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.

 

[Chandelier]

News article about this study:

Long COVID Patients Should Focus on This Training

Currently, there are over 600 new COVID-19 infections per day in Germany.1 Although most affected individuals recover well, around 5 to 10 percent of patients suffer from long COVID symptoms afterward. A recent study shows how a specific training can provide relief. Follow the FITBOOK channel on...

uk.style.yahoo.com

AI summary:

Long COVID Patients Should Focus on This Training

Strength Training as a Promising Therapy
A recent study suggests that strength training can help long COVID patients recover physically and mentally. In Germany, around 5 to 10 percent of COVID-19 patients continue to experience long-term symptoms. Scottish researchers found that targeted strength exercises could serve as an effective therapy for these individuals, improving their quality of life and overall health. Because reliable data on long COVID cases is limited, developing effective treatments is seen as increasingly important.

Study Design and Participants
The study was conducted by the University of Glasgow in cooperation with the University of Dundee and three Scottish hospitals. It included 233 patients—146 women and 87 men, with an average age of 53.6—who had suffered from COVID-19 within the previous year and continued to experience long COVID symptoms. Participants were divided into two groups: one received personalized strength training in addition to standard treatment, while the other received only the usual care. Progress was measured using the “Shuttle Walk Test,” which assesses endurance and physical capacity.

Results of the Training Program
After three months, the strength-training group showed clear improvement. These participants were able to walk 83 meters farther than before, while the control group improved by only 47 meters. On average, strength training added 36.5 meters more to walking distance compared to no training. Participants in the training group also reported better quality of life, less anxiety and depression, and improved grip strength. According to Professor Colin Berry, the lead author, these findings confirm the benefits of strength training for long COVID recovery.

Practical Application and Limitations
While the results are promising, general recommendations are difficult because the training was personalized. Depending on their condition, patients exercised lying down, sitting, or standing. Upper-body exercises were introduced first, followed by lower-body ones after three weeks. Professional supervision would likely be required to tailor programs effectively. Professor Stuart Gray emphasized that the exercises were designed to be safe and easy to perform anywhere, making them adaptable for broader use. However, it remains uncertain whether endurance or other types of training would yield similar benefits. Long COVID patients are advised to consult their doctors before starting such programs.

 

[dave30th]

The primary outcome had results below MCID

is that clearly the case? by the reference cited, it did meet the MCID from a 2019 analysis. But as ME/CFS skeptic pointed out, their power calculations used a different value.

 

[forestglip]

Someone added a comment to the paper (scroll to the bottom):

Misleading interpretation of the null results?
First paragraph:

In the Statistical Analysis plan, the authors state that "[t]he minimum clinically important between-group difference in the ISWT at follow-up (3 months) = 46 m, SD=105 [20]." The adjusted mean difference between the groups was 36.5 m, well below the threshold of MCID.

 

[forestglip]

that seems to be unclear. by the standard cited, it did meet the MCID.

As far as I can tell, they didn't actually cite the 35 m minimum clinically important difference in the present paper. That was a quote from the preprint:

Resistance Exercise Therapy for Long COVID: a Randomized, Controlled Trial, 2025, Research Square

A 12-week program of personalized resistance exercise in a population of community- and post-hospitalized individuals with Long COVID improved exercise capacity. The effect size exceeded the minimum clinically important difference of 35.0 m [13].

But they removed that mention of the MCID in the peer-reviewed paper. And I don't see any other mention of an MCID in the paper, apart from the power analysis in the supplementary protocol file which used 46 m.

And I might be missing something, but in the paper they cited for an MCID of 46 m, it looks like it's supposed to be 47 m:

Use of exercise testing in the evaluation of interventional efficacy: an official ERS statement, 2016, European Respiratory Journal

The MCID value for the ISWT was set at 47 m [180, 184], with additional benefits reported at 79 m [184] (table 2).

There's also this newer 2025 meta-analysis of minimum important differences for the ISWT which might be better to rely on than the older studies.

Determining the minimum important differences for field walking tests in adults with long–term conditions: a systematic review and meta-analysis, 2025, European Respiratory Review

The MID for the ISWT was 48 m (39–57 m) for respiratory conditions and 70 m (55–85 m) for cardiac conditions.

 

[dave30th]

That was a quote from the preprint:

Ah, thanks for noting that. I'll have to take a closer look. that does sound quite fishy.

 

[dave30th]

we recently discussed another study with some confusion over the MCID for the ISWT

Post in thread 'Post-Hospitalisation COVID-19 Rehabilitation (PHOSP-R): A randomised controlled trial of exercise-based rehabilitation, 2025, Daynes et al'

Mar 1, 2025

Apologies for the mess of cross-references, I’m struggling with formating in my phone!

There was an improvement in the ISWT distance following face-to-face rehabilitation (mean 52 [95% CI 19 to 85]m, p=0·002) and remote rehabilitation (mean 34 [95% CI 1 to 66]m, p=0·047) compared to usual care alone.

The face-to-face rehabilitation group improved from 285 [219 to 351] m to 312 [244 to 380] m (p<0·001).

@dave30th :

After the intervention, the average increase in the IWST for the face-to-face and remote groups was...

• Utsikt

• 

I mentioned the issues in that study related to the MCID in this post.

 

[rvallee]

News article about this study:

Long COVID Patients Should Focus on This Training

Currently, there are over 600 new COVID-19 infections per day in Germany.1 Although most affected individuals recover well, around 5 to 10 percent of patients suffer from long COVID symptoms afterward. A recent study shows how a specific training can provide relief. Follow the FITBOOK channel on...

uk.style.yahoo.com

AI summary:

After three months, the strength-training group showed clear improvement. These participants were able to walk 83 meters farther than before, while the control group improved by only 47 meters. On average, strength training added 36.5 meters more to walking distance compared to no training.

It doesn't get more pathetic than just trying to make this into something meaningful. Balance bracelets have a more compelling marketing pitch and they're totally worthless. It reminds me of this picture, it's exactly as convincing:



"Take those expensive supplements and after several weeks, you too could look a bit redder and puffier, as long as you clench really, really hard"

Plus, what the hell does strength training even have to do with walking 37 metres, when it's such a short distance that it obviously requires zero training whatsoever?

Humanity is suffering from a crisis of lack of shame. Everyone involved in this should be deeply ashamed of pretending this is worth even a single damn cent. But they're not, because basic responsibility and accountability are just plain gone.

 

[Utsikt]

I have no idea how you’d qualify as being a patient if you could walk >1000m during an ISWT at baseline.

From @dave30th

A 2013 study called “Age-specific normal values for the incremental shuttle walk test in a healthy British population” found that the average distance walked during the ISWT by those in their 40s, 50s, 60s, and over 70 were, respectively, 824 meters, 788 meters, 699 meters, and 633 meters.

So the mean distance walked after 3 months is still half of a healthy 50-60 year old. This study:

median age, 53.6 years [IQR, 43.8-60.8 years].

Some poor soul only made it 40 meters. I’d be able to do more, and I’ve been bedbound for more than a year.