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A
Multicenter Randomized Double-Blind Study of Ginkgo
Biloba Extract Versus Placebo in the Treatment of
Tinnitus
B.
Meyer
Service d'Oto-Rhino
Laryngologie, Hospital Saint-Antoine, F 75012 Paris
Summary
This important
multicenter study of 103 tinnitus out-patients during a 13-month treatment
period was carried out by ten E.N.T. specialists, using the double blind,
drug versus placebo method. The results were conclusive as regards the
effectiveness of Ginkgo Biloba Extract and made it possible to determine
the prognostic value of different parameters. Of special importance among
these parameters were site and periodicity of the disease. However,
the Ginkgo Biloba Extract treatment improved the condition of all the
tinnitus patients, irrespective of the prognostic factor.
Tinnitus, a very frequent
symptom, troublesome both for the patient and for the physician who has
difficulty-when he is able to do so-in being explicit about the physiopathological
mechanism and lacks certainty as to what therapeutic posture to adopt.
The fact that tinnitus
is relatively benign when present alone explains why it is encountered
most frequently in everyday practice. In order to study tinnitus cases
of recent onset, that is, less than a year old, it was necessary to carry
out a private study, despite the complexity of organization.
This study had the
purpose of qualifying the efficacy of treatment of recent tinnitus with
Ginkgo Biloba Extract (EGb 761, Rokan, Intersan), a product widely prescribed
in this indication because of the etiopathogenic hypothesis considered.
Ginkgo Biloba Extract (EGb) has been found active in ischemic processes,
in membral exchanges, and on certain neurotransmitters. This study also
sought to demonstrate prognostic factors making it possible to determine
profiles for patients responding to treatment.
*Rokan (Ginkgo Biloba).
Recent results in Pharmacology and Clinic Edited by E.W. Funfgeld Springer-Verlag
Berlin Heidelberg New York 1998, pp 245-250
Methodology
Ten otorhinolaryngology
specialists in private practice participate in the study and contributed
103 case histories in 12 months. After randomization, the patients were
treated in a double-blind for three months either with EGb or with a placebo
strictly identical in appearance. The dosage was 4 mL/day in two doses.
The duration of treatment could not be less than one month in order to
draw conclusions as to a possible therapeutic failure.
The patients included
had recent tinnitus, that is, appearing less than a year earlier. Excluded
from the study were patients suitable for surgical or anti-infectious
treatment, those suffering with acute inner or middle ear infections (otitis,
Eustachian salpingitis), or associated pathological disorders capable
of skewing analysis of results.
Also excluded were
patients already under treatment and for whom the evolution was favorable,
as well as those who required medical treatment which might interfere
with evaluation of the results.
The criteria for establishment
of the diagnosis and for monitoring were essentially clinical and comprised
the definition of the patients and description of the tinnitus: timbre,
schedule, rhythm, impairment, intensity, overall evolution, and time before
disappearance; other associated ORL symptoms such as vertigo and hypoacusis
were routinely investigated.
The paraclinical examinations
comprised essentially tonal audiometry performed at the time the diagnosis
was given and possible repeated on the basis of the clinical condition.
The performance of other tests (impedancemetry, electronystagmography)
were left to the discretion of the physician.
Statistical analysis
was by means of the X test for the qualitative variables and the Student
t-test for the quantitative variables. In order to evaluate the influence
of the various parameters on the evolution, a step-by-step decreasing
logistic regression was done.2
Results
Comparability
of the groups at the time of admission.
After breaking of
the double-blind, both treatment groups were analyzed in order to very
comparability at the time of admission to the study; 161 variables were
analyzed.
The mean value of
severity, graded from 1 to 4, was identical in both groups, but distribution
by class presented a slight difference. This corresponds to a broader
distribution within the placebo group, and more centered around the values
of 2 and 3 in the EGb group. Therefore one group was not more severely
affected than the other.
The intensity of the
tinnitus, graded from 0 to 3, was comparable in the two groups. Impairment,
coded from 0 to 3, was also comparable in both groups (Table I).
| Table
I
Comparison
of the groups at the time of admission |
| Criteria |
Grade
|
Placebo |
Ginkgo Biloba Extract |
Statistical
Calculation |
| Severity
|
1
(mil) |
8 |
3 |
X2=8.956
P<0.03
3 degrees
of freedom
|
| 2
(moderate |
11 |
25 |
| 3
(troublesome) |
21 |
27 |
| 4
(severe) |
4 |
1 |
| Average
= |
2.47 |
2.46 |
| Intensity |
0 |
0 |
0 |
X2=0.708
3 degrees
of freedom
-not significant
|
| 1 |
9 |
9 |
| 2 |
30 |
37 |
| 3 |
4 |
9 |
| Impairment |
0 |
2 |
1 |
X2=0.578
2
degrees of freedom
-not significant |
| 1 |
16 |
18 |
| 2 |
20 |
29 |
| 3 |
7 |
10 |
| Both
groups were also comparable for length of time the syndrome had been
present, age and sex: -time syndrome had been present: EGb, 127 days;
placebo, 143 days; t=0.67; -age: EGb, 50.97 years; placebo, 49.76
years; t=0.39; -sex: EGb, 29 men, 29 women; placebo, 25 men, 20 women
(X2=0.31-1 degree of freedom). |
| Table
2
Overall
Evolution |
| Patient
Condition |
Ginkgo
Biloba Extract |
Placebo |
| 1-2
3
4
5
6
7 |
|
|
| 1-2=exacerbation;
3=no change; 4=slightly improved; 5=improved; 6=much improved; 7=suspension
because of intolerance. |
| Table
3
Percent of Good
Evolution |
| Prognostic Classification |
Placebo |
Ginkgo
Biloba Extract |
| Class
1, old, bilateral, intermittent
Class 2, recent,
unilateral, permanent
Class 3, recent,
bilateral, permanent
Class 4, old,
unilateral, permanent
Class 5, old,
bilateral, permanent |
|
|
There was also no
difference with respect to the consumption of tobacco or alcohol, the
ORL history (effect on the middle ear, barotraumas, phonotrauma, ototoxic
involvement), and the associated syndromes (vertigo, hypoacusis).
Analysis of the
tonal audiometry performed at the time of admission to the study also
showed no difference between the two groups.
Analysis
of therapeutic efficacy
Overall
evolution: comparison of the two groups showed a significant difference
in favor of the EGb group (X2=4.44-2 degrees of freedom, P=0.05)(Table
2).
Time
before disappearance, or distinct improvement: there is a statistically
significant difference in favor of the group treated with EGb, the evolution
of which was much faster (X2=3.90-1 degree of freedom, unilateral test
P=0.03).
Thus,
the median, that is to say the time before disappearance or distinct
improvement in 50% of the tinnitus cases, was 70 days in EGb group and
119 days in the placebo group.
Evolution
of intensity of the tinnitus between the first and last consultations:
this appeared to be statistically better in the EGb group. Difference
in intensity: EGb=1.00; placebo=0.67; Student t-test=1.79; unilateral
P test=0.03.
Decrease
in impairment between the first and the last consultations: this was
greater for the treated group (0.84) than for the control group (0.59);
this difference is at the limit of significance (Student t-test=1.38;
unilateral P test=0.08).
Study
of the prognostic variables
Statistical
analysis showed that three variables have prognostic value: the history
of the disease (more than 30 days, less than 30 days), the site (unilateral,
bilateral), and periodicity (permanent, intermittent). Study of the
links among these three variables made it possible to demonstrate five
different prognostic classes (Table 3).
Conclusion
This
multicenter study, performed by ORL specialists in private practice,
with a rigorous methodology, despite the difficulties which this includes
in a field in which the subjective component is significant, as it confirms
the results of treatment with placebo, brought together 103 case histories
of recent tinnitus.
It was thus possible
to meet the two objectives established:
-
to
verify the efficacy of treatment with EGb;1
-
to
analyze the prognostic value of the various parameters by demonstrating
those whose influence was determinant (history, site and periodicity),
as well as to specify the modalities of their interaction.
Tinnitus characterized
as recent, unilateral and intermittent, has a good prognosis. Treatment
with EGb improves the evolution of the tinnitus regardless of its prognostic
factors.
-
Meyer
B: Etude multicentrique des acouphenes, epidemiologie et therapeutique.
Annal. ORL 1986, 103, 185-188.
-
Nakache
J.P., Guegen A., Pierart H.: Utilisation du modele logistique dans
l'etude de l'influence des variables initiales et du traitement sur
l'evolution de l'acouphene. Revue de Statistique Appliquee (sous presse).
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