Background Ginkgo biloba extract EGb 7 61 and pentoxifylline are frequently prescribed for the treatment of tinnitus. Objective To compare the treatment effects of Ginkgo biloba extract EGb 761R and pentoxifylline. Setting The study was performed at Department of Otorhinolaryngology of University Hospital Královské Vinohrady and 3rd Medical Faculty, Charles University in Prague. Method Patients with sub-chronic or chronic tinnitus were enrolled in double-blind trial and randomized to receive 120 mg EGb 761 or 600 mg pentoxifylline, each twice a day and in double-dummy fashion over a 12-week period. Main outcome measure changes in 11-Point Box Scales for tinnitus loudness and annoyance, the abridged Tinnitus Questionnaire (Mini-TQ), the Hospital Anxiety and Depression Scale (HADS), and the Sheehan Disability Scale (SDS). Results Full analysis set for efficacy analysis comprised 197 patients (EGb 761 , 99; pentoxifylline 98). For both treatment groups, significant improvements were observed in the Mini-TQ, the 11-Point Box Scales for tinnitus loudness and annoyance, the HADS anxiety score and the SDS. There was no relevant difference with regard to tinnitus-related out - comes between the two treatment groups. 20 adverse events were documented in EGb 761 group and 36 adverse events were reported for pentoxifylline group. No serious adverse event was reported during the study. Conclusion EGb 761 and pentoxifylline were similarly effective in reducing the loudness and annoyance of tinnitus as well as overall suffering of the patients. The incidence of adverse events was lower in the EGb 761 group. Keywords Effectiveness · Ginkgo biloba · Pentoxifylline · Tinnitus Impact on practice Introduction Tinnitus is a sound perceived by the patient although there EGb 761 and pentoxifylline have essentially similar is no corresponding external source of such a sound. It efficacy. represents a widespread medical problem. The aetiology With lower rates of adverse events, EGb 761 may be the of tinnitus is multiple and may vary from cochlear lesions safer choice. and disturbances in hearing pathways to metabolic, cardio- vascular or musculoskeletal disorders [1, 2]. Tinnitus is a major health problem, with an estimated prevalence of 9.6%  and a 10-year cumulative incidence rate of 12.7% in the United States . In a United Kingdom economic study, the average annual healthcare cost of tinnitus was estimated The original version of this article was revised due to a retrospective Open Access order. at 717 GBP (828 EUR) per patient 750 million GBP (867 million EUR) for the National Health Service . The treat- * Klára Procházková ment of tinnitus is difficult, not least due to the individual firstname.lastname@example.org psychological reactions of the aec ff ted patients [ 6, 7]. Drugs Department of Otorhinolaryngology, University Hospital used for tinnitus treatment include local anaesthetics, anti- Kralovske Vinohrady, Šrobárova 50, 10034 Prague, depressants, benzodiazepines, drugs that aim at enhancing Czech Republic blood flow in the cochlea and brain (Ginkgo biloba extract Third Faculty of Medicine, Charles University, Prague, ® EGb 761 , pentoxifylline, betahistine), drugs lowering the Czech Republic Vol.:(0123456789) 1 3 1336 International Journal of Clinical Pharmacy (2018) 40:1335–1341 inflammatory reaction (prednisolone, dexamethasone) or absorption. Any drugs taken to treat tinnitus had to be dis- drugs improving neuroplasticity (EGb 761 ) . continued at least 8 weeks (Ginkgo extracts at least 12 weeks before baseline. Patients who needed drugs that could possi- bly interfere with the ee ff cts of the investigational treatments Aim of study (e.g. due to agonistic or antagonistic action on common pharmacodynamics pathways), who were taking anticoagu- The objective of this randomized, double-blind, reference- lants or who were known to be allergic to the investigational controlled single-centre trial was to compare the treatment drugs were also excluded. Female patients of childbearing effects of Ginkgo biloba extract EGb 761 and pentoxifyl- age were only included under safe contraception. line in subjects with sub-chronic or chronic tinnitus focusing on psycho-social problems. The safety and tolerability of the Randomization and interventions two treatments were assessed as secondary outcome. The random allocation sequence was generated by the sponsor using a validated computer program matching drug Ethics approval numbers to treatments in a 1:1 ratio. The randomisation sequence was concealed by using identical labels and pack- The study was conducted in accordance with the Interna- ages for both treatments with ascending drug numbers. The tional Conference on Harmonisation (ICH) Good Clinical list matching drug numbers with treatments was unavail- Practice (GCP) guideline , the Declaration of Helsinki able to persons involved in conducting the study. Double- and its later amendments, and national laws. The study pro- blinding was achieved by the double-dummy technique, i.e. tocol and conduct were approved by the independent Ethics all patients received the same number of tablets, either EGb Committee of the Královské Vinohrady University Hospi- 761 and pentoxifylline-like placebo or pentoxifylline and tal, Prague, Czech Republic. All subjects received oral and EGb 761 -like placebo. Tablets containing active drug and written information about the trial and gave their written the corresponding placebo tablets were indistinguishable in informed consent before enrolment and before undergoing texture, colour, shape and size. any study-related procedures. For the duration of 12 weeks, the subjects randomized to receive EGb 761 took one film-coated tablet of 120 mg EGb 761 together with one pentoxifylline-like placebo tab- Methods let twice a day; those randomized to pentoxifylline took one extended-release tablet of 600 mg pentoxifylline together Study design and study population with one EGb 761 -like placebo tablet twice a day. EGb ®1 761 is a dry extract from Ginkgo biloba leaves (35–67:1), The trial was designed as a randomized, double-blind, dou- extraction solvent: acetone 60% (w/w). The extract is ble-dummy, parallel-group, single-centre trial at the Depart- adjusted to 22.0–27.0% ginkgo flavonoids calculated as ment of Otorhinolaryngology of the Královské Vinohrady ginkgo flavone glycosides and 5.0–7.0% terpene lactones University Hospital, Prague, Czech Republic. It was reg- consisting of 2.8–3.4% ginkgolides A, B, C and 2.6–3.2% istered in the public clinical trials register ISRCTN under bilobalide and contains less than 5 ppm ginkgolic acids. number 68772788. We enrolled male and female patients aged ≥ 30 years Outcomes with unilateral or bilateral chronic or subchronic tinnitus of at least 3 months’ duration. Subjects were eligible for par- The therapeutic effects of EGb 761 and pentoxifylline ticipation if their tinnitus was maskable (by noise masking), were assessed using tinnitus-related rating scales as well as the degree of annoyance by tinnitus was rated at least 3 on assessments of psychological symptoms and functioning. an 11-Point Box Scale (type of numeric analogue scale) at Two separate 11-Point Box Scales for tinnitus loudness screening and baseline visits, they scored at least 5 on the (extending from 0 = no tinnitus at all to 10 = extremely loud abridged Tinnitus Questionnaire (Mini-TQ)  at baseline tinnitus) and annoyance by tinnitus (extending from 0 = not and had given informed consent. annoying at all to 10 = unbearably annoying) were filled in Patients were excluded from the study if they had acute every day. The evaluation of the scales was based on mean or chronic otitis media, vestibular neuritis or drug-induced tinnitus, if they were taking any other treatment for tinnitus, if they had severe cardiovascular, renal or hepatic disor- Manufacturer: Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, ders, malignant diseases, insulin-dependent diabetes mel- ® Germany. EGb 761 is a registered trademark of Dr. Willmar litus or gastro-intestinal disorders leading to impaired drug Schwabe GmbH & Co. KG. 1 3 International Journal of Clinical Pharmacy (2018) 40:1335–1341 1337 weekly values per subject. The Mini-TQ  is an abridged, Results 12-item version of the Tinnitus Questionnaire (TQ) . It was designed to reflect tinnitus-related psychological Participant flow and treatment compliance distress and to investigate the dimensions of the complaint about tinnitus such as subjective perception, coping attitudes Patients were recruited in one investigational centre from and beliefs about tinnitus. September 2012 to April 2014. In total, 202 subjects were The Hospital Anxiety and Depression Scale (HADS) screened for inclusion in the study, 2 subjects terminated the [12, 13] was designed to assess the presence and severity of study before the baseline visit and were not randomized. All mild, even sub-syndromal degrees of anxiety and depression. remaining 200 subjects were included in the double-blind Since no somatic items are included, the scale is feasible to treatment phase; they were randomized to and received EGb measure depression in somatic illnesses. The Sheehan Dis- 761 (n = 100) or pentoxifylline (n = 100). ability Scale (SDS)  is a brief 3-item self-rating tool, All subjects who received at least one dose of the treat- designed to measure the extent to which three major sectors ment were analysed with regard to safety measures (safety in the patient’s life (work/school, social life, family life) are analysis set, SAF). The full analysis set (FAS) for efficacy impaired by panic, anxiety, phobic or depressive symptoms. included all subjects of the SAF having at least one post- Safety and tolerability of both investigational products baseline measurement of one of the 11-Point Box Scales. were assessed by physical examination, otological exami- The disposition of patients is depicted in Fig. 1. nation, ECG measurements, laboratory tests and vital signs measurements. Demographics and baseline characteristics Statistical analysis Both treatment groups were similar with respect to demo- graphics and baseline scores of the outcome measures For each of the effectiveness outcomes the EGb 761 group (Table 1). All subjects were white/caucasian. was compared to the pentoxifylline group using descrip- The assessment of compliance was based on the differ - tive data analysis methods. The comparison of the treat- ence between the numbers of tablets dispensed and returned, ment groups with respect to the 11-Point Box Scales and expressed as percentage of tablets due to be taken from the the Mini-TQ total score was performed using an analysis of day of first to the day of last intake. Median compliance was covariance (ANCOVA) with treatment as the factor and the 99.4% for the total treatment period in the EGb 761 group baseline value (in the case of 11-Point Box Scales: average and 98.8% in the pentoxifylline group. value of the week until baseline) of the respective effective- ness variable as a covariate. The confidence intervals of the Therapeutic effects differences in the least square means (LS means) were com- puted to compare the effectiveness of the treatments. For the Patients of both treatment groups improved significantly HADS and the SDS changes from baseline were compared during the 12-week treatment period on all tinnitus-related between the EGb 761 group and the pentoxifylline group scales, in anxiety and disability scores, with no significant by the Wilcoxon rank sum test. Changes for ordinal variables differences between the two treatment groups. Details are over time were modelled with generalized estimating equa- shown in Tables 2 and 3. tions (GEEs) for ordinal responses. Slight improvements in the depression score of the HADS Descriptive statistics were computed to describe the were not statistically significant at 12 weeks. However, in empirical distributions; 95% confidence intervals were cal- the prospectively specified subgroup of patients with ele- culated within the treatment groups and between the pen- vated depression scores (HADS subscore depression ≥ 8, toxifylline and the EGb 761 group. Since no confirmatory with 8 to 10 points representing borderline depression and hypotheses were formulated, an adjustment of the type-one 11 points or more indicating clinical caseness ), the error rate was not performed and no formal sample size cal- improvements on the three tinnitus-related scales were par- culation was done. All p values presented are two-sided and ticularly pronounced under EGb 761 treatment (Mini-TQ: should be interpreted in an exploratory sense. The presented − 2.19 [− 3.96; − 0.42]; 11-Point Box Scale loudness: − 0.74 results are based on the full analysis set (FAS) using the last [− 1.45; − 0.02]; 11-Point Box Scale annoyance: − 1.06 observation carried forward method (LOCF) to replace miss- [− 1.93; − 0.18]). Such an effect modification by depression ing values. Furthermore, all analyses were also performed was not seen in the pentoxifylline group. based on observed cases (OC). The results based on the OC Of 95 patients in the EGb 761 group and 90 patients were generally very consistent with those for the FAS and in the pentoxifylline group who had HADS anxiety scores are therefore not presented. 1 3 1338 International Journal of Clinical Pharmacy (2018) 40:1335–1341 Fig. 1 Patient disposition before and after treatment, 34 (36%) and 29 (32%), respec- in Table 4. No clinically relevant changes regarding mean tively, had abnormal scores at baseline. These numbers values of laboratory parameters (haematology, blood chem- decreased to 22 (23%) and 23 (26%), respectively, during istry including liver enzymes and coagulation parameters), treatment (Fig. 2). The changes were significant in the EGb physical examination, blood pressure, heart rate or weight 761 group, but not in the pentoxifylline group (p = 0.005 were observed between screening and end of treatment. In and p = 0.105, respectively, two-sided likelihood score two subjects of the EGb 761 group relevant changes were test for changes over time modelled by GEEs for ordinal observed with regard to the 12-lead ECG between screening responses). and end of treatment. In both cases, the causal relationship was assessed as unlikely. Safety and tolerability During the active treatment and subsequent 2-day risk Discussion phase (i.e. until active substances were washed out), 19/100 (19.0%) subjects in the EGb 761 group experienced a total The objective of this randomized, double-blind, reference- of 20 AEs leading to an overall incidence rate of 0.0024 controlled single-centre trial was to compare the treatment AEs/day of exposure. In the pentoxifylline group, 27/100 effects of Ginkgo biloba extract EGb 761 and pentoxifyl- (27.0%) subjects experienced a total of 36 AEs leading to line in subjects with sub-chronic or chronic tinnitus focusing an overall incidence rate of 0.0048 AEs/day of exposure. on psycho-social problems. We found significant improve- Therefore, in the pentoxifylline group the incidence rate for ments under both treatments on a self-rating scale assessing AEs was twice as high as in the EGb 761 group. A causal the psychological burden of tinnitus (Mini-TQ), on numeric relationship with the investigational product could not be analogue scales (11-Point Box Scales) for tinnitus loudness excluded for 18 AEs in 17/100 (17%) subjects in the EGb and annoyance, the anxiety subscale of a questionnaire for 761 group, in the pentoxifylline group, a causal relationship anxiety and depression (HADS) and a brief rating of illness- with the investigational product could not be excluded for 32 related disability. AEs in 24/100 (24%) subjects. No serious adverse event was The treatment of chronic tinnitus is a very challeng- reported during the study. The most frequent AEs are listed ing task in everyday practice, especially due to its various 1 3 International Journal of Clinical Pharmacy (2018) 40:1335–1341 1339 Table 1 Demographics and baseline characteristics; absolute (rela- This is influenced by the patient’s medical history, risk fac- tive) frequency or mean ± SD [95% CI for mean] tors, concomitant diseases and precipitating events. The aeti- ology might be otological, neurological, metabolic, cardio- EGb 761 (n = 99) Pentoxifylline (n = 98) vascular, endocrinological, musculoskeletal or mental. The Women 58 (58.6%) 59 (60.2%) use of EGb 761 and pentoxifylline in this trial was based Age (years) 55.4 ± 10.5 53.1 ± 10.9 on the fact that both drugs are frequently used in many Euro- [53.3; 57.5] [50.9; 55.3] pean countries . Perfusion-enhancing properties that act Weight (kg) 82.6 ± 16.2 77.8 ± 13.7 in the brain and inner ear [16–18] are assumed to contribute [79.4; 85.8] [75.0; 80.5] to the clinical benefits. BMI (kg/m ) 27.2 ± 4.4 25.9 ± 3.5 Despite the efforts of strict categorization, tinnitus [26.3; 28.0] [25.2; 26.5] changes and modulates with time. The physicians there- Duration of tinnitus 79.6 ± 77.9 84.6 ± 94.5 fore have to cope with the central processing of tinnitus as (months) [64.0; 95.1] [65.7; 103.6] well as the various psychological reactions of the patients Patients with tinni- 74 (74.7%) 75 (76.5%) to the tinnitus. Psychological and social aspects of tinnitus tus > 2 years can severely affect patients’ quality of life. The evaluation Patients with hearing 97 (98.0%) 92 (93.9%) of the treatment effects was therefore extended from single loss subjective perception of the ear sound to include anxiety, Mini-TQ 10.5 ± 4.3 11.0 ± 4.3 depression and overall disability symptoms of the subjects. [9.62; 11.35] [10.12; 11.84] In this respect, the anxiolytic  and antidepressant-like 11-Point Box Scale 5.3 ± 1.3 5.6 ± 1.2 loudness effects [20, 21] of EGb 761 , as well as its influence on [4.99; 5.52] [5.37; 5.87] neuroplasticity, involving neurogenesis and synaptogenesis 11-Point Box Scale 5.2 ± 1.3 5.5 ± 1.3 annoyance , may play a role. [4.95; 5.46] [5.30; 5.80] The majority of the study patients had been suffering HADS anxiety score 6.2 ± 3.3 5.9 ± 3.5 from chronic tinnitus for many months (average duration [5.53; 6.86] [5.23; 6.61] 7 years) and had already undergone many therapeutic pro- HADS depression score 4.7 ± 3.1 4.4 ± 3.0 cedures. Only very few (7/197) were treated with any medi- [3.94; 5.26] [3.40; 4.79] cation shortly before enrolment into the study. Hence, the 7.5 ± 5.7 8.9 ± 5.9 SDS global impairment study population appears to represent those patients who [6.31; 8.61] [7.72; 10.11] are most difficult to manage [23, 24]. In view of this, the statistically significant decrease in subjective perception of origins. Tinnitus itself cannot be considered as a disease but tinnitus (Mini-TQ, 11-Point Box Scales for loudness and rather as a symptom. The pharmacological or non-pharma- annoyance) points to benefits of both tested medications. cological therapeutic approach should take the suspected Patients with tinnitus often have sub-syndromal depres- possible cause in each individual case into consideration. sion or anxiety, which may be reactive in nature or due to a Table 2 Changes from baseline to week 12 in tinnitus-related outcomes; least square mean (95% CI) and p values from ANCOVA for within- and between-group comparisons EGb 761 p value (within- Pentoxifylline p value (within- p value group) group) (between- group) Mini-TQ − 1.57 (− 2.25; − 0.89) < 0.0001 − 1.94 (− 2.64; − 1.25) < 0.0001 0.4514 11-Point Box Scale loudness − 0.41 (− 0.68; − 0.15) 0.0021 − 0.43 (− 0.69; − 0.17) 0.0015 0.9284 11-Point Box Scale annoyance − 0.56 (− 0.84; − 0.27) 0.0002 − 0.54 (− 0.83; − 0.25) 0.0003 0.938 Table 3 Changes from baseline to week 12 in affective symptoms and disability; mean (95% CI) and two-sided p values from Wilcoxon rank sum test for between-group comparisons EGb 761 Pentoxifylline p value HADS anxiety score − 1.3 (− 1.82; − 0.85) − 1.1 (− 1.55; − 0.56) 0.2523 HADS depression score − 0.4 (− 0.89; 0.15) − 0.5 (− 0.92; 0.01) 0.5753 SDS global impairment − 0.6 (− 0.90; − 0.28) − 0.6 (− 0.91; − 0.27) 0.9485 1 3 1340 International Journal of Clinical Pharmacy (2018) 40:1335–1341 Fig. 2 Numbers of patients with normal and abnormal scores at baseline and week 12 in the HADS anxiety subscale (scores of 0–7 are considered normal, 8–10 borderline, and ≥ 11 indicate clinical caseness); *two-sided p value for likeli- hood score test for changes over time (modelled by GEEs for ordinal responses) = 0.005 for EGb 761 (non-significant (n.s.) at p = 0.105 for pentoxifylline) Table 4 Most frequently reported adverse events (5% or more) under of tinnitus [25–27]. It adds to current knowledge the direct EGb 761 and pentoxifylline treatment, respectively comparison of the two drugs in terms of efficacy and toler - ability. There is no evident superiority of one investigational System organ class/eventEGb 761 Pentoxifylline product over another in terms of efficacy; however, tolerabil- Gastrointestinal disorders 2 11 ® ity of EGb 761 is clearly better. During the study period, Diarrhoea 2 the total numbers of AEs differed considerably. In the EGb Abdominal discomfort 1 ® 761 group the risk of an adverse event was about half the Abdominal distension 2 risk observed in the pentoxifylline group. Upper abdominal pain 4 Further studies to disentangle the direct effects of EGb Dyspepsia 1 ® 761 on tinnitus and presumable indirect effects that may Nausea 2 result from improvements in anxiety and depression are Unspecified symptom 1 warranted. Ear and labyrinth disorders 6 4 Worsening of tinnitus 5 3 Ear discomfort 1 Conclusion Vertigo 1 Infections and infestations 2 5 In summary, the two drugs, EGb 761 and pentoxifylline are Bronchitis 1 1 similarly effective in reducing the suffering of patients with Nasopharyngitis 1 2 sub-chronic or chronic tinnitus. The EGb 761 treatment Gastroenteritis 1 group showed a more pronounced improvement in patients Pertussis 1 with elevated depression scores and a higher incidence of improved patients in anxiety score categories. The incidence of ADEs was clearly lower in the EGb 761 group. common organic origin . It is therefore noteworthy that EGb 761 has stronger effects in patients with depression Funding None. and decreases anxiety levels. Conflicts of interest None. The relatively large sample size and the high treatment adherence may be considered as strengths of this trial; Open Access This article is distributed under the terms of the Crea- limitations are the reliance on tablet count for the deter- tive Commons Attribution 4.0 International License (http://creat iveco mination of adherence and the monocentric setting. The mmons.or g/licenses/b y/4.0/), which permits unrestricted use, distribu- tion, and reproduction in any medium, provided you give appropriate present results are in line with and extend earlier findings that demonstrated the efficacy of both drugs in the treatment 1 3 International Journal of Clinical Pharmacy (2018) 40:1335–1341 1341 credit to the original author(s) and the source, provide a link to the hypotensive ischaemia [Zur Wirkung von Ginkgo-biloba-Extrakt Creative Commons license, and indicate if changes were made. (Tebonin) auf die Wasserstoff-Auswaschvorgänge an der Coch- leabasis unter hypotensiver Ischämie.]. 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Effects of Ginkgo biloba extract (Tebonin) on hydrogen washout from the cochlea base under 1 3
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Published: Jun 1, 2018
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