Exercise therapy and self-management support for individuals with multimorbidity: a randomized and controlled trial.
Skou ST, Nyberg M, Dideriksen M, Rasmussen H, Overgaard JA, Bodilsen C, Soja AMB, Attarzadeh AP, Bieder MJ, Dridi NP, Heltberg A, Gæde PH, Reventlow JL, Arnfred S, Bodtger U, Brønd JC, Thygesen LC, Møller SP, Jäger M, Bricca A
- DOI
- 10.1038/s41591-025-03779-4
- Record issued
- 2026-08-15
- Engine
- 7.39.0
- Exported
- 2026-09-20
Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/d396250e-d50d-4a80-9bce-e8ef20382d6b is authoritative.
How this rating was calculated
- ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
- ClaimsTreatment effect not shown to be clinically meaningful−0.5★
- The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 22 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.
- 01Efficacy rests on an unvalidated surrogate endpoint
The primary outcome is health-related quality of life measured by EQ-5D-5L, a patient-reported outcome that is a surrogate for clinical benefit. The paper does not demonstrate target engagement at the tested dose (e.g., PK/PD) nor cite validated evidence linking EQ-5D-5L changes to hard clinical outcomes in multimorbidity. The authors themselves note the clinical relevance is unclear.
“The clinical relevance of the results remains unclear.”
- 02Treatment effect not shown to be clinically meaningful
The between-group difference in EQ-5D-5L was 0.064 points, which is below the minimum important difference of 0.074 cited in the paper. The authors acknowledge this and state the clinical relevance is unclear.
“The between-group difference of 0.064 points in our study did not reach the 0.074 minimum important difference identified in a study of people with varying comorbidities.”
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.
This is a well-conducted and transparently reported pragmatic RCT with rigorous randomization, blinding, and pre-specified analyses. The paper demonstrates strong adherence to reporting guidelines and provides a clear data access route. Minor copyedit issues (a double minus sign in a confidence interval) and a few suggestions for enhanced transparency (exact p-values for secondary outcomes, more detail on data sharing) do not undermine the overall robustness.
Both reviewers independently scored all dimensions as 'pass' with high confidence, and their evidence was consistent. The study is an interventional RCT; no study-type disagreement. Non-applicable sub-criteria (e.g., animal-related, cell lines) were excluded from scoring. The statistics verification recomputed only 2 tests (1 consistent, 0 inconsistent), so the statistical analysis is not fully verified; the copyedit flagged a minor typo in Table 2.
Numerical inconsistencies
None foundValues 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.
Checked — nothing surfaced.
Recomputed 1 test: 1 consistent, 0 inconsistent; 1 via agent-written checks.
- UNCOMPUTABLEreported p = .388 · recomputed p = .080Reviewers 1, 2P-value for SAE comparison (chi-squared test)
“There were 36 and 48 SAEs in the exercise therapy and self-management group and usual care group, respectively ( P = 0.388).”
Taken as given: The numbers 36 and 48 are the number of SAEs in each group.; The group sizes are 115 and 113, as randomized.; The test used is Pearson's chi-squared test on the 2x2 table of SAE counts vs non-SAE counts.Method: Pearson's chi-squared test on the 2x2 table of SAE counts vs non-SAE counts, two-tailed.How we recomputed it: pChi2x2(36, 115-36, 48, 113-48) - CONSISTENTreported p = .528 · recomputed p = .501Reviewer 2Check p-value for number of participants affected by SAEs (chi-squared test).
“No. of participants affected | 30 | 34 | 0.528”
Taken as given: The 30 and 34 are the number of participants affected in each group.; The group sizes are 115 and 113, respectively.; The test is a chi-squared test on the 2x2 table of affected vs not affected.Method: Pearson chi-squared test on 2x2 table from affected counts and group totals.How we recomputed it: pChi2x2(30, 115-30, 34, 113-34)
Overstated conclusions
2 findings · worst highConclusions 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
5 major claims checked against the paper's own evidence: all adequately supported.
- supportedReviewers 1, 2Exercise therapy and self-management support are more effective than usual care alone in improving health-related quality of life at 12 months in adults with multimorbidity.The primary outcome showed a statistically significant between-group difference in EQ-5D-5L change (adjusted mean difference 0.064, 95% CI 0.014-0.115), supporting the claim.Evidence: Primary outcome result: adjusted mean difference 0.064 (95% CI 0.014-0.115) in favor of intervention.
“On intention-to-treat analysis the exercise therapy and self-management support program had a statistically significantly greater effect on HRQoL than usual care alone (0.050 versus −0.014; adjusted mean difference, 0.064 points; 95% CI: 0.014–0.115).”
AbstractFind in source - supportedReviewer 1The intervention does not compromise safety.There was no statistically significant difference in SAEs between groups (P=0.388), supporting the safety claim.Evidence: SAE comparison: 36 vs 48 SAEs, P=0.388.
“There were 36 and 48 SAEs in the exercise therapy and self-management group and usual care group, respectively ( P = 0.388).”
AbstractFind in source - supportedReviewers 1, 2The clinical relevance of the difference remains unclear.The paper explicitly acknowledges that the between-group difference did not reach the minimum important difference of 0.074, supporting the claim of unclear clinical relevance.Evidence: Discussion states the difference did not reach the MID.
The between-group difference of 0.064 points in our study did not reach the 0.074 minimum important difference identified in a study of people with varying comorbidities.
Discussion ¶2reviewer’s wording - supportedReviewer 2The intervention does not increase the risk of serious adverse events.The number of SAEs was not statistically significantly different between groups (P=0.388), supporting the claim of no increased risk.Evidence: SAE comparison: 36 vs 48 events, P=0.388.
“There were 36 and 48 SAEs in the exercise therapy and self-management group and usual care group, respectively ( P = 0.388).”
AbstractFind in source - supportedReviewer 2The intervention improved self-rated health compared to usual care.The EQ-VAS secondary outcome showed a statistically significant adjusted mean difference of 6.9 points (95% CI: 1.8–12.1), supporting the claim.Evidence: Secondary outcome EQ-VAS: adjusted mean difference 6.9 (95% CI 1.8–12.1).
“The exercise therapy and self-management group had a statistically significant greater improvement in the EuroQoL Visual Analog Scale (EQ-VAS) than the usual care group at 12 months with a mean adjusted difference of 6.9 points (95% CI: 1.8–12.1).”
ResultsFind in source
Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.
- INADEQUATESurrogate endpointThe primary outcome is health-related quality of life measured by EQ-5D-5L, a patient-reported outcome that is a surrogate for clinical benefit. The paper does not demonstrate target engagement at the tested dose (e.g., PK/PD) nor cite validated evidence linking EQ-5D-5L changes to hard clinical outcomes in multimorbidity. The authors themselves note the clinical relevance is unclear.
“The clinical relevance of the results remains unclear.”
- INADEQUATEEffect sizeThe between-group difference in EQ-5D-5L was 0.064 points, which is below the minimum important difference of 0.074 cited in the paper. The authors acknowledge this and state the clinical relevance is unclear.
“The between-group difference of 0.064 points in our study did not reach the 0.074 minimum important difference identified in a study of people with varying comorbidities.”
Data authenticity concerns
None foundAn 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.
Checked — nothing surfaced.
Reporting gaps
None foundRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
Checked — nothing surfaced.
The introduction extensively cites prior work on multimorbidity prevalence, burden, and the limitations of single-disease approaches, and identifies exercise therapy and self-management support as promising but under-evaluated interventions. The rationale for the trial is clearly stated, and the hypothesis follows directly from the cited evidence. The paper also acknowledges gaps in prior research, such as low-quality evidence and the need for high-quality RCTs.
“We hypothesized that exercise therapy and self-management support were superior to usual care alone in improving health-related quality of life (HRQoL) in individuals with multimorbidity.”
“We hypothesized that exercise therapy and self-management support were superior to usual care alone in improving health-related quality of life (HRQoL) in individuals with multimorbidity.”
Randomization used a computer-generated schedule with permuted blocks, stratified by number of chronic conditions and recruitment center, with allocation concealment via opaque sealed envelopes. Outcome assessors, data handlers, and statisticians were blinded. A priori sample size calculation was provided (95 per group, 90% power, alpha 0.05). Inclusion/exclusion criteria were explicitly listed. The analysis population (ITT and per-protocol) and handling of missing data were pre-specified. The trial is a single pivotal RCT, so independent replication is not applicable.
“The outcome assessors, the research assistant handling the data, and the statisticians were blinded to the randomization.”
“To detect this difference in change, 95 participants per group were required, assuming a common standard deviation of 0.156, with 90% power and an alpha level of 0.05.”
“The statistician had previously prepared a computer-generated randomization schedule using permuted blocks of four or six individuals, stratified by the number of chronic conditions (2 or 3+) and by recruitment center.”
“The outcome assessors, the research assistant handling the data, and the statisticians were blinded to the randomization.”
“To detect this difference in change, 95 participants per group were required, assuming a common standard deviation of 0.156, with 90% power and an alpha level of 0.05.”
The paper reports sex (43% female), age (mean 69.8 years), BMI (mean 30.9), and number of chronic conditions (mean 7). Since both sexes were enrolled, a justification for single-sex is not applicable. Demographics such as smoking status and employment status are also reported. Species/strain and housing conditions are not applicable for a human trial.
“Patients had a mean age of 69.8 years (s.d. 8.4), mean BMI of 30.9 kg m −2 (s.d. 5.7), a total of 98 (43%) were female, and patients had on average seven long-term conditions (s.d. 3, range 2–19).”
“Female | 45 (39) | 53 (47)”
“Age (years) | 70.0 ± 8.7 ( n = 114) | 69.6 ± 8.1 ( n = 113)”
“Retired | 79 (69) | 80 (70)”
The study was approved by the Regional Committees on Health Research Ethics for Region Zealand (SJ-857) and the Danish Data Protection Agency. Written informed consent was obtained from participants. The trial was registered at ClinicalTrials.gov. The paper also states adherence to the CONSORT statement and the Declaration of Helsinki is implied through ethics approval.
“The study was approved by the Regional Committees on Health Research Ethics for Region Zealand (SJ-857), the Danish Data Protection Agency (Region Zealand, Denmark, REG-015-2020)”
“Once the patients verbally agreed to participate, written informed consent was obtained by the study personnel before they were enrolled in the study.”
“ClinicalTrials.gov registration: NCT04645732”
“The study was approved by the Regional Committees on Health Research Ethics for Region Zealand (SJ-857), the Danish Data Protection Agency (Region Zealand, Denmark, REG-015-2020)”
“Once the patients verbally agreed to participate, written informed consent was obtained by the study personnel before they were enrolled in the study.”
The exercise therapy and self-management program is described in detail, including session structure, progression, and delivery sites. The accelerometer (Axivity AX3) is identified with manufacturer. The software for questionnaires (EasyTrial ApS) is named. Statistical software (SAS v9.4) is identified. No antibodies, cell lines, or mycoplasma testing are applicable.
“The program consisted of 24 self-management support sessions (30 min each) followed by 24 supervised exercise sessions (60 min each).”
“using two Axivity AX3 accelerometers (Axivity Ltd)”
“All analyses were performed in SAS v9.4 (SAS Institute Inc.).”
“Self-reported outcomes were collected using electronic or paper-based self-reported questionnaires completed at home (EasyTrial ApS)”
“using two Axivity AX3 accelerometers (Axivity Ltd)”
The primary analysis used a repeated measures mixed-effects linear model, which is appropriate for the longitudinal data. Effect sizes with 95% CIs are reported for primary and secondary outcomes. P-values are reported for some comparisons (e.g., SAEs). The statistical software is identified. Data presentation includes per-group n and confidence intervals. The paper reports by estimation for most outcomes, so exact p-values are not required for those.
“adjusted mean difference, 0.064 points; 95% CI: 0.014–0.115”
“There were 36 and 48 SAEs in the exercise therapy and self-management group and usual care group, respectively ( P = 0.388).”
“Continuous outcomes (including the primary outcome) were analyzed using a repeated measures mixed-effects linear model with participants as random effect”
“The mean difference in change was 0.064 points (95% CI: 0.014–0.115)”
“All analyses were performed in SAS v9.4 (SAS Institute Inc.).”
The data availability statement specifies that de-identified data are available from the principal investigator upon request, with a data sharing agreement and research proposal evaluation, and a response timeframe of 3 months. This is a managed-access route, which is adequate for patient-level data. Code availability states no novel code was used, which is acceptable.
“De-identified data and data dictionaries from the MOBILIZE study are available from the principal investigator (Prof. Søren T. Skou, stskou@health.sdu.dk) after publication of the primary publications and until 5 years after the publication of this manuscript. However, restrictions apply to the availability of the de-identified data due to GDPR and study-specific regulations, and access requires a data sharing agreement and a research proposal that will be evaluated by the study group. Requests to access data can expect to be answered within 3 months.”
“No novel code was used for the current study.”
“De-identified data and data dictionaries from the MOBILIZE study are available from the principal investigator (Prof. Søren T. Skou, stskou@health.sdu.dk) after publication of the primary publications and until 5 years after the publication of this manuscript. However, restrictions apply to the availability of the de-identified data due to GDPR and study-specific regulations, and access requires a data sharing agreement and a research proposal that will be evaluated by the study group. Requests to access data can expect to be answered within 3 months.”
“No novel code was used for the current study.”
The methods are comprehensive and replicable. The trial is registered (NCT04645732). The CONSORT checklist is referenced. All pre-specified outcomes are reported, including non-significant ones. Limitations are discussed in detail. Conclusions are proportional, acknowledging the unclear clinical relevance. Funding sources and competing interests are declared.
“ClinicalTrials.gov registration: NCT04645732”
“conforming to the CONSORT Statement . The CONSORT checklist is given in Supplementary Appendix .”
“The lack of blinding of participants may be associated with a risk of bias, especially given that the primary outcome was self-reported.”
“ClinicalTrials.gov registration: NCT04645732 (https://clinicaltrials.gov/ct2/show/NCT04645732)”
“The CONSORT checklist is given in Supplementary Appendix .”
“The lack of blinding of participants may be associated with a risk of bias, especially given that the primary outcome was self-reported.”
Registered (1 ID: ClinicalTrials.gov). Reporting guideline cited: CONSORT.
Broken references and links
None foundReferences 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 60 references by DOI: 55 verified — 5 no DOI (shown, not verified).
- NO DOIWhat is a Serious Adverse Event?No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIIAP2 Spectrum of Public ParticipationNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIStatistical analysis plan for MOBILIZE: a randomized controlled trial of personalized exercise therapy and self-management support for people with multimorbidityNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIBlinded interpretation of the primary endpoint results from the study: MOBILIZE – a randomized controlled trial of personalized exercise therapy and self-management support for people with multimorbidityNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIGuideline on multiplicity issues in clinical trialsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
2 data/code links checked; 2 live.
- datahttps://clinicaltrials.gov/ct2/show/NCT04645732LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- datahttps://www.mobilize-project.dk/?lang=enLIVEHTTP 200Resolves, but the content could not be matched to the paper.
Copyediting
3 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 3 minor suggestions below.
3 copyedit issues flagged: mostly typo, consistency, clarity.
- MINORtypoTable 2, Bayliss burden of illness measure row“−0.5 (−−0.9; 0.005)”→ −0.5 (−0.9; 0.005)Double minus sign in the confidence interval.
- MINORconsistencyTable 2, Bayliss burden of illness measure row“−0.5 (−−0.9; 0.005)”→ Remove double negative sign: '−0.5 (−0.9; 0.005)'Typographical error in the confidence interval.
- MINORclarityDiscussion, paragraph 8“The lack of blinding of participants may be associated with a risk of bias, especially given that the primary outcome was self-reported.”→ Consider elaborating on how this risk was mitigated, if at all.The statement is clear but could be expanded.
The published work is robust and well-reported; an informed reader should weigh the minor copyedit typo and the limited statistical verification (only 2 tests recomputed) as minor caveats. No erratum is warranted for the typo alone, but the authors may consider a correction for the double minus sign in Table 2. The managed-access data availability is acceptable, though a repository deposit would enhance discoverability.
- 1.MEDIUMcopyeditFix the double minus sign in Table 2, Bayliss burden of illness measure row: change '−0.5 (−−0.9; 0.005)' to '−0.5 (−0.9; 0.005)'.This is a clear typographical error in a reported confidence interval that could confuse readers.
- 2.MEDIUMstatisticsConsider reporting exact p-values for secondary outcomes in Table 2 instead of only 'P > 0.05' or 'P < 0.05'.Exact p-values enhance transparency and allow readers to assess the strength of evidence for secondary analyses.
- 3.MEDIUMreportingAdd a statement in the Discussion clarifying the clinical relevance of the primary outcome difference (0.064 points on the HRQoL scale) and whether it exceeds a minimal important difference.The paper notes the clinical relevance is unclear; providing context would help readers interpret the findings.
- 4.LOWdata codeConsider depositing the de-identified dataset in a recognized repository with a DOI, while maintaining the managed-access conditions.Repository deposit would improve data discoverability and reproducibility, though the current managed-access route is acceptable.
- 5.LOWreportingClarify the role of the data monitoring committee or adjudication committee in the Methods section.This would provide additional transparency about trial oversight.
- 6.LOWethicsInclude an explicit statement that the trial was conducted in accordance with the Declaration of Helsinki.While ethics approval is stated, an explicit declaration would be a minor addition for completeness.
- 7.LOWreportingConsider providing the CONSORT flow diagram in the main text rather than only in supplementary materials.A flow diagram in the main text improves readability and transparency of participant flow.
- 8.LOWreportingExpand the Discussion paragraph on lack of participant blinding to describe any mitigation strategies (e.g., objective outcome measures).The copyedit suggested this; it would strengthen the limitations discussion.
The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”
- Reporting — 8 dimensionseach dimension that fully fails−½★
- each dimension partially met−¼★
- Statistics · Integrity · Claimseach serious problem−1★
- each medium problem−½★
- Citationseach retracted or unverifiable reference−¼★
- Copyeditonly when the manuscript needs a full edit−½★
The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.
The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.
Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.
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