Rigor Reviewed

Rigor-Reviewed Manuscript

External trigeminal nerve stimulation in youth with ADHD: a randomized, sham-controlled, phase 2b trial.

Name: Adcurare Rigor Record — External trigeminal nerve stimulation in youth with ADHD: a randomized, sham-controlled, phase 2b trial.
Item: External trigeminal nerve stimulation in youth with ADHD: a randomized, sham-controlled, phase 2b trial.
Rating: 100
Author: Adcurare

Conti AA, Bozhilova N, Eraydin IE, Stringer D, Johansson L, Marhenke R, Bilbow A, El Masri S, Hyde J, Giaroli G, Liang H, Fiori F, Mehta MA, Santosh P, Carter B, Cortese S, Rubia K

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Adcurare Rigor Review — 4.5★ (Strong), 0 critical, 2 high issues for “External trigeminal nerve stimulation in youth with ADHD: a randomized, sham-controlled, phase 2b trial.”

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Adcurare Editorial

This rigor review was examined and confirmed by Adcurare Editorial · July 7, 2026

Adcurare Rigor Review

Rigor Reviewed

4.5 / 5

Strong — minor issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern−0.5★

Model-reported confidence: highReviewer agreement: highEngine: 7.6.0Source: full text

Not verified in this report

Declared data/code links were not checked for liveness or content.

Problems surfaced1 type

Internal contradictions in the reported numbers

This Adcurare Rigor Review uses AI 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.

This is a well-conducted and well-reported confirmatory phase 2b RCT of TNS for ADHD. The manuscript is strong across all eight rigor dimensions, with minor gaps in statistical reporting (model assumptions not explicitly verified) and a few copyedit issues (Table 1 percentage error, Table 3 formatting).

Three independent reviewers (all AI) scored all dimensions and fully agreed on pass/fail status for every dimension. Reviewers diverged only on the sub-criterion 'assumptions verified' (R1: reported but inadequate; R2, R3: reported and adequate). The copyedit pass flagged 5 minor issues, mostly in tables. Citation verification found no retracted or unresolved references. Statistics verification successfully recomputed 2 tests with consistent results (coverage limited to tests with full statistics).

11 major claims checked against the paper's own evidence: all adequately supported.

Recomputed 2 tests: 2 consistent, 0 inconsistent, 2 via agent-written checks.

1 integrity concern flagged (0 high).

Reporting

Eight Dimensions8 pass

The introduction cites the pilot RCT (McGough et al.) that showed symptom improvement with TNS, acknowledges its limitations (small sample, limited age range, no long-term follow-up, inadequate sham), and presents a logical rationale for the current confirmatory trial. The limitations of prior work are explicitly addressed in the design of the improved sham condition and the inclusion of adolescents.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper establishes a clear scientific premise by citing prior research, including the pilot RCT that led to FDA clearance, and provides a logical rationale for the study.

Evidence

direct quote[Introduction, paragraph 4]

“The evidence for FDA clearance was based on a pilot double-blind RCT in 62 unmedicated children, showing that 4 weeks of nightly real versus sham TNS significantly decreased parent-rated ADHD symptoms on the ADHD Rating Scale (ADHD-RS), with medium effect size (Cohen’s d = 0.5).”

direct quote[Introduction, paragraph 5]

“Furthermore, the pilot study did not assess effects beyond 4 weeks and was limited to very young children aged 8−12 years.”

direct quote[Introduction, paragraph 5]

“To address this need, we conducted a confirmatory, multicenter, double-blind, randomized, sham-controlled, parallel-group, phase 2b trial investigating both short-term (4 weeks) and longer-term (6 months) efficacy of real versus sham TNS not only in children but also in adolescents with ADHD.”

PASSReviewer 2· 95% conf

The study clearly establishes its scientific foundation by citing prior research on ADHD, TNS, and the pilot trial, and provides a logical rationale for the current confirmatory trial.

Evidence

direct quote[Introduction, paragraphs 1-3]

direct quote[Introduction, paragraph 3]

“These promising findings call for replication in a definitive, multicenter trial.”

direct quote[Introduction, paragraph 3]

“...the pilot study did not assess effects beyond 4 weeks and was limited to very young children aged 8−12 years.”

PASSReviewer 3· 95% conf

The paper clearly establishes the scientific premise by citing prior work, including the pilot RCT that led to FDA clearance, and provides a logical rationale for the study.

Evidence

direct quote[Introduction, paragraph 4]

direct quote[Introduction, paragraph 5]

“Furthermore, the pilot study did not assess effects beyond 4 weeks and was limited to very young children aged 8−12 years.”

direct quote[Introduction, paragraph 5]

The trial uses minimization randomization with stratification by sex, medication status, site, and age. Blinding is described for participants, parents, researchers, and analysts, with a formal blinding assessment. A power analysis is reported. Inclusion and exclusion criteria are clearly pre-specified. The primary analysis is ITT, and a CACE analysis is also pre-specified. The sham condition is designed to enhance blinding.

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The study design is rigorous for a human RCT, with adequate randomization, blinding, power analysis, and pre-specified inclusion/exclusion criteria.

Evidence

direct quote[Methods, Randomization and blinding]

“Randomization was done by minimization by sex (male/female), medication status (on medication, off medication/naive), site (London, Southampton) and age (8–13.5 years, 13.6−19 years) using a validated, online, web-based system from King’s Clinical Trials unit.”

direct quote[Methods, Randomization and blinding]

“Participants, parents/carers, postdoctoral research associates, principal investigator, co-investigators and analysts were blinded to treatment group except for the trial manager (L.J.) and trial manager assistants (S.E.M. and J.H.)... Blinding was assessed by a questionnaire administered to participants, parents/carers and researchers after 1 week and 4 weeks of TNS treatment.”

direct quote[Methods, Sample size justification]

“The estimated sample size of 128 participants (64:64) was calculated using a baseline to posttreatment correlation of 0.5, 90% power, 5% type I error and an anticipated effect size of 0.5 for a reduction in ADHD symptoms at 4 weeks.”

PASSReviewer 2· 95% conf

The trial design is rigorous with adequate randomization, blinding, and a pre-specified statistical analysis plan.

Evidence

direct quote[Methods: Randomization and blinding]

direct quote[Results: Blinding]

“Blinding appeared successful at week 1, with high rates of 'don't know' responses across children (40%), parents (50%) and researchers (75.3%).”

direct quote[Methods: Sample size justification]

PASSReviewer 3· 95% conf

The study design is rigorous for a phase 2b clinical trial, with adequate randomization, blinding, a pre-specified power analysis, and clear inclusion/exclusion criteria.

Evidence

direct quote[Methods, Randomization and blinding]

direct quote[Methods, Sample size justification]

Sex at birth is reported for all participants (64.7% male). Age is reported as mean and s.d. and also categorized per the randomization stratifier. Detailed demographics including ethnicity, handedness, and Index of Multiple Deprivation are provided. Health status is described via ADHD diagnosis, comorbidities, and medication status. 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 (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Key biological variables for a human clinical trial, including sex, age, and demographics, are well-reported.

Evidence

direct quote[Results, Participant disposition, Table 1]

“150 (97 males, 64.7%) were enrolled in the study”

direct quote[Results, Participant disposition, Table 1]

“Participants had a mean age (s.d.) of 12.6 years (2.8)”

direct quote[Table 1]

“Child ethnicity: White 119 (79.3%), Black, African, Caribbean or Black British 5 (3.3%), Asian or Asian British 7 (4.7%), Mixed or multiple ethnic groups 15 (10.0%), Other ethnic groups 4 (2.7%)”

PASSReviewer 2· 90% conf

Key biological variables and subject characteristics, including age, sex, ADHD subtype, and medication status, are reported in detail.

Evidence

direct quote[Results, Table 1]

“Age (mean, s.d.) | 12.6 (2.8) | 12.6 (2.8) | 12.6 (2.8)”

direct quote[Results]

“150 (97 males, 64.7%) were enrolled in the study...”

PASSReviewer 3· 95% conf

Key biological variables for a human clinical trial, including sex, age, and demographics, are well-reported.

Evidence

direct quote[Results, Participant disposition, Table 1]

“Child sex at birth | Male | 49 (65.3) | 48 (64.0) | 97 (64.7) | | Female | 26 (34.7) | 27 (36.0) | 53 (35.3)”

direct quote[Results, Participant disposition, Table 1]

“Age (mean, s.d.) | 12.6 (2.8) | 12.6 (2.8) | 12.6 (2.8)”

direct quote[Results, Participant disposition, Table 1]

“Child ethnicity | | White | 61 (81.3) | 58 (77.3) | 119 (79.3)”

The trial was approved by the West Midlands–Solihull NHS Research Ethics Committee with a specific REC reference and IRAS number. Informed consent/assent is described for both children and parents. Compliance with the Declaration of Helsinki is stated. The trial is also registered (ISRCTN82129325).

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approvals are clearly reported, including a named ethics committee, informed consent, and regulatory compliance.

Evidence

direct quote[Methods, Trial design]

“The trial was approved by the West Midlands–Solihull NHS Research Ethics Committee (REC; Ref21:/WN/0169; IRAS: 299703)”

direct quote[Methods, Participants]

“Children/adolescents and their parents/carers provided both digital and written informed consents/assents”

direct quote[Methods, Trial design]

“It was conducted in accordance with the 1975 Declaration of Helsinki”

PASSReviewer 2· 95% conf

The trial is properly registered and ethical approvals from a named committee, informed consent, and regulatory compliance are explicitly stated.

Evidence

direct quote[Methods: Trial design]

“The trial was approved by the West Midlands–Solihull NHS Research Ethics Committee (REC; Ref21:/WN/0169; IRAS: 299703) and the Medicines and Healthcare products Regulatory Agency (MHRA; Ref: CI/2022/0003/GB).”

direct quote[Methods: Participants]

“Children/adolescents and their parents/carers provided both digital and written informed consents/assents...”

direct quote[Methods: Trial design]

“It was conducted in accordance with the 1975 Declaration of Helsinki...”

PASSReviewer 3· 95% conf

Ethical approvals are clearly reported, including a named ethics committee, informed consent procedures, and regulatory compliance.

Evidence

direct quote[Methods, Trial design]

direct quote[Methods, Participants]

“Children/adolescents and their parents/carers provided both digital and written informed consents/assents and were reimbursed for travel costs and received up to £350...”

direct quote[Methods, Trial design]

“It was conducted in accordance with the 1975 Declaration of Helsinki and is reported following CONSORT guidelines.”

The investigational device, the Monarch TNS System by NeuroSigma, Inc., is named with its manufacturer. The sham device is described as identical in appearance. Key software tools are identified: Stata 18, MACRO Electronic Data Capture system (version 4.15.0.116), Tobii Pro Lab (version 1.207), and Empatica E4 wristband (version 2.0.3 (5119)). Antibodies, cell lines, and organisms are not applicable for this human device trial.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The investigational product (Monarch TNS System) is identified with manufacturer, and key software tools are identified with versions.

Evidence

direct quote[Methods, Intervention]

“Real and sham TNS was performed with the Monarch TNS System (NeuroSigma, Inc.).”

direct quote[Methods, Statistical analysis]

“Analyses were performed in Stata 18 (StataCorp LLC, version 18.0)”

direct quote[Methods, Procedures and Outcome measures]

“Study data were entered and managed using the MACRO Electronic Data Capture system (version 4.15.0.116).”

PASSReviewer 2· 90% conf

The key resource—the TNS device and its sham version—are identified with manufacturer and detailed specifications. Software tools are identified with name and version.

Evidence

direct quote[Methods: Intervention]

“Real and sham TNS was performed with the Monarch TNS System (NeuroSigma, Inc.).”

direct quote[Methods: Statistical analysis]

“Analyses were performed in Stata 18 (StataCorp LLC, version 18.0)...”

direct quote[Methods: Procedures]

“Study data were entered and managed using the MACRO Electronic Data Capture system (version 4.15.0.116).”

PASSReviewer 3· 95% conf

The investigational product (Monarch TNS System) is identified with manufacturer, and key software tools are identified with versions.

Evidence

direct quote[Methods, Intervention]

“Real and sham TNS was performed with the Monarch TNS System (NeuroSigma, Inc.).”

direct quote[Methods, Statistical analysis]

“Analyses were performed in Stata 18 (StataCorp LLC, version 18.0) following a prespecified statistical analysis plan...”

direct quote[Methods, Procedures]

“Study data were entered and managed using the MACRO Electronic Data Capture system (version 4.15.0.116).”

The primary analysis uses a longitudinal linear mixed model with specific covariates. Secondary outcomes use MMRM. Exact p-values and 95% CIs are reported for the primary and secondary outcomes. Effect sizes (Cohen's d) are reported. Statistical software (Stata 18) is identified. Data presentation includes a CONSORT diagram, temporal plots with error bars, and tables with per-group n. The paper states that no custom code was generated. Mathematical plausibility checks on the reported means and Ns for the primary outcome at baseline (e.g., 35.4 * 75 = 2655, which is plausible for integer ADHD-RS scores) do not reveal any obvious errors.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityPASS

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical methods are well-described, including named tests, a pre-specified analysis plan, and appropriate data presentation. Exact p-values and confidence intervals are reported for the primary and secondary outcomes.

Evidence

direct quote[Methods, Statistical analysis]

“For the primary analysis, a longitudinal linear mixed model was used, fitting 4-week ADHD symptom scores as a continuous outcome, with continuous time as a covariate using actual observed time of assessments and an interaction between time and trial group to estimate treatment effects at week 1, 2, 3 and 4 using post-estimation.”

direct quote[Results, Primary outcome, Table 2]

“aMD (95% CI) = 0.83 (−2.47 to 4.13); P = 0.622”

direct quote[Results, Primary outcome, Table 2]

“Cohen’s d (95% CI) = 0.09 (−0.26 to 0.43)”

PASSReviewer 2· 90% conf

Statistical tests are named, the primary analysis is pre-specified, effect sizes with CIs are reported, and exact p-values are provided. The analysis plan is detailed.

Evidence

direct quote[Methods: Statistical analysis]

“For the primary analysis, a longitudinal linear mixed model was used...”

direct quote[Results, Table 2 and Table 3]

“aMD = 0.83; 95% confidence interval: –2.47 to 4.13; P = 0.622; Cohen's d = 0.09”

direct quote[Methods: Statistical analysis]

“Analyses were performed in Stata 18 (StataCorp LLC, version 18.0) following a prespecified statistical analysis plan...”

PASSReviewer 3· 95% conf

Statistical methods are well-described, including named tests, a pre-specified analysis plan, and appropriate data presentation. No arithmetic errors were detected.

Evidence

direct quote[Methods, Statistical analysis]

direct quote[Results, Primary outcome, Table 2]

“aMD (95% CI) | Cohen’s d (95% CI) | P value | ... 0.83 (−2.47 to 4.13) | 0.09 (−0.26 to 0.43) | 0.622”

direct quote[Methods, Statistical analysis]

“Analyses were performed in Stata 18 (StataCorp LLC, version 18.0)”

The paper states that all data supporting the findings have been deposited in the figshare repository and are publicly available at a specific DOI. This is a concrete access route, meeting the standard for reported_and_adequate. The paper also explicitly states that no custom code was generated, making code_sharing not applicable.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositADEQUATE

data availability statementADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Data are deposited in a public repository with a DOI, and a data availability statement is present. No custom code was generated.

Evidence

direct quote[Data availability section]

“All data supporting the findings of this study have been deposited in the figshare repository and are publicly available at 10.6084/m9.figshare.29414744.v1.”

direct quote[Data availability section]

“No custom code was generated or used in this study.”

PASSReviewer 2· 95% conf

Data are deposited in a public repository with a DOI. No custom code was generated.

Evidence

direct quote[Data availability]

“All data supporting the findings of this study have been deposited in the figshare repository and are publicly available at 10.6084/m9.figshare.29414744.v1.”

direct quote[Data availability]

“No custom code was generated or used in this study.”

PASSReviewer 3· 95% conf

Data are deposited in a public repository with a DOI, and a data availability statement is present. Code sharing is not applicable as no custom code was generated.

Evidence

direct quote[Data availability]

“All data supporting the findings of this study have been deposited in the figshare repository and are publicly available at 10.6084/m9.figshare.29414744.v1.”

direct quote[Data availability]

“No custom code was generated or used in this study.”

The trial is registered (ISRCTN82129325). The paper states it is reported following CONSORT guidelines. Limitations are explicitly discussed, including missing teacher data, potential biases in parent ratings, and reliance on self-reported adherence. Conclusions are proportional, stating TNS is safe but not effective. Funding sources and a detailed conflicts-of-interest statement are provided. Methods are detailed enough for replication.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The manuscript is well-reported, with a trial registration, adherence to CONSORT guidelines, a limitations discussion, proportional conclusions, and a funding/COI statement.

Evidence

direct quote[Abstract, Methods]

“Trial registration: ISRCTN82129325 (http://www.isrctn.com/ISRCTN82129325)”

direct quote[Methods, Trial design]

“It was conducted in accordance with the 1975 Declaration of Helsinki and is reported following CONSORT guidelines.”

direct quote[Discussion, paragraph 8]

“Limitations include a high rate of missing data on teacher ratings (80%) due to low teacher participation.”

PASSReviewer 2· 95% conf

The trial is registered, follows CONSORT guidelines, discusses limitations, draws proportional conclusions, and provides funding and COI statements.

Evidence

direct quote[Methods: Trial design]

“This UK multicenter (King's College London and University of Southampton), phase 2b, double-blind, parallel group, sham-controlled confirmatory RCT was preregistered (trial registration: ISRCTN82129325)...”

direct quote[Discussion, last paragraph]

“Limitations include a high rate of missing data on teacher ratings (80%) due to low teacher participation.”

direct quote[Acknowledgements and Competing interests]

“This project was funded by the Efficacy and Mechanism Evaluation (EME) Programme (NIHR130077)...”

PASSReviewer 3· 95% conf

The manuscript is well-reported, with a trial registration number, adherence to CONSORT guidelines, a limitations section, proportional conclusions, and a funding/COI statement.

Evidence

direct quote[Abstract]

“Trial registration: ISRCTN82129325 (http://www.isrctn.com/ISRCTN82129325).”

direct quote[Methods, Trial design]

“It was conducted in accordance with the 1975 Declaration of Helsinki and is reported following CONSORT guidelines.”

direct quote[Discussion, paragraph 8]

“Although this RCT study was rigorously conducted, with an improved and more rigorous control condition over previous trials, it had some limitations.”

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

Checked 63 references: 3 verified — 60 not checked.

Reproducibility

Registered (1 ID: ISRCTN). Reporting guideline cited: CONSORT.

Adcurare Rigor Action ItemsFinal pass before journal submission

Ready to submit after minor edits. The two most important fixes are: (1) correct the percentage error in Table 1 for left/mixed handedness (currently 50.6%, should be 25.3%), and (2) add a brief statement verifying the linear mixed model assumptions (e.g., residual plots or a reference justifying robustness). Addressing the other copyedit issues and reviewer suggestions will polish the manuscript for a clean submission.

1.
HIGHcopyedit
Correct the percentage for 'Left/mixed handed' in the overall column of Table 1: 38 out of 150 participants is 25.3%, not 50.6%. Verify and correct the actual numbers or the percentage.
This is a demonstrable arithmetic error that could lead to reviewer scrutiny about data quality.
2.
HIGHstatistics
Add a brief statement in the Methods (Statistical analysis) that the assumptions of the linear mixed model (e.g., normality of residuals, homoscedasticity) were checked via residual plots or similar diagnostics, or cite a reference justifying their robustness for the sample size.
Explicitly verifying model assumptions strengthens the statistical reporting and preempts reviewer concerns.
3.
MEDIUMreporting
Include the pre-specified statistical analysis plan (SAP) as a supplementary file or explicitly reference the protocol supplement where it can be found.
Improves reproducibility and transparency, as one reviewer suggested.
4.
MEDIUMreporting
In the Discussion, explicitly note that the positive finding on the MEWS (commission errors) should be considered exploratory due to the lack of correction for multiple comparisons, even if pre-specified.
Prevents over-interpretation of a single significant secondary outcome amidst null primary results.
5.
MEDIUMcopyedit
Fix the formatting error in Table 3 for the commission errors row: change '0.95 1 (0.80, 1.13)' to '0.95 (0.80, 1.13)' or '0.951 (0.80, 1.13)' as appropriate.
The extra space and digit are a typographical error that should be corrected for clarity.
6.
MEDIUMreporting
Clarify whether the decision to not analyze teacher-rated secondary outcomes due to high missing data (80%) was a pre-specified criterion or a post-hoc decision, and state this in the Results.
Transparency about deviations from the analysis plan is important for integrity.
7.
MEDIUMreporting
Add exact p-values for all reported secondary outcomes in the text (currently only in Table 3 and for MEWS in text), as suggested by one reviewer.
Consistency in reporting p-values improves completeness and reader trust.
8.
MEDIUMreporting
Report the blinding assessment data for the 6-month follow-up if it was collected, to fully characterize blinding integrity over the longer term.
Provides a more complete picture of blinding success for the entire trial duration.
9.
LOWreporting
Consider adding a brief note in the Methods on how missing data for the primary outcome were handled in the mixed model (e.g., under missing-at-random assumption).
Clarifies the missing data handling approach, which is good practice for clinical trials.
10.
LOWreporting
Add a reference for the anticipated effect size or the formula used in the sample size calculation.
Minor addition to improve completeness of the power analysis justification.

Full text (61,776 chars)Analyzed: Jul 7, 2026

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