Blacker CVR, Greenwood DT, Wesnes KA, Wilson R, Woodward C, Howe I, Ali T. Effect of Galantamine Hydrobromide in Chronic Fatigue SyndromeA Randomized Controlled Trial. JAMA. 2004;292(10):1195-1204. doi:10.1001/jama.292.10.1195
Author Affiliations: Department of Health and Social Sciences, University of Exeter, Exeter, England (Dr Blacker); Marix Drug Development Ltd, Cardiff, England (Dr Greenwood); PPD Development, Cambridge, England (Ms Woodward); Cognitive Drug Research Ltd, Goring-on-Thames, England (Dr Wesnes); Spica Consultants Ltd, East Grafton, England (Dr Wilson); Shire Pharmaceutical Development Ltd, Hampshire, England (Dr Howe); and Bioenvision Ltd, Edinburgh, Scotland (Mr Ali).
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
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.
Chronic fatigue syndrome (CFS) is a complex disorder characterized by
long-term disability. The rate of spontaneous recovery in CFS is low1 and no consistently effective treatment is available.
Hypoactivity of the hypothalamic-pituitary-adrenal axis has been demonstrated
in some patients with CFS and fibromyalgia.2- 7 Some
evidence suggests that CFS patients may have enhanced sensitivity of the peripheral
cholinergic vascular system and an exaggerated pyridostigmine-stimulated growth
hormone release response.8 Acetylcholine is
implicated in vagal tone, baroreceptor reflexes, and in transmission at the
nicotinic sympathetic ganglia and at the neuromuscular junctions. Patients
with CFS are often intolerant of the anticholinergic adverse effects of tricyclic
antidepressants and these symptoms are similar to the symptoms of CFS. The
frequent complaint of cognitive impairment in CFS also is consistent with
the cholinergic hypothesis of cognition.
A functional deficiency of cholinergic neurotransmission offers one
possible explanation for the findings of a hypoactive hypothalamic-pituitary-adrenal
axis; under conditions of stress, acetylcholine facilitates the release of
corticotrophin-releasing hormone. Cholinergic stimulation also releases growth
hormone with consequent increases in levels of insulin-like growth factor
I, which plays an important role in the regenerative functions of the peripheral
nerves and skeletal muscles.9 In addition,
sleep disturbances are commonly reported in patients with CFS, and it has
been proposed that a disturbance of slow wave sleep, an increase in rapid
eye movement (REM), sleep latency, and prolongation of REM sleep with diminished
REM density may be indicative of a central cholinergic deficiency. In animal
models, the triggering and maintenance of REM sleep has been shown to be under
the control of cholinergic neurons; in humans, cholinergic agonists or cholinesterase
inhibitors lead to an earlier onset of REM sleep.10,11
Galantamine hydrobromide is a selective, reversible, inhibitor of acetylcholinesterase
that is active both peripherally and in the central nervous system by virtue
of its ability to cross the blood-brain barrier. Galantamine is also an allosteric
modulator that enhances the effects of acetylcholine at cholinergic nicotinic
Galantamine was first introduced clinically as an anticurare agent and
has been used to treat Alzheimer disease,12,13 various
neurological disorders,14 and mania.15 When given intravenously, this agent rapidly increases
plasma cortisol levels.16 Additionally, galantamine
decreases REM sleep latency and increases REM density.11 Thus,
several pharmacological properties of galantamine might potentially benefit
patients with CFS; a previous pilot trial with CFS patients suggested that
the drug might be therapeutic.17
In this multicenter, randomized, double-blind, placebo-controlled trial
conducted June 1997 through July 1999, patients with CFS were randomly assigned
to 1 of 5 treatment groups to receive galantamine hydrobromide or matching
placebo. Randomization was in balanced blocks of 5 patients (1:1:1:1:1 ratio)
according to a schedule produced using SAS statistical software (version 6.12,
SAS Institute Inc, Cary, NC). Patients who satisfied all entry criteria at
the randomization visit were assigned at each center the next available (lowest)
patient (randomization) number.
The trial comprised an initial 2-week screening period after which patients
were randomized to receive galantamine or placebo—the doses of which
were both increased by gradual titration over 3 to 8 weeks followed by maintenance
treatment at the target dose for a total of 16 weeks. The 16-week trial duration
was chosen due to the fluctuating nature of CFS; the need to allow adequate
time for a dose titration to minimize patient withdrawal in case of nausea
(based on experiences with galantamine in Alzheimer patients); and to allow
time for sufficient exposure to the highest dose. Assessment visits were scheduled
at 4-week intervals with a follow-up assessment at 4 weeks after the final
dose. In the event of early withdrawal, 2 final assessments took place: 4
weeks after the last dose of medication and again at the originally scheduled
end of treatment (week 16).
Between-center comparisons were planned from the outset on the basis
of potential sample differences between clinic types (rheumatology, neurology,
psychiatry, immunology, and miscellaneous). A separate analysis also was planned
to compare the United States with other countries.
Eligibility requirements included age between 18 and 65 years, modified
US Centers for Disease Control and Prevention diagnosis for CFS,18 and
illness duration of less than 7 years. Patients with a primary diagnosis of
fibromyalgia (defined by the American Rheumatologic Association criteria19) were eligible if they also fulfilled the US Centers
for Disease Control and Prevention modified criteria. The majority of the
study participants were recruited from primary care sources; a few came from
tertiary referral centers. Patients were excluded if they had any of the following
concurrent Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition psychiatric diagnoses: major depressive disorder, psychotic
disorders, panic disorder, substance misuse, somatization disorder, anorexia
or bulimia nervosa, obesity, and sleep disorders. Patients were also excluded
if they had received inpatient psychiatric care, had previously attempted
suicide, or had both. Other exclusions included irritable bowel syndrome,
peptic ulcer, severe asthma, endocrine or metabolic disease, human immunodeficiency
virus infection, neurological disease (eg, epilepsy or multiple sclerosis),
known sensitivity to cholinergic agents, possible exposure to organophosphate
compounds, or a diagnosis of Gulf War syndrome. Pregnant or lactating women
and women with menstrual irregularities associated with fatigue were excluded.
Women of childbearing potential required a negative pregnancy result before
randomization and were requested to use a barrier method of contraception
throughout the trial (in addition to any oral contraception). Participation
in cognitive behavioral therapy or graded exercise programs was not permitted
during the study.
Except for the occasional use of minor analgesics (eg, paracetamol/acetaminophen
and aspirin), no concomitant medication was allowed. Patients taking antidepressant
drugs were required to discontinue use within a minimum of 12 weeks before
randomization. Patients taking any other psychotropic medication were required
to discontinue use 6 weeks prior to randomization. Patients were not allowed
to take the following drugs within 3 months prior to enrollment: cholinergic
agonist or antagonist properties, antihypertensives, drugs interfering with
neuromuscular transmission, corticosteroids, antihistamines, or any other
investigational drugs. Because the most likely unwanted effect of galantamine
was anticipated to be nausea, a nonantimuscarinic antiemetic (domperidone)
was permitted and sometimes was required.
All patients were provided with an information leaflet about the study
and encouraged to take the information home and discuss the trial with their
family. All patients were given the opportunity to ask questions and to receive
adequate responses prior to providing consent for the study. Investigators
in the United States and Europe indicated a patient's ethnicity from a list
containing "white, black, Indian subcontinent, Asian, Hispanic, other (specify)."
All patients provided written informed consent.
Ethics approval was obtained locally at each site before any patients
were screened. The investigators at each site were responsible for obtaining
ethics approval. Regulatory approval was obtained by the study sponsor in
each country that required it according to local regulations.
Following an initial 2-week screening period, patients were randomly
assigned to receive identical tablets of placebo or 1 of 4 doses of galantamine
hydrobromide 3 times per day (2.5 mg [7.5 mg/d]), 5 mg [15 mg/d], 7.5 mg [22.5
mg/d], or 10 mg [30 mg/d]). Patients had their medication dose titrated over
a 3- to 8-week period, commencing at 2.5 mg/d with weekly increments of between
2.5 mg and 7.5 mg depending on the target dose, which was then maintained
for another 8 weeks. The total duration of treatment was 16 weeks.
There is no generally accepted instrument for reliably measuring the
severity or change in symptoms of CFS. However, the Clinician Global Impression
(CGI) Scale has proven validity and reliability in the measurement of change
and is extensively used in therapeutic trials.20 Furthermore,
an analytical review of 24 controlled trials in fibromyalgia advocated the
use of the CGI Scale as the most sensitive and appropriate instrument for
the assessment of change in this closely related condition.21 We
adopted the CGI Scale as the primary measure of outcome (a score of zero indicated
very much improved; 1, much improved; 2, minimally improved; 3, no change;
4, minimally worse; 5, much worse; and 6, very much worse). Following recommendations
by the UK Medicines Control Agency, the outcome categories were dichotomized
for analyses into response or no response in which the scores of zero and
1 were combined to define a positive patient response while all other scores
of 2 through 6 were defined as a nonresponse to treatment. This was on the
advice of the investigators who were primarily interested in detecting a change
that was clinically significant.
Secondary outcome measures focused on change in fatigue intensity, functional
impairment, sleep and quality of life using the Chalder Fatigue Rating Scale,22 the Fibromyalgia Impact Questionnaire,23 the
Pittsburgh Sleep Quality Index,24 and the Nottingham
Health Profile.25 Cognitive function was assessed
with a computerized assessment system (Cognitive Drug Research Ltd, Reading,
This computerized assessment system has been extensively validated and
used in worldwide clinical trials since the mid-1980s. It consists of a series
of computer-administered cognitive tasks, which assess core aspects of attention,
working, and episodic secondary memory. The tests are highly sensitive to
cholinergic compounds and can detect the effects of anticholinesterases including
galantamine in individuals with dementia.26- 33 The
selection of tests used in this study (simple and choice reaction time, digit
vigilance, articulatory and spatial working memory, immediate and delayed
word recall, and word and picture recognition) has been described in detail
previously31 and took between 20 and 25 minutes
to perform. The information is presented on computer monitors and the patients
respond by pressing either a "yes" or "no" button on a response module. Parallel
forms of the tests are automatically selected by the system and presented
at each testing session. Each patient underwent 2 training sessions on the
tests during screening. The same test administrators oversaw the computerized
cognitive assessment at each visit and at the same time of day throughout
Plasma-free cortisol was measured at baseline and after 8, 12, and 16
weeks of treatment. Fasting blood samples for cortisol were obtained at 10:00 AM (±1 hour). For female patients, cortisol assessments were
performed on days 1 through 7 of the menstrual cycle, with day 1 defined as
the first day of bleeding.
Safety assessments included physical and mental examinations, vital
signs, hematology studies, and urinalysis. Adverse events were recorded at
each assessment. Details of menstrual irregularities (eg, breakthrough bleeding)
were also recorded. Mood was monitored throughout using the Beck Depression
Inventory; an increase of 6 points or more compared with baseline or a total
score of 16 or more at any point during treatment necessitated mandatory withdrawal.
The protocol followed a sequential design that provided for interim
analyses of the primary efficacy and safety data; these analyses were conducted
at preplanned intervals by an independent data monitoring committee. Interim
analyses were conducted after the first 50 patients had completed the 16-week
treatment and at intervals of 50 completed patients thereafter. The interim
efficacy analyses of the 16-week CGI assessments were based on the intent-to-treat
(ITT)–retrieved population. This population included all randomized
patients receiving at least 1 dose of study medication. Patients who withdrew
prior to week 16, but who were recalled and reassessed at week 16, were included
with this week 16 assessment, and those who did not return had their last
observation carried forward (LOCF).
At each interim analysis, each galantamine dose was compared with placebo
using the lower stopping boundary of the triangular test.34 The
design had a presumed advantage that any potentially ineffective treatment
dose(s) could be identified and randomization of subsequent patients could
be optimized. Sample size was calculated to detect a 25% or greater improvement
compared with placebo as assessed by the CGI—anything less was considered
The original sample size assumptions allowed a significance level of
5% (2-tailed) and a power of 90% to detect an improvement in the response
rate of 10% with placebo and of 35% with galantamine. Allowance was made for
a withdrawal rate of 30%. Sample size assumptions were reviewed at each interim
analysis. The target sample size was based on the preliminary power calculations
and the second interim analysis of 400 patients (80 per treatment group).
The study design was finalized after consultation with independent clinical
CFS experts, the UK Medicines Control Agency, and prior to the participation
of the US centers, the US Food and Drug Administration.
The primary population for the final analysis was the ITT LOCF population,
which was defined as using only the last treatment assessment. Noncompliant
patients (those who did not take medication, which was measured by tablet
count at each visit) for more than 7 days were permitted to remain in the
study as the primary analysis was planned using an ITT population. The final
analyses were conducted after all patients had completed the study and were
performed on the ITT LOCF and ITT retrieved populations. The models used for
the final analysis tested for an overall treatment effect and consisted of
2-sided tests at the 5% significance level. The null hypothesis considered
that there was no evidence of a difference in the response rate between any
of the galantamine and the placebo treatment groups.
Two analyses of the CGI end point were performed. A logistic regression
was used to analyze the percentage of responders. Factors were fitted for
treatment and country and the latter were excluded from the model if not statistically
significant at the 5% level. The analysis was performed for each analysis
population with and without data imputation for missing data. The CGI score
at end point was also analyzed using the Cochran Mantel-Haenszel test with
modified ridits. In addition to treatment, country (United States vs other
countries), and treatment-by-country interaction, potential prognostic factors
included in the model were speed of symptom onset (gradual, subacute, or acute),
preceding episode of flu (yes or no), duration of illness, and primary symptoms
of CFS. All possible terms (covariates, factors, and interactions) were included
in the first fitted model. The sequential process consisted of removing the
least statistically significant term from the model starting with the interaction
terms and then the covariates and factors. The treatment term was forced to
remain in the model irrespective of the significance level obtained. In addition,
no data imputation was performed in the final exploratory analyses.
Correlation between compliance and CGI response was also investigated.
In the main analysis of the secondary efficacy end points, an analysis of
variance with type 3 sums of squares was performed at the last patient assessment
that complied with the respective analysis population. The model included
treatment and country as factors, and investigated the treatment-by-country
interaction, which was treated in the same way as in the analysis of the primary
end point. The model was applied to each secondary efficacy end point and
tested for an overall treatment effect. Statistically significant treatment
effects were investigated using Dunnett test accounting for multiple comparisons.
Separate treatment comparisons with placebo were made in the event of statistically
significant findings. Due to distributional issues for some secondary end
points, the data were also analyzed using the Kruskal-Wallis test.
A total of 434 patients were recruited from 35 centers (17 in the United
Kingdom, 14 in the United States, 2 in the Netherlands, 1 in Sweden, and 1
in Belgium). The patient population and the number of patients included in
the analysis populations by treatment group are summarized in Figure 1. Patients in the 5 treatment groups were well matched with
regard to demographic characteristics (Table 1). Of all patients randomized, 304 (70.0%) completed the
study and 130 (30.0%) withdrew. A total of 422 patients (97.2%) provided valid
data for inclusion in the ITT LOCF population and 423 (97.5%) for inclusion
in the ITT retrieved population.
Primary End Point. The CGI scores are summarized
in Table 2 and the differences
in percentage of responders compared with placebo during the course of the
trial appears in Figure 2. Responders
were defined as those with CGI scores of zero or 1 (very much or much improved).
The difference between galantamine and placebo response rates was, in all
instances, less than the prespecified level for clinical significance (25%).
Even though more patients were categorized as responders during weeks 12 and
16 in all of the galantamine groups, logistic regression conducted on the
ITT LOCF and ITT retrieved populations failed to demonstrate any statistically
significant difference between any of the groups. Results from the Cochran
Mantel-Haenszel test showed no statistically significant differences in the
distribution of patients in the 7 categories of the CGI Scale for both the
ITT LOCF and the ITT retrieved populations.
The planned exploratory analysis was performed for all centers with
no data imputation to investigate possible influence of the prespecified prognostic
factors. None was found to have a statistically significant influence on the
CGI of either ITT population. Irrespective of treatment (active drug or placebo),
patients who improved during the 16-week double-blind phase exhibited relapse
after withdrawal of medication (Table 2). Logistic regression found no significant differences in outcome
between the different treatment centers (60 for neurology; 24, immunology;
38, rheumatology; 51, infectious disease; 124, psychiatry; and 137, miscellaneous).
Secondary End Points. Observed changes from
baseline for the ITT LOCF population for each of the secondary end points
after 16 weeks of treatment are summarized in Table 3.
Chalder Fatigue Rating Scale. The largest mean
improvement was observed in the physical score for patients in the 5-mg galantamine
group. However, no significant difference was observed in comparison with
placebo. A statistically significant difference was found between the treatment
groups in the mental score for both ITT populations with the greatest difference
between the 5-mg galantamine group and the other dosage groups. However, no
significant difference was observed in comparison with placebo. Patients in
the 5-mg galantamine group who reported memory loss had a greater mean improvement
in the mental score on the Chalder Fatigue Rating Scale.
Fibromyalgia Impact Questionnaire. At 16 weeks,
all but the highest galantamine dose group showed greater mean improvements
in the physical and psychological factor scores in comparison with placebo.
However, the differences were not statistically significant. For the global
well-being factor, all groups exhibited improvements. The greatest mean improvement
was in the 5-mg galantamine group, but this was not statistically significant
compared with placebo. However, there was, a significant country effect for
both ITT populations. The US patients exhibited greater improvement compared
with European patients (P = .01).
Pittsburgh Sleep Quality Index. There were
no statistically significant differences between the galantamine and placebo
groups in total Pittsburgh Sleep Quality Index score or any of the various
subscale scores. Statistically significant (P = .002)
country effects were again observed in both the total score and many of the
subscale scores. The largest mean improvement from baseline was observed in
sleep latency scores in US patients treated with placebo.
Nottingham Health Profile. The greatest mean
improvements were observed in the 2.5- and 5-mg galantamine group (part I
and part II scales, respectively), but neither group was statistically different
from placebo. A country-by-treatment interaction was observed for part II
scales (P = .02). The greatest mean improvements
were observed in European patients in the 2.5-mg galantamine group and in
US patients in the 5-mg galantamine group.
Plasma-Free Cortisol. Plasma levels of cortisol
exhibited an overall decrease from baseline in all treatment groups and both
ITT populations, the greatest mean decrease occurred in the 2.5-mg galantamine
group. However, none of the observed changes were statistically significant.
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.
Analysis of variance was conducted on the ITT LOCF group change from
predosing data, terms being fitted for country, treatment, and the interaction
between them. There were no significant main effects of treatment. However,
the 3 measured effects observed between treatment and country (US vs Europe)
reflected minor differences within active treatments between countries as
opposed to differential placebo-active responding. There was no pattern for
improvement for galantamine compared with placebo (Table 3). Changes in the placebo group were small (the 3 attention
tasks showed a 1.5% overall improvement in speed, while the 4 memory tasks
showed an overall improvement of 3.5% in the sensitivity indices), indicating
that the placebo response did not account for the the absence of treatment
Safety Evaluation. Of the 434 patients who
were recruited, 304 completed the scheduled 16 weeks of treatment; 351 patients
(80.9%) received galantamine hydrobromide; 389 patients (89.6%) reported adverse
events, of which 88 (22.6%) of 389 patients withdrew. The rate of withdrawal
due to adverse events in the placebo group was 15%. Overall, the number of
adverse events increased with higher dosages of galantamine and fewer patients
withdrew from the 2.5-mg galantamine group or from the placebo group compared
with the groups receiving higher dosages. Although there was no statistical
significance between the groups. Of the 130 patients who withdrew, 113 (86.9%)
did so before the midpoint of the trial.
As expected from previous experience with galantamine, the most common
adverse events reported by patients were nausea and headache, but these were
also the most common adverse events reported by those taking placebo. Emergent
depression was another adverse event, which led to 4 patient randomization
breaks during the study. One patient committed suicide in the 10-mg galantamine
group and 3 patients (one in the 2.5-mg galantamine group, one in the 7.5-mg
galantamine group, and one in the placebo group) showed signs of depression
with suicidal ideation. These 4 patients were included in the ITT analysis.
There were 8 serious adverse events, but none was judged to be attributable
to the drug (1 suicide, 1 nonfatal car crash, 4 surgical interventions, 1
lumbar disc prolapse, and 1 transient neurological disorder leading to hospitalization).
The suicide was judged to be unrelated to the trial medication by an independent
safety review panel and the coroner.
To our knowledge, this is the largest completed trial of CFS patients.
Previous trials have been compromised by small sample size, poor randomization,
retrospective analyses, short duration, and lack of standardized outcome measures.35 This study failed to reveal galantamine as a clinically
effective treatment for CFS and fibromyalgia.
Logistic regression analyses failed to identify any consistent factor
predictive of outcome for any of the secondary efficacy measures including
speed of onset (gradual, subacute, or acute), a preceding episode of viral
illness (yes or no), duration of illness, type of clinic referral, or primary
symptoms of CFS.
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.
The small reductions in cortisol levels seen in galantamine and placebo
treatment groups across the 16-week trial were clinically insignificant, but
may reflect reduction of stress secondary to the clinical attention that the
patients were receiving.
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.
Irrespective of treatment, the clinical improvement was consistently
greater in patients treated in the United States compared with the European
centers. This was not explicable on the basis of differences in severity or
demographics, was independent of the treatment group, but it was observed
most often in the 5-mg galantamine group and in the placebo group. There was
no evidence of unblinding of the assessors involved, which could have introduced
a bias in the various outcome measures.
Significant differences between patients in the United States and European
centers were seen in some of the secondary end points with active treatment.
However, the largest observed difference between US and European patients
was seen in those taking placebo. The reasons for this are unclear but could
include a greater willingness of CFS patients in the United States to report
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.
In conclusion, in this study, galantamine did not provide a significant
clinical benefit in the treatment of patients with CFS.