Trial Report Resistance Exercise Therapy for Long COVID: a Randomized, Controlled Trial 2025 Berry et al.

[ME/CFS Science Blog]

Now published, see post #9
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Abstract
Long COVID, reflected by persistent symptoms, including breathlessness and fatigue, after coronavirus disease-19 (COVID-19) infection, presents an unmet therapeutic need. In this study, the effects of a resistance exercise intervention on exercise capacity and health status in individuals with Long COVID were investigated.

A two-arm randomized, controlled clinical trial including adults with a hospital or community diagnosis of COVID-19 in the preceding 12 months was undertaken. Participants were randomized to usual care or usual care plus a personalized resistance exercise intervention for 12 weeks. The primary outcome was the incremental shuttle walk test undertaken three months after randomization, with secondary outcomes including health-related quality of life (EQ-5D-5L), anxiety and depression (Patient Health Questionnaire) and grip strength. Adverse events and the DePaul Symptom Questionnaire (Short Form) were also assessed.

Between May 2021 and April 2024, 233 individuals (median (interquartile range) 53.6 (43.8, 60.8) years; 146 (62.7%) female, 91 (39.1%) hospitalized with COVID-19) were randomized (n = 117 (50.2%) intervention group, n = 116 (49.8%) control group). The median (interquartile range) percentage adherence with the exercise intervention was 71.0 (47.8, 96.8). The mean (SD) distances achieved in the incremental shuttle walk test at baseline and at follow-up were 328 (225) m and 389 (249) m, in 224 and 193 individuals, respectively. The change in incremental shuttle walk test distance at three months compared to baseline was 83 (118) m in the intervention group (n = 94) and 47 (95) m in the control group (n = 98) (effect estimate (95%) confidence interval 36.4 (6.6, 66.2) m; p = 0.017). By three months, compared to the control group, greater improvements in the intervention group were also observed for the health-related quality of life utility score (EQ-5D-5L) (0.06 (0.01, 0.11); p = 0.020), Patient Health Questionnaire category (0.5 (0.2, 0.8); p = 0.013) and handgrip strength (2.54 (0.89, 4.19) kg; p = 0.003). In 99 individuals who completed the DePaul questionnaire, post-exertional malaise occurred in 40 (83.3%) individuals in the intervention group and 42 (82.4%) individuals in the control group. Five individuals in the control group and 1 individual in the intervention group experienced a serious adverse event (hospitalization) (p = 0.119).

In conclusion, a 12-week program of personalized resistance exercise in a community- and post-hospitalized population with Long COVID improved exercise capacity, health-related quality of life, anxiety and depression, and grip strength. Adherence with exercise was high and post-exercise malaise and adverse events were not increased.

Registration: Clinicaltrials.gov ID NCT04900961
https://www.researchsquare.com/article/rs-6269439/v1

 

[ME/CFS Science Blog]

Similar to a previous exercise study found an effect of 36.4 meter on the primary outcome the incremental shuttle walk test. They argue that "The effect size exceeded the minimum clinically important difference of 35.0 m [13]"

But in the power calculation in their protocol, they used a minimal important difference of 46 meter and a different reference. It reads (my bolding):

The minimum clinically important between-group difference in the ISWT at follow-up (3 months) = 46 m, SD=105 [20], sample size for 80% power, 5% significance, no loss to follow-up (LTFU) = a minimum of 85 / group; allowing for LTFU and incomplete data, the sample size is n=110/group (n=220 total).

https://assets-eu.researchsquare.com/files/rs-6269439/v1/ecc24ac01fb440394a418945.pdf

So I wonder how and why this changed. Reference 13 that argues the MCID is 35 meter was published in 2019, so it was already available when the protocol was written. So it's not like its a new estimate that only became available afterwards.

 

[ME/CFS Science Blog]

MCID estimates are a bit imprecise and vague, so not arguing that one is necessarily better than the other. But it seemed that they changed their MCID choice after seeing the data, without explaining this in their paper.

The correct way would probably to argue that their result may or may not be clinically significant, that it is too precise and close to the MCID estimates to tell for sure.

 

[ME/CFS Science Blog]

The also claim significant effects for hand grip and quality of life but they tested so many variables (including VO2 peak and fatigue severity, which showed no effect) and did not control for multiple testing.

The trial design was also A versus A + B, with the control group receiving no intervention, only usual care that the intervention group also received.

 

[Eleanor]

Health-related quality of life, psychological wellbeing and grip strength were improved indicating the intervention led to benefits in health and wellbeing and physical strength. Illness perception also improved but the change was not statistically significant. On the other hand, measures of physical activity, including objective measurement by accelerometry, did not improve.

The daily exercises were unsupervised and adherence was self-reported. Participants in the intervention group received more contact with site staff compared to participants in the control group, and this difference may have influenced the patient reported outcome measures.

 

[Utsikt]

The median (interquartile range) percentage adherence with the exercise intervention was 71.0 (47.8, 96.8).

71 % self-reported adherence is quite bad.

 

[Utsikt]

Figure 2.
Incremental shuttle walk test (ISWT) (mean ± 95% confidence interval) at baseline (blue) and 3-months follow-up (red) in the intervention and control groups, respectively.

 

[Utsikt]

Between May 2021 and April 2024, 250 individuals were screened and 233 individuals (median (interquartile range) 53.6 (43.8, 60.8) years), 146 (62.7%) female) were randomized. One hundred and seventeen (50.2%) individuals were assigned to the intervention group, and one hundred and sixteen (49.8%) individuals were assigned to the control group. Almost two thirds of the population experienced symptoms ≥ 90 days following the diagnosis of COVID-19 (Table 1).

Are they saying that more than 1/3 did not experience symptoms after 90 days?
It seems like it:

 

[SNT Gatchaman]

Now published as —


Resistance Exercise Therapy After COVID-19 Infection: A Randomized Clinical Trial

Spoiler: Authors

Colin Berry; Gemma McKinley; Hannah K Bayes; David Anderson; Chim Choy Lang; Adam Gill; Andrew Morrow; Robert Sykes; Diann Taggart; Anna Kamdar; Paul Welsh; Susan Dawkes; Alex McConnachie; Stuart R Gray

IMPORTANCE
Long COVID presents an unmet therapeutic need.

OBJECTIVE
To determine the effects of a resistance exercise intervention on exercise capacity, health status, and safety among adults after COVID-19 infection.

DESIGN, SETTING, AND PARTICIPANTS
A 2-arm, multicenter, randomized clinical trial including 233 adults with a hospital or community diagnosis of COVID-19 infection in the preceding 12 months was undertaken from June 1, 2021, to April 26, 2024. The intervention group comprised 117 individuals, and the control group comprised 116 individuals. A total of 224 individuals at baseline and 193 individuals at 3 months completed Incremental Shuttle Walk Tests.

EXPOSURES
The intervention group received the personalized resistance exercise intervention for 3 months, and the control group received treatment as usual.

MAIN OUTCOMES AND MEASURES
The primary outcome was the distance achieved (in meters) in the Incremental Shuttle Walk Test undertaken 3 months after randomization. Secondary outcome measures included health-related quality of life (measured by the European Quality of Life 5-Dimension 5-Level Instrument [EQ-5D-5L]), anxiety and depression (measured by the Patient Health Questionnaire), and grip strength.

RESULTS
A total of 233 adults (median age, 53.6 years [IQR, 43.8-60.8 years]; 146 women [62.7%]; 91 [39.1%] hospitalized with COVID-19 infection) were randomized (117 [50.2%] to the intervention group and 116 [49.8%] to the control group). The median percentage adherence with the exercise intervention was 71.0% (IQR, 47.8%-96.8%), equivalent to performing the exercises 5 days per week. The mean (SD) distance achieved in the Incremental Shuttle Walk Test was 328 (225) m for 224 individuals at baseline and 389 (249) m for 193 individuals at follow-up. The mean (SD) change in Incremental Shuttle Walk Test distance at 3 months compared with baseline was 83 (118) m in the intervention group (n = 94) and 47 (95) m in the control group (n = 98) (adjusted mean difference, 36.5 m [95% CI, 6.6-66.3 m];P = .02). By 3 months, compared with the control group, greater improvements in the intervention group were also observed for the health-related quality of life utility score (EQ-5D-5L) (0.06 [95% CI, 0.01-0.11];P = .02), Patient Health Questionnaire category (0.5 [95% CI, 0.2-0.8];P = .01), and handgrip strength (2.6 kg [95% CI, 0.9-4.2 kg];P = .002).

CONCLUSIONS AND RELEVANCE
In this randomized clinical trial, a 3-month program of resistance exercise among adults after COVID-19 infection appeared to improve walking distance, health-related quality of life, anxiety, depression, and grip strength. This pragmatic intervention may be a generalizable therapy for individuals with persisting physical symptoms after COVID-19 infection.

TRIAL REGISTRATION
ClinicalTrials.gov Identifier:NCT04900961

Web | PDF | JAMA Network Open | Open Access

 

[Utsikt]

Seems like the authors are unable to recognise a null result when it’s right in front of them. Shame on them and the editors for that matter.

 

[dave30th]

a null result

you mean because of questions over the MCID? What makes these null results rather than results that appear to be on the margins of clinical significance even if they're statistically significant?

 

[Utsikt]

you mean because of questions over the MCID? What makes these null results rather than results that appear to be on the margins of clinical significance even if they're statistically significant?

The primary outcome had results below MCID, and the other few secondary outcomes that had p<0.05 show so small differences that they aren’t meaningful.

So null result = can’t reject the hypothesis that there is no difference between the groups.

By 3 months, compared with the control group, greater improvements in the intervention group were also observed for the health-related quality of life utility score (EQ-5D-5L) (0.06 [95% CI, 0.01-0.11]; P = .02), Patient Health Questionnaire category (0.5 [95% CI, 0.2-0.8]; P = .01), and handgrip strength (2.6 kg [95% CI, 0.9-4.2 kg]; P = .002).

A change of at least 0.262 and 7.5 for the EQ-5D-5L index and VAS represented the MCID, respectively. Only the EQ-5D-5L VAS showed acceptable discrimination between individuals who were classified as “improved” and those classified as “stable/not improved” (area under the curve = 0.78), although with a low Youden index (Youden index, 0.39; sensitivity, 46.2%; specificity, 93.1%).

Minimal Clinically Important Differences in EQ-5D-5L Index and VAS after a Respiratory Muscle Training Program in Individuals Experiencing Long-Term Post-COVID-19 Symptoms - PMC

The primary aim of this study was to determine the minimal clinically important difference (MCID) for the EuroQol-5D questionnaire (EQ-5D-5L) index and visual analogic scale (VAS) in individuals experiencing long-term post-COVID-19 symptoms. In ...

pmc.ncbi.nlm.nih.gov

Additional, more rigorous, studies are needed to identify MCIDs for grip strength. In the meantime changes of 5.0 to 6.5 kg may be reasonable estimates of meaningful changes in grip strength.

Minimal clinically important difference for grip strength: a systematic review - PMC

[Purpose] The minimal clinically important difference (MCID) in grip strength is critical to interpreting changes in hand strength over time. This review was undertaken to summarize extant descriptions of the MCID for grip strength. [Methods] A ...

pmc.ncbi.nlm.nih.gov

PHQ-4 doesn’t have an MCID as far as I can tell, but on a scale from 0 to 3, a change of 0.5 isn’t much to write home about. But it’s on a questionnaire with unblinded participants, so it’s not really relevant data for clinical practice even if you could argue that it’s a meaningful change.