ORIGINAL RESEARCH ARTICLE Clin Drug Invest 2002; 22 (11): 731-740

1173-2563/02/0011-0731/$25.00/0

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Nicergoline in Balance Alterations

in Adult and Elderly Patients
A Double-Blind, Placebo-Controlled Study
Giovanni Felisati1, Angelo Battaglia2, Maria Grazia Papini2, Bianca Maria Rossini2 and
Oreste Pignataro3 on behalf of the Nicergoline Dizziness Study Group*
1 ENT Department, San Paolo Hospital, Milan University Medical School, Milan, Italy
2 Medical Department, Pharmacia Italia, Milan, Italy
3 2nd ENT Department, Milan University Medical School, Milan, Italy

* See page 739 for members of the study group.

Abstract Objective: To evaluate the efficacy and safety of nicergoline in the treatment of
balance disorders of central origin in adult and elderly patients.
Design and setting: Prospective, double-blind, placebo-controlled, parallel-
group, randomised trial of nicergoline 30mg twice daily and placebo administered
for 3 months. After baseline evaluation, patients were assessed monthly for
efficacy and safety. The study was carried out in outpatients in five centres in Italy.
Patients: Eighty-nine adult and elderly outpatients (mean age 67.1 years) with
balance disorders of central origin.
Interventions: At baseline, a complete clinical and instrumental otoneurological
examination was carried out and the Vertigo-Dizziness Differential Diagnosis
Score was calculated. Efficacy was assessed by the Dizziness Assessment Rating
Scale (DARS), Dizziness Handicap Inventory (DHI) and static posturography.
The safety evaluation included monitoring of adverse events, vital signs, haema-
tology and blood chemistry.
Main outcome measures and results: The DARS total score was significantly
reduced by both treatments; however, score change from baseline was signifi-
cantly greater in the nicergoline group compared with the placebo group from the
first month of treatment (p = 0.002). The between-treatment difference further
increased (p < 0.001) in the following 2 months of treatment up to the end of the
study. The DHI score change from baseline was also significantly greater in the
nicergoline group compared with placebo (p < 0.001) at all timepoints, both for
the total score and for all domains (functional, emotional and physical). A strong
correlation was observed between DARS and DHI total score change from base-
line. Static posturography measurements indicated an improvement for almost
all considered variables in the nicergoline group, although no statistically signi-
ficant difference was observed compared with placebo; however, significant
changes from baseline were observed only in the nicergoline group. Adverse
events were observed in 4.5% of the nicergoline and 4.4% of the placebo patients.
Conclusions: Nicergoline is an effective and well tolerated treatment for the
clinical symptoms related to central vertigo and improves the quality of life of
patients with dizziness.
732
Balance is the result of the integration of multi-
ple sensory inputs, including auditory, visual,
propioceptive and vestibular signals, that allows
the correct appraisal of the body’s static and
dynamic position in space. During aging, a pro-
gressive deterioration of the sensory systems is
likely to occur;[1] moreover, a concurrent reduced
efficiency of central processing may determine a
marked reduction of the physiological redundancy
of control systems, even in the absence of clinical
manifestations of dysequilibrium. In older adults
in particular, equilibrium may be considered as the
final result of many compensatory adjustments
following the accumulated effects of impairments
of sensory inputs at the expense of the system’s
redundancy. Under these circumstances, even
minor malfunctions in the system may impair func-
tional capacity. Balance disorders in the elderly
often arise as a result of a functional insufficiency
of a system that can no longer successfully cope
with progressively failing sensory input.
Older patients often complain of dizziness, a
feeling of imbalance or unsteadiness, due to loss of
global efficiency of the balance system. Vertigo,
on the contrary, arises from specific damage or im-
pairment of a sensory modality.[2-5] Some authors
have suggested terms such as ‘presbyequilibrium’
or ‘presbyastasis’ to define the paraphysiological
decline in balance function during aging (primary
dysequilibrium of aging).[6,7]
In the past two decades, geriatric research has
attempted to correlate the decline of select brain
functions with the deficit of specific neurotrans-
mitters. Recently a different view is gaining accep-
tance, that in complex systems, such as balance
control, multiple transmitters interact within the
neural network to support function. Therefore, the
disruption of a specific sensory or integrative
pathway leads to the neurochemical and functional
resetting of the entire neural network. The failure
of this compensatory mechanism results in the
clinical appearance of symptoms.
In balance compensation, especially during the
failure of vestibular input, substitute mechanisms
seem to prevail when signals from other sources
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Felisati et al.
are used as substitute sensory information, inte-
grated with new behavioural strategies.[8] This
neurofunctional hypothesis is supported by the
positive effect exerted on vestibular compensation
by drugs affecting learning and memory processes
as corticotrophin (ACTH) fragments[9-13] and N-
methyl-D-aspartate (NMDA) receptor agonists.[14]
Based on these considerations, other drugs that
positively affect cognitive processes may also
improve compensation within the balance system.
Nicergoline (Sermion®,1 Pharmacia, Italy) is a
semisynthetic ergoline derivative used for the
treatment of cognitive impairment in various forms
of dementia. A clinically and statistically signifi-
cant effect compared with placebo of long-term
treatment with nicergoline on key symptoms of
the disease has been observed in clinical studies
carried out in patients with primary degenerative,
multi-infarct and mixed forms of dementia.[15-18]
Animal studies have shown that the drug exhibits
a broad spectrum of actions on cellular and molec-
ular mechanisms involved in the pathophysiology
of dementia: it enhances cholinergic and cate-
cholaminergic neurotransmitter function and im-
proves age-related cognitive deficits, stimulates
phosphoinositide turnover, modulates transloca-
tion of protein kinase C (PKC) and PKC-mediated
α-secretase processing of amyloid precursor pro-
tein, protects neurons from death induced by
oxidative stress or apoptosis, and interacts with
endogenous nerve growth factor-mediated pro-
cesses providing trophic support to cholinergic
neurons.[19] In animal models of labyrinth lesions,
the drug has been specifically shown to be effec-
tive on vestibular compensation.[20]
The clinical effect of nicergoline in the treat-
ment of vestibular disturbances has been investi-
gated in a number of clinical open-label studies.[21-25]
This paper presents the results of a double-blind,
placebo-controlled, randomised study of nicergol-
ine 60mg daily administered for 3 months to adult
and elderly patients complaining of dizziness.
1 Use of tradenames is for product identification only and
does not imply endorsement.
Clin Drug Invest 2002; 22 (11)
Nicergoline in Balance Disorders
Patients and Methods
Patients
Female and male outpatients 50–85 years of
age with symptoms of balance disorders of central
origin were selected. To ensure a homogeneous
group, patients were evaluated through a complete
clinical and instrumental otoneurological exami-
nation and scored according to the Vertigo-Dizzi-
ness Differential Diagnosis Score (VDDDS).[22]
The VDDDS is a tool to summarise the clinical and
instrumental diagnostic procedures, and rates clin-
ical features associated with peripheral or central
vertigo (table I). The scores are weighted for pe-
ripheral vertigo. The single scores are summed to
provide a total score: higher values indicate pe-
ripheral origin. Cut-off points are: ≤4 (probable
central origin); 5–6 (possible central origin); ≥7
(probable peripheral origin).
Patients with peripheral vertigo were excluded,
as were: patients with neurological disease of vas-
cular, infectious, neoplastic, toxic or degenerative
nature; patients with severe and/or unstable organ,
body system or toxic-metabolic diseases; patients
with orthostatic hypotension or severe hyperten-
sion, not pharmacologically controlled; patients
Table I. Scoring system for the Vertigo-Dizziness Differential Diag-
nosis Scale (VDDDS)[22]
Features that apply to patient
Dizziness: nonspecific symptom of imbalance, a feeling
of instability/unsteadiness rather than vertigo
Rotatory vertigo
Sudden onset, temporally well defined
Gradual onset, temporally not well defined
Associated nausea
Associated vomiting
Dizziness also on lying down
Dizziness worsened by sharp movements of the head
Bedridden during dizziness
Restricted daily life activities
Spontaneous nystagmus, unidirectional
Barré harmonic vestibular syndrome (all spontaneous
vestibular signs toward damaged side)
Concomitant cochlear symptoms (tinnitus, impaired
hearing, fullness)
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733
treated with antivertigo drugs (betahistine, pheno-
thiazine, papaverine) or with calcium channel ant-
agonists such as flunarizine or nimodipine or with
other ergot alkaloids such as hydergine or di-
hydroergocristine; patients treated with nootropic
or vasoactive medications; women of childbearing
potential; unreliable or uncooperative patients.
Concomitant treatment for coexisting diseases was
allowed within the limits indicated in the exclusion
criteria.
Each patient provided written informed con-
sent. The trial was carried out according to Good
Clinical Practice guidelines and the trial proce-
dures were in accordance with the ethical stand-
ards of institutional committees on human experi-
mentation and with the Helsinki Declaration.
Study Design
This was a randomised, double-blind, placebo-
controlled, parallel-group, prospective clinical
trial. After a 2-week washout period, eligible
patients were randomly allocated to placebo or
nicergoline 60mg daily, in two separate daily
doses, for 3 months, according to a computer-
generated randomisation code. Assessments were
performed at baseline (before the first dose) and
then every month for efficacy and safety. The 3-
month evaluation, or the endpoint assessment, was
considered as the primary efficacy endpoint.
Point
value Efficacy Evaluation
0
The primary efficacy parameter was the Dizzi-
2
ness Assessment Rating Scale (DARS).[22] The
2
0
DARS is a semiquantitative severity scale that as-
1 sesses imbalance, standing and walking, severity
2 of present dizziness, severity of dizziness in the
1 previous week, and confusion/disorientation; it
1 also provides a physician’s and patient’s global
2 assessment (table II). Severity of symptoms is
1
scored according to a 7-point scale (0 = none or
2
normal; 6 = severe) Specific and detailed instruc-
2
tions for four anchor scores (0, 2, 4, 6) were
3 provided to reduce interindividual variability of
response.[22]
Clin Drug Invest 2002; 22 (11)
734
Table II. Scoring system for the Dizziness Assessment Rating
Scale (DARS) [22]
Dysequilibrium (standing)
Dysequilibrium (walking)
Dizziness (now)
Dizziness (past week)
Feeling confused or disoriented
Global impression (physician)
Global impression (patient)
Score: 0 = none; 1 = very mild; 2 = mild; 3 = mild to moderate;
4 = moderate; 5 = moderate to severe; 6 = severe.
Additional measures were the Dizziness Hand-
icap Inventory (DHI)[26] and static posturogram
(French Association of Posturology) with the
Amplifon SVeP.[27]
The DHI, a self-assessment scale, evaluates the
self-perceived handicapping effects imposed by
the balance system disorder. It includes 25 items
subgrouped into three domains representing func-
tional, emotional and physical aspects of dizziness
and unsteadiness. Handicap is scored as 0 = none,
2 = occasional, 4 = present.
Static posturography provides precise, repeat-
able information regarding a person’s posture and
subsequent postural strategy by measuring dis-
placements of the centre of gravity during time.
Static posturography was performed using a stand-
ard platform.[27] Sway area (area of displacement
of the centre of gravity) and tracing length (length
of the trajectory of adjustments of the centre of
gravity) were recorded (with eyes open and
closed). Posturography was assessed at baseline
and after 3 months of treatment.
Safety Evaluation
Safety evaluation included monitoring of
adverse events, vital signs, haematology and blood
chemistry. Haematology and blood chemistry were
assessed at baseline and at the last assessment.
Statistical Analysis
A study sample size of 84 patients was calcu-
lated to provide 80% power with a level of 0.05
(two-tailed) to detect at least 3.4 points difference
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Felisati et al.
(30%) between treatment groups on the DARS;
standard deviation was assumed to be equal to 5.5
points. All hypothesis tests were two-sided; statis-
tical significance was set at a critical level of p <
0.05.
The characteristics at entry were described and
tested for comparability. Continuous demographic
variables were analysed using Student’s t-test for
independent samples and categorical variables by
means of the chi-squared (χ2) test. Efficacy and
safety analyses were performed on an intention-to-
treat (ITT) patient sample, including all patients
randomised to treatment who received at least one
dose of the study drug and who were assessed at
least once post-treatment. When the endpoint
assessment was missing, the last-observation-
carried-forward (LOCF) method was used. More-
over, observed case analysis ‘per protocol’ (PP)
was performed on randomised patients fulfilling
all protocol criteria and assessed at designated
times. Analysis of covariance (ANCOVA) was
used to assess the differences in efficacy measures
due to time, treatment and their interaction, and the
DARS baseline value was considered as a covari-
ate. Additionally, the same statistical approach was
applied to two subgroups of patients selected ac-
cording to age (<65 years, >65 years). DARS total
score at endpoint and score change from baseline
were considered as the primary efficacy measures.
DHI total and subgroup scores, sway area and trace
length (with eyes open and closed) values were
evaluated in terms of change from baseline by
Student’s t-test for independent samples. In addi-
tion, a further index[28] of the influence of visual
input over posture control was calculated as:
area eyes closed − area eyes open
× 100
area eyes closed + area eyes open
to classify patients into two groups: <0, nonvisual
preferential strategy; >0, visual preferential strat-
egy. McNemar’s test was used to evaluate varia-
tion of control modality between treatment groups.
A further additional categorical description of
DARS and DHI results was performed to evaluate
Clin Drug Invest 2002; 22 (11)
Nicergoline in Balance Disorders
the rate of response to treatment in the nicergoline
and placebo groups and was expressed as percent-
age distribution of patients exhibiting <30%,
30–50% or >50% score improvement at endpoint.
In addition, parametric (Pearson’s) and nonpar-
ametric (Spearman’s) tests were used to evaluate
linear correlation between the DARS and DHI
scores; partial correlation coefficients were calcu-
lated in order to have the actual relationship be-
tween the scores of the two instruments after
weighting for the main variables (treatment, age,
basal scores).
Adverse events were described and analysed for
frequency and severity. Individual patient changes
in laboratory tests or vital signs were evaluated
taking into consideration values outside the normal
range.
Results
Eighty-nine patients, 34 male and 55 female,
mean age 67.1years (SD 7.8) were randomised to
treatment, 44 to nicergoline and 45 to placebo. Of
the 89 patients, 50 (56%) were aged more than 65
years, 28/44 (64%) in the nicergoline group and
22/45 (49%) in the placebo group. Three patients
(3.4%) discontinued treatment: one in the
nicergoline group and two in the placebo group –
one patient was evaluated only at baseline, and two
patients discontinued treatment after 1 and 2
months. The baseline characteristics for the ITT-
LOCF patient sample are listed in table III. The
PP dataset included 86 patients whose baseline
characteristics closely reflected the ITT data.
Treatment groups were comparable for all baseline
characteristics.
Table III. Baseline demographic data
Characteristic
Male (%)
Female (%)
Age (y) [mean ± SD]
Height (cm) [mean ± SD]
Weight (kg) [mean ± SD]
Vertigo Dizziness Differential Diagnosis Score (VDDDS) [mean ± SD]
Dizziness Assessment Rating Scale (DARS) total baseline score (mean ± SD)
Dizziness Handicap Inventory (DHI) total baseline score (mean ±± SD)
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735
With regard to disease characteristics, only 9%
of all patients experienced rotatory vertigo; 80%
of patients presented with specific chronic or re-
curring symptoms of unsteadiness or imbalance.
Onset of symptoms was smooth in 60% of all
cases. Autonomic symptoms of nausea and vomit-
ing were reported by 62% of placebo recipients
and 43% of nicergoline-treated subjects; 89% of
nicergoline and 67% of placebo recipients pre-
ferred to lie down when experiencing symptoms.
Disease severity was rated as mild to moderate in
62% of patients and as moderate to severe in 38%
of patients.
Efficacy
Dizziness Assessment Rating Scale
During the study, the DARS total score was sig-
nificantly reduced compared with baseline condi-
tions (p < 0.001) with both treatments; however,
score reduction from baseline was significantly
greater in the nicergoline group compared with the
placebo group from the first month of treatment
(p = 0.002). The between-treatment difference
further increased (p < 0.001) until the end of the
study. Percentage score decrement at endpoint was
57.2% for nicergoline and 27% for placebo recip-
ients. Score values at all assessments, score change
from baseline and percentage change are shown in
table IV. The total score distribution by age group
indicated a less pronounced response in ‘older’
placebo patients compared with the corresponding
‘younger’ placebo group; response to nicergoline
treatment was comparable irrespective of age
(table V). Responders’ analysis also indicated a
greater proportion of nicergoline patients showing
Nicergoline (n = 44) Placebo (n = 45)
43.2 33.3
56.8 66.7
68.3 ± 7.9 65.9 ± 7.7
165.9 ± 7.5 165.0 ± 8.4
70.3 ± 8.6 67.3 ± 10.8
3.3 ± 1.5 3.2 ± 1.6
21.5 ± 6.9 20.7 ± 7.3
49.1 ± 24.1 49.2 ± 23.0
Clin Drug Invest 2002; 22 (11)
736 Felisati et al.

more than 50% improvement and a lower pro-

portion showing less than 30% improvement com- 80 Nicergoline

pared with placebo patients (figure 1). Placebo

70
60
Secondary Assessments

Patients (%)
DHI total score (table VI) also improved in both 50

experimental groups, but to a significantly greater 40

extent with nicergoline treatment (p < 0.001).
Score change from baseline at all timepoints and at
endpoint was significantly more pronounced (p <
0.001) in the nicergoline group compared with the
placebo group. The total score was significantly
reduced compared with placebo as early as from
the first month of nicergoline treatment (p =
0.006). The improvement observed in nicergoline
patients was evenly distributed within the three
main domains evaluated: functional, emotional
and physical. A significant difference between
treatment groups in favour of nicergoline was ob-
served for the score change from baseline within
each domain (p < 0.001). Moreover, whereas in the
nicergoline group the individual score of all do-
mains was significantly reduced compared with
baseline at all timepoints, in the placebo group sig-
nificant responses within each domain were not
as consistently distributed (table VI). The
overall drug-placebo difference of effect was: 15.4
± 2.4 points (95% CI 10.5–20.2) for the total score;
30
20
10
0
<30% 30–50% >50%
Improvement vs baseline
Fig. 1. Dizziness Assessment Rating Scale (DARS) total score:
frequency distribution of patients with <30%, 30–50%, and
>50% score change at endpoint compared with baseline.
5.1 ± 1.2 points (95% CI 2.8–7.4) for the functional
domain; 5.3 ± 1.1 points (95% CI 3.0–7.6) for the
emotional domain; 4.9 ± 1.1 points (95% CI 2.7–
7.2) for the physical domain.
As already observed for DARS data above, the
DHI responder analysis indicated a more favour-
able distribution of response in the nicergoline
treatment group, rates of 30–50% and >50% im-
provement being observed more frequently in the
nicergoline patients while <30% improvement

Table IV. Dizziness Assessment Rating Scale (DARS) total score (mean ± SD) at baseline and after 1, 2 and 3 months of treatment in the
two experimental groups (intent-to-treat–last-observation-carried-forward [ITT-LOCF] analysis). Score changes from baseline are significant
in both experimental groups
Group Baseline Month 1 Month 2 Month 3 Change from Change (%)
baseline
Nicergoline (n = 44) 21.5 ± 6.9 15.0 ± 7.3a 11.5 ± 6.4b 9.2 ± 6.4b 12.3 ± 5.9b 57.2
Placebo (n = 45) 20.7 ± 7.4 17.4 ± 7.4 16.7 ± 8.1 15.1 ± 8.2 5.6 ± 6.0 27.0
a p = 0.002 vs placebo.
b p < 0.001 vs placebo.

Table V. Dizziness Assessment Rating Scale (DARS) total score (mean ± SD), distribution according to age group (intent-to-treat–last-ob-
servation-carried-forward [ITT-LOCF] analysis)
Age (y) Treatment Change from Drug-placebo difference p-Value
baseline (95%CI)
≤ 65 Nicergoline (n = 16) 12.1 ± 5.7 5.7 ± 1.9 (1.7 – 9.8) 0.007
Placebo (n = 23) 6.4 ± 6.4
>65 Nicergoline (n = 28) 12.0 ± 6.2 7.5 ± 1.7 (4.2 – 10.9) 0.001
Placebo (n = 22) 4.5 ± 5.5

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Nicergoline in Balance Disorders 737

Table VI. Dizziness Handicap Inventory (DHI) total score (mean ± SD) at baseline and after 1, 2 and 3 months of treatment in the two
experimental groups (per-protocol analysis)
Score Baseline Month 1 Month 2 Month 3 Change from baseline
Nicergoline (n = 43)
Total score 49.1 ± 24.1 37.5 ± 21.0a,b 31.6 ± 22.6b,c 27.3 ± 19.7b,c 21.8 ± 11.7c
Functional 17.9 ± 9.0 14.4 ± 8.2b
11.9 ± 8.6 b
10.2 ± 7.3b
7.6 ± 5.4
Emotional 16.5 ± 10.5 11.7 ± 8.6b 10.2 ± 9.2b 8.7 ± 7.8b 7.7 ± 5.1
Physical 14.8 ± 6.5 11.4 ± 5.6b 9.5 ± 6.0b 8.3 ± 5.9b 6.5 ± 5.6

Placebo (n = 43)
Total score 49.2 ± 23.0 43.8 ± 24.8d 44.5 ± 26.5e 42.7 ± 26.2b 6.5 ± 10.6
Functional 18.1 ± 9.4 16.1 ± 9.8f
16.1 ± 10.3 f
15.5 ± 9.9f 2.5 ± 5.4
Emotional 16.9 ± 10.4 15.2 ± 10.2 15.1 ± 10.6 14.5 ± 10.0f 2.4 ± 5.4
Physical 14.3 ± 5.6 12.6 ± 6.2f 13.3 ± 6.8 12.7 ± 7.5 1.5 ± 4.8
a p = 0.006 vs placebo.
b p < 0.001 vs baseline.
c p < 0.001 vs placebo.
d p = 0.001 vs baseline.
e p = 0.002 vs baseline.
f p < 0.01vs baseline.

rates were more frequently observed in placebo
patients (figure 2).
A strong correlation was observed between
DARS and DHI total score change from baseline.
The correlation also remained strong after weight-
ing for treatment, age and basal scores (table VII).
A good correlation was also observed between
DARS total score and DHI domains.
Static posturography measurements indicated
an improvement for almost all considered vari-
ables in the nicergoline group; although no statis-
tically significant difference in measured para-
meters was observed compared with placebo,
coherent significant changes from baseline of post-
urography measures were observed only in the
was statistically significant for three of four meas-
ures in the nicergoline group; in the placebo group
statistical significance was observed only for the
sway area (EC). At baseline, sway area measure-
ments were within normal limits in 71% (EO) and
47% (EC) of all patients; likewise the measure-
ment of trace length did not exceed the normal
range in 73% (EO) and 65% (EC). The normal
range for sway area is 0–280.0mm2 EO and 0–
70 Nicergoline
Placebo
60
50
Patients (%)

nicergoline group. 40
Baseline values for sway area were 489.1 ± 30
843mm2 with eyes open (EO) and 905 ± 1248mm2 20
with eyes closed (EC) in the nicergoline group, and 10
387 ± 539.5mm2 (EO) and 986 ± 1520mm2 (EC) 0
in the placebo group. Baseline values for trace <30% 30–50% >50%
length were 485.3 ± 333mm (EO) and 770 ± Improvement vs baseline
457.5mm (EC) in the nicergoline group and 448 ± Fig. 2. Dizziness Handicap Inventory (DHI) total score: frequen-
329.4mm (EO) and 930 ± 1361mm (EC) in the cy distribution of patients with <30%, 30–50%, and >50% score
placebo group. Change compared with baseline change at endpoint compared with baseline.

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738 Felisati et al.

Table VII. Partial correlation coefficients between Dizziness As-
sessment Rating Scale (DARS) total score and Dizziness Handicap
Inventory (DHI) total score and DHI domains, corrected for treat-
ment, age and baseline score. Coefficients were calculated in
relation to change from baseline on the whole patient sample
DHI score Correlation with p-Value
DARS total score
DHI total score 0.5829 <0.001
DHI functional 0.3812 <0.001
DHI emotional 0.3545 0.001
DHI physical 0.4981 <0.001
426.4mm2 EC; trace length values range between
148.8 and 531.2mm EO and 120.3 and 832.7mm
EC.[29] Posturography results are summarised in ta-
ble VIII. The strategy of postural control (visual
versus nonvisual) was modified in 32.6% of
nicergoline patients and in 23.8% of placebo
patients; the difference between treatments was not
significant.
Safety
Adverse events were observed in 4.5% of
nicergoline and 4.4% of placebo patients. Two
nicergoline patients showed increases in plasma
uric acid level slightly above the upper limit of the
normal range that were of no clinical significance;
no action was required. Two placebo patients com-
plained of heartburn and abdominal pain requiring
dosage reduction, two nicergoline patients showed
a temporary rise in arterial blood pressure and
gastric pain, both requiring temporary interruption
of treatment. All events were followed by sponta-
neous recovery. No clinically or statistically sig-
nificant change in vital signs was observed. Co-
morbidity was observed in 44/89 patients (50%),
equally in the two treatment groups, and was re-
presented by arterial hypertension (18%), cardio-
vascular diseases (15%), arthritis (12%) and endo-
crine and metabolic diseases (9%). Concomitant
diseases were consistent with age and previous
clinical conditions. Twenty-five and 32 concomi-
tant treatments were administered to 18 nicergol-
ine and 20 placebo patients, respectively.
Discussion
In elderly patients in particular, a loss of effi-
ciency of central control over posture and a reduc-
tion in functional redundancy combine to present
a syndrome characterised by disorientation and un-
steadiness, representing a significant interference
with perceived quality of life. A patient presenting
with vague dysequilibrium and occasional epi-
sodic vertigo is a common occurrence in general
otolaryngology practice; many patients spontane-
ously improve over time, but elderly patients often
have mild persisting symptoms and treatment may
be required.
The results of this study indicate that nicergol-
ine is an effective and well tolerated treatment for
the clinical symptoms related to central vertigo and
that it improves the quality of life in patients with
dizziness. The drug improves symptoms both in
subjects of presenile age (50–65 years) and in
geriatric patients (>65 years). The effect of the
drug can be equally observed in the ITT-LOCF
dataset and in the PP cases, adding to the robust-
ness of the study findings.
The positive effects of nicergoline treatment are
well represented by the 57.2% improvement
measured by the DARS scale. Patients with
chronic dizziness are more likely to report worsen-
ing of health, mood, social activities and confi-

Table VIII. Static posturography: change from baseline after 3 months of treatment in the two experimental groups (per-protocol analysis)
Variable Nicergoline (n = 43) Placebo (n = 43) Drug-placebo p-Value
change from p-value change from p-value difference
baseline baseline
Sway area 90% (mm2) – eyes open 142.6 ± 81 0.086 72.9 ± 86.3 0.403 69.7 ± 118.4 NS
Sway area 90% (mm2) – eyes closed 412 ± 167.6 0.018 480.7 ± 226.7 0.040 –68.6 ± 280.9 NS
Trace length (mm) – eyes open 85.5 ± 36.9 0.026 32.8 ± 44.1 0.462 52.8 ± 57.5 NS
Trace length (mm) – eyes closed 255.6 ± 64.8 0.000 362.7 ± 210 0.092 –107.1 ± 217.6 NS
NS = nonsignificant.

 Adis International Limited. All rights reserved. Clin Drug Invest 2002; 22 (11)
Nicergoline in Balance Disorders
dence in performing daily activities.[5] Conven-
tional vestibulometric techniques are inadequate
for quantifying the impact of dizziness on every-
day life. The clinical effect of the drug was there-
fore substantiated by the significant improvement
measured by the DHI, which is a reliable measure
of self-perceived dizziness handicap. The inven-
tory clearly differentiated the effect of the drug
from that of placebo, not only on the total score but
also on each domain (functional, emotional and
physical).
The posturographic assessment is in accordance
with the clinical results. Three of four variables
referring to sway area and trace length were signif-
icantly improved compared with baseline in the
nicergoline group versus only one in the placebo
group. No significant difference was observed be-
tween treatments; however, it has to be pointed out
that the study was planned to show a significant
difference on the DARS scale and that posturo-
graphy was considered to be a secondary explor-
atory variable. Based on previous observational
results, an estimate of the sample size needed
to detect a statistically significant difference in
posturography variables indicates that five times
more patients would be required than in the present
study.[30] This study provides preliminary informa-
tion for future investigations aimed at evaluating
treatment effect based on posturography measures.
The strategy of postural control showed little
change in either treatment group. The significant
clinical improvement observed in the nicergoline
patients suggests that the drug exerts its effect
through a paraphysiological compensatory mech-
anism that allows the patient to preserve consoli-
dated postural strategies, which are altered by
more aggressive therapeutic approaches.[28]
Nicergoline was well tolerated, the frequency
and severity of adverse events being comparable
in the two treatment groups.
The results of this study are supported by the
findings of previous animal research: nicergoline
was shown to be effective in reducing age-depend-
ent severity of behavioural symptoms of vestibular
deficit, as evaluated by nystagmus rate and falls in
 Adis International Limited. All rights reserved.
739
the rotorod test,[31] and to reduce the severity of
sensory-motor deficits after peripheral vestibular
lesions in elderly rats. The behavioural effect is
associated with a rebalancing of age- and lesion-
induced alterations in glutamic acid decarboxylase
mRNA expression in several brain areas, including
those involved in cerebellovestibular projection
and extrapyramidal control of posture and move-
ment.[20]
Conclusions
Overall, these results support the use of
nicergoline in the long-term treatment of dizziness
and vertigo of central origin in late adult and elder-
ly patients. The drug causes improvement of clin-
ical conditions as well as of perceived quality of
life.
Members of the Nicergoline
Dizziness Study Group
A. Di Girolamo, MD, E Bruno, MD, M Alessandrini,
MD, ENT Department, Tor Vergata University Medical
School, Rome, Italy; G Guidetti, MD, D Monzani, MD, AM
Beldi, MD, ENT Department, Modena University Medical
School, Modena, Italy; E. Mira, MD, M Benazzo, MD, ENT
Department, S. Matteo Hospital, Pavia, Italy; E Pallestrini,
MD, G Caligo, MD, ENT Department, S. Martino Hospital,
Genova, Italy; F Piragine, MD, A Cusani, MD, ENT Depart-
ment, S. Chiara Hospital, Pisa, Italy.
Acknowledgements
The authors wish to thank the contract research organ-
isations GIAEL and OPIS for their efforts in the management
of the study and for statistical analysis. The study was
supported by a grant from Pharmacia, Italy.
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Correspondence and offprints: Dr Angelo Battaglia, Medical
Department, Pharmacia Italia, Market Company Italy, via
R. Koch 1.2, 20152 Milan, Italy.
E-mail: angelo.battaglia@pharmacia.com
Clin Drug Invest 2002; 22 (11)