Effect of Galantamine Hydrobromide in Chronic Fatigue Syndrome A Randomized Controlled Trial, 2004, Blacker et al.

[ME/CFS Skeptic]

(Note that this is an old study from 2004)

Abstract
Context: There is no established pharmacological treatment for the core symptoms of chronic fatigue syndrome (CFS). Galantamine hydrobromide, an acetyl cholesterone inhibitor, has pharmacological properties that might benefit patients with CFS.

Objective: To compare the efficacy and tolerability of galantamine hydrobromide in patients with CFS.

Design, setting, and patients: Randomized, double-blind trial conducted June 1997 through July 1999 at 35 outpatient centers in the United Kingdom (n = 17), United States (n = 14), the Netherlands (n = 2), Sweden (n = 1), and Belgium (n = 1) involving 434 patients with a clinical diagnosis of CFS (modified US Centers for Disease Control and Prevention criteria).

Interventions: A total of 89 patients were randomly assigned to receive 2.5 mg of galantamine hydrobromide; 86 patients, 5.0 mg; 91 patients, 7.5 mg; and 86 patients, 10 mg (these patients received medicine in the tablet form 3 times per day); a total of 82 patients received matching placebo tablets 3 times per day.

Main outcome measures: The primary efficacy variable was the global change on the Clinician Global Impression Scale after 4, 8, 12, and 16 weeks of treatment. Secondary outcomes were changes in core symptoms of CFS on the Chalder Fatigue Rating Scale, the Fibromyalgia Impact Questionnaire, and the Pittsburgh Sleep Quality Index; changes in quality of life on the Nottingham Health Profile; and assessment of plasma-free cortisol levels and cognitive performance on a computer-based battery of tests.

Results: After 16 weeks, there were no statistically significant differences between any of the galantamine or placebo groups in clinical condition on the Clinician Global Impression Scale, or for any of the secondary end points. Exploratory regression analysis failed to detect any consistent prognostic factor that might have influenced the primary or any secondary outcome measures.

Conclusion: This trial did not demonstrate any benefit of galantamine over placebo in the treatment of patients with CFS.

https://jamanetwork.com/journals/jama/fullarticle/199392

 

[ME/CFS Skeptic]

This is apparently the largest drug trial ever done in ME/CFS patients. It tested the use of galantamine (an acetyl-cholinesterase inhibitor that is used to treat cognitive decline in for example Alzheimer's) at 4 different doses against a placebo.

434 ME/CFS participated in the trial in multiple centers around the world (including Belgium). Unfortunately, no positive effect was found for any of the doses of galantamine.

I had never heard of the trial. Does anyone know more about it and the driving forces behind it?

 

[Hutan]

Thanks for posting the trial @Michiel Tack.

Certainly a lot of effort was put into it, and it seems to have been well done.

Some of the baseline data is interesting and potentially useful, given that it comes from a large and geographically diverse sample. See for example this finding for cognitive function:

Cognitive Function. Patients in this trial showed marked and significant slowing (all P<.02 or better) on all measures of response speed compared with an age-matched control group selected from the CDR normative database (simple reaction time: 329 ms vs 254 ms; choice reaction time: 490 ms vs 424 ms; digit vigilance speed: 441 ms vs 400 ms; articulatory working memory speed: 827 ms vs 695 ms; spatial working memory speed: 950 ms vs 897 ms; word recognition speed: 947 ms vs 815 ms; and picture recognition speed: 1014 ms vs 923 ms, respectively). While the ability to detect the targets in the digit vigilance task was also significantly impaired, the patients did not show impaired accuracy on the working and recognition memory tasks.

To illustrate the magnitude of the impairments, the simple reaction time for patients with a mean age range of 37 to 39.1 years was 329 ms, which is longer than the simple reaction time of 308 ms from the normative database32 for the highest age cohort of 80 to 87 years. All response measures were normally distributed.

The lack of effect of galantamine on cognitive performance was surprising given the extent of the patients' cognitive impairment at baseline. The computerized cognitive assessment system used in this study has shown sensitivity to improvements with galantamine, particularly to attentional deficits in 4 previous trials in cohorts of Alzheimer patients.28-30,33 Given the known benefits of anticholinesterases in Alzheimer disease, this suggests that the cognitive deficits seen in CFS are not due to cholinergic dysfunction.

 

[Hutan]

This was interesting re placebo response rates:

Of potential interest for future studies of CFS is the nature and magnitude of the placebo response we observed. Sharpe et al36 and Warren et al37 state that placebo response rates in CFS are high, but (in contrast to placebo response rates in trials of psychiatric disorders) the present study obtained a rate of only 16.5%. We found that placebo response rates were higher in patients recruited from the United States, which may reflect recruitment biases.

I expect placebo response rates depend on how strongly the treatment is 'sold'.

An important finding of the present investigation was that the proportion of placebo responders (defined as CGI score of 0 or 1) increased steadily over the the trial (4 weeks, 10.5%; 8 weeks, 16.6%; 12 weeks, 15.0%; 16 weeks, 18.4%). After medication (galantamine or placebo) was withdrawn, the placebo response of 50% dropped sharply by week 4 follow-up to 9%. We believe that the improvement we observed across time (Figure 2) was due to nonspecific aspects of the trial setting. This has important implications for the interpretation of outcomes from various treatment programs for CFS patients who continue to improve while in contact with specialist services, but relapse when discharged back to primary care.

This study may be useful when explaining the issues with subjective outcomes in unblinded trials with inadequate controls.

 

[James Morris-Lent]

Isn't there still some interest in pyridostigmine? This result would seem to make that less plausible as these drugs both act by increasing acetylcholine activity.

Seems to be a pretty impressive trial that has flown under the radar.

 

[adambeyoncelowe]

This study was also included in the current (draft) NICE pharma evidence review, if that helps.

 

[MSEsperanza]

This study may be useful when explaining the issues with subjective outcomes in unblinded trials with inadequate controls.

And may be also for arguing that there exist useful objective measures to assess cognitive performance, e.g. response speed? (see Hutan's post before the one I quoted.)

@Snow Leopard @Woolie @Jonathan Edwards @Carolyn Wilshire

(Discussion on that topic here. )

 

[ME/CFS Skeptic]

Seems that the study was funded by a pharmaceutical company. It reads:

Funding/Support: This research was sponsored and funded by Shire Pharmaceutical Development Ltd, Andover, England

Some of the researchers involved in the study: Behan in the UK, Van der Meer in the Netherlands, De Meirleir in Belgium, Klimas in the US etc. Michael Sharpe was on the Data Monitoring Committee.

 

[Hutan]

Posts about another paper have been moved to a new thread:
Exploratory open label, randomised study of acetyl- and propionylcarnitine in CFS, 2004, Vermeulen and Scholte