Comparative effectiveness of [CBT], modafinil, and their combination for treating fatigue in multiple sclerosis (COMBO-MS), 2024, Braley et al

Full title:
Comparative effectiveness of cognitive behavioural therapy, modafinil, and their combination for treating fatigue in multiple sclerosis (COMBO-MS): a randomised, statistician-blinded, parallel-arm trial

Background
Fatigue is one of the most disabling symptoms reported by people with multiple sclerosis. Although behavioural and pharmacological interventions might be partly beneficial, their combined effects have not been evaluated for multiple sclerosis fatigue, or examined with sufficient consideration of characteristics that might affect treatment response. In this comparative effectiveness research trial, we compared the effectiveness of cognitive behavioural therapy (CBT), modafinil, and their combination for treating multiple sclerosis fatigue.

Methods
This randomised, analyst-blinded, parallel-arm, comparative effectiveness trial was done at two universities in the USA. Adults (aged ≥18 years) with multiple sclerosis and problematic fatigue (Fatigue Severity Scale [FSS] score ≥4) were randomly assigned (1:1:1), using a web-based treatment assignment system with minimisation, to receive CBT, modafinil, or both for 12 weeks. Statisticians were masked to group assignment, but participants, study neurologists, CBT interventionalists, and coordinators were not masked to treatment assignment. The primary outcome was the change in Modified Fatigue Impact Scale (MFIS) from baseline to 12 weeks, assessed using multiple linear regression, adjusted for age, sex, study site, anxiety, pain, baselines MFIS score, and physical activity. Analyses were done by intent to treat. The trial was registered with clinicaltrials.gov, NCT03621761, and is completed.

Findings
Between Nov 15, 2018, and June 2, 2021, 336 participants were randomly assigned treatment (114 assigned to CBT, 114 assigned to modafinil, and 108 assigned to combination therapy). At 12 weeks, CBT (n=103), modafinil (n=107), and combination therapy (n=102) were associated with clinically meaningful within-group MFIS reductions of 15·20 (SD 11·90), 16·90 (15·90), and 17·30 (16·20) points, respectively. Change in MFIS scores from baseline to 12 weeks did not differ between groups: relative to combination therapy, the adjusted total mean difference in MFIS change score was 1·88 (95% CI –2·21 to 5·96) for CBT and 1·20 (–2·83 to 5·23) for modafinil. Most common adverse events for modafinil-containing treatment groups included insomnia (eight [7%] for modafinil and eight [7%] for combination therapy) and anxiety (three [3%] for modafinil and nine [8%] for combination therapy).

Interpretation
Modafinil, CBT, and combination therapy were associated with similar reductions in the effects of multiple sclerosis fatigue at 12 weeks. Combination therapy was not associated with augmented improvement compared with the individual interventions. Further research is needed to determine whether effects of these interventions on multiple sclerosis-related fatigue is influenced by sleep hygiene and sleepiness. No serious adverse events related to the study drug were encountered.

Funding
Patient-Centered Outcomes Research Institute and National Multiple Sclerosis Society.

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00354-5/abstract

(Paywalled)

Spoiler: Citation

Braley, Tiffany J et al. 2024, Comparative effectiveness of cognitive behavioural therapy, modafinil, and their combination for treating fatigue in multiple sclerosis (COMBO-MS): a randomised, statistician-blinded, parallel-arm trial, The Lancet Neurology, Volume 23, Issue 11, 1108 - 111, https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00354-5/abstract

 

"The primary outcome was the change in Modified Fatigue Impact Scale (MFIS) from baseline to 12 weeks, assessed using multiple linear regression, adjusted for age, sex, study site, anxiety, pain, baselines MFIS score, and physical activity."


"Change in MFIS scores from baseline to 12 weeks did not differ between groups: relative to combination therapy, the adjusted total mean difference in MFIS change score was 1·88 (95% CI –2·21 to 5·96) for CBT and 1·20 (–2·83 to 5·23) for modafinil."

Would have been interesting to add two more groups: 4) Active Placebo (drug containing another stimulating substance, e.g. caffeine) and 5) Sham CBT

Paywalled so was not able to skim-read beyond abstract.


Edit after a quick online search showed reviews stating Modafinil was effective for MS fatigue, but not sure how good the control was, as short-term stimulating effects of Modafinil are pretty obvious.

 

So, the new common formula of "compare useless things with a weak and biased methodology that attempts to influence subjective outcomes, and conclude from the lack of differences that they are equally effective". I don't think the inventors of comparative trials had in mind this creative perversion of the process, but that it has so easily become normalized in recent years says a lot about the total dysfunction in the clinical trials industry.

Unless the paper has decided to keep those secret for paid users, it looks like this is still not the case. Not that anyone has actually managed to pull this off, ever. Have they perhaps considered asking patients to draw images of their bodies then do spurious analyses? Maybe that will not help at all but, hey, gotta be creative when you built a complete strawman for decades and have to drag its long-desiccated corpse Week-end at Bernie's style.

This is frankly bizarre, but seems to just be a usual "give us money in the future". It just makes no sense to put it there, just some weird pocket sand to deflect from the obvious failure of yet another waste of a useless study.

Also remarkable is the new normal of "we can't blind or control for anything, but our statistical analysts are blinded" is basically the election fraud equivalent of "yes, we trucked boxes of stuffed ballots to every polling place, but the people who counted the votes didn't know that so it's not election fraud" and that it was just as easily accepted as a new standard. All while flagship organizations like Cochrane still, from one corner of their mouth, pretend that such trials are not reliable, but from the other side not only don't mind them, but seem to encourage this practice as a new lowered standard. All they have to do is keep the words saying otherwise and no one cares. What a brave new world we are living in. Like yelling right under a giant "Silence!" banner, about how quiet is good and noise is bad. With trumpets and jackhammers. But the banner, though. But the banner!

I've been watching the upcoming changes in US medical research, how some segments of society are very enthusiastic about pointing out waste and fraud in research, listing specific studies and mocking them as useless, but complete BS like this is never on anyone's radar, and in fact fits perfectly with the new future they have in mind. I wouldn't be surprised if we see yet another round of cancer personalities and other BS. It's all very 'current' and fashionable after all.

 

Discussion on aspects of the trial related to bias due to the lack of blinding see the discussion thread here.

(And sorry, won't be able to read /contribute for a while).