.62 (95% confidence interval (CI): −1.43, −0.08)).”

ResultsFind in source

“No statistical tests of comparisons were done for secondary and exploratory outcomes; only a descriptive analysis and an estimation of effect sizes are reported.”

Statistical analysisFind in source

WARNReviewer 2· 80% conf

Statistical methods are appropriate and well-described, but the primary analysis excluded ~30% of evaluation weeks, and some p-values are reported as thresholds.

Evidence

“The primary outcome was compared between the two treatments using a paired Wilcoxon signed-rank test (performed on the intra-patient differences).”

Statistical analysisFind in source

paraphrase[Results, Efficacy outcomes]

“the percentage over total target ... was significantly reduced under A-dopamine when compared with oral treatment alone (P = 0.027)”

paraphrase[Table 3]

“Hedge’s g = −0.62 (95% CI: −1.43, −0.08)”

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositNOT REPORTED

data availability statementINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 85% conf

Data availability is stated but the access route is vague; code availability is not reported.

Evidence

“The data supporting the results will also be available on reasonable request from the corresponding author and C.M. (caroline.moreau@chu-lille.fr).”

Data availabilityFind in source

“Statistical analyses were carried out independently by A. Duhamel and J.L. at the Lille University Hospital Biostatistics Department.”

Data availabilityFind in source

WARNReviewer 2· 80% conf

Data availability is stated with a managed-access procedure, but no code is shared and the statement is somewhat vague.

Evidence

Data availabilityFind in source

“Statistical analyses were carried out independently by A. Duhamel and J.L. at the Lille University Hospital Biostatistics Department.”

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 trial registration, detailed methods, and discussion of limitations.

Evidence

“ClinicalTrials.gov registration: NCT04332276”

AbstractFind in source

“However, this is a proof-of-concept study with several limitations that need to be discussed.”

Discussion ¶4Find in source

“The study was funded by InBrain Pharma, France, a spin-off of the research academic team UMR-S 1172”

AcknowledgementsFind in source

PASSReviewer 2· 90% conf

The manuscript is transparent with detailed methods, trial registration, and discussion of limitations.

Evidence

“ClinicalTrials.gov registration: NCT04332276”

AbstractFind in source

“However, this is a proof-of-concept study with several limitations that need to be discussed. Firstly, the number of patients involved was limited.”

Discussion ¶4Find in source

AcknowledgementsFind in source

Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.

Broken references and links

None found

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.

Checked — nothing surfaced.

Checked 34 references by DOI: 34 verified.

2 data/code links checked; 2 live.

Copyediting

5 minor

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

No major wording or formatting errors. 5 minor suggestions below.

5 copyedit issues flagged: mostly consistency, typo, clarity.

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHrigor
Add a formal sample size recalculation for the revised 12-patient target, including assumptions for effect size and power, in the Methods section.
The sample size was revised without a formal recalculation, which is a major methodological gap that could affect the interpretation of the primary endpoint.
2.
HIGHreporting
Clarify the blinding status for secondary outcomes and justify the open-label design for those measures in the Methods.
The open-label design for secondary outcomes is a potential source of bias that should be explicitly acknowledged and justified.
3.
HIGHstatistics
Report exact p-values for all secondary outcomes where hypothesis tests are performed, or explicitly state that only effect sizes are reported.
Threshold-only p-values and missing p-values for secondary outcomes reduce transparency and hinder interpretation.
4.
HIGHdata code
Enhance the data availability statement to include a specific access mechanism, conditions, and expected timeframe for data requests.
The current 'on reasonable request' statement is vague and does not meet modern data-sharing expectations.
5.
HIGHdata code
Add a code availability statement, even if stating that no custom code was used, in the Code availability section.
Lack of code sharing hinders reproducibility and is a common reviewer concern.
6.
MEDIUMstatistics
Include a statement on whether assumptions for the Wilcoxon test (e.g., symmetry of differences) were checked, in the Statistical analyses section.
Verifying assumptions strengthens the statistical analysis and addresses a reviewer concern.
7.
MEDIUMreporting
Consider depositing de-identified individual patient data in a repository like Vivli or YODA to improve data accessibility.
Repository deposit would significantly improve data availability and reproducibility.
8.
MEDIUMreporting
Mention the reporting guideline used for the results (e.g., CONSORT) in the Methods or Reporting summary.
Explicitly stating the reporting guideline improves transparency and completeness.
9.
MEDIUMreporting
Provide a CONSORT flow diagram in the main text to improve transparency of patient flow.
A flow diagram clarifies patient disposition and is a standard requirement for clinical trials.
10.
MEDIUMreporting
Include a statement on whether any patients were excluded from the safety analysis and why.
Clarifying exclusions from safety analysis is important for completeness.
11.
MEDIUMreporting
Specify the version of the Flowonix pump and catheter used, and any relevant lot numbers.
Detailed device identification is important for reproducibility and safety assessment.
12.
MEDIUMreporting
Add a note on the generalizability of the results given the small sample size and single-center design.
Acknowledging limitations in generalizability is important for balanced interpretation.
13.
MEDIUMcopyedit
Fix the typo 'Univeristy of Lille' to 'University of Lille' in the author affiliations.
Correcting typos in affiliations is a basic copyedit requirement.
14.
MEDIUMcopyedit
Verify the arithmetic in Table 4 LEDD reduction row; the mean of the listed values appears to be 43.75, not 42.
An internal inconsistency in reported summary statistics could undermine data credibility.
15.
MEDIUMcopyedit
Verify the arithmetic in Table 2 LEDD reduction row; the mean and median appear inconsistent with the listed values.
Similar arithmetic inconsistency in another table suggests a potential data entry error.
16.
LOWcopyedit
Clarify whether the washout period is included in the 4-week treatment period or additional in the Methods, Phase 2.
Ambiguity in the crossover design description could confuse readers about the study timeline.

Full text (79,559 chars · analyzed ~94%, head + tail)Analyzed: Aug 16, 2026